Pharmacotherapy Review Packet

Alabama Medicaid Agency 

Pharmacy and Therapeutics Committee Meeting 

Pharmacotherapy Review of the Anthelmintics 

AHFS 080800 

October 27, 2004 

I. Overview 

In the United States, helminthic infections are most frequently seen in recent immigrants from 

Southeast Asia, the Caribbean, Mexico, and Central America. 1 There is a higher incidence of 

helminthic infections in the southern states. Other populations that have a high risk of infestation 

include institutionalized patients (both young and elderly), preschool children in day care centers, 

residents of Native American reservations, and homosexual individuals. Certain conditions and 

drugs (fever, corticosteroids, and anesthesia) can cause atypical localization of worms. 

Additionally, immunocompromised hosts can be overwhelmed by some helminthic infections, 

such as strongyloidiasis. 

The majority of intestinal helminthic infections are not associated with clearly defined 

manifestation of disease, but they can cause significant pathology. One factor that determines the 

pathogenicity of helminthes is their population density. Light infections may be fairly well 

tolerated, whereas high populations of intestinal helminthes can result in predictable disease 

presentations. Significant advances have occurred in the past 20 years in the drugs available to 

treat parasitic helminthes. Single-dose treatments are available for most of the common species of 

worms. After reviewing clinical data, the World Health Organization had endorsed concomitant 

use of praziquantel and albendazole to treat intestinal worms and schistosomiasis. 2 

There are two main types of helminthic infections, those caused by flatworms (tapeworms and 

flukes) and those caused by roundworms (pinworm, whipworm, ascaris, and strongyloides). 

Helminthic diseases are caused by nematodes and include hookworm disease, ascariasis and 

enterobiasis. Morbidity and disease with intestinal nematodes is related to the intensity of 

infection or worm burden; subjects with transient exposure have less-severe disease. Adverse 

events of intestinal nematodes are malnutrition, fatigue, and diminished work capacity. Treatment 

with anthelmintic agents results in complete eradication and significant change in well-being. 

Hookworm 

Hookworm is caused by an infection of the small intestine caused by either Ancylostoma 

duodenale or Necator americanus. N. americanus is found in the southeastern U.S., where the 

temperature and humidity provide the proper envorinment. 1 Ancylostoma is rare in the U.S. The 

life cycles of both species of hook worm are similar. The adult worms live in the small intestine 

attached to the mucosa. The females liberate eggs, which are eliminated in the feces and develop 

into larvae. Infective larva enter the host in contaminated food or water, or penetrate the skin, 

where a papular eruption with localized edema and erythema can result. Injury to the small 

intestine can cause mechanical and lytic destruction of tissue and the loss of blood can lead to 

anemia and hypoproteinemia. Eosinophilia (30-60%) is present in patients with chronic infection. 

Stool should be examined for eggs and larvae. 

Ascariasis 

This infection is caused by the giant roundworm Ascaris lumbricoides. Female worms can range 

from 20-35cm in length. The worm is found worldwide, but more commonly in areas where 

sanitation is poor. 1 In the United States., endemic areas include southeastern parts of the 

Appalachian and the Gulf coast states. Estimates place nearly 4 million people in the U.S. with 

ascariasis. Clinical manifestations of this disease include pneumonitis, fever, cough, eosinophilia, 

and pulmonary infiltrates, as the larvae migrate through the lungs. Diagnosis is made by 

demonstrating the characteristic egg in the stool. 

1

Enterobiasis 

Also known as pinworm infection, is caused by Enterobius vermicularis. The pinworm is a small 

thread-like spindle-shaped worm about cm in length. It is the most widely distributed helminthic 

infection in the world. There are estimates of 42 million cases in the United States, a majority of 

which are children. The most common problem with infection is cutaneous irritation in the 

perianal region, made by the migrating females or presence of eggs. Scratching can lead to 

dermatitis and secondary bacterial infections. 

This review encompasses all dosage forms and strengths. Table 1 lists the drugs included in this review. 

Table 1. Anthelmintics in this Review 

Generic Name Formulation Example Brand Name Rx vs. OTC 

Albendazole Oral Tablet Albenza Rx 

Ivermectin Oral Tablet Stromectol Rx 

Mebendazole Oral Chewable Tablets *Vermox Rx 

Praziquantel Oral Tablet Biltricide Rx 

Pyrantel Pamoate Oral Liquid/Soft Gel Capsules Antiminth (D/c’d 11-2003), Pin-X, OTC 

Reeses’s Pinworm Medicine, Pinworm 

Treatment 

Thiabendazole Oral Suspension, Chewable Tablets Mintezol Rx 

*Generic Available. 

II. 

Evidence Based Medicine and Current Treatment Guidelines 

The Centers for Disease Control and Prevention have instituted recommendations for preventing 

opportunistic infections among hematopoietic stem cell transplant (HSCT) recipients, and includes 

prevention of helminthic infections. 3 Recommendations include treatments for Strongyloides 

stercoralis. Recipients should avoid contact with out houses and cutaneous exposure to soil or 

other surfaces that might be contaminated with human feces. All recipients who work in the 

health care industry (hospitals or institutions) where they might be exposed to fecal matter, should 

wear gloves. 

Travel and residence histories should be obtained for all patients before HSCT to determine any 

exposures to high-risk areas (e.g., such moist temperate areas as the tropics, subtropics, or the 

southeastern United States and Europe). 3 HSCT candidates who have unexplained peripheral 

eosinophilia or who have resided in or traveled to areas endemic for strongyloidiasis, even during 

the distant past, should be screened for asymptomatic strongyloidiasis before HSCT. Serologic 

testing with an enzyme-linked immunosorbent assay is the preferred screening method and has a 

sensitivity and specificity of >90%. FDA-licensed or -approved screening tests should be used. 

Although stool examinations for strongyloidiasis are specific, the sensitivity obtained from >3 

stool examinations is 60%-70%; the sensitivity obtained from concentrated stool exams is, at best, 

80%. A total of >3 stool examinations should be performed if serologic tests are unavailable or if 

strongyloidiasis is clinically suspected in a seronegative patient. 

HSCT candidates whose screening tests before HSCT are positive for Strongyloides species, and 

those with an unexplained eosinophilia and a travel or residence history indicative of exposure to 

Strongyloides stercoralis should be empirically treated before transplantation, preferably with 

ivermectin, even if seronegative or stool-negative. 

2

To prevent recurrence among HSCT candidates with parasitologically confirmed strongyloidiasis, 

cure after therapy should be verified with >3 consecutive negative stool examinations before 

proceeding with HSCT. Data are insufficient to recommend a drug prophylaxis regimen after 

HSCT to prevent recurrence of strongyloidiasis. HSCT recipients who had strongyloidiasis before 

or after HSCT should be monitored carefully for signs and symptoms of recurrent infection for 6 

months after treatment. Hyperinfection strongyloidiasis has not been reported after autologous 

HSCT; however, the same screening precautions should be used among autologous recipients. 

Indications for empiric treatment for strongyloidiasis before HSCT are the same among children 

or adults except for children weighing

III. 

Comparative Indications of the Anthelmintic Antibiotics 

Table 2 lists the FDA-approved indications for the anthelmintic antibiotics. Mebendazole is indicated for use as described in Table 2, and is also indicated 

for single or mixed infections. Table 3 further describes the major intestinal parasites and the treatments of choice. 

Table 2. FDA-Approved Indications for the Anthelmintics 5-7 

Drug Neurocysticercosis 

Hydatid 

Disease 

Strongyloidiasis 

Onchocerciasis 

Pinworm 

Albendazole 

✔ ✔ * 

Whipworm 

(Trichuris 

richiura) 

Roundworm 

(Ascaris) 

Hookworm 

(Common 

and 

American) 

All species 

of 

Schistosoma 

Liver 

Flukes 

Clonorchis 

sinensis / 

Opisthorchis 

viverrini 

Cutaneous 

Larva 

Migrans 

(creeping 

eruption) 

Visceral 

Larva 

Migrans 

Trichinosis 

Ivermectin 

✔ ✔ 

Mebendazole 

✔ ✔ ✔ ✔ 

Praziquantel 

✔ ✔ ✔ 

Pyrantel 

Pamoate 

✔ ✔ 

Thiabendazole 

✔ ✔ ** ✔ ■ ✔ ■ ✔ ■ ✔ ✔ ✔ 

* Disease of the liver, lung, and peritoneum caused by the larval form of the dog tapworm, Echinococus granulosus. 

**Thiabendazole is usually inappropriate as first-line therapy for enterobiasis (pinworm). However, when enterobiasis occurs with any of the indications listed for thiabendazole, additional therapy is not 

required for most patients. 

■ Only indicated when more specific therapy is not available or cannot be used or when further therapy with a second agent is desirable. 

4

Table 3. Major Intestinal Parasites, Causative Organisms, and Treatments of Choice 7 

Intestinal 

Nematodes 

Tissue 

Nematodes 

Cestodes 

Trematodes 

Major Parasite Infections 

Infection (common name) Organism Drug(s) of Choice 

Ascariasis 1 (Roundworm) Ascaris lumbricoides Mebendazole, Pyrantel pamoate or Diethylcarbamazine 

Uncinariasis (Hookworm) Ancylostoma duodenale Mebendazole or Pyrantel pamoate 2 

Necator americanus 

Strongyloidiasis (Threadworm) 

Strongyloides stercoralis Thiabendazole 

Trichuriasis (Whipworm) Trichuris trichiura Mebendazole 

Enterobiasis 3 (Pinworm) Enterobius vermicularis Mebendazole, Pyrantel pamoate or Albendazole 

Capillariasis 

Capillaria philippinensis Mebendazole, Thiabendazole or Albendazole 

Trichinosis Trichinella spiralis Steroids for severe symptoms plus Thiabendazole, 

Albendazole, Flubendazole 6 or Mebendazole 2 

Cutaneous larva migrans 

(Creeping eruption) 

Ancylostoma braziliense 

and others 

Thiabendazole, Albendazole or Ivermectin 4 

Onchocerciasis (River blindness) Onchocerca volvulus Suramin 5 , Diethylcarbamazine or Ivermectin 4 

Dracontiasis (Guinea worm) 

Angiostrongyliasis (Rat 

lungworm) 

Dracunculus medinensis Thiabendazole or Mebendazole 

Angiostrongylus 

cantonensis 

Thiabendazole or Mebendazole 

Loiasis Loa loa Diethylcarbamazine 

Taeniasis (Beef tapeworm) Taenia saginata Praziquantel 2 or Niclosamide 6 

(Pork tapeworm) Taenia solium Praziquantel 2 , Niclosamide 6 or Albendazole 

Diphyllobothriasis (Fish Diphyllobothrium latum Praziquantel 2 or Niclosamide 6 

tapeworm) 

Dog tapeworm Dipylidium caninum Praziquantel 2 

Hymenolepiasis (Dwarf 

tapeworm) 

Hydatid cysts 

Schistosomiasis 

Hymenolepis nana Praziquantel 2 or Niclosamide 6 

Echinococcus 

granulosus 

Schistosoma mansoni 

Schistosoma japonicum 

Schistosoma 

haematobium 

Schistosoma mekongi 

Albendazole or Praziquantel 

Praziquantel or Oxamniquine 

Praziquantel 

Praziquantel 

Praziquantel 

Hermaphroditic Flukes 

Fasciolopsiasis(Intestinal fluke) Fasciolopsis buski Praziquantel 

Clonorchiasis (Chinese liver 

fluke) 

Heterophyes heterophyes 

Metagonimus yokogawai 

Clonorchis sinensis 

Praziquantel 

Praziquantel 

Fascioliasis (Sheep liver fluke) Fasciola hepatica Praziquantel or Bithionol 4 

Opisthorchiasis (Liver fluke) Opisthorchis viverrini Praziquantel 

Paragonimiasis (Lung fluke) Paragonimus 

westermani 

1 Thiabendazole is also indicated in Ascariasis. 

2 Unlabeled use. 

3 Thiabendazole is also indicated in Enterobiasis. 

4 Available from the CDC. 

5 Available from the CDC, although generally not recommended. 

6 Not available in the US. 

Praziquantel or Bithionol 4 (alternate) 

5

IV. 

Pharmacokinetic Parameters 

Table 4 lists the pharmacokinetic parameters and mechanisms of action of the anthelmintic 

antibiotics. 

Table 4. Pharmacokinetic Parameters of the Anthelmintic Agents 5-7 

Drug Mechanism of Action Bioavailability Protein 

Binding 

Albendazole 

Ivermectin 

Mebendazole 

Praziquantel 

Pyrantel 

Pamoate 

Thiabendazole 

Has an inhibitory effect on 

tubulin polymerization, 

which results in the loss of 

cytoplasmic microtubules. 

Binds selectively to 

glutamate-gated chloride 

ion channels in 

invertebrate nerve and 

muscle cells, leading to an 

increase in the 

permeability of the cell 

membrane to chloride ions 

with hyperpolarization of 

the nerve or muscle cell, 

resulting in paralysis and 

death of the parasite. 

Inhibits the formation of 

the worms’ microtubules 

and irreversibly blocks 

glucose uptake, depleting 

endogenous glycogen 

stores. 

Increases cell membrane 

permeability, resulting in a 

loss of intracellular 

calcium, massive 

contractions, and paralysis 

of the musculature. 

Activity further results in 

vacuolization and 

disintegration of the 

schistosome tegument. 

Works as a depolarizing 

neuromuscular blocking 

agent, resulting in spastic 

paralysis of the worm. 

Vermicidal or vermifugal 

activity. 

Poorly absorbed; 

systemic activity is 

due to the 

metabolite 

albendazole 

sulfoxide. Oral 

bioavailability is 

higher by up to 5 

fold when given 

with a fatty meal. 

Plasma 

concentrations are 

proportional to the 

dose. 

Poorly absorbed 

orally 

(5-10%) 

Rapidly absorbed 

(80%) 

Metabolis 

m 

Active 

Metabolites 

Elimination 

70% Liver Yes Biliary;

V. Drug Interactions 

There are no level 1 (most severe and life-threatening) drug interactions with the anthelmintic 

agents in this class. 8 No drug interactions for ivermectin were documented in any of the resources 

used to complete this section of the review, nor where any reported in the manufacturers package 

insert. 

Table 5. Drug Interactions of the Anthelmintic Agents 8 

Drug Significance Interaction Mechanism 

Albendazole Level 4 (moderate, 

possible) 

Albendazole and grapefruit juice Inhibition of albendazole metabolism (CYP3A4) in 

the small intestine by grapefruit juice is suspected, 

increasing plasma concentrations of albendazole, 

and increasing the risk of side-effects. 

Mebendazole Level 4 (delayed, 

moderate, possible) 

Mebendazole and carbamazepine Mechanism is unknown. The pharmacologic 

effects of mebendazole may be decreased. 

Mebendazole Level 4 (delayed, Mebendazole and hydantoins Mechanism is unknown. The pharmacologic effects 

Praziquantel 

Praziquantel 

Praziquantel 

Praziquantel 

Thiabendazole 


Level 2 (delayed, 

moderate, probable) 

Level 4 (rapid, 







Moderate, suspected) 

Praziquantel and cimetidine 

Praziquantel and carbamazepine 

Praziquantel and hydantoins 

Praziquantel and grapefruit juice 

Thiabendazole and theophyllines 

(xanthine derivatives) 

of mebendazole may be decreased. 

Cimetidine may inhibit the first-pass metabolism of 

praziquantel causing plasma concentrations of 

praziquantel to be elevated. This increases both the 

effectiveness and risk of adverse reactions. 

Mechanism is unknown. Serum praziquantel 

concentrations may be reduced, possibly leading to 

treatment failures. 

Mechanism is unknown. Serum praziquantel 

concentrations may be reduced, possibly leading to 

treatment failures. 

Inhibition of intestinal first-pass metabolism of 

praziquantel by grapefruit juice is suspected. 

Plasma concentrations of praziquantel may be 

elevated, increasing the pharmacologic and adverse 

effects. 

The exact mechanism is unknown, however, 

metabolic inhibition is suspected, and can lead to 

increased theophylline serum levels with possible 

toxicity. Theophylline levels should be monitored. 

Other interactions (per manufacturers labeling): 5 

• Pyrantel and piperazine = These drugs have antagonistic modes of action and, therefore, they 

should not be administered concomitantly. 

• Mebendazole and cimetidine = Preliminary evidence suggests that cimetidine inhibits 

mebendazole metabolism and may result in increased plasma concentrations of the drug. 

• Albendazole and cimetidine (precipitant drug) = Albendazole sulfoxide concentrations in bile 

and cystic fluid were increased ( 2-fold) in hydatid cyst patients treated with cimetidine. 

• Albendazole and praziquantel (precipitant drug) = Praziquantel (40 mg/kg) increased mean 

maximum plasma concentration and AUC of albendazole sulfoxide by 50% in healthy 

subjects. 

• Albendazole and dexamethasone (precipitant drug) = Steady-state trough concentrations of 

albendazole sulfoxide were 56% higher when 8 mg dexamethasone was coadministered with 

each dose of albendazole (15 mg/kg/day) in eight neurocysticercosis patients. 

7

VI. 

Adverse Drug Events of the Anthelmintic Agents 

Albendazole adverse events, although usually mild, differ between hydatid disease and 

neurocysticercosis. Treatment discontinuations are predominantly due to leucopenia (0.7%) or 

hepatic abnormalities (3.8% in hydatid disease). In addition to the events reported in Table 6, 

acute renal failure related to albendazole therapy has been observed, as well as allergic reactions, 

rash urticaria, and other hematologic adverse events. 

In comparative trials, patients treated with ivermectin experienced more abdominal distention and 

chest discomfort than patients treated with albendazole. However, ivermectin was better tolerated 

than thiabendazole in comparative studies involving 37 patients treated with thiabendazole. 5 

Adverse events may also be more frequent and/or serious in patients with a heavy worm burden. 

Historical data have also shown that microfilaricidal drugs, such as diethylcarbamazine citrate, 

might cause cutaneous and/or systemic reactions of varying severity, known as the Mazzotti 

reaction. This reaction can involve ophthalmological reactions in patients with onchocerciasis. It 

is believed the reactions are due to allergic and inflammatory responses to the death of 

microfilariae. 

Table 6. Common Adverse Events (%) Reported for the Anthelmintic Agents 5-7 

Adverse Event 

Albendazole 

(Hydatid Ds) 

Albendazole 

(Neurocysticercosis) 

Ivermectin Mebendazole Praziquantel Pyrantel Thiabendazole 

Body as a Whole 

- - - - 

- - 

Malaise 

b 

Cardiovascular 

- - - - - - 

Edema 

Hypotension 

b 

Hypertension 

Digestive System 

Abdominal Pain 

6.0 

0 

0.9 

b 

b 

b 

b 

Nausea / Vomiting 

3.7 

6.2 

1.8/0.9 

b 

b 

b 

Diarrhea 

1.8 

b 

b 

b 

Epigastric distress 

b 

Appetite decrease 

0.9 

b 

b 

Central Nervous System 

Dizziness/Vertigo 

1.2 

VII. 

Dosing and Administration for the Anthelmintic Agents 

Table 7. Dosing for the Anthelmintic Agents 5-7 

Drug Availability Dose /Frequency/Duration 

Albendazole 200mg oral tablet Dosing depends on which parasitic infection is being treated. 

Hydatid Disease 

60kg or greater: 400mg BID with meals (28-day cycle followed by a 14-day 

albendazole-free interval, for a total of 3 cycles). 

85 150micrograms/kg 

Mebendazole 100mg chewable tablets If a patient is not cured 3 weeks after treatment, a second course of treatment is advised. 

The same dose and dose schedule applies to children and adults. 

9

Pinworm Whipworm Common Roundworm Hookworm 

Dose: 1 tablet, 1 tablet, 1 tablet, 1 tablet, 

Once. morning morning morning 

and evening and evening and evening 

for 3 consecutive for 3 consecutive for 3 consecutive 

days. days. days. 

Praziquantel 600mg oral tablet Schistosomiasis: 

3 doses of 20mg/kg of bodyweight as a 1 day treatment. 

Clonorchiasis and Opisthorchiasis: 

3 doses of 25mg/kg of bodyweight as a 1 day treatment. 

The interval between the doses should not be < 4 and not > 6 hours. 

Tablets should be swallowed unchewed with some liquid during meals. Keeping the 

tablets or the segments thereof in the mouth may reveal a bitter taste that can produce 

gagging or vomiting. 

Pyrantel Pamoate 

Thiabendazole 

Soft gel 180mg 

capsules, 50mg/ml oral 

suspension, 50mg/ml 

liquid 

Oral Suspension 

500mg/5ml, oral 

chewable 500mg tablets 

Segments are broken off by pressing the score (notch) with thumbnails. If ¼ of a tablet 

is required, this is best achieved by breaking the segment from the outer end. 

Maximum total dose is 1 g. Dosage in mg/kg is the same for adults and children. 

Nematode infections: 

11mg/kg (max. 1gram) given as a single dose; the dose should be repeated after 2 weeks 

in patients with enterobiasis. 

Intestinal Hookworm (Ancylostoma duodenale or Necator americanus) or 

eosinophilic enterocolitis (Ancylostoma caninum): 

11mg / kg (max. 1 gram) once daily for 3 consecutive days. A repeated stool 

examination should be performed 2 weeks after treatment and the regimen should be 

repeated if results are positive. 

Moniliformis: 

11mg / kg given once; this dosage should be repeated twice at 2-week intervals. 

May be administered without regard to ingestion of food or time of day. Purging is not 

necessary. May be taken with milk or fruit juices. 

The usual dosage schedule for all conditions is 2 doses per day. Maximum daily dose is 

3 g after meals if possible. Dose is determined by body weight. 

Weight Each Dose (g) ml 

30lb 0.25g (1/2 tablet) 2.5ml (1/2 teaspoon) 

50lb 0.5g (1 tablet) 5.0ml (1 teaspoon) 

75lb 0.75g (1.5 tablets) 7.5ml (1.5 teaspoons) 

100lb 1.0g (2 tablets) 10ml (2 teaspoons) 

125lb 1.25g (2.5 tablets) 12.5ml (2.5 teaspoons) 

150lb & over 1.5g (3 tablets) 15ml (3 teaspoons) 

Regimens Based on Indication 

Indication Regimen Comments 

Strongyloidiasis 1 2 doses/day for 2 successive days. May also use 

Ascariasis 1 

single dose of 

Uncinariasis 1 

20mg/lb (44mg/kg) 

Trichuriasis 1 

but with higher sideeffects. 

Cutaneous larva migrans 2 doses/day for 2 successive days. A second course is 

(creeping eruption) 

recommended if 

if active lesions are still 

10

present 2 days after end 

of therapy. 

Trichinosis 1 2 doses/day for 2-4 successive days. Optimal dosage has not 

Individualize dosage. 

been established. 

Visceral larva migrans 2 doses/day for 7 successive days. Safety and efficacy data 

On the 7 day treatment 

are limited. 

1 

Clinical experience with thiabendazole in children weighing < 13.6 kg (30 lbs) is limited. 

Special Dosing Considerations 

Table 8. Special Dosing Considerations for the Anthelmintic Agents 5-7, 9 

Drug Renal 

Dosing 

Hepatic 

Dosing 

Pediatric Use Pregnancy 

Category 

Albendazole No No Experience in age

VIII. Comparative Effectiveness of the Anthelmintic Agents 

Not all of the agents in this class can be used for the same helminthic infections. 

Table 9. Additional Outcomes Evidence for the Anthelmintics 

Study Sample Treatment / 

Duration 

Albanese 

G, et al. 12 n=56 Albendazole, 

thiabendazole and 

combinations with 

cryotherapy 

Muchiri 

EM, et 

al. 13 n=1,186 4 and 6 month 

repeated treatment 

with albendazole or 

mebendazole 

Legesse 

M, et al. 14 - Mebendazole 100mg 

BID for 3 days vs. 

albendazole 400mg 

single dose 

Legesse Four 

M, et al. 15 treatment 

Albendazole 400mg 

single dose vs. three 

Results 

In comparing albendazole, thiabendazole, and combinations of both drugs with 

cryotherapy for the treatment of creeping eruption caused by nematodes of the 

Ancylostoma species: 

• Thirteen patients received cryotherapy alone, one received 

thiabendazole plus cryotherapy, six received thiabendazole, two 

received albendazole plus cryotherapy, and 34 received albendazole 

alone. 

• A prompt and definitive cure was achieved in all 56 patients. 

• The therapeutic effectiveness of the various methods used is 

equivalent. 

• The authors in this study felt albendazole should be the first choice for 

treatment due to the drug’s tolerability and favorable patient 

compliance. 

In evaluating the effectiveness of four and six month repeated treatment with 

albendazole 600mg or mebendazole 600mg on helminth infections on children 

(age 4-19) in six primary schools in Kenya: 

• Overall, albendazole produced better cure rates and egg reduction rates 

for geohelminths. The cure rates for albendazole were 92.4% for 

hookworm infection, 83.5% for Ascaris lumbricoides, and 67.8% for 

Trichuris trichiura. 

• Mebendazole given either 2 or 3 times in a year had cure rates of 50 

and 55.0% (respectively) for hookworm, 79.6 and 97.5% for A. 

lumbricoides, and 60.6 and 68.3% for T. trichiura infection. 

• The geometric mean intensity of hookworm eggs per gram (epg) of 

stool decreased by 96.7% after albendazole treatment compared with 

66.3 and 85.1%, respectively, for 2 or 3 doses of mebendazole (p < 

0.05) over the same period. 

• Reductions in epg for A. lumbricoides and T. trichiura were 

comparable for both drugs. Results indicate that treatment with 

albendazole at a six month interval was more effective than 

mebendazole regimens and may be the best choice for use in the 

control of the three geohelminths. 

In comparing mebendazole versus albendazole for the treatment of single or 

mixed Ascaris lumbricoides and Trichuris trichiura: 

• Both drugs were found to be highly effective against Ascaris 

lumbricoides infection, with cure rate of over 96% and egg reduction 

of over 99.8%. 

• The efficacy of the two drugs against Trichuris trichiura infection was 

low. 

• Mebendazole appeared to be more effective against Trichuris trichiura 

in that it exhibited a cure rate of 34.7% and egg reduction of 92.3% as 

opposed to albendazole, which exhibited a cure rate and egg reduction 

rate of 13.9% and 63.4%, respectively. 

• The two drugs appeared to have little effect on Schistosoma mansoni 

infection. 

• More complaints were reported by individuals treated with 

albendazole than with mebendazole. 

• Summary: mebendazole appears to be safer and more effective for the 

treatment of single or mixed infections with Trichuris trichiura and 

Ascaris lumbricoides as compared to albendazole. 

In evaluating albendazole and three brands of mebendazole for the treatment of 

single or mixed Ascaris lumbricoides and Trichuris trichiura: 

12

groups 

of school 

children 

brands of 

mebendazole at doses 

of 100mg BID for 3 

days 

Datry A, 

et al. 16 n=60 Albendazole 

400mg/day for 3 days 

vs. ivermectin 150- 

200 micrograms/kg in 

a single dose 

Tabi TE, n=99 Albendazole 400mg 

et al. 17 for 3 days vs. placebo 

Simonsen 

PR, et 

al. 18 n=1,829 Ivermectin 150-200 

micrograms/kg alone 

or in combination 

with albendazole 

400mg 

• The percentage cure rate and egg reduction rate obtained with 

albendazole and mebendazole from the three brands were not 

significantly different in the treatment of ascariasis. 

• However, significant differences were found among the percentage 

cure rates and egg reduction rates of the four treatment groups in the 

treatment of trichuriasis. Comparatively, high cure rate (89.8%) and 

egg reduction rate (99.1%) were observed in the Vermox (Janssen) 

treated group followed by the Unibios (India) treated group (53.3% 

and 96.53% cure and egg reduction rates, respectively), whereas low 

cure rate (17.1%) and egg reduction rate (69.8%) were seen in the 

albendazole treated group. 

• The results of this study suggest that in areas where single or mixed 

infections with Trichuris trichiura and/or Ascaris lumbricoides are 

common, this disease is a public health problem. When laboratory 

facilities are not available to make parasite identification, mebendazole 

would be the drug of choice to treat trichuriasis and ascariasis. 

• However, either mebendazole from the different brands or albendazole 

is effective in the treatment of ascariasis in areas where trichuriasis is 

not prevalent. 

In a randomized trial comparing ivermectin with albendazole in patients with 

confirmed Strongyloides stercoralis infection: 

• Parasitological cure was obtained in 24 of the 29 patients treated with 

ivermectin (83%) and in 9 of the 24 patients who were given 

albendazole (38%); ivermectin was significantly more effective than 

albendazole (p < 0.01). 

• Clinical and biological adverse reactions were negligible in both 

treatment groups. 

• The 20 patients who failed therapy were given a second treatment 

course with 150-200 micrograms/kg of ivermectin in a single dose or on 

two consecutive days. Sixteen patients were cured and the other four 

had only incomplete follow-up. 

• Ivermectin therefore constitutes an acceptable therapeutic alternative for 

uncomplicated strongyloidiasis. 

In this double-blind, placebo-controlled, crossover clinical trial of albendazole 

vs. placebo for the treatment of loiasis: 

• Because of life-threatening, post-treatment reactions in patients with 

loiasis treated with ivermectin, other treatments are necessary. 

• Patients received treatment for three days and were followed for 180 

days, and then were crossed over and followed for an additional 180 

days. 

• In those initially receiving albendazole (ALB/PLAC), microfilarial 

levels decreased significantly by day 90 (p < 0.043), but returned to 

baseline by day 180. In those receiving albendazole at day 180 

(PLAC/ALB), microfilarial levels also decreased following 

albendazole (p = 0.005). 

• Blood eosinophil and antifilarial IgG levels did not change 

significantly for either group, although antifilarial IgG4 levels did in 

the ALB/PLAC group at day 180. 

• Most subjects continued to have elevations in microfilaremia, 

suggesting that more intensive regimens of albendazole will be 

necessary to reduce Loa microfilaremia to levels safe enough to allow 

for ivermectin use. 

In evaluating the efficacy of a single dose of ivermectin alone or in combination 

with albendazole in children in six primary schools in coastal Tanzania: 

• Both treatment regimens resulted in a considerable decrease in mean 

microfilaria (mf) intensities, with overall reductions being slightly but 

statistically significantly higher for the combination than for 

ivermectin alone. 

• The difference in effect between the two regimens was most 

pronounced at six months, whereas it was minor at 12 months after 

13

Makunde - Albendazole 400mg in 

al. 19 ivermectin 150mcg/kg 

WH, et 

combination with 

Awadzi 

K, et al. 20 n=42 Ivermectin 

(200mcg/kg) plus 

albendazole (400mg) 

vs. ivermectin alone 

(200mcg.kg) 

Safdar A, n=25 Frequency of 

et al. 21 Strongyloides 

stercoralis infestation 

treatment. 

• The relative effect of treatment on mean circulating filarial antigen 

(CFA) units was less pronounced than on microfilaria. 

• For both treatment regimens, reductions in CFA intensity appeared to 

be higher in children who were both CFA and mf positive before 

treatment, which may suggest that treatment mainly affected the 

survival and/or production of mf, rather than the survival of adult 

worms. 

• Adverse reactions were few and mild in both groups, and mainly 

reported from pre-treatment mf and CFA positive children. 

In order to use ivermectin with albendazole for the elimination of lymphatic 

filariasis, the potential risk of adverse events in individuals infected with both 

lymphatic filariasis and onchocerciasis was compared in this crossover, doubleblind 

study (for patients with co-infections): 

• Patients with a single infection of bancroftian filariasis underwent an 

open design comparing two treatments, where one group received a 

single dose of albendazole (400mg) plus ivermectin (150microg/kg) 

(Group C) while the other group received a single dose of albendazole 

(400mg) alone (Group D). 

• For co-infection, one group was allocated a single dose of ivermectin 

(150micrograms/kg) plus albendazole (400mg) (Group A). The other 

group received placebo (Group B). Five days later the treatment 

regimen was reversed, with the Group A receiving placebo and Group 

B receiving treatment. 

• In individuals co-infected with bancroftian filariasis and 

onchocerciasis, treatment with ivermectin and albendazole was safe 

and tolerable. 

• Physiological indices showed no differences between groups with coinfection 

(W. bancrofti and O. volvulus) or single infection (W. 

bancrofti). 

• The frequency of adverse events in co-infected individuals was 63% 

(5/8, Group A, albendazole + ivermectin) and 57% (4/7, Group B, 

placebo) with mild or moderate intensity. 

• In single W. bancrofti infection the frequency of adverse events was 

50% (6/12, Group C, albendazole + ivermectin) and 38% (5/13, Group 

D, albendazole) and of a similar intensity to those experienced with coinfection. 

• There were no differences in adverse events between treatment groups. 

• There was no significant difference in the reduction of microfilaraemia 

following treatment with albendazole and ivermectin in groups with 

single or co-infection. 

This randomized, double-blind, placebo-controlled trial was conducted to 

determine if co-administration of ivermectin with albendazole is safe and 

effective against Onchocerca volvulus compared to ivermectin alone, and 

whether a significant pharmacokinetic interaction occurs: 

• The co-administration of ivermectin with albendazole did not produce 

more severe adverse effects than ivermectin alone. 

• Both nodule examiners found that the combination was not 

macrofilaricidal and that it was not clearly superior to ivermectin alone 

in the effects on reproductive activity; this was supported by the 

similar efficacy of the two regimens in the suppression of skin 

microfilariae. 

• There was no significant pharmacokinetic interaction. 

• Although the co-administration of ivermectin with albendazole appears 

safe, it offers no advantage over ivermectin alone in the control of 

onchocerciasis. 

• The combination does not require an alteration in the dosage of either 

component. 

This retrospective analysis of S. stercoralis infection in patients with cancer 

undergoing cancer treatment showed: 

• The overall S. stercoralis infection frequency was approximately 1.0 per 

14

and complications in 

patients with cancer 

between 1971 and 

2003 

Belizario 

VY, et 

al. 22 n=784 Single doses of 

albendazole, 

ivermectin, and 

diethylcarbamazine 

(all given with 

placebo), and of the 

combination of 

albendazole + 

ivermectin and 

albendazole + 

diethylcarbamazine 

10,000 new cancer cases between 1971 and 2003. 

• Twenty-two of 25 patients (88%) were U.S. residents (19 from Texas; one 

each from Mississippi, Tennessee, and Puerto Rico), and the remaining 

three (13%) were from Latin America. 

• Thirteen (52%) had solid-organ malignancies, whereas 12 (48%) had 

hematologic malignancies (lymphoma or multiple myeloma, n=8; leukemia, 

n=3; aplastic anemia, n=1). 

• Twelve patients (48%) received systemic corticosteroids, 9 (36%) received 

antineoplastic therapy, and 2 underwent hematopoietic stem cell 

transplantation (HSCT). 

• Diarrhea was reported in 13 patients (57%), and eosinophilia was observed 

in 11 patients (48%); four patients (16%) had probable hyperinfection 

syndrome (in three cases of polymicrobial gram-negative bacteremia, one 

patient had Klebsiella pneumoniae pneumonia, whereas one patient 

presented with K. pneumoniae lung infection alone). Evidence of definite 

pulmonary hyperinfection syndrome was observed in 2 HSCT recipients 

(8%). 

• Fourteen (74%) of 19 patients responded to thiabendazole therapy. Two 

patients with definite pulmonary hyperinfection syndrome developed fatal 

S. stercoralis hemorrhagic alveolitis despite receiving high-dose 

thiabendazole plus ivermectin therapy. 

• In the current study, strongyloidiasis was uncommon in patients with cancer 

and remained localized in individuals with solid-organ malignancies. 

Definite pulmonary accelerated autoinfections were observed only in HSCT 

recipients. 

In evaluating the efficacy of various single dose treatments against the common 

intestinal helminthiases caused by Ascaris and Trichuris species in this randomized, 

placebo-controlled trial: 

• Albendazole, ivermectin and the drug combinations gave significantly 

higher cure and egg reduction rates for ascariasis than diethylcarbamazine. 

• For trichuriasis, albendazole + ivermectin gave significantly higher cure and 

egg reduction rates than the other treatments: the infection rates were lower 

180 and 360 days after treatment. 

• Summary: Because of the superiority of albendazole + ivermectin against 

both lymphatic filariasis and trichuriasis, this combination appears to be a 

suitable tool for the integrated or combined control of both public health 

programs. 

Additional Evidence 

Dose Simplification: In most cases, the anthelmintic agents in this class are given as a single dose or for a 

brief duration (acute use), depending on the infection being treated. When given for longer durations, dosing 

is QD-BID. Therefore, research into dose simplification within this class is not an applicable. 

Stable Therapy: Limited clinical data is available on resistance to the anthelmintic medications in humans. 

Interestingly, more studies have been published on resistance to helminthic infections in horses, pigs, and 

sheep. One study from the region of Mali showed that in evaluating a standard egg hatch assay, patients from 

Mali with N. americanus (hookworm) infections were more resistant to benzimidazoles compared with a 

laboratory-maintained strain that had not been exposed to anthelmintics, suggesting increased drug resistance 

from drug failures. In this study, single-dose mebendazole was ineffective against hookworm infections in 

Mali. 23 Although the clinical evidence does not suggest problems with resistance patterns in the U.S, 

resistance to the anthelmintic drugs should be considered in patients who have previously been treated for 

helminthic infections and in those with apparent treatment failure. 

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal clinical literature 

relevant to use of the anthelmintics and their impact on physician visits. 

15

IX. 

Conclusions 

Mebendazole and pyrantel pamoate are available to patients due to their over-the-counter status and generic 

availability. Mebendazole and pyrantel can be used to treat pinworm, whipworm, roundworm, and 

hookworm infections (pyrantel = pinworm and roundworm only), which are the more common helminthic 

infections found in the United States. Mebendazole and pyrantel are the treatments of choice for these 

helminthic infections. 

Other less common helminthic infections in the United States include strongyloides, schistosoma, liver 

flukes, onchocerciasis, neurocysticercosis, and hydatid disease. These infections are rarely found in the U.S, 

but may occur in immunocompromised patients or in patients who have traveled to endemic areas. At this 

time, treatment of these helminthic infections is considered outside the scope of general use of the drugs 

within this class. Because albendazole, ivermectin, praziquantel and thiabendazole have indications for these 

infections, they should be available for special needs/circumstances that require medical justification through 

the prior authorization process. Proper medical justification will provide patient access to these agents. 

For these reasons, mebendazole and pyrantel pamoate offer clinical advantages when used for their respective 

treatment indications. These agents are available OTC and with generic formulations. The remaining 

anthelmintic drugs in this class (albendazole, ivermectin, praziquantel and thiabendazole) are comparable to 

each other and to the generics and OTC products in this class and offer no significant clinical advantage over 

other alternatives in general use. 

X. Recommendations 

No brand anthelmintic is recommended for preferred status. 

16

References 

1. Anandan JV. Parasitic Diseases. In: Pharmacotherapy. A Pathophysiologic Approach, Fifth Edition. 

Dipiro JT, Talbert RL, Yee GC, et al. Eds. McGraw-Hill. New York. 2002. Pg. 1967-581980. 

2. Hall A. Anthelmintics: drugs for treating worms. Afr Health 1998 Sep;20(6):4-6. 

3. Centers for Disease Control and Prevention (CDC). Guidelines for preventing opportunistic infections 

among hematopoietic stem cell transplant recipients. MMWR Oct 20 2000;49;RR-10. 

4. MMWR. Palmar pallor as an indicator for anthelmintic treatment among ill children aged 2-4 years-western 

Kenya, 1998. JAMA June 14 2000;283(22):2925-2927. 

5. Murray L, Senior Editor. Package inserts. In: Physicians’ Desk Reference, PDR Edition 58, 2004. 

Thomson PDR. Montvale, NJ. 2004. 

6. McEvoy GK, Ed. American Hospital Formulary Service, AHFS Drug Information. American Society of 

Health-System Pharmacists. Bethesda. 2004. 

7. Kastrup EK, Ed. Drug Facts and Comparisons. Facts and Comparisons. St. Louis. 2004. 

8. Tatro, Ed. Drug Interaction Facts. Facts and Comparisons. St. Louis. 2004. 

9. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. A reference guide to fetal and 

neonatal risk. Sixth Edition. Lippincott, Williams, & Wilkins, Philadelphia, 2002. 

10. Tarr PE, Miele PS, Peregory KS, et al. Case report: rectal administration of ivermectin to a patient with 

Strongyloides hyperinfection syndrome. Am J Trop Med Hyg Apr 2003;68(4):453-455. 

11. Chiodini PL, Reid AJC, Wiselka MJ, et al. Parenteral ivermectin in strongyloides hyperinfection. Lancet Jan 

1, 2000;355(9197):43-44. 

12. Albanese G, Venturi C, Galbiati G, et al. Treatment of larva migrans cutanea (creeping eruption): a 

comparison between albendazole and traditional therapy. Int J Dermatol 2001 Jan;40():67-71. 

13. Muchiri EM, Thiong’o FW, Mangnussen P, et al. A comparative study of different albendazole and 

mebendazole regimens for the treatment of intestinal infections in school children of Usigu Division, western 

Kenya. J Parasitol 2001 Apr;87(2):413-8. 

14. Legesse M, Erko B, Medhin G. Efficacy of albendazole and mebendazole in the treatment of Ascaris and 

Trichuris infections. Ethiop Med J 2002 Oct;40(4):335-43. 

15. Legesse M, Erko B, Medhin G. Comparative efficacy of albendazole and three brands of mebendazole in the 

treatment of ascariasis and trichuriasis. East Afr Med J 2004 Mar;81(3):134-8. 

16. Datry A, Hilmarsdottir I, Mayorga-Sagastume R, et al. Treatment of Strongyloides stercoralis infection with 

ivermectin compared with albendazole: results of an open study of 60 cases. Trans R Soc Trop Med Hyg 

1994 May-Jun:88(3):344-5. 

17. Tabi TE, Befidi-Mengue R, Nutman TB, et al. Human loiasis in a Camemroonian village: a double-blind, 

placebo-controlled, crossover clinical trial of a three-day albendazole regimen. Am J Trop Med Hyg 2004 

Aug;71(2):211-215. 

18. Simonsen PE, Magesa SM, Dunyo SK, et al. The effect of single dose ivermectin alone or in combination 

with albendazole on Wuchereria bancrofti infection in primary school children in Tanzania. Trans R Soc 

Trop med Hyg 2004 Aug;98(8):462-72. 

19. Makunde WH, Kamugisha LM, Massaga JJ, et al. Treatment of co-infection with bancroftian filariasis and 

onchocerciasis: a safety and efficacy y study of albendazole with ivermectin compared to treatment of single 

infection with bancroftian filariasis. Filaria J 2003 Nov 6;2(1):15. 

20. Awadzi K, Edwards G, Duke BO, et al. The co-administration of ivermectin and albendazole—safety, 

pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol 2003 Mar;97(2):165- 

78. 

21. Safdar A, Malathum K, Rodriguez SJ, et al. Strongyloidiasis in patients at a comprehensive cancer center in 

the United States. Cancer 2004 Apr 1;100(7):1531-6. 

22. Belizario VY, Amarillo ME, de Leon WU, et al. A comparison of the efficacy of single doses of albendazole, 

ivermectin, and diethylcarbamazine alone or in combinations against Ascaris and Trichuris species. Bull 

World Health Organ 2003;81(1):35-42. 

23. De Clercq D, Sacko M, Behnke J, et al. Failure of mebendazole in treatment of human hookworm infections 

in the southern region of Mali. Am J Trop Hyg 1997 Jul;57(1):25-30. 

17



Pharmacotherapy Review of the Aminoglycosides 

AHFS 081202 


I. Overview 

The aminoglycosides are generally active against aerobic gram-negative bacteria and gram-positive bacteria 

and are used for serious infections, including septicemia (including neonatal sepsis), bone and joint 

infections, skin and soft-tissue infections, respiratory tract infections, uncomplicated urinary tract infections, 

and postoperative and intra-abdominal infections. The drugs in this class work by creating fissures in the 

outer membrane of the bacterial cell. 1 Due to in vitro synergism, concomitant use of an aminoglycoside with 

an extended-spectrum penicillin with antipseudomonal activity, has been recommended. 2 However, in vitro 

inactivation of aminoglycosides by β-lactam antibiotics indicates that the drugs should be administered 

separately and in vitro mixing of these drugs should be avoided. 

Aminoglycosides are also used in conjunction with a β-lactam antibiotic, a carbapenem, an extendedspectrum 

penicillin, or a fixed combination of an extended-spectrum penicillin and a β-lactamase inhibitor for 

empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients. Additionally, 

most strains of enterococci are resistant to aminoglycosides alone, and penicillin therapy alone is usually 

inadequate in infections caused by these organisms; however, due to synergism, gentamicin or streptomycin 

used together with penicillin G or ampicillin is often effective in the treatment of enterococcal endocarditis. 2 

Gentamicin and ampicillin can be used for prophylaxis of bacterial endocarditis in adults and children 

undergoing certain genitourinary or nonesophageal GI tract procedures likely to cause transient bacteremia. 

The American Academy of Pediatrics states that in invasive enterococcal infections, including endocarditis 

and meningitis, ampicillin and vancomycin combined with an aminoglycoside (usually gentamicin) should be 

administered until in vitro susceptibility is known and appropriate combination therapy can be selected. 2 The 

Centers for Disease Control and Prevention suggest a regimen of IM or IV gentamicin in combination with 

IV clindamycin as one possible parenteral regimen for the treatment of acute pelvic inflammatory disease 

(PID). 

In general, the choice of a specific parenteral aminoglycoside should be based on the usual spectrum and 

pattern of aminoglycoside resistance in the hospital or community until results of in vitro tests are available. 

Generally, when given a susceptible organism, amikacin, gentamicin, kanamycin, and tobramycin appear to 

be equally effective when administered in appropriate doses. Resistance to the aminoglycosides is rare, but 

increasing in frequency. 1 Amikacin may be effective in infections caused by gentamicin, kanamycin, and/or 

tobramycin resistant organisms, especially P. rettgeri, P. stuartii, S. marcescens, K. pneumoniae, and Ps. 

Aeruginosa. However, there are also strains of bacteria resistant to amikacin that may be susceptible to 

gentamicin and/or tobramycin. 

In looking at oral use of the aminoglycosides, kanamycin and neomycin are both used orally for preoperative 

intestinal antisepsis as an adjunct to mechanical cleansing of the large intestines. Regimens of oral neomycin 

and oral erythromycin are sometimes used for perioperative prophylaxis in patients undergoing colorectal 

surgery. Neomycin is also used orally as an adjunct to fluid and electrolyte replacement in the treatment of 

severe diarrhea caused by susceptible strains of enteropathogenic E. coli. 

Finally, the aminoglycosides can be used when administered by oral inhalation for the management of 

bronchopulmonary Ps. aeruginosa infections in cystic fibrosis patients. This type of treatment is generally 

long-term suppressive therapy for prophylaxis of exacerbations of infections and is not routinely 

recommended for the treatment of acute exacerbations. 

This review encompasses all dosage forms and strengths. Table 1 lists the drugs in this review. 

18

Table 1. Aminoglycosides in this Review 

Generic Name Formulation Example Brand Name 

Amikacin Sulfate Parenteral Amkin*, Amkin Pediatric* 

Gentamicin Sulfate Parenteral Garamycin* 

Kanamycin Sulfate Parenteral, Oral Kantrex* (oral is brand only) 

Neomycin Sulfate Oral Neo-Fradin* (oral solution is brand only) 

Streptomycin Sulfate Parenteral Streptomycin* 

Tobramycin Sulfate 


Oral Inhalation, 

Parenteral 

Nebcin* (injection is generic, powder for 

injection is brand), Tobi 

II. 


Despite the introduction of newer, less toxic antimicrobial agents, aminoglycosides continue to serve a useful 

role in the treatment of serious enterococcal and gram-negative bacillary infections. 1 According to an article 

from the American Academy of Family Physicians, gentamicin is the aminoglycoside used most often 

because of its reliable activity against gram-negative aerobes, and in general, gentamicin, tobramycin, and 

amikacin are used in similar circumstances, often interchangeably. 1, 3 Tobramycin may be the 

aminoglycoside of choice for use against P. aeruginosa because it has shown greater in vitro activity. 

Amikacin is particularly effective when used against bacteria that are resistant to other aminoglycosides, 

since its chemical structure makes it less susceptible to inactivating enzymes. 3 Depending on local resistance 

patterns, amikacin may be the preferred agent for serious nosocomial infections caused by gram-negative 

bacilli. 

When selecting anti-infectives for prophylaxis of recurrent rheumatic fever or prophylaxis of bacterial 

endocarditis, the current recommendations published by the American Heart Association should be consulted. 

Additionally, hospital and community resistance patterns are important considerations. The following table 

highlights drugs of choice for multiple types of microorganisms. 

Table 2. Aminoglycosides as Drugs of Choice 4 

Microorganism 

Drug 

Gram-Positive Cocci Enterococcus faecalis, serious infections (endocarditis, 

meningitis, pyelonephritis with bacteremia) 

Ampicillin (or penicillin G) + 

gentamicin or streptomycin 

Streptococcus, viridans group 

Penicillin G ± gentamicin a 

Staphylococcus aureus / Staphylococcus epidermidis, Vancomycin ± gentamicin or rifampin 

methicillin (oxacillin) –resistant 

Gram-Negative Cocci - - 

Gram-Positive Bacilli - - 

Gram-Negative Bacilli Acinetobacter species Imipenem or meropenem either ± 

aminoglycoside (per sensitivities; 

amikacin usually most effective) 

Enterobacter species 

Imipenem, meropenem, or cefepime 

plus aminoglycoside (per sensitivities) 

Klebsiella pneumoniae (UTI only) 

Aminoglycoside (per sensitivities) 

Pseudomonas aeruginosa 

UTI only 

Piperacillin or ceftazidime plus 

aminoglycoside (per sensitivities) 

Aminoglycoside (per sensitivities) 

Serratia marcescens Third-generation cephalosporin ± 

gentamicin 

Misc. Microorganisms - - 

Spirochetes - - 

a 

Gentamicin should be added if tolerance or moderately susceptible (MIC >0.1g/ml) organisms are encountered; streptomycin is used but may be more 

toxic. 

19

Additionally, the following table reflects susceptibilities to the aminoglycosides. 

Table 3. Organisms Generally Susceptible to Aminoglycosides 5, 6 

Organisms Amikacin Gentamicin Kanamycin Streptomycin Tobramycin 

Gram-positive Mycobacterium tuberculosis 1 2 

Staphylococci 3 3 

S. aureus 3 

S. epidermidis 

Streptococci 2 

S. faecalis 2 2 2 

Gram-negative Acinetobacter sp. 

Brucella sp. 

Citrobacter sp. 

Enterobacter sp. 

Escherichia coli 

Hemophilus influenzae 2 

Hemophilus ducreyi 

Klebsiella sp. 2 

Morganella morganii 

Neisseria sp. 

Proteus sp. 4 4 4 4 

Providencia sp. 

Pseudomonas sp. 

P. aeruginosa 2 

Salmonella sp. 

Serratia sp. 

Shigella sp. 

Yersinia (Pasteurella) pestis 

1 

= generally susceptible 

3 Penicillinase-producing and nonpenicillinase-producing. 

2 Usually used concomitantly with other anti-infectives. 

4 Indole-positive and indole-negative. 

20

III. 

Comparative Indications of the Aminoglycoside Antibiotics 

Aminoglycosides should be reserved for treatment of infections caused by organisms not sensitive to less toxic agents. Safety for treatment 

periods greater than 14 days has not been established and many of the aminoglycosides should not be used long-term due to adverse events. 

Table 4. FDA-Approved Indications for the Aminoglycosides 2, 6 

Drug Infections (General) Gram Negative 

Infections 

Amikacin Sulfate 

✔ 

Bacterial septicemia; infections of 

the respiratory tract, joints, bones, 

skin and soft tissue; meningitis; 

intra-abdominal infections; burns; 

post-operative infections; 

complicated and recurrent UTI’s. 

✔ 

Consider as initial therapy in 

suspected gram-negative 

infections; therapy may be 

instituted before obtaining 

the results of susceptibility 

testing. It is effective in 

infections caused by 

gentamicin- or tobramycinresistant 

strains of gramnegative 

organisms, 

particularly P. rettgeri, P. 

stuartii, S. marcescens and 

P. aeruginosa. 

Staphylococcal Infections Neonatal Sepsis Intrathecal 

Administration 

✔ 

Initial therapy under certain 

conditions in the treatment of 

known or suspected 

staphylococcal disease, such as: 

Severe infections where the 

causative organism may be either 

a gram-negative bacterium or a 

staphylococcus; infections 

caused by susceptible strains of 

staphylococci in patients allergic 

to other antibiotics; and in mixed 

staphylococcal/gram-negative 

infections. 

✔ 

In severe infections, 

concomitant therapy 

with a penicillin-type 

drug may be indicated 

because of the 

possibility of 


gram-positive 

organisms, such as 

streptococci or 

pneumococci. 

Other 

- - 

Gentamicin Sulfate 

✔ 

Serious infections caused by 

susceptible strains of 

Pseudomonas aeruginosa, 

Proteus sp. (indole-positive and 

indole-negative), Escherichia coli, 

Klebsiella sp., Enterobacter sp., 

Serratia sp., Citrobacter sp. and 

Staphylococcus sp. (coagulasepositive 

and coagulase-negative). 

Effective in bacterial neonatal 

sepsis; bacterial septicemia; 

meningitis, urinary tract, 

respiratory tract, GI tract, skin, 

bone and soft tissue (including 

burns). 

✔ 

Consider as initial therapy in 

suspected or confirmed 

gram-negative infections. 

✔ 

While not the antibiotic of first 

choice, consider gentamicin 

when penicillins or other less 

toxic drugs are contraindicated, 

when bacterial susceptibility 

tests and clinical judgment 

indicate its use and in mixed 

infections caused by susceptible 

strains of staphylococci and 

gram-negative organisms. 

✔ 

✔ 

Indicated as 

adjunctive therapy to 

systemic gentamicin 

in the treatment of 

serious CNS 

infections 

(meningitis, 

ventriculitis) caused 

by susceptible 

Pseudomonas sp. 

- 

21


Infections 

Kanamycin Sulfate 

✔ 

✔ 

Initial therapy for one or more of Indicated for initial therapy 

the following: Escherichia coli, of severe infections thought 

Proteus sp. (both indole-positive to be susceptible in patients 

and indole-negative), allergic to other antibiotics, 

Enterobacter aerogenes, 

or in mixed 

Klebsiella pneumoniae, Serratia staphylococcal/gramnegative 

marcescens and Acinetobacter sp. 

infections. 

Also initial therapy with a 

penicillin or cephalosporin before 

obtaining results of susceptibility 

testing. 



Not the drug of choice for 

staphylococcal infections. 

✔ - 

Other 

Oral only: 

Suppression of 

intestinal bacteria 

and hepatic coma. 

Neomycin Sulfate - - - - - ✔ 

Suppression of 

bowel intestinal 

bacteria (e.g. 

preoperative 

preparation of the 

bowel); hepatic 

coma. 

22


Infections 

Streptomycin Sulfate 

✔ 

✔ 

Use only in infections caused by Gram-negative bacilli 

organisms shown to be 

(in bacteremia, with 

susceptible, and when less 

another agent). 

potentially hazardous therapeutic 

agents are ineffective or 

contraindicated. Organisms 

usually sensitive include: 

Pasteurella pestis (plague); 

Francisella tularensis (tularemia); 

Brucella, Calymmatobacterium 

granulomatis (donovanosis, 

granuloma inguinale); 

Haemophilus ducreyi (chancroid); 

H. influenzae (in respiratory, 

endocardial and meningeal 

infections with another agent); K, 

pneumoniae pneumonia (with 

another agent); E. coli, Proteus 

sp., A. aerogenes, K. pneumoniae 

and Entercoccus faecalis in 

urinary tract infections; 

Streptococcus viridans and E. 

faecalis (in endocardial infections 

with penicillin). 



Other 

- - - ✔ 

Mycobacterium 

tuberculosis: The 

Advisory Council for 

the Elimination of 

TB, the American 

Thoracic Society and 

the CDC recommend 

either streptomycin or 

ethambutol be added 

as a fourth drug in a 

regimen containing 

isoniazid, rifampin 

and pyrazinamide for 

initial treatment of 

TB unless the 

likelihood of INH or 

rifampin resistance is 

very low. Reassess 

the need for a fourth 

drug when 

susceptibility testing 

results are known. 

Streptomycin is also 

indicated for therapy 

of TB when one or 

more of the above 

drugs is 

contraindicated 

because of toxicity or 

intolerance. 

23


Infections 

Tobramycin Sulfate 

✔ 

✔ 

Treatment of serious bacterial In patients where serious 


life-threatening gramnegative 

susceptible strains of 

infection is 

Pseudomonas aeruginosa, suspected, including 

Escherichia coli, Proteus sp. 

those in whom 

(indole-positive and indolenegative) 

concurrent therapy with 

including P. 

a penicillin or 

mirabilis, Morganella 

cephalosporin and an 

morganii and P. vulgaris, aminoglycoside may be 

Providencia sp. including 

indicated, initiate 

Klebsiella-Enterobacter- 

tobramycin before 

Serratia group, Citrobacter susceptibility study 

sp. and staphylococci 

results are obtained. 

including S. aureus 

Base decision to 

(coagulase-positive and 

continue therapy on 

coagulase-negative). 

these results. 

Infections including: 

Septicemia (neonates, 

children, adults, lower 

respiratory tract infections, 

serious CNS infections 

(meningitis), intra-abdominal 

infections, including 

peritonitis, 

skin, bone and skin structure 

infections, 

complicated and recurrent 

urinary tract infections 

(UTIs). 



✔ 

Tobramycin may be considered 

in serious staphylococcal 

infections when penicillin or 

other potentially less toxic drugs 

are contraindicated and when 

bacterial susceptibility testing 

and clinical judgment indicate its 

use. 

Other 

✔ - ✔ 

Cystic Fibrosis 

(nebulizer only) 

24

IV. 

Pharmacokinetic Parameters of the Aminoglycoside Antibiotics 

Absorption 

Aminoglycosides are poorly absorbed from the GI tract, but are well absorbed following 

parenteral administration. 2 Intramuscular administration can result in interpatient variations in 

plasma concentrations achieved with a specific IM dose, due to differences in rates of absorption 

from injection sites. Aminoglycosides are also rapidly and almost completely absorbed following 

topical administration during surgical procedures or from surgical sites. 

Distribution 

Following absorption, aminoglycosides are widely distributed into body fluids, primarily in the 

extracellular fluid volume. Streptomycin appears to be 35% bound to plasma proteins, where 

other aminoglycosides are only minimally protein bound. 2 Additionally, a small portion of each 

aminoglycoside does accumulate in body tissues and is tightly bound intracellularly. Most body 

compartments and tissues including the inner ear and kidneys become progressively saturated with 

an aminoglycoside over the course of therapy, and the drug is slowly released from these areas. 

This may account for the ototoxicity and nephrotoxicity associated with these agents. The agents 

in this class differ in their affinity for renal tissue; streptomycin has less affinity for renal tissue 

than the other aminoglycosides. 

Elimination 

The plasma elimination half-life of aminoglycosides is usually 2-4 hours in adults with normal 

renal function. 2 Plasma concentrations are higher and plasma elimination half-lives are more 

prolonged in patients with impaired renal function. These concentrations are not usually affected 

by hepatic impairment, however, the plasma elimination half-life of streptomycin has been 

reported to be more prolonged in patients with both renal and hepatic impairment than in patients 

with renal impairment alone. In infants, aminoglycoside plasma elimination half-lives are 

inversely proportional to birthweight and gestational age and reflect renal maturity. 

Aminoglycosides are not metabolized and are excreted unchanged in urine by glomerular 

filtration. With normal renal function, 40-97% of a single IM or IV dose of an aminoglycoside is 

excreted in the urine within 24 hours. Complete recovery of a dose in the urine, in a patient with 

normal renal function requires approximately 10-20 days. Aminoglycosides are readily removed 

by hemodialysis and to a lesser extent by peritoneal dialysis. Table 5 illustrates the 

pharmacokinetic parameters of the aminoglycosides. 

Table 5. Pharmacokinetic Parameters of the Aminoglycosides 2,6 

Various Pharmacokinetic Parameters of the Aminoglycosides 

Therapeutic Toxic serum 

Half-life (hrs) serum levels levels(mcg/ml) Dose 

Aminoglycoside Normal ESRD (peak) Peak 1 Trough 2 (mg/kg/day) 

(mcg/ml) 

(normal Ccr) 

Amikacin 2-3 24-60 16-32 > 35 > 10 15 

Gentamicin 2 24-60 4-8 > 12 > 2 3-5 

Kanamycin 2-3 24-60 15-40 > 35 > 10 15 

Neomycin 2-3 12-24 - - - - 

Streptomycin 2.5 100 20-30 > 50 -- 15 

Tobramycin 2-2.5 24-60 4-8 > 12 > 2 3-5 

1 Measured 1 hour after IM administration. 

2 Measured immediately prior to next dose. 

25


Neurotoxic, ototoxic, or nephrotoxic effects may be additive, concurrent and/or sequential with use 

of an aminoglycoside and other drugs with similar toxic potentials (e.g. other aminoglycosides, 

acyclovir, amphotericin B, bacitracin, capreomycin, cephalosporins, colistin, cisplatin, 

methoxyflurane, polymyxin B, vancomycin) should be avoided, if possible. 2 In addition, due to 

increased risk of ototoxicity, from additive effects or altered serum and tissue concentrations, 

aminoglycosides should not be given concurrently with ethacrynic acid, furosemide, urea, or 

mannitol. 

Concurrent use of aminoglycosides with general anesthetics or neuromuscular blocking agents may 

potentiate neuromuscular blockage and cause respiratory paralysis. When used together, patients 

should be observed for signs of respiratory depression. 

Oral neomycin may potentiate the effects of oral anticoagulants, thereby interfering with GI 

absorption or synthesis of vitamin K. 2 Prothrombin times should be monitored and the dose of the 

anticoagulant adjusted as required. Oral neomycin has been reported to decrease GI absorption of 

digoxin and methotrexate. Serum digoxin concentrations should be monitored when oral neomycin 

therapy is initiated or discontinued in patients previously stabilized on digoxin. Oral neomycin is 

also reported to decrease the rate but not the extent of absorption of spironolactone. 

In vitro studies indicate that the antibacterial activity of aminoglycosides, as mentioned previously, 

and β-lactam antibiotics or vancomycin may be additive or synergistic against some organisms 

including enterococci and Ps. aeruginosa. 2 Studies also indicate that aminoglycosides and 

extended-spectrum penicillins also exert a synergistic bacterial effect against some 

enterobacteriaceae. Serum aminoglycoside concentrations should be monitored in patients 

receiving concomitant therapy, especially when very high doses of the penicillin are used or if the 

patient has impaired renal function. Additionally, chloramphenicol, clindamycin, and tetracycline 

have been reported to antagonize the bactericidal activity of aminoglycosides. 

Indomethacin has been reported to increase trough and peak serum aminoglycoside concentrations 

in premature neonates who were receiving the drugs together. 2 Increases in serum aminoglycoside 

concentrations appeared to be related to indomethacin-induced decreases in urine output. It also 

has been proposed that inhibitors of prostaglandin synthesis (e.g. aspirin) may increase 

nephrotoxicity of aminoglycosides. Monitoring is important in premature neonates who are 

receiving an aminoglycoside and indomethacin. Table 6 describes the level 1 and level 2 (the most 

severe) drug-drug interactions with the aminoglycosides. 

26

Table 5. Drug Interactions of the Aminoglycosides 7 


Aminoglycosides Level 1 Aminoglycosides and 

nondepolarizing muscle 

relaxants 

Aminoglycosides Level 1 Aminoglycosides and loop 

diuretics 


NSAIDs 


penicillins 


succinylcholine 


cephalosporins 


digoxin 

Possible pharmacologic synergism. Actions of the nondepolarizing 

muscle relaxants may be enhanced. 

Mechanism is not exactly known. But possible synergistic 

auditory toxicity is suspected. Auditory toxicity may be 

increased. Hearing loss of varying degrees may occur. 

Irreversible hearing loss has occurred. 

NSAIDs may cause an accumulation of aminoglycosides by 

reducing the glomerular filtration rate. Plasma aminoglycoside 

concentrations may be elevated. 

Mechanism is unknown. Certain parenteral penicillins may 

inactivate certain aminoglycosides. Do not mix parenteral 

aminoglycosides and penicillins in the same solution. 

Aminoglycosides may be additive or synergistic with 

succinylcholine secondary to their ability to stabilize the 

postjunctional membrane and impair prejunctional calcium influx 

and acetylcholine output. The resulting effect is that 

aminoglycosides can potentiate the neuromuscular effects of 

succinylcholine. 

Mechanism is unknown. Nephrotoxicity may be increased. 

Bactericidal activity against certain pathogens may be enhanced. 

The mechanism for the reduction in rate and extent of absorption is 

unknown. The potential for decreased metabolism is presumed to 

be caused by neomycin’s killing of intestinal bacteria that contribute 

to the formation of digoxin-reduction products. The rate and extent 

of digoxin absorption may be reduced, which could reduce the 

pharmacologic effect of the drug. However, in a small number of 

patients (15g of the drug should be observed carefully for signs of eighth cranial nerve 

damage. Loss of hearing has occurred with kanamycin, even with normal renal function. 

Aminoglycosides should be used with extreme caution in patients with neuromuscular disorders 

such as myasthenia gravis or parkinsonian syndrome, since these drugs can aggravate muscle 

weakness and result in a potential to produce neuromuscular blockade. 

Table 7 reports the common adverse events, by percentage, for the aminoglycosides. 

27

Table 7. Common Adverse Events (%) Reported for the Aminoglycosides 6 

Central/Peripheral Nervous 

System 

Adverse Reaction Amikacin Gentamicin Kanamycin Neomycin Streptomycin Tobramycin 

Headache rare 1 rare 

Encephalopathy 

Confusion 

Fever 

Lethargy 

Disorientation 

Neuromuscular blockade 

Paresthesia rare rare 

Convulsions 

Muscle twitching 

Myasthenia gravis-like syndrome 

Numbness 

Peripheral neuropathy 

Skin tingling 

Vomiting rare rare 

GI 

Nausea rare rare 

Diarrhea 

rare 

Anemia 

Eosinophilia 

rare 

rare 

Hematologic 

Leukopenia 

Thrombocytopenia 

Granulocytopenia 

Rash rare rare 

Hypersensitivity 

Lab test 

abnormalities 

Renal 1 

Urticaria 

Itching 

Anaphylaxis/Anaphylactoid 

reaction 

Increased AST/ALT 

Increased bilirubin 

Increased serum LDH 

Oliguria 

Proteinuria 

Rising serum creatinine 

Casts 

Nephrotoxicity 

Rising BUN 

Red and white cells in urine 

Azotemia 

28

Rising NPN 

Decreasing Ccr 

Dizziness 

Tinnitus 

Vertigo 

Special senses 

Roaring in ears 

Hearing loss/deafness 2 

Ototoxicity 

Loss of balance 2 

Visual disturbances/blurred vision 

Apnea 

Miscellaneous 

Drug fever rare rare 

Pain/Irritation at injection site 

Hypotension 

rare 

Acute muscular paralysis 

Decreased serum Ca, Na, K, Mg 

Malabsorption syndrome (incr. fecal 

fat) 

C. difficile associated colitis 

1 

= Reported; no incidence given. 

2 Partially reversible to irreversible bilateral hearing loss. 

VII. 

Dosing and Administration for the Aminoglycoside Antibiotics 

Current clinical evidence suggests that once-daily administration of aminoglycosides is at least as 

effective as, and may be less toxic than, conventional dosage regimens employing multiple daily 

doses of the drugs. 2 Further controlled studies are needed in children, patients with renal 

impairment, and other special groups, to determine optimal use. 

Because therapeutic and toxic concentrations of the aminoglycosides may be narrow, peak and 

trough concentrations should be determined periodically, especially in patients with renal 

impairment. 

Table 8. Dosing for the Aminoglycoside Agents 5-6 


Amikacin Sulfate Injection: 50mg/ml 

(pediatric), 250mg/ml 

Ideal body weight should be used for dosage calculation. 

Injection for IV infusion: 

500mg ADD-Vantage system 

and 500mg in 0.9% sodium 

chloride 

Administer IM or IV at 15mg/kg/day divided into 2 or 3 equal doses at 

equally divided intervals, over 30-60 minutes. Dosing in heavier patients 

should not exceed 1.5g/day. In uncomplicated UTIs, use 250mg twice 

daily. 

Neonates: Loading dose of 10mg/kg, followed by 7.5mg/kg every 

12 hours. Preliminary IM studies in newborns of different weights (< 

1.5kg, 1.5 to 2kg, > 2kg) at a dose of 7.5mg/kg revealed that, like other 

aminoglycosides, serum half-life values were correlated inversely with 

postnatal age and renal clearances of amikacin. Lower dosages may be 

safer during the first 2 weeks of life. 

29

Gentamicin Sulfate 

Injection: 10mg/ml 



60, 80, or 100mg ADD- 

Vantage system, 40, 60, 70, 

80, 90, 100, and 120mg in 

0.9% sodium chloride 

Duration: Usual duration of treatment is 7 to 10 days. Do not exceed 

15mg/kg/day. For treatment beyond 10 days, monitor amikacin serum 

levels and renal, auditory and vestibular functions daily. Uncomplicated 

infections caused by sensitive organisms should respond in 24 to 48 

hours. If definite clinical response does not occur within 3 to 5 days, stop 

therapy and reevaluate. Failure of the infection to respond may be 

because of resistance of the organism or to the presence of septic foci 

requiring surgical drainage. Peak and trough concentrations should be 

monitored. 

May be given IM or IV. 

For serious infections and normal renal function, give 3mg/kg/day in 3 

equal doses every 8 hours. For life-threatening infections, administer up 

to 5mg/kg/day in 3 or 4 equal doses. Reduce dosage to 3mg/kg/day as 

soon as clinically indicated. 

Obese patients: Base dosage on an estimate of lean body mass. 

Children: 6 to 7.5mg/kg/day (2 to 2.5mg/kg every 8 hours). 

Infants and neonates: 7.5mg/kg/day (2.5mg/kg every 8 hours). 

Premature or full term neonates (≤1 week of age): 

5mg/kg/day (2.5mg/kg every 12 hours). A regimen of either 

2.5mg/kg every 18 hours or 3mg/kg every 24 hours may also 

provide satisfactory peak and trough levels in preterm infants < 32 

weeks gestational age. 

Prevention of bacterial endocarditis: 

(In dental, oral or upper respiratory tract procedures (alternate regimen)) 9 : 

1 to 2g (50mg/kg for children) ampicillin plus 1.5mg/kg (2mg/kg 

for children) gentamicin not to exceed 80mg, both IM or IV onehalf 

hour prior to procedure, followed by 1.5g (25mg/kg for 

children) amoxicillin 6 hours after initial dose or repeat parenteral 

dose 8 hours after initial dose. 

GU or GI procedures (standard regimen): 

2g (50mg/kg for children) ampicillin plus 1.5mg/kg (2mg/kg for 

children)gentamicin not to exceed 80mg, both IM or IV one-half 

hour prior to procedure followed by 1.5mg (25mg/kg for children) 

amoxicillin. 

Intrathecal: Administer only the 2 mg/ml intrathecal preparation without 

preservatives. Dosage will vary depending upon factors such as age and 

weight of the patient, site of injection, degree of obstruction to CSF flow 

and the amount of CSF estimated to be present. 

Duration: Usually 7 to 10 days. In difficult and complicated infections, 

a longer course of therapy may be necessary. In such cases, monitor 

renal, auditory and vestibular function, since toxicity is more apt to occur 

with treatment extended beyond 10 days. Reduce dosage if clinically 

indicated. 

30

Kanamycin Sulfate 

Neomycin Sulfate 

Oral: 500mg capsules 

Injection: 37.5/ml 

(pediatric), 250mg/ml, and 

333mg/ml 

Oral: 500mg tablets, 

125mg/5ml oral solution 

Oral: 

Suppression of intestinal bacteria 

As an adjunct to mechanical cleansing of the large bowel in short-term 

therapy - 1g every hour for 4 hours, followed by 1g every 6 hours for 36 

to 72 hours. 

Hepatic coma: 

8 to 12g/day in divided doses. 

Injection: Based on ideal body weight. 

Do not exceed a total of 1.5 g/day by any route. 

IM: 

Inject deeply into the upper outer quadrant of the gluteal muscle. For 

adults or children, 7.5mg/kg every 12 hours (15mg/kg/day). If 

continuously high blood levels are desired, give the daily dose of 

15mg/kg in equally divided doses every 6 or 8 hours. Usual treatment 

duration is 7 to 10 days. Doses of 7.5mg/kg give mean peak levels of 

22mcg/ml. At 8 hours after a 7.5mg/kg dose, mean serum levels are 

3.2mcg/ml. 

IV: 

Adults: 

Do not exceed 15mg/kg/day. Give slowly. Prepare by adding 

contents of 500mg vial to 100 to 200ml sterile diluent (Normal 

Saline or 5% Dextrose in Water) or the contents of a 1g vial to 200 

to 400ml of sterile diluent. Give over 30 to 60 minutes. Divide 

daily dose into 2 to 3 equal doses. 

Children: 

Use sufficient diluent to infuse the drug over 30 to 60 minutes. 

Other routes: 

Intraperitoneal: 500 mg diluted in 20ml sterile distilled water instilled 

through a polyethylene catheter into the wound. 

Aerosol: 250 mg 2 to 4 times a day. Withdraw 250 mg (1 ml) from 

500mg vial, dilute with 3ml Normal Saline and nebulize. 

Hepatic coma: 

Adults: 

4 to 12g/day in divided doses for 5-6 days. 

Children: 

50 to 100mg/kg/day in divided doses. Continue treatment over a 

period of 5 to 6 days; during this time, return protein to the diet 

incrementally. Chronic hepatic insufficiency may require up to 

4g/day over an indefinite period. 

Preoperative intestinal antisepsis: 

Neomycin is given for 24 hours, not to exceed 72 hours, at a usual adult 

dose of 1g each hour for 4 doses, then 1g every 4 hours for the balance of 

the 24 hours. A low residue diet should be prescribed, and a saline 

cathartic should be given immediately preceding initiation of neomycin. 

For the 2-3 day regimen, the usual daily dose for adults and children is 

88mg/kg in 6 equally divided doses at 4 hour intervals. Alternatively, it 

has been recommended that the following regimen be used for scheduled 

surgery at 8:00am: 1g neomycin and 1g erythromycin base administered 

at 1pm, 2pm, and 11pm on the day preceding surgery, as an adjunct to 

mechanical cleansing of the intestine. 

31

Streptomycin 

Sulfate 

Injection: 1g (200mg/ml 

Lyophilized cake/powder) 

Injection for IM use: 

400mg/ml 

Administer by the IM route. 

Tuberculosis: 

The standard regimen for the treatment of drug-susceptible TB has been 2 

months of INH, rifampin and pyrazinamide followed by 4 months of INH 

and rifampin (patients with concomitant TB and HIV infection may 

require treatment for a longer period). When streptomycin is added to 

this regimen because of suspected or proven drug resistance, the 

recommended dosing for streptomycin is as follows: 

Streptomycin Dosing for TB 

Daily Twice weekly Thrice weekly 

Children 

Adults 

20-40mg/kg 

max 1g 

15mg/kg 

max 1g 

25-30mg/kg 

max 1.5g 

25-30mg/kg 

max 1.5g 

25-30mg/kg 

max 1.5g 

25-30mg/kg 

max 1.5g 

Streptomycin is usually administered daily as a single IM injection. Give 

a total dose of 120 g over the course of therapy unless there are no other 

therapeutic options. In patients > 60 years of age, use a reduced dosage. 

Therapy with streptomycin may be terminated when toxic symptoms have 

appeared, when impending toxicity is feared, when organisms become 

resistant, or when full treatment effect has been obtained. The total period 

of drug treatment of TB is a minimum of 1 year. 

Tularemia: 

1 to 2g daily in divided doses for 7 to 14 days until the patient is afebrile 

for 5 to 7 days. 

Plague: 

2g daily in two divided doses for minimum of 10 days. 

Bacterial endocarditis: 

Streptococcal: 

Streptomycin may be used for 2 week treatment concomitantly 

with penicillin in penicillin-sensitive alpha and non-hemolytic 

streptococcal endocarditis (penicillin MIC 0.1 mcg/ml): 1g twice 

daily for 1 week, 0.5g twice daily for the second week. If patient is 

> 60 years of age, give 0.5g twice daily for the entire 2 week 

period. 

Enterococcal: 

1g twice daily for 2 weeks and 0.5g twice daily for 4 weeks in 

combination with penicillin. Ototoxicity may require termination 

of streptomycin prior to completion of the 6-week course of 

treatment. 

Concomitant agents: 

For use with other agents to which infecting organism is also sensitive, 

streptomycin is a secondary choice for treatment of gram-negative 

bacillary bacteremia, meningitis and pneumonia; brucellosis; granuloma 

inguinale; chancroid; UTI. 

Adults: 

1 to 2g in divided doses every 6 to 12 hours for moderate to severe 

infections. Doses should generally not exceed 2g per day. 

Children: 

20 to 40mg/kg/day (8 to 20mg/lb/day) in divided doses every 6 to 12 

hours. (Take particular care to avoid excessive dosage in children.) 

32

Tobramycin 

Sulfate 

Oral Inhalation for 

Nebulization: 300mg/5ml 

Injection: 10mg/ml 



1.2g bulk package, 60 or 

80mg Add-Vantage system, 

60 and 80mg in 0.9% sodium 

chloride 

Use the patient's ideal body weight for dosage calculation; for obese 

patients, use patient's estimated lean body weight plus 40% of the excess as 

the basic weight on which to calculate mg/kg dosing. 

Adults: 

Administer 3mg/kg/day IV or IM in three equal doses every 

8 hours for serious infections or 5mg/kg/day IV or IM in three or 

four equal doses for life-threatening infections reduced to 

3mg/kg/day as soon as clinically indicated. To prevent increased 

toxicity caused by excessive blood levels, do not exceed 

5mg/kg/day, unless serum levels are monitored. 

Children: 

Administer 6 to 7.5mg/kg/day in 3 or 4 equally divided doses (2 to 

2.5mg/kg every 8 hours or 1.5 to 1.9mg/kg every 6 hours). 

Premature or full-term neonates (≤1 week of age): 

Administer 4mg/kg/day in 2 equal doses every 12 hours. 

Preliminary data suggest that 2.5mg/kg every 18 hours or 3mg/kg 

every 24 hours may achieve safe and effective peak and trough 

serum concentrations in newborn infants weighing 6 years of age and older the dose is 300mg Q12hours 

for 28 days. 

Duration: 

Usual duration of treatment is 7 to 10 days. A longer course may 

be necessary in difficult and complicated infections. In such cases, 

monitor renal, auditory and vestibular functions; toxicity can occur 

when treatment extends > 10 days. 

33


2, 5, 6 

Table 9. Special Dosing Considerations for the Aminoglycoside Antibiotics 

Drug Renal Hepatic Pediatric Use Pregnancy 

Amikacin 

Sulfate 

Gentamicin 

Sulfate 

Kanamycin 

Sulfate 

Neomycin 

Sulfate 

Streptomycin 

Sulfate 

Tobramycin 

Sulfate 

Dosing 

Yes 

Dosing 

and/or 

frequency 

Yes 

Dosing 

and/or 

frequency 

Yes 

Adjust 

frequency 

Dosing 

No 

No 

No 

Yes 

Neonates and 

infants 

Yes 

Neonates and 

infants 

Yes 

Children and 

infants 

Yes No Children only (no 

specific age limits 

found) 

Yes 

Dosing 

and/or 

frequency 

Yes 

Dosing 

and/or 

frequency 

No 

No 

Children only (no 

specific age limits 

found) 

Yes 

Children and 

premature or fullterm 

infants 

Category 

C 

C 

D 

C 

D 

C 

Stability 

Amikacin is stable for 24 hours at room 

temperature at concentrations of 0.25 and 

5mg/ml in 0.9% sodium chloride and 5% 

dextrose. Amikacin products are also stable 

for 24 hours at room temperature at the same 

concentrations after being refrigerated at 4 

degrees C for 60 days or frozen for 30 days 

at –15 degrees C, thawed, and stored at 25 

degrees C. Amikacin should not be mixed 

with other drugs. 

Gentamicin sulfate is stable for 24 hours at 

room temperature in most IV infusion fluids 

including 0.9% sodium chloride and 5% 

dextrose. These mixtures should not be 

mixed with other drugs. 

Kanamycin is stable for 24 hours at room 

temperature in most IV infusion fluids 

including 0.9% sodium chloride and 5% 

dextrose. The drug should not be mixed 

with other drugs. 

Neomycin oral solution should be stored in 

tight, light-resistant containers, at 

15-30 degrees C. 

Sterile reconstituted solutions of 

streptomycin sulfate are stable for one week 

when stored at room temperature and 

protected from light, however, streptomycin 

sulfate powder for injection contains no 

preservatives and the possibility of microbial 

contamination of reconstituted solutions 

must be considered. 

Following reconstitution of the sterile 

powder, tobramycin solutions containing 

40mg/ml are stable for 24 hours at room 

temperature or 96 hours at 2-8 degrees C. 

Tobramycin sulfate is stable for 24 hours at 

room temperature in most IV infusion 

solutions, however, the drug is incompatible 

with IV solutions containing alcohol. 

Commercially available tobramycin solution 

for oral inhalation should be stored at 

2-8 degrees C. When refrigeration is not 

available, intact or opened foil pouches 

containing ampules of the solution may be 

stored at room temperature up to 25 degrees 

C for up to 28 days. 

34

VIII. Comparative Effectiveness of the Aminoglycoside Antibiotics 

The aminoglycosides have been available for use for many years. Streptomycin and kanamycin 

are the oldest drugs in the class. Recent clinical data largely focuses on resistance patterns with 

the aminoglycosides. Other clinical evidence has evaluated once-daily administration versus 

multiple daily dosing. Clinical support for the aminoglycosides is presented in Table 9. 

Table 10. Additional Outcomes Evidence for the Aminoglycosides 

Study Sample Study/Treatment 

/ Duration 

Ioannidis DG, 

et al. 10 

Metaanalysis 

of 

24 studies 

published 

between 

1991 and 

2003 

Variable therapy 

duration; drugs 

evaluated were 

amikacin (9 

studies), gentamicin 

(11), tobramycin 

(2), netilmicin (2), 

and tobramycin or 

netilmicin (1). 

Results 

In evaluating the efficacy and toxicity of multiple daily dosing (MDD) and 

once-daily dosing (ODD) for the aminoglycoside class, 24 studies in 

children were evaluated and showed: 

Efficacy 

• There was no significant difference between ODD and MDD in 

the clinical failure rate, microbiologic failure rate, and combined 

clinical or microbiologic failure rates, but trends favored ODD 

consistently. 

• A statistically significant benefit was seen with ODD over MDD 

in trials using amikacin, whereas no statistical difference was seen 

in trials using other antibiotics. 



the primary nephrotoxicity outcomes. Secondary nephrotoxicity 

outcomes were significantly better with ODD. 

Ototoxicity 


the primary ototoxicity outcomes. 

• Studies noting only the clinical impression of hearing impairment 

also failed to identify any toxicity (ODD: 114 cases; MDD:114 

cases). 

Subgroup and Bias Analysis (Summary) 

• No statistically significant differences between ODD and MDD 

in any of the examined subgroups (neonatal intensive care unit, 

cystic fibrosis, cancer, or urinary tract infection), with respect to 

combined clinical or microbiologic failure outcomes, primary 

nephrotoxic outcomes, or ototoxicity, when sufficient data were 

available. 

• Clinical failures were uncommon in the pediatric trials, and if 

anything, fewer clinical failures tended to occur with ODD. 

• There was no evidence to show any reduction in the risk of 

primary nephrotoxicity outcomes with ODD. However, the event 

rate was much lower among children, compared with adults, and 

the secondary nephrotoxicity outcomes favored ODD. 

• Although single trials have been small, the available randomized 

evidence supports the general adoption of ODD with 

aminoglycosides in pediatric clinical practice. Advantages of 

ODD include: simplification of administration, similar or 

potentially improved efficacy and safety, compared with MDD. 

Shawar RM, 

et al. 11 n=508 - In vitro activity of tobramycin was compared with those of six other 

antimicrobial agents against 1,240 Pseudomonas aeruginosa isolates 

collected from 508 patients with cystic fibrosis during pretreatment visits: 

• Tobramycin was the most active drug tested and also showed 

good activity against isolates resistant to multiple antibiotics. 

• The isolates were less frequently resistant to tobramycin 

(5.4%) than to ceftazidime (11.1%), aztreonam (11.9%), amikacin 

(13.1%), ticarcillin (16.7%), gentamicin (19.3%), or ciprofloxacin 

(20.7%). 

35

Mithani H, et 

al. 12 n=200 100 consecutive 

patients treated with 

QD dosing were 

evaluated via 

retrospective chart 

review, while 100 

consecutive patients 

treated with 

conventional 

regimens over the 

same calendar 

period were 

evaluated. 

• Of 56 isolates for which the tobramycin minimum inhibitory 

concentration (MIC) was > or = 16mcg/ml and that were 

investigated for resistance mechanisms, only seven (12.5%) 

were shown to possess known aminoglycoside-modifying 

enzymes; the remaining were presumably resistant by an 

incompletely understood mechanism often referred to as 

"impermeability." 

This retrospective analysis was designed to compare once-daily with 

conventional aminoglycoside administration, in terms of efficacy and 

toxicity. 

• Although this was a pharmacoeconomic analysis, only 

clinical efficacy data will be shared in this review. 

• Eighty-nine patients were cured or improved with once-daily 

administration versus 90 patients with conventional 

administration. 

• One patient in each group developed definite aminoglycosideinduced 

renal toxicity. 

• Summary: Once-daily administration of aminoglycosides is 

as effective and well tolerated, compared with 

aminoglycoside treatment utilizing conventional regimens. 

King JW, et 

al. 13 - - This prospective study was done because of growing resistance to 

gentamicin and tobramycin in isolates of aerobic and facultative gramnegative 

bacteria. The study tracked resistance, bacteremic episodes, and 

bacteremia-associated deaths before and after institution of amikacin as the 

sole preferred aminoglycoside: 

• From June 1984-June 1987 (before amikacin became 

preferred), resistance to gentamicin, tobramycin, and 

amikacin among aerobic and facultative gram-negative 

bacterial isolates were 12.8%, 10.8%, and 5.9%, respectively. 

• Once amikacin became preferred, over the next 30 months, 

the rates of resistance to gentamicin, tobramycin, and 

amikacin were 6.3%, 5.0%, and 3.3%, respectively. 

• Also, during the 30 months with amikacin was preferred, the 

incidence of both bacteremia and bacteremia-associated death 

decreased significantly. 

• Summary: Hospitals where resistance to gentamicin or 

tobramycin is increasing among gram-negative flora, may 

benefit from use of amikacin as the principal aminoglycoside. 

Gerding DN, 

et al. 14 - - For 10 years, the 700 bed Minneapolis Veterans Affairs Medical Center in 

Minnesota has monitored and carefully controlled aminoglycoside usage and 

resistance of over 25,000 aerobic and faculatative gram-negative bacillary 

isolates to the aminoglycosides. A summary of their findings includes: 

• Introduction of amikacin at a high level of usage in the 1980’s was 

associated with a significant reduction in resistance to gentamicin 

and tobramycin among gram-negative bacilli. 

• Rapid introduction of gentamicin usage in 1982 after use of 

amikacin was associated with a significant and rapid increase in 

gentamicin and tobramycin resistance. However, in 1986, 

gentamicin was again reintroduced to the institution and the usage 

of gentamicin was gradually increased over a 15-month period 

without significant change in resistance to gentamicin, tobramycin, 

or amikacin. 

• A move to a new hospital in June 1988 was associated with an 

additional significant decline in resistance to all aminoglycosides 

(p

Muscato JJ, et 

al. 15 - 3-month period 

when amikacin was 

restricted and 

tobramycin and 

gentamicin were 

unrestricted 

(baseline), followed 

by a period of 12 

months when 

amikacin was the 

primary 

aminoglycoside. 

Evans DA, et 

al. 16 - Qualitative 

overview of 

randomized trials 

comparing two or 

more of the 

following: 

amikacin, 

gentamicin, 

netilmicin, 

sisomicin, and 

tobramycin 

Lewis RT. 17 n=215 Double-blind, 

placebo-controlled, 

randomized trial of 

combined oral and 

systemic antibiotics 

vs. systemic 

antibiotics; also a 

meta-analysis of 

randomized studies 

comparing 

combined versus 

systemic antibiotics 

in elective colon 

surgery 

This study in 12 cancer treatment centers in the United States, was designed 

to evaluate the potential for increased resistance to amikacin with 

unrestricted use: 

• Amikacin usage increased from a mean of 20.1% to a mean 

of 83.9% of aminoglycoside patient-days. 

• A reduction in the use of tobramycin and gentamicin were 

observed with means of 66.1 and 10%, and 13.9 and 6.1%, 

respectively for the two periods. 

• Resistance to amikacin was 0.85% at baseline and 1.3% at 

end-point, which was not clinically significant (p=0.614). 

• Baseline resistance was 6.5 and 7.6%, while final resistance 

was 2.6 and 4.8%, respectively, for tobramycin (p=0.001) and 

gentamicin (p=0.052). 

In evaluating randomized trials comparing aminoglycosides with respect to 

efficacy, nephrotoxicity, and auditory toxicity: 

• The results of most trials showed no significant differences, 

although sample sizes were, in general, smaller than 

necessary to detect moderate differences. 

• Quantitative overviews may be a useful means of detecting 

real differences in risk that are not apparent from the results 

of several individual small trials. 

In comparing the efficacy of combined oral (neomycin and metronidazole) 

and systemic antibiotics (amikacin and metronidazole) versus the same 

systemic antibiotics alone in preventing surgical site infection: 

• Wound infections occurred in 5 patients in the combined 

group but in 17 of the systemic group (p < 0.01, RR = 0.29, 

95% CI 0.11-0.75). 

• Bacteria isolated from wound infections and wound fat were 

similar to those found in the colon. They were more frequent 

in the colon in the systemic group (p < 0.001) and occurred in 

wound fat in the systemic group twice as often as in the 

combined group (p < 0.001). 

• By stepwise logistic regression, the presence of bacteria in 

wound fat at surgery was the strongest predictor of 

postoperative wound infection (p < 0.002). 

In the meta-analysis (of studies from 1975-1995) of randomized studies 

comparing combined versus systemic antibiotics, studies indicated: 

• The summary weighted risk difference in surgical site infections 

between groups and the summary risk ratios both favored 

combined prophylaxis = 0.56, 95% CI 0.26-0.86; RR = 0.51, 95% 

CI 0.24-0.78; p < 0.001). 

• Summary: In elective surgery of the colon, combined oral and 

systemic antibiotics are superior to systemic antibiotics in 

preventing surgical site infections. Orally administered antibiotics 

add value by reducing bacterial load of the colon and would fat 

contamination, both associated with postoperative wound 

infection. 

Song F, et 

al. 18 - 147 relevant 

randomized, 

controlled trials 

were identified in a 

systematic review 

To access the relative efficacy of antimicrobial prophylaxis for the 

prevention of postoperative wound infection in patients undergoing 

colorectal surgery: 

• The results confirm that the use of antimicrobial prophylaxis is 

effective for the prevention of surgical wound infection after 

colorectal surgery. 

• There was no significant difference in the rate of surgical wound 

infections between many different regimens. 

• However, certain regimens appear to be inadequate (e.g. 

metronidazole alone, doxycycline alone, piperacillin alone, oral 

neomycin plus erythromycin on the day before operation). 

37

Mitch WE, et 

al. 19 n=14 5-7 days before and 

during oral 

neomycin or 

kanamycin 

• A single dose administered immediately before the operation (or 

short-term use) is as effective as long-term postoperative 

antimicrobial prophylaxis (odds ratio 1.17 (95% confidence 

interval 0.90-1.53)). 

• There is no convincing evidence to suggest that the newgeneration 

cephalosporins are more effective than first-generation 

cephalosporins (odds ratio 1.07 (95% CI 0.54-2.12)). 

• Summary: Antibiotics selected for prophylaxis in colorectal 

surgery should be active against both aerobic and anaerobic 

bacteria (e.g. aminoglycosides plus metronidazole). 

Administration should be timed to make sure that the tissue 

concentration of antibiotics around the wound area is sufficiently 

high when bacterial contamination occurs. 

In patients with severe chronic renal failure who received long-term 

nutritional therapy with protein restriction and supplements of amino acids 

or their nitrogen free analogues, nitrogen balance was studied during 

administration of neomycin or kanamycin: 

• There was a significant improvement in nitrogen balance 

during the antibiotic period when compared to the control 

period, averaging +0.80g of nitrogen per day (p

(92%) in the SD group (Mantel-Haenszel odds ratio 0.36; CI 95%, 

1.19-0.64; p = 0.0004). 

• Summary: In human brucellosis the treatment of rifampicin and 

doxycycline presents a greater number of recurrence and lower 

number of cure than the classical treatment with streptomycin and 

tetracycline drugs. 


Dose Simplification: Clinical data has been presented above on once-daily versus multiple daily 

dosing of the aminoglycosides. Single daily dosing of the aminoglycosides is possible because of 

their rapid concentration-dependent killing and post-antibiotic effect and has the potential for 

decreased toxicity. Single daily dosing appears to be safe and efficacious, although, in some 

clinical situations (endocarditis and pediatric use), traditional multiple dosing is still usually 

recommended. 1 There was no significant difference between ODD and MDD in the clinical failure rate, 

microbiologic failure rate, and combined clinical or microbiologic failure rates. 

Stable Therapy: Stable therapy is of particular interest to all classes of antibiotic use, including 

aminoglycosides, as changing therapies can lead to drug resistance. 

In the interest of preferred drug list management, little scientific research is available on 

antimicrobial switching. Antimicrobial switching can be used as a mechanism to reduce or 

prevent antimicrobial resistance. This is often the case with nosocomial gram-negative organisms 

that can rapidly develop resistance. 4 The Centers for Disease Control is currently researching 

antimicrobial switch programs in an effort to better define resistance patterns within a therapy 

class caused by overuse of a particular agent. Research is also looking at whether discontinuation 

of an agent in a class can restore susceptibility. 

Some institutions have formed an antibiotic subcommittee to join local representatives from 

microbiology, infection control, pharmacy, infectious disease, and multiple disciplines of medical 

practice, in an effort to monitor resistance patterns and recommend treatment guidelines. 

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal specific 

clinical data on the impact of medical utilization and use of the aminoglycosides. Medical 

resources utilized are dependent on the severity of the infection and the condition of the patient. 

IX. 

Conclusions 

Efficacy of the aminoglycosides is dependent on the target indication for use and resistance 

patterns, or susceptibility of the identified organism to the drugs in this class. Gentamicin, 

tobramycin, and amikacin are considered similar in efficacy for the treatment of gram-negative 

organisms including Ps. aeruginosa. Gentamicin is the most commonly used aminoglycoside. 

Amikacin is likely the aminoglycoside of choice when gentamicin resistance is strongly 

suspected. 22 Neomycin use is limited mainly to oral therapy for surgical bowel preparation or 

hepatic coma. Streptomycin has only a few specific indications, as newer agents are available that 

have broader spectrums of activity. Kanamycin is indicated in serious gram-negative infections in 

which Ps. aeruginosa is not a likely causative agent. 

There is at least one available generic formulation for each aminoglycoside reviewed in this class. 

As a result, all brand products within the class reviewed are comparable to each other and to the 

generics and OTC products in this class and offer no significant clinical advantage over other 

alternatives in general use. 

39

Recommendations 

No brand aminoglycoside is recommended for preferred status. 

40

References 

1. Gonzalez LS III, Spencer JP. Aminoglycosides: A Practical Review. Am Fam Physician 1998 

Nov 15;58(8):1811-20. 

2. McEvoy GK, Ed. American Hospital Formulary Service, AHFS Drug Information. American 

Society of Health-System Pharmacists. Bethesda. 2004. 

3. Chambers HF, Sande MA. The aminoglycosides. In: Hardman JG, Limbird LE, eds. Goodman 

and Gilman’s The pharmacological basis of therapeutics. 9 th ed. New York: McGraw-Hill, 

1996;1103-21. 

4. Abate BJ, Barriere SL. Antimicrobial Regimen Selection. In: Pharmacotherapy. A 

Pathophysiologic Approach, Fifth Edition. Dipiro JT, Talbert RL, Yee GC, et al. Eds. McGraw- 

Hill. New York. 2002. Pg. 1817-29. 

5. Murray L, Senior Editor. Package inserts. In: Physicians’ Desk Reference, PDR Edition 58, 

2004. Thomson PDR. Montvale, NJ. 2004. 



8. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. A reference guide to fetal 

and neonatal risk. Sixth Edition. Lippincott, Williams, & Wilkins, Philadelphia, 2002. 

9. Dajani AS, Bisno AL, Chung KJ, et al. Prevention of bacterial endocarditis. Recommendations 

by the American Heart Association. JAMA1990;264:2919-2922. 

10. Contopoulos-Ioannidia DG, Giotis ND, Baliatsa DV, et al. Extended-interval aminoglycoside 

administration for children: a meta-analysis. Pediatrics 2004 Jul;114(1):e111-8. 

11. Shawar RM, MacLeod DL, Garber RL, et al. Activities of tobramycin and six other antibiotics 

against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents 

Chemother 1999 Dec;43(12):2877-80. 

12. Mithani H, Brown G. The economic impact of once-daily versus conventional administration of 

gentamicin and tobramycin. Pharmacoeconomics 1996 Nov;10(5):494-503. 

13. King JW, White MC, Todd JR, et al. Alterations in the microbial flora and in the incidence of 

bacteremia at a university hospital after adoption of amikacin as the sole formulary 

aminoglycoside. Clin Infect Dis 1992 Apr;14(4):908-15. 

14. Gerding DN, Larson TA, Hughes RA, et al. Aminoglycoside resistance and aminoglycoside 

usage: ten years of experience in one hospital. Antimicrob Agents Chemother 1991 

Jul;35(7):1284-90. 

15. Muscato JJ, Wilbur DW, Stout JJ, et al. An evaluation of the susceptibility patterns of gramnegative 

organisms isolated in cancer centers with aminoglycoside usage. J Antimicrob 

Chemother 1991 May;27 Suppl C:1-7. 

16. Evans DA, Buring J, Mayrent S, et al. Qualitative overview of randomized trials of 

aminoglycosides. Am J Med 1986 Jun30;80(6B):39-43. 

17. Lewis RT. Oral versus systemic antibiotic prophylaxis in elective colon surgery: a randomized 

study and meta-analysis send a message from the 1990s. Can J Surg 2002 Jun;45(3):173-80. 

18. Song F, Glenny AM. Antimicrobial prophylaxis in colorectal surgery: a systematic review of 

randomized controlled trials. Br J Surg 1998 Sep;85(9):1232-41. 

19. Mitch WE, Walser M. Effects of oral neomycin and kanamycin in chronic uremic patients: II. 

Nitrogen balance. Kidney Int 1977 Feb;11(2):123-7. 

20. Boulanger LL, Ettestad P, Fogarty JD, et al. Gentamicin and tetracyclines for the treatment of 

human plague: review of 75 cases in New Mexico, 1985-1999. Clin Infect Dis 2004 Mar 

1;38(5):663-9. 

21. Solera J, Martinez-Alfaro E, Saez L. Meta-analysis of the efficacy of the combination of rifampin 

and doxycycline in the treatment of human brucellosis. Med Clin (Barc) 1994 May 

21;102(19):731-8. 

22. Brewer NS. Antimicrobial agents—Part II. The aminoglycosides: streptomycin, kanamycin, 

gentamicin, tobramycin, amikacin, neomycin. Mayo Clin Proc 1977 Nov;52(11):675-9. 

41

I. Overview 



Pharmacotherapy Review of the Antifungal Agents 

AHFS 081400 


There are three major types of complications caused by the approximately 200 known species of 

fungi that infect humans. These complications are allergies, mycotoxicoses and mycoses. A few 

dozen fungi are the etiology for 90% of mycoses. The incidence of superficial and systemic 

mycotic infections has increased dramatically over the past decade. The two major factors 

contributing to this shift in epidemiology are related to two specific immunocompromised patient 

populations: patients undergoing transplantation and chemotherapy and patients with HIV and/or 

AIDS. In response to the increasing incidence of fungal infections, several oral and injectable 

agents that are effective against systemic fungal pathogens have been developed. 1-17 

The availability over the past two decades of the azole antifungal agents represents a major 

advance in the management of systemic fungal infections. The relative broad spectrum of the 

azoles against common fungal pathogens (Candida sp., Cryptococcus neoformans, Blastomyces 

dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Parcoccidioides brasiliensis, 

Sporothix schenckii and Aspergillus sp), ease of administration, and limited toxicity are highly 

attractive features. Fluconazole, itraconazole, ketoconazole, and voriconazole are azole 

antifungals that inhibit the CYT P450 dependent synthesis of ergosterol, the principal sterol in the 

fungal cell membrane, and are approved to treat systemic mycoses. Griseofulvin, an oral agent, is 

only effective in the treatment of superficial dermatophytes. Terbinafine is a synthetic allylamine 

derivative that inhibits squalene epoxidase, a key enzyme in sterol biosynthesis in fungi, resulting 

in a deficiency in ergosterol within the fungal cell membrane and cell death. Terbinafine is only 

approved to treat topical onychomycosis of the fingernails and toenails. Among the azoles, 

fluconazole possesses the most desirable pharmacologic properties, including high bioavailability, 

high water solubility, a low degree of protein binding, a wide volume of distribution into body 

tissues and fluids including cerebrospinal fluid, and urine, and long half-life. In addition, 

fluconazole and itraconazole are better tolerated and more effective than ketoconazole. 

Voriconazole is an azole antifungal agent derived from the structure of fluconazole. It was 

designed to enhance the potency and spectrum of activity of fluconazole. In addition to the 

original indications (invasive aspergillosis, refractory infection due to Scedosporium sp. or 

Fusarium sp.) voriconazole has recently been approved for treatment of esophageal candidiasis. 

One potential limitation of the azole antifungals is the drug-drug interactions, which are more 

significant with itraconazole and ketoconazole. 

Though the incidence of mycosis has increased, there remains a limited population in which headto-head 

comparative trials for the most common fungi can be conducted. Hence, comparative 

efficacy data are limited. Studies are available for topical infections such as onychomycosis and 

systemic infections in the HIV population. It is also important to note that duration of treatment is 

based on the severity of the patient's underlying disease, level of immunosuppression, and clinical 

response. 1-17 Table 1 lists the agents included in this review. This review encompasses all 

dosage forms and strengths. 

42

Table 1. Antifungal Agents in this Review 

Generic Name Antifungal Type Formulation Example Brand Name (s) 

Amphotericin B Polyene Injection *Fungizone ® , *Amphocin ® 

Amphotericin B Cholesteryl 

Polyene Injection Amphotec ® (ABCD) 

Sulfate Complex 

Amphotericin B Lipid 

Polyene Injection Abelcet ® (ABLC) 

Complex 

Amphotericin B Liposomal Polyene Injection AmBisome ® 

Caspofungin Acetate Echinocandin Injection Cancidas ® 

Fluconazole Azole Oral/ Injection *Diflucan ® 

Flucytosine Pyrimidine Oral Ancobon ® 

Itraconazole Azole Oral/ Injection Sporanox ® 

Ketoconazole Azole Oral *Nizoral ® 

Nystatin Polyene Oral *Mycostatin ® 

Terbinafine Allylamine Oral Lamisil ® 

Voriconazole Azole Oral / Injection Vfend ® 

Griseofulvin Microsize Misc. Antifungal Oral Fulvicin U/F ® , Grifulvin V ® 

Griseofulvin Ultramicrosize Misc. Antifungal Oral *Gris-PEG ® 


II. 


Treatment guidelines for the antifungal agents range from the treatment of opportunistic infections 

in patients with human immunodeficiency virus (HIV), to neutropenic patients with cancer, 

cryptococcemia, candidiasis, transplantation, and treatment of onychomycosis. For purposes of 

the scope of this review, treatment guidelines for onychomycosis and candidiasis will be briefly 

reviewed. 

Candidiasis 

Candida species are the most common cause of fungal infections. 18, 19 This species produces 

infections that range from non-life-threatening mucocutaneous illness to invasive, full-blown 

infections that may involve multiple organs. Due to the broad range of infections, an equally 

broad range of diagnostic and therapeutic strategies are necessary. 

43

Table 2. Guidelines for the Treatment of Candidiasis 


• Knowledge of the infecting species is highly predictive of likely susceptibility and can be 

used as a guide to therapy. 

• Invasive Candidiasis: Extensive data from randomized trials is available only for therapy 

of acute hematogenous candidiasis in the nonneutropenic patient. Choice of therapy for 

other forms of candidiasis is based on case series and anecdotal reports. In general, 

amphotericin B-based agents, the azole antifungal agents, and the echinocandin antifungal 

agents play a large role in treatment. Choice of therapy is guided by weighing the greater 

activity of amphotericin B-based agents and the echinocandin antifungal agents for some 

non-albicans species (e.g. Candida krusei) against the availability of oral and parenteral 

formulations for the azole antifungal agents. Flucytosine has activity against many 

isolates of Candida but is infrequently used. 

Initial therapy usually involves caspofungin, fluconazole, amphotericin B, or a 

combination of fluconazole and amphotericin B. Experience with caspofungin in adults is 

still somewhat limited. Neonates with disseminated candidiasis are usually treated with 

amphotericin B, and fluconazole has been used successfully in small numbers of neonates. 

The guidelines comment in detail on specific susceptibilities with Candida species. 

• Mucocutaneous Candidiasis: Therapy for mucosal infections is dominated by the azole 

antifungal agents. These drugs can be used topically or systemically and are safe and 

efficacious. Some patients may have repeated relapses with possible induction of 

resistance with prolonged or repeated exposure. Initial episodes can be treated with 

clotrimazole troches or nystatin. Oral fluconazole is as effective as, and in some studies, 

superior to topical therapy. Itraconazole solution is as efficacious as fluconazole. 

Ketoconazole and itraconazole capsules are less effective than fluconazole, because of 

variable absorption. Systemic therapy is required for effective treatment of esophageal 

candidiasis. 

• Prevention of Invasive Candidiasis: Prophylactic strategies are useful in those 

populations where risk is high, such as patients undergoing therapy that produces 

prolonged neutropenia (bone marrow transplant or solid-organ transplant). For 

neutropenic patients, fluconazole or itraconazole is appropriate therapy for patients at a 

significant risk for invasive candidiasis. Institutions where high rates of invasive 

candidiasis in adult or neonatal ICU exist despite standard infection control procedure 

could consider fluconazole prophylaxis for carefully selected patients in these areas. 

Onychomycosis 

Onychomycosis accounts for one-third of fungal skin infections. Because only one-half of nail 

dystrophies are caused by fungus, diagnosis should be confirmed by potassium hydroxide 

preparation, culture, or histology prior to treatment being inititiated. 20 Terbinafine and 

itraconazole are the agents of choice for the treatment of onychomycosis, while fluconazole has 

not been specifically indicated for the treatment of onychomycosis, but early data has been 

promising in its use. Table 3 describes treatment guidelines for onychomycosis and Table 4 

discusses information highlighted in a Food and Drug Administration Public Health Advisory 

concerning safety of itraconazole and terbinafine for the treatment of onychomycosis. 

44

Table 3. Guidelines for the Treatment of Onychomycosis 21 


• Complete a comprehensive history of presenting symptoms with attention to history of 

onset, duration, morphology of nail, predisposing factors, and prior treatments and 

outcomes. 

• Physician exam looking at degree of severity: nail color, texture, nail base angle, plate 

firmness and adherence to the nail bed. Severe onychomycosis is considered >80% of 

the nail surface and/or matrix involvement of at least one toenail (excluding the 5 th 

metatarsal). 

• Diagnostic tests: microscopy, Wood’s lamp examination, skin/nail biopsy, and fungal 

culture (if considering long-term oral therapy). Differential diagnosis include lichen 

planus, psoriasis, myxoid cyst, yellow nail syndrome, peripheral vascular disease, and 

trauma. 

• Lifestyle modifications may aid in the prevention of onychomycosis. Important 

modifications include: wearing properly fitting shoes, using shower shoes in community 

showers, washing feet daily with soap and water, wearing hosiery made of synthetic 

materials, and supplying manicurist with personal pedicure/manicure tools. 

• *Amorolfine (Loceryl) 5% applied once weekly for 24 weeks in combination with 

itraconazole (Sporanox) 200mg orally every day for 12 weeks is strongly suggested as 

the most effective means of mycological and clinical cure for severe non-dermatophyte 

onychomycosis. Amorolfine (Loceryl) 5% applied once weekly for 15 months in 

combination with terbinafine (Lamisil) 250mg orally every day for 12 weeks is strongly 

supported as the most effective means of mycological and clinical cure for severe 

dermatophyte onychomycosis. Amorolfine is not available in the United States at this 

time. 

• Use of 40% Urea (Carmol 40) is recommended when applied 1-2 times daily until 

complete chemical avulsion of the nail is achieved. This is indicated for moderate to 

severe nail involvement in patients >18 years of age. Some evidence suggests beneficial 

effects of 40% Urea as a preparatory agent to avulse the nail and leave the nail bed more 

permeable to treatment with a topical antifungal. 

• Oral antifungals as monotherapy have been strongly supported for the treatment of 

moderate to severe onychomycosis. Terbinafine 250mg orally every day for 6 weeks for 

fingernails and 12-16 weeks for toenails has been shown to be the most effective 

treatment of dermatophyte infection. Itraconazole 200mg administered orally every day 

for 12 weeks of pulse therapy (400mg PO QD x one week Q4 weeks for 12-16 weeks) 

has been shown to be the most effective treatment of non-dermatophyte infection, with 

greater efficacy in favor of the pulse therapy. Fluconazole 150mg once weekly for 24 

weeks demonstrated lower efficacy in clinical and mycological cure of non-dermatophyte 

infections. 

• Complete blood count and liver function tests should be monitored prior to, during, and at 

the end of treatment with oral antifungals. When using nail lacquer treatments, nails 

should be cut and filed monthly by a healthcare professional. 

• Referral should be made to a podiatrist for severe and relapsing cases. 

*Amorolfine is not available in the United States at this time. 

45

FDA Public Health Advisory 

In April 2001, the FDA issued a Public Health Advisory for itraconazole and terbinafine for the 

use of onychomycosis. 22 The advisory came after the announcement of safety-related updates to 

the labeling of itraconazole and terbinafine tablets. 

The FDA advised that physicians not prescribe itraconazole to treat fungal infections 

(onychomycosis) in patients who have congestive heart failure (CHF), or a history of CHF. The 

updated labeling also includes contraindications and precautions with certain medicines. 

The advisory alerted the public that itraconazole and terbinafine have been associated with serious 

liver problems including liver failure and death. The advisory did not pertain to terbinafine cream 

and solution. As a result of the advisory, the FDA recommended revisions to labeling for both 

drugs, indicating that healthcare professionals should obtain nail specimens for laboratory testing 

to confirm the diagnosis of onychomycosis, prior to prescribing these medications. 

Table 4. FDA Public Health Advisory: Use of Itraconazole and Terbinafine for Onychomycosis 22 

FDA Recommendation Highlights 

• Itraconazole Cardiac Risk: As of April 2001, the FDA received and reviewed 94 cases 

in which patient’s taking the drug developed congestive heart failure. In 58 of the cases, 

the FDA ruled the drug contributed to or may have been the cause of the CHF. Although 

the causal relationship is unclear, death was reported in 13 cases. 

• Itraconazole and Terbinafine Hepatic Risk: As of March 2001, the FDA reviewed 24 

cases of liver failure possibly associated with itraconazole, including 11 deaths. There 

were 16 reviewed cases for the same timeframe of terbinafine associated liver failure, 

including 11 deaths and two liver transplant patients. 

III. 

Comparative Indications of the Antifungal Agents 

The azole antifungal drugs are contraindicated in those patients who have a hypersensitivity to 

other azole derivatives. Terbinafine is contraindicated in patients with a hypersensitivity to 

terbinafine, naftifine or any component of the drug. The griseofulvin drugs are contraindicated in 

those with a hypersensitivity to griseofulvin or any component of the formulation, porphyria 

(interferes with porphyrin metabolism), and hepatocellular failure. Amphotericin B should not be 

used in patients with a hypersensitivity to the drug or any other component of the formulation 

unless the condition requiring treatment is life-threatening and amenable only to amphotericin B 

therapy. The lipid formulation amphotericin agents are contraindicated in patients with known 

hypersensitivity to any amphotericin B product or any other constituents of the product unless, if 

the benefits of therapy outweigh the risk. 

Additionally, both itraconazole and ketoconazole have black box warnings as part of their 

labeling. Details on each drug’s warnings are included in bold in Table 5. 

46

1-17, 23-25 

Table 5. FDA-Approved Indications for the Antifungal Agents 

Drug 

Indication 

Amphotericin B 

Deoxycholate 



Potentially life-threatening fungal infections including: 

• Aspergillosis 

• North American blastomycosis 

• Systemic candidiasis 

• Coccidioidomycosis 

• Cryptococcosis 

• Histoplasmosis 

• Paracoccidioidomycosis 

• Sporotrichosis 

• Zygomycosis 

• Protozoal infections (leishmaniasis and primary amebic 

meningoencephalitis caused by Naegleria fowleri) 

The drug also can be used for empiric antifungal therapy in febrile 

neutropenic patients and as secondary prophylaxis to prevent 

recurrence or relapse of fungal infections listed above. 

For the treatment of invasive aspergillosis in patients where renal 

impairment or unacceptable toxicity precludes the use of amphotericin 

B deoxycholate in effective doses, and in patients with invasive 

aspergillosis where prior amphotericin B deoxycholate therapy has 

failed. 


Complex 

For the treatment of invasive fungal infections in patients who are 

refractory to or intolerant of conventional IV amphotericin B. 

Amphotericin B Liposomal • Empirical therapy for presumed fungal infections in febrile, 

neutropenic patients. 

• Treatment of Cryptococcal meningitis in HIV infected patients. 

• Treatment of patients with Aspergillosis species, Candida species, 

and/or Cryptococcus species refractory to amphotericin B 

deoxycholate, or in patients where renal impairment or 

unacceptable toxicity precludes the use of amphotericin B 

deoxycholate. 

• For the treatment of visceral leishmaniasis. In 

immunocompromised patients with visceral leishmaniasis treated 

with amphotericin B liposomal, relapse rates were high following 

initial clearance of parasites. 

Caspofungin Acetate • Candidemia and the following Candida infections: intraabdominal 

abscesses, peritonitis and pleural space infections. The 

drug has not been studied in endocarditis, osteomyelitis, and 

meningitis due to Candida. 

• Esophageal candidiasis. 

• Invasive aspergillosis in patients refractory to or intolerant of other 

therapies (e.g. amphotericin B including lipid formulations, and/or 

itraconazole). The drug has not been studied as initial therapy for 

invasive aspergillosis. 

Fluconazole • Vaginal candidiasis 

• Oropharyngeal and esophageal candidiasis 

• Cryptococcal meningitis 

Flucytosine 

Serious infections caused by susceptible strains of Candida and/or 

Cryptococcus. 

Itraconazole • Blastomycosis 


• Aspergillosis 

• Onychomycosis of the toenail/fingernail 

47

Black Box Warning: 

CHF: 

Do not administer itraconazole for the treatment of onychomycosis in 

patients with evidence of ventricular dysfunction, such as CHF or a 

history of CHF. Discontinue if signs and symptoms of CHF occur 

during treatment. If signs and symptoms of CHF occur during 

treatment, reassess the continued use of itraconazole. When 

itraconazole was administered by IV to dogs and healthy human 

volunteers, negative inotropic effects were seen. 

Drug interactions: 

Coadministration of cisapride, pimozide, dofetilide, or quinidine with 

itraconazole is contraindicated. Itraconazole is a potent inhibitor of the 

cytochrome P450 3A4 isoenzyme system and may raise plasma 

concentrations of drugs metabolized by this pathway. Serious 

cardiovascular events, including QT prolongation, torsades de pointes, 

ventricular tachycardia, cardiac arrest, and/or sudden death have 

occurred in patients taking itraconazole concomitantly with cisapride, 

pimozide, or quinidine, which are inhibitors of the cytochrome P450 

3A4 system (see contraindications, warnings, and drug Interactions). 

Ketoconazole • Candidiasis 

• Chronic mucocutaneous candidiasis 

• Oral thrush 

• Blastomycosis 

• Coccidioidomycosis 


• Chromomycosis 

• Paracoccidioidomycosis 

• Recalcitrant cutaneous dermatophyte infection 

Black Box Warning: 

When used orally, ketoconazole has been associated with hepatic 

toxicity, including some fatalities. Patients receiving this drug should 

be informed by the physician of the risk and should be closely 

monitored. See Warnings and Precautions sections. 

Coadministration of terfenadine with ketoconazole tablets is 

contraindicated. Rare cases of serious cardiovascular adverse events, 

including death, ventricular tachycardia and torsades de pointes have 

been observed in patients taking ketoconazole tablets concomitantly 

with terfenadine, due to increased terfenadine concentrations induced 

by ketoconazole tablets. See contraindications, warnings, and 

precautions sections. 

Pharmacokinetic data indicate that oral ketoconazole inhibits the 

metabolism of astemizole, resulting in elevated plasma levels of 

astemizole and its active metabolite desmethylastemizole, which may 

prolong QT intervals. Coadministration of astemizole with 

ketoconazole tablets is therefore contraindicated. See 

contraindications, warnings, and precautions sections. 

Coadministration of cisapride with ketoconazole is contraindicated. 

Serious cardiovascular adverse events including ventricular 

tachycardia, ventricular fibrillation and torsades de pointes have 

occurred in patients taking ketoconazole concomitantly with cisapride. 

See contraindications, warnings, and precautions sections. 

Nystatin • Nonesophageal membrane GI candidiasis (cutaneous and 

mucocutaneous). 

• Prevention of fungal infections (HIV, transplant, and cancer). 

Terbinafine • Onychomycosis of toenail/fingernail. 

48

Voriconazole • Invasive aspergillosis 

• Esophageal candidiasis 

• Serious fungal infections caused by Scedosporium apiospermum 

(asexual form of Pseudallescheria boydii) and Fusarium spp. 

including Fusarium solani, in patients intolerant of, or refractory 

to, other therapy. 

Griseofulvin Ultramicrosize 

Griseofulvin Microsize 

Use only in minor or trivial infections that will not respond to 

topical agents alone. Effective only against dermatophytes. 

• Tinea pedis, tinea cruris, tinea corporis, tinea barbae, tinea capitis, 

and tinea unguium due to: 

• Trichophyton rubrum 

a. Trichophyton mentagrophytes 

b. Trichophyton tonsurans 

• Epidermophyton floccosum 

• Microsporum canis 

• Microsporum audouini 

• Microsporum gypseum 

• Trichophyton interdigitalis 

c. Trichophyton verrsusom 

d. Trichophyton megninii 

• Trichophyton gallinae 

e. Trichophyton crateriform 

f. Trichophyton sulphureum 

g. Trichophyton schoenleinii 

IV. 

Pharmacokinetic Parameters of the Antifungal Agents 

Table 6 describes the pharmacokinetic parameters of the antifungal agents in this class, while 

Table 7 details the kinetic properties of the amphotericin B formulations. 

As there appears to be striking differences in the pharmacokinetics of the amphotericin B lipid 

formulations, the clinical efficacy of the three formulations has turned out to be identical. 26 For 

example, the volume of distribution for the amphotericin B lipid complex is reported to greatly 

exceed that for liposomal amphotericin B. Some of the kinetic differences have been observed in 

numerous studies investigating time-concentration profiles of lipid formulations of amphotericin B 

and have been ascribed to the different particle sizes and shapes of the three lipid formulations. 

The Infectious Diseases Society of America does not recommend a preferred lipid amphotericin B 

product of the three available formulations. 

In a comparative pharmacokinetic evaluation of conventional amphotericin B, liposomal 

amphotericin B (AmBisome), and amphotericin B colloidal dispersion (Amphotec), the authors 

developed a chromatographic method for the separate measurement of lipid-formulated 

amphotericin B and amphotericin B (non-lipid) which has been liberated from its lipid binding. 26 

The liberated fraction of amphotericin B is bound to proteins in the plasma because amphotericin 

B is insoluble in water. Different kinetic characteristics were found for the liposomal 

amphotericin B and the colloidal dispersion amphotericin B, in particular for their lipid-formulated 

fractions. Although the mechanisms of liberation of amphotericin B from lipid binding are poorly 

understood, data suggests that after infusion of liposomal amphotericin B or colloidal dispersion, 

significant amounts of amphotericin B are liberated from the lipid moiety during circulation in the 

plasma. The pharmacokinetic properties of the liberated fraction are rather similar for both of the 

different formulations and resemble those of conventional amphotericin B. 

From a pharmacodynamic point of view, the equivalence in clinical efficacy of the different 

formulations supports a model that considers the liberated fraction of amphotericin B to be the 

active form. 26 

49

The lipid amphotericin formulations offer better therapeutic index without the toxicity seen with 

conventional amphotericin B. AmBisome is the only true liposome; Abelcet has a ribbon-like 

structure, and Amphotec is composed of disc-like structures. All of the lipid formulations contain 

amphotericin B, but they differ in shape, size, reticuloendothelial clearance (Cmax), AUC and 

visceral diffusion. 27 

1-17, 23-25 

Table 6. Pharmacokinetic Parameters of the Antifungal Agents 

Drug Bioavailability Protein 

Binding 

Metabolism Active 

Metabolites 

Elimination 

Caspofungin Acetate - 97% Hepatic - Renal 41%, 

Fecal 35% 

Half-Life 

Biphasic: 

1 st =9-11 

hours / 

2 nd =40-50 

hours 

Fluconazole >90% 11-12% Hepatic No Renal 60-80% 30 hours 

Flucytosine 75-90% 2-4% (at 

conc. 2- 

55mcg/ml) 

Minimal 

amounts are 

metabolized 

Itraconazole 40-55% 99.8% Hepatic 

CYP3A4 

No Renal 75- 

90%; 

unabsorbed 

drug is 

excreted in 

feces 

Yes Fecal 3-18%, 

Renal 40% 

Ketoconazole 75% 99% Hepatic No Fecal 57%, 

Renal 13% 

Nystatin 

Terbinafine 


from GI tract and 

mucous membranes; 

no detectable blood 

levels are obtained 

40% (1 st pass 

metabolism) 

- - - Almost 

entirely fecal 

>99% Hepatic: CYP 

2C19, CYP2C9 

and CYP 3A4 

Voriconazole 96% 58% Hepatic: 

CYP2C19, CYP 

2C9, CYP3A4 



(20-50) 

2.5-6 hours 

21 hours 

Biphasic: 

1 st =2 hours 

/ 2 nd =8 

hours 

- 

No Renal 70% 36 hours 

No Hepatic 98%; 

Renal 2% 

- - Hepatic - Urine (

Table 7. Pharmacokinetic Parameters of the Amphotericin B Agents after Multiple Doses 23 

Drug 

Peak Conc. 

(micrograms/ml) 

AUC 0-24 Clearance 

(mL/h•kg) 


Deoxycholate 

(given at 

0.6mg/kg/day for 

42 days a ) 


Cholesteryl Sulfate 

Complex* 


Lipid Complex* 

(given at 

5mg/kg/day for 5-7 

days 


Liposomal* 

(5mg/kg/day) 

1.1 ± 0.2 (n=5) 17.1 ± 5 

(n=5) 

38 ± 15 

(n=5) 

2.9 36 0.028 

(L/h/kg) 

Volume of 

Distribution 

(Vd area ) 

(L/kg) 

Terminal 

Elimination 

Half-Life 

(hours) 

5 ± 2.8 (n=5) 91.1 ± 40.9 

(n=5) 

Amt. Excreted in 

Urine Over 24 hours 

after Last Dose (% of 

dose) d 

9.6 ± 2.5 (n=8) 

1.1 39 - 

436 ± 131 ± 57.7 173.4 ± 78 

1.7 ± 0.8 (n=10) b 14 ± 7 

(n=14) b, c 188.5 

(n=14) b, c (n=8) c (n=8) c 

83.0 ± 35.2 555 ± 

311 

0.9 ± 0.4 (n=8) c 

11 ± 6 0.10 ± 0.07 6.8 ± 2.1 - 

* The assay used to measure amphotericin B in the blood after administration does not distinguish amphotericin B that is complexed with the 

phospholipids of Abelcet or AmBisome or cholesteryl sulfate, from amphotericin B that is uncomplexed. 

a 

Data from patients with mucocutaneous leischmaniasis. Infusion rate was 0.25mg/kg/h. 

b Data from studies in patients with cytology proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven 

fungal infection. Infusion rate was 2.5mg/kg/h. 

c Data from patients with mucocutaneous leischmaniasis. Infusion rate was 4mg/kg/h. 

d Percentage of dose excreted in 24 hours after last dose. 

V. Drug Interactions of the Antifungal Agents 

All Level 1 interactions are highlighted in Table 8, along with other common drug-drug 

interactions with the antifungal agents. Level 1 interactions are the most life-threatening, and are 

usually rapid or delayed in onset, of major severity, and documentation has been established, is 

probable, or suspected. 

The lipid amphotericin B formulations have not been formally studied with regards to drug-drug 

interactions. The drugs known to interact with conventional amphotericin B are likely to also 

interact with the lipid formulations of the drug. There are no significant clinical differences 

among the three lipid formulations with regards to drug-drug interactions. As with conventional 

amphotericin B, caution should be used when the lipid amphotericin B formulations are 

administered together with other nephrotoxic medications such as aminoglycosides and 

pentamidine. 

Additionally, some antifungals have contraindications due to significant drug-drug interactions: 

Drug Interaction Contraindications 

Itraconazole (Sporanox): The following drugs are contraindicated with concomitant use of 

23, 28 

itraconazole, due to increased plasma concentration of the additional drug. Contraindicated 

drugs include: oral midazolam, pimozide, quinidine, dofetilide, and triazolam. The HMG-CoA 

reductase inhibitors, lovastatin and simvastatin, are also contraindicated. 

Ketoconazole (Nizoral): Both dofetilide and oral triazolam are contraindicated for 

23, 28 

coadministration with ketoconazole. Use of midazolam and triazolam has resulted in elevated 

plasma concentrations of the latter drugs, and may potentiate and prolong hypnotic and sedative 

effects, especially with repeated dosing or chronic administration. 

51

Voriconazole (Vfend): Coadministration of voriconazole and the CYP 3A4 substrates (pimozide, 

quinidine) is contraindicated since increased plasma concentrations of these drugs can lead to QT 

prolongation and rare occurrences of torsade de pointes. Voriconazole should also not be used in 

combination with sirolimus. Voriconazole should not be given with rifampin, carbamazepine, and 

long-acting barbiturates since these drugs are likely to decrease plasma concentrations of 

voriconazole. Use of rifabutin and voriconazole is contraindicated because voriconazole 

significantly increases rifabutin plasma concentrations and rifabutin also significantly reduces 

voriconazole plasma concentrations. Finally, voriconazole should not be used together with the 

ergot alkaloids (ergotamine and dihydroergotamine) because the drug can increase the 

concentrations of the ergot alkaloids and may lead to ergotism. 

23, 28 

Table 8. Clinically Significant Drug Interactions 


Amphotericin B No Level 1 

interactions 

Level 2 

Others: 

• Cyclosporine and 

amphotericin B 

• Pentamidine 

The exact mechanism is unknown. The nephrotoxic 

effects of cyclosporine appear to be increased. The 

interaction occurs a few days following addition of 

amphotericin B to cyclosporine therapy and it is 

unknown how soon renal dysfunction resolves once 

amphotericin has been discontinued. 

Acute, reversible renal failure has been reported in at 

least 4 four patients who received amphotericin B 

concomitantly with IV or IM pentamidine. 


Formulations 

(Cholesteryl Sulfate 

Complex, Lipid 

Complex, and 

Liposomal) 

No Level 1 

interactions 

• Drugs affected by 

potassium depletion 

Others: • Antineoplastic drugs 

• Corticosteroids and 

corticotrophin 

• Cyclosporin and 

tacrolimus 

• Digoxin 

• Flucytosine 

• Skeletal Muscle 

Relaxants 

Conventional amphotericin B can induce 

hypokalemia, patients receiving cardiac glycosides 

may be predisposed to glycoside-induced 

cardiotoxicity and may enhance the effects of skeletal 

muscle relaxants. 

Enhancement of the potential for renal toxicity, 

bronchospasm, and hypotension. 

May potentiate hypokalemia leading to cardiac 

dysfunction. 

In a randomized trial, adults and children 

receiving cyclosporine or tacrolimus in addition 

to Amphotec had a significantly lower rate of 

renal toxicity (31%, 16/51), compared to the 

conventional amphotericin B patients receiving 

cyclosporine or tacrolimus (68%, 17/49). 

Concurrent use with amphotericin B may 

induce hypokalemia and potentiate digoxin 

toxicity. 

Concurrent use may increase the toxicity of 

flucytosine by increasing cellular uptake and/or 

impairing its excretion. 

Amphotericin B induced hypokalemia may 

enhance the curariform effect of drugs such as 

tubocurarine, due to hypokalemia. 

52

Caspofungin Acetate 

Does not inhibit any of 

the CYP 450 enzymes 

• Tacrolimus 

Caspofungin reduced the peak concentration of 

tacrolimus by 16%, the AUC by 20%, and 12-hour 

blood concentration by 26%. 

• Cyclosporine 

In two clinical trials, cyclosporine increased the AUC 

of caspofungin by approximately 35%. Caspofungin 

did not increase levels of cyclosporine. 

Fluconazole 

Inhibits the metabolic 

activity of CYP 2C9, 

CYP 2C19, and 

CYP3A4. 

Level 1 

Level 1 

• Rifampin 

Warfarin and fluconazole 

Vincristine/vinblastine and 

fluconazole 

When given concomitantly with caspofungin, studies 

have shown a 30% decrease in caspofungin trough 

levels. This suggests other inducers of drug 

clearance (efavirenz, nevirapine, phenytoin, 

dexamethasone, and carbamazepine) may result in 

clinically meaningful reductions in caspofungin 

concentrations. 

Inhibition of warfarin metabolism. The anticoagulant 

effect of warfarin may be increased. 

Possible inhibition of vinca alkaloid metabolism 

(CYP3A4) by fluconazole, and all azole antifungal 

agents. 

Others: 

• Rifampin and 

cimetidine 

Increase the metabolism of fluconazole. 

• Oral contraceptives 

Fluconazole may decrease the effect of oral 

contraceptives. 

• HMG-CoA reductase 

inhibitors 

Azoles may inhibit the first-pass metabolism of the 

HMG-CoA reductase inhibitors, resulting in 

increased side-effects and plasma levels of these 

drugs. 

Flucytosine 

Itraconazole 


Significance 

not reported 

Others: 

• Cyclosporine, 

phenytoin, 

sulfonylureas, 

warfarin, triazolam, 

alprazolam, 

midazolam, 

tacrolimus, 

nortriptyline, rifabutin, 

zidovudine, and 

saquinavir. 

• Hydrochlorothiazide 

Cytosine arabinoside and 

flucytosine 

• Drugs that impair 

glomerular filtration 

may prolong the 

biological half-life of 

flucytosine. 

• Antifungal synergism 

between flucytosine 

and polyene antibiotics 

(amphotericin B) has 

been reported. 

Fluconazole increases the plasma concentration of 

these drugs. 

Concomitant administration resulted in significant 

fluconazole levels. 

Cytosine is a cytostatic agent and has been reported 

to inactivate the antifungal activity of flucytosine by 

competitive inhibition. 

Level 1 Warfarin and itraconazole Inhibition of warfarin metabolism. The anticoagulant 


53

activity of CYP 2C9 

and CYP 3A4. 

Level 1 

Pimozide and itraconazole 

Azole antifungals, including itraconazole, may inhibit 

the metabolism of pimozide. The risk of lifethreatening 

cardiac arrhythmias may be increased. 

Level 1 

Vinblastine / vincristine and 

itraconazole 


(CYP3A4) by fluconazole, and all azole antifungal 

agents. 

Others: 

• H-2 blockers, antacids, 

sucralfate, and 

omeprazole decrease 

the absorption of 

itraconazole. 

Studies have shown that absorption of itraconazole is 

impaired when gastric acid production is decreased. 

• Digoxin, 

carbamazepine, 

rifabutin, busulfan, 

alprazolam, diazepam, 

dihydropyridines, 

atorvastatin, 

cyclosporine, 

tacrolimus, sirolimus, 

oral hypoglycemics, 

protease inhibitors, 

buspirone, and 

methylprednisolone. 

The plasma concentration of these drugs may be 

increased by itraconazole. 

• Carbamazepine, 

phenytoin, 

phenobarbital, 

isoniazid, rifampin, 

rifabutin, antacids, H-2 

antagonists, proton 

pump inhibitors, 

nevirapine. 

These drugs may decrease the plasma concentration 

of itraconazole. 

Ketoconazole 


activity of CYP 3A4, 

CYP2C19, CYP 2C9 

and CYP 1A2 

Level 1 

Level 1 

• Clarithromycin, 

erythromycin, 

indinavir, ritonavir. 

Pimozide and ketoconazole 

Warfarin and ketoconazole 

These drugs may increase the plasma concentration 

of itraconazole. 

Azole antifungals, including ketoconazole, may 

inhibit the metabolism of pimozide. The risk of lifethreatening 




Level 1 

Pimozide and ketoconazole 

Azole antifungals, including ketoconazole, may 

inhibit the metabolism of pimozide. The risk of lifethreatening 


Level 1 

Vinblastine / vincristine and 

ketoconazole 


(CYP3A4) by ketoconazole, and all azole antifungal 

agents. 

Level 1 

Dofetilide and ketoconazole 

Inhibition of the renal cation transport system which 

is responsible for dofetilide elimination, resulting in 

elevated dofetilide plasma concentrations. 

54

Others: • H-2 antagonists, 

antacids, sucralfate, 

and omeprazole 

• Isoniazid, rifampin, 

phenytoin, and 

Pphenobarbital 

• Tacrolimus, 

cyclosporine, 

methylprednisolone, 

phenytoin, 

sulfonylureas, 

warfarin, 

benzodiazepines, 

indinavir, and 

ritonavir. 

Nystatin - Since nystatin absorption is 

insignificant, it is unlikely drug 

interactions would occur with 

nystatin and other 

concomitantly administered 

drugs. No interactions are 

Terbinafine 


activity of CYP 2D6 

No Level 1 

Interactions 

Level 2 

reported for nystatin lozenges. 

Tricyclic antidepressants 

(desipramine, imipramine, 

nortriptyline) and terbinafine. 

Decreased absorption of ketoconazole. 

Increase the metabolism of ketoconazole. 

Ketoconazole increases the plasma concentration of 

these drugs. 

- 

Inhibition of tricyclic antidepressant metabolism by 

CYP 2D6, resulting in increased pharmacologic and 

toxic effects of the tricyclic antidepressants. 

Level 2 

Others: 

Cyclosporine and terbinafine 

• Beta-blockers 

• SSRIs, MAOIs, and 

TCAs 

• Rifampin 

• Cimetidine 

Terbinafine may increase cyclosporine metabolism 

causing decreased cyclosporine concentrations. 

Terbinafine increases the clearance of cyclosporine 

by 15%. 

Decreased efficacy of beta-blockers. 

Increased toxicity of MAOIs, SSRIs, and TCAs. 

Rifampin increases terbinafine clearance by 100%. 

Cimetidine decreases terbinafine by 33%. 

Voriconazole 

Inhibits metabolic 

activity of CYP 2C19, 

CYP 2C9, and CYP 

• No data is available on 

terbinafine when given 

with oral 

contraceptives, 

hormone replacement 

therapy, 

hypoglycemics, 

theophyllines, 

phenytoins, thiazide 

diuretics, and calcium 

channel blockers. 

Level 1 Rifamycins and voriconazole Rifamycins increase metabolism of voriconazole and 

voriconazole inhibits the metabolism of rifabutin. 

55

3A4 Level 1 

Level 1 

Level 1 

Level 1 

Level 1 

Level 1 

Others: 

Griseofulvin No Level 1 

interactions. 

Level 2 

Level 2 

Level 2 

Others: 

Pimozide and voriconazole 

Barbiturates (Phenobarbital) and 

voriconazole 

Ergot Derivatives and 

voriconazole 

Carbamazepine and 

voriconazole 

Quinidine and voriconazole 

Warfarin and voriconazole 

Cyclosporine, phenytoin, 

sulfonylureas, triazolam, 

alprazolam, midazolam, 

loratadine, felodipine, 

nifedipine, statins, omeprazole, 

and tacrolimus. 

Barbiturates (Phenobarbital) and 

griseofulvin 

Warfarin and griseofulvin 

Oral contraceptives and 

griseofulvin 

• Cyclosporine and 

salicylates 

• Ethanol 

Voriconazole may inhibit the metabolism of 

pimozide, causing increased risk of life-threatening 

arrhythmias. 

Long-acting barbiturates may increase the 

metabolism of voriconazole, decreasing the 

therapeutic effect. 

Voriconazole may inhibit the metabolism of ergot 

derivatives causing increased risk of ergot toxicity. 

Carbamazepine may increase the metabolism of 

voriconazole, causing a decreased therapeutic effect 

of voriconazole. 

Voriconazole may inhibit the metabolism of 

quinidine, causing risk of life-threatening cardiac 

arrhythmias. 



Voriconazole increases the plasma concentration of 

these drugs. 

Decreased griseofulvin absorption and increased 

hepatic metabolism by phenobarbital result in 

decreased serum levels of griseofulvin. 

Mechanism is unknown. The anticoagulant activity 

of warfarin may be decreased. 

Griseofulvin induction of oral contraceptive hepatic 

metabolism is suspected, possibly leading to loss of 

oral contraceptive efficacy. 

Griseofulvin may decrease the efficacy of these 

drugs. 

Ethanol may increase griseofulvin toxicity, resulting 

in tachycardia and flushing. 

VI. 

Adverse Drug Events of the Antifungal Agents 

The most common adverse reactions with the amphotericin B products are infusion related chills 

23, 24 

and/or fever. Although full doses of amphotericin B may be tolerated by some patients, most 

will exhibit some intolerance, which can be improved with prophylactic treatment with aspirin, 

acetaminophen, antihistamines, or antiemetics. In a study designed to evaluate the incidence of 

infusion reactions occurring in patients receiving conventional amphotericin B, 71% of patients 

had at least one infusion-related reaction during the first seven days of therapy; fever and chills 

occurred in 28-51% and nausea and headache occurred in 9-18% of patients. 24 Additionally, 

meperidine has been shown to decrease the duration of shaking chills and fever that may 

accompany the infusion. Some benefit can be achieved with intravenous administration of small 

doses of adrenal corticosteroids just prior to or during the amphotericin B infusion, to decrease 

56

febrile reactions. Infusion related adverse reactions with Amphotec occur most frequently with 

the first dose of the drug (35% vs. 14% by the seventh dose). Tables 9 and 10 describe common 

adverse events with all of the antifungal drugs. 

Table 9. Common Adverse Events (%), by System, Reported for the Antifungal Agents 23 

Adverse Event 


Chest Pain 

Generalized Pain 

Hypertriglyceridemia 


Edema 

Hemorrhage 

Hypotension 

Hypertension 

Tachycardia 



Nausea 

Vomiting 

Diarrhea 

Dyspepsia 


Taste disturbance 

Flatulence 

Cramping Epigastric Pain 


Chills/shaking 

Dizziness 

Fatigue 

Fever 

Headache 

Hallucinations 

Malaise 

Vertigo 

Insomnia 

Emotional Lability 

Nervousness 

Depression 

Hepatic 

Abnormal LFTs (incr.) 

Cholestatic jaundice 

Hepatitis 

Skin and Appendages 

Alopecia 

Rash 

Pruritus 

Hematologic 

Neutropenia 

Anemia 


Renal 

Abnormal kidney function 

Acute kidney failure 

Other 

Allergic reaction 

Decreased libido 

Visual disturbance 

Weight Loss 

Injection Site Pain/Rxn 

Face Edema 

Weight Gain 

Multiple Organ Failure 

Sepsis 

Amphotericin 

B* 

11.6 

b, 12.8 

b 

b, 21.5 

16.3 

20.9 

21.8 

b, 38.7 

b, 43.9 

b, 27.3 

b 

b 

b, 75.9 

b 

b, 20.9 

b 

14.2 

ALT 14 

AST 12.8 

24.4 

10.2 

b, 42.2 

(creatinine 

increase) 

b 

b 

11.3 

Cholesteryl Sulfate 

(Amphotec) 

>5 

>5 

>5 

>5 

>5 

1-5 

>5 

>5 

b 

35 

>5 

35 

1-5 

>5 

1-5 

1-5 

1-5 (hepatic failure) 

1-5 

>5 

>5 

57 

Lipid Complex 

(Abelcet) 

3 

5 

8 

5 

4 

9 

8 

6 

7 

b 

b 

18 

14 

6 

b 

b 

b 

b 

4 

b 

>5 4 

1-5 

1-5 

11 

5 

Liposomal 

(AmBisome) 

12 

14 

14.3 

14.3 

7.9 

13.4 

19.8 

39.7 

31.8 

30.3 

47.5 

19.8 

17.2 

ALT 14.6 

AST 12.8 

24.8 

10.8 

22.4 (creatinine 

increase) 

>5 

14 

bAdverse event reported; specific percentages not available 

*Only most common adverse events are reported here. 

**Rash tends to appear more frequently in immunocompromised patients receiving immunosuppressive medications. 

1-5 

>5 

>5 

>5 

b 

b 

b 

b 

11 

7 

Fluconazole 

Itraconazole 

oral capsules 

(Systemic, 

onychomycosis) 

b 0, 3 

1.7 

3.7 

1.7 

1.5 

1.0 

1.9 

b 

b 

b 

4 

1 

3, 2 

2, 4 (general GI) 

11 

5 

3 

1 

2 

3 

3 

4, 1 

1, 1 

0, 1 

b 

b 

3, 4 

b 

1.8 9**, 3 

3, 3 

b 

b 

1 (albuminuria) 

1

Table 10. Common Adverse Events (%), by System, Reported for the Antifungal Agents 23 

Adverse Event Ketoconazole Caspofungin Flucytosine Nystatin Terbinafine Voriconazole Griseofulvin 


Chest Pain 

Generalized Pain 

Hypertriglyceridemia 


Edema 

Hemorrhage 

Hypotension 

Hypertension 

Tachycardia 



Nausea 

Vomiting 

Diarrhea 

Dyspepsia 


Taste disturbance 

Flatulence 

Cramping Epigastric Pain 


Chills/shaking 

Dizziness 

Fatigue 

Fever 

Headache 

Hallucinations 

Malaise 

Vertigo 

Insomnia 

Emotional Lability 

Nervousness 

Depression 

Hepatic 


Cholestatic jaundice 

Hepatitis 


Alopecia 

Rash 

Pruritus 

Hematologic 

Neutropenia 

Anemia 


Renal 

Abnormal kidney function 


Other 

Allergic reaction 

Decreased libido 

Visual disturbance 

Weight Loss 

Injection Site Pain/Rxn 

Face Edema 

Weight Gain 

Multiple Organ Failure 

Sepsis 

Rare 

1.2 

3 

3 

23- 25 

Table 11. Dosing for the Antifungal Agents 

Availability 

Dose /Frequency/Duration 


Deoxycholate (Fungizone ® ) 

50mg vials Infection Treatment regimen Dose 1 

(mg/kg/day) 

Aspergillosis up to 3.6 g total dose 1 to 1.5 

Blastomycosis 4 to 12 weeks 0.5 to 0.6 

Candidiasis 4 to 12 weeks 0.5 to 1 

Coccidioidomycosis 4 to 12 weeks 0.5 to 1 

Cryptococcosis 4 to 12 weeks 0.5 to 0.7 

Histoplasmosis 4 to 12 weeks 0.5 to 0.6 

Mucormycosis 4 to 12 weeks 1 to 1.5 

Rhinocerebral 

phycomycosis 

3 to 4 g total dose 0.25 to 0.3 up to 1 to 1.5 

Sporotrichosis up to 2.5 g total dose 0.5 



(Amphotec ® ) 


Complex (Abelcet ® ) 

Amphotericin B Liposomal 

(AmBisome ® ) 

Caspofungin Acetate 

(Cancidas ®) 

Powder for injection: 

50mg in 20ml vial and 

100mg in 50ml vial, 

single use only 

Suspension for injection: 

100mg/20ml, in 10 and 

20ml single use vial 


50mg, single use vial 


70mg and 50mg single 

use vials 

A test dose may be preferred due to patient variability in tolerance: 1mg in 

20 ml of 5% dextrose delivered IV over 20 to 30 minutes. 

1 

Some dosages not FDA Approved. 

Fungal infection, systemic: 

A test dose is advisable (e.g., 10 ml of final preparation containing 1.6 to 

8.3 mg infused over 15 to 30 min). The recommended dose is 3 to 

4mg/kg/day prepared as a 0.6mg/ml (range, 0.16 to 0.83mg/ml) infusion 

delivered at a rate of 1mg/kg/hr. Do not filter or use an in-line filter. 


The recommended dose is 5mg/kg/day prepared as a 1mg/ml infusion 

and delivered at a rate of 2.5mg/kg/hour. For pediatric patients and 

patients with cardiovascular disease, the drug may be diluted to a final 

concentration of 2mg/ml. If the infusion exceeds 2 hours, mix the 

contents by shaking the infusion bag every 2 hours. Do not use an in-line 

filter. 

Fungal infection, empirical: 

3mg/kg/day of liposomal amphotericin B using a controlled infusion 

device over 120 minutes; infusion time may be reduced to 60 minutes if 

well tolerated. 


3 to 5mg/kg/day prepared as a 1 to 2mg/ml infusion delivered initially 

over 120 minutes; infusion time may be reduced to 60 minutes if well 

tolerated. Lower infusion concentrations of 0.2 to 0.5 mg/ml may be 

appropriate for infants and small children to provide sufficient volume 

for infusion. 

Cryptococcal meningitis in HIV: 

6mg/kg/day using a controlled infusion device over 120 minutes; 

infusion time may be reduced to 60 minutes if well tolerated or increased 

if patient experiences discomfort. 

Leishmaniasis: 

3mg/kg/day on days 1 through 5, 14, and 21 to immunocompetent 

patients; a repeat course of therapy may be useful if parasitic clearance is 

not achieved. Administer 4mg/kg/day on days 1 through 5, 10, 17, 24, 

31, and 38 to immunosuppressed patients; seek expert advice regarding 

further therapy if parasitic clearance is not achieved. 

Loading dose: 70mg should be administered on day 1 

Maintenance: 50 mg daily 

Administer by slow IV infusion of 1 hour. Duration of treatment should be 

based upon the severity of the patient's underlying disease, recovery from 

immunosuppression, and clinical response. The efficacy of a 70 mg dose 

regimen in patients who are not clinically responding to the 50 mg daily 

dose is not known. Limited safety data suggests that an increase in dose to 

59

Fluconazole (Diflucan ® ) 

Injection: 2mg/ml in 

100ml and 200ml 

Oral: 50mg, 100mg, 

150mg, 200mg tablets; 

powder for oral 

suspension in 10mg/ml 

and 40mg/ml 

70 mg daily is well tolerated. The safety and efficacy of doses >70 mg have 

not been adequately studied. 

Dosing for oral and IV administration is the same. 

Adults: 

Single-dose: 

Vaginal candidiasis: 

150mg as a single oral dose. 

Oropharyngeal candidiasis: 

200mg on the first day, followed by 100mg once daily for 2 weeks 

to decrease the likelihood of relapse. 

Esophageal candidiasis: 

200mg on the first day, followed by 100mg once daily. Doses up 

to 400 mg/day may be used based on response. Duration should 

be a minimum of 3 weeks and for 2 weeks or more following 

resolution of symptoms. 

Candidiasis, other: 

For candidal urinary tract infections (UTIs) and peritonitis, 50 to 

200mg/day has been used. For systemic candidal infections 

(including candidemia, disseminated candidiasis, and pneumonia), 

optimal dosage and duration have not been determined, although 

doses of 400mg/day or less have been used. 

Prevention of candidiasis in bone marrow transplant: 

400mg once daily. In patients anticipated to have severe 

granulocytopenia (less than 500neutrophils/mm 3 ), start 

fluconazole prophylaxis several days before anticipated onset of 

neutropenia, and continue 7 days after neutrophil count rises 

above 1000cells/mm 3 . 

Cryptococcal meningitis: 

400mg on the first day followed by 200mg once daily. A dosage 

of 400mg once daily may be used based on the patient's response 

to therapy. The duration of treatment for initial therapy of 

cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal 

fluid (CSF) becomes culture negative. The dosage of fluconazole 

for suppression of relapse of cryptococcal meningitis in patients 

with AIDS is 200mg once daily. 

60 

Children: 

Equivalent Fluconazole Dosage in 

Children vs. Adults 

Children Adults 

3 mg/kg 100 mg 

6 mg/kg 200 mg 

12 mg/kg 1 400 mg 

Neonates: 

Experience in neonates is limited to pharmacokinetic studies in 

premature newborns. Based on the prolonged half-life seen in 

premature newborns (gestational age, 26 to 29 weeks), administer 

the same dosage (mg/kg) to neonates in the first 2 weeks of life as 

in older children, but administer every 72 hours. After the first 2 

weeks, dose neonates once daily. 


6mg/kg on the first day, followed by 3mg/kg once daily. 

Administer treatment for at least 2 weeks to decrease the 

likelihood of relapse. 


6mg/kg on the first day followed by 3mg/kg once daily. Doses up 

to 12mg/kg/day may be used based on the patient's response to 

therapy. Treat patients with esophageal candidiasis for a 

minimum of 3 weeks and for at least 2 weeks following the 


Systemic Candida infections: 

Daily doses of 6 to 12mg/kg/day have been used in an open,

61 

noncomparative study of a small number of children. 

Cryptococcal meningitis: 

12mg/kg on the first day, followed by 6mg/kg once daily. A 

dosage of 12mg/kg once daily may be used based on medical 

judgment of the patient's response to therapy. The recommended 

duration of treatment for initial therapy of cryptococcal meningitis 

is 10 to 12 weeks after the CSF becomes culture negative. For 

suppression of cryptococcal meningitis relapse in children with 

AIDS, the recommended dose is 6 mg/kg once daily. 

1 Some older children may have clearances similar to that of adults. Absolute doses 

more than 600mg/day are not recommended. 

Flucytosine (Ancobon ® ) 250 and 500mg capsules Usual dosage is 50 to 150mg/kg/day in divided doses at 6-hour intervals. To 

reduce or avoid nausea or vomiting, take capsules a few at a time over a 15- 

minute period. 

Itraconazole (Sporanox ® ) 

Injection: 10mg/ml (kit) 

Oral: 100mg capsules, 

10mg/ml oral 

solution 

Itraconazole oral solution and capsules cannot be used interchangeably. 

Itraconazole capsules should be taken with a full meal to ensure absorption. 

The oral solution should be taken without food if possible. 

Capsules: 

Aspergillosis: A daily dose of 200 to 400mg is recommended. 

Blastomycosis/histoplasmosis: 

200mg once daily. If there is no obvious improvement or there is 

evidence of progressive fungal disease, increase the dose in 

100mg increments to a maximum of 400mg/day. Give doses 

above 200mg/day in 2 divided doses. 

Life-threatening situations: 

Although clinical studies did not provide for a loading dose, it is 

recommended, based on pharmacokinetic data, that a loading dose 

of 200mg 3 times/day be given for the first 3 days of treatment. 

Continue treatment for a minimum of 3 months (at 200-400mg 

QD-BID) and until clinical parameters and laboratory tests 

indicate that the active fungal infection has subsided. An 

inadequate period of treatment may lead to recurrence of active 

infection. 

Treatment of onychomycosis (fingernails only): 

Two treatment pulses, each consisting of 200mg twice daily for 1 

week. The pulses are separated by a 3-week period without 

itraconazole. 

Treatment of onychomycosis (toenails with or without fingernail 

involvement): 200mg/day for 12 weeks. 

Oral Solution: 


100mg/day for a minimum treatment of 3 weeks. Continue 

treatment for 2 weeks following resolution of symptoms. Doses up 

to 200mg/day may be used based on medical judgment of the 

patient's response to therapy. Vigorously swish the solution in the 

mouth (10mL at a time) for several seconds and swallow. 

Empiric therapy in neutropenic patients with suspected fungal 

infections: 

After approximately 14 days of IV therapy, continue treatment 

with oral solution 200mg twice daily until resolution of clinically 

significant neutropenia. The safety and efficacy of itraconazole 

use exceeding 28 days in this population is not known. 


200mg/day for 1 to 2 weeks. Vigorously swish the solution in the 

mouth (10ml at a time) for several seconds and swallow. For 

patients with oropharyngeal candidiasis unresponsive/refractory to 

treatment with fluconazole tablets, the recommended dose of 

itraconazole is 100mg twice daily. Expect clinical response in 2 to 

4 weeks. Patients may be expected to relapse shortly after 

discontinuing therapy. Limited data on the safety of long-term use 

(more than 6 months) of the oral solution are available at this time.

Injection: 

Use only the components provided in the kit for preparation of the injection. 

Blastomycosis, histoplasmosis, and aspergillosis: 

200mg IV twice daily for 4 doses, followed by 200mg/day. Infuse 

each IV dose over 1 hour. Itraconazole can be given as oral 

capsules or IV. The safety and efficacy of the injection 

administered for more than 14 days are not known. 

Continue total itraconazole therapy (injection followed by 

capsules) for a minimum of 3 months and until clinical parameters 

and laboratory tests indicate that the active fungal infection has 

subsided. An inadequate period of treatment may lead to 

recurrence of active infection. 

Empiric therapy in febrile neutropenic patients with suspected fungal 

infections: 

200mg twice daily for 4 doses, followed by 200mg once daily for 

up to 14 days. Infuse each IV dose over 1 hour. Continue 

treatment with 200mg itraconazole oral solution (20 ml) twice 

daily until resolution of clinically significant neutropenia. The 

safety and efficacy of itraconazole use exceeding 28 days in ETFN 

is not known. 

Ketoconazole (Nizoral ® ) 200mg tablets Adults: 

Initially, 200mg once daily. In very serious infections, or if clinical 

response is insufficient, increase dose to 400mg once daily. 

Children: 

(> 2 years of age): 

3.3 to 6.6mg/kg/day as a single daily dose. 

(< 2 years of age): 

Daily dosage has not been established. 

Minimum treatment for candidiasis is 1 or 2 weeks and 6 months for the 

other indicated systemic mycoses. Chronic mucocutaneous candidiasis 

usually requires maintenance therapy. Minimum treatment of recalcitrant 

dermatophyte infections is 4 weeks in cases involving glabrous skin. Palmar 

and plantar infections may respond more slowly. Apparent cures may 

subsequently recur after discontinuation of therapy in some cases. 

Nystatin (Mycostatin ® ) 

500,000unit tablets 

100,000units/ml oral 

suspension 

200,000unit 

pastilles/troches 

Oral powder for 

suspension: 

50 million units 



1 billion units 



Oral tablets for nonesophageal GI candidiasis: 1 to 2 tablets (500,000 

to 1,000,000units) TID continued for 48 hours after clinical cure to prevent 

relapse. 

Oral Suspension, adults and children: 400,000 to 600,000units QID 

(one half of dose in each side of mouth, retaining the drug as long as 

possible before swallowing). Infants: 200,000units 4 times daily 

(100,000units in each side of mouth). 

Pastilles / troches: 200,000 to 400,000units 4-5 times daily for up to 

14 days or until 48 hours after disappearance of oral symptoms. 

This dosage form must be allowed to dissolve slowly in the mouth, 

not chewed or swallowed whole 

Powder for extemporaneous compounding: 

Adults and children: 

Add 1/8 tsp ( 500,000units) to 1/2 cup of water and stir well. 

Administer 4 times daily. Use immediately after mixing; do not store. 

Continue local treatment at least 48 hours after perioral signs and 

symptoms have disappeared and cultures have returned to normal. 

To improve oral retention of the drug, nystatin (250,000units) has been 

administered for oral candidiasis in the form of flavored frozen popsicles. 

Terbinafine (Lamisil ® ) 250mg tablet Onychomycosis: 

Fingernail= 250mg QD for 6 weeks 

Toenail= 250mg QD for 12 weeks 

Voriconazole (Vfend ® ) 

Oral: 50mg and 200mg 

tablets; powder for oral 

62 

Invasive aspergillosis and serious fungal infections: 

Loading dose= 6 mg/kg IV every 12 hours for 2 doses

suspension 40mg/ml 


200mg, single use vials 

Maintenance dose= 4 mg/kg IV every 12 hours 

Once the patient can tolerate oral medication, the tablet form or 

oral suspension of voriconazole may be used at a dose of 200mg 

every 12 hours in patients who weigh more than 40kg or in those 

who weigh less than 40kg, the maintenance dose is 100mg every 

12 hours. If patient response is inadequate, the oral maintenance 

dose may be increased from 200 mg every 12 hours to 300mg 

every 12 hours and for patients weighing less than 40kg, the oral 

maintenance dose may be increased from 100mg every 12 hours 

to 150mg every 12 hours. 


(Fulvicin ® U/F, 

Grifulvin ® V) 


(Gris-PEG ® , 

Fulvicin ® PG) 

250mg capsule 

250mg and 500mg tablet 

125mg and 250mg tablet 

and oral suspension 

125mg/5ml with alcohol 

0.2% (120ml) 

125 and 250mg tablet 

165mg, 250mg and 

330mg tablet 

Esophageal Candidiasis: 

Oral dose of 200mg every 12 hours for patients who weigh 40kg 

or more. Adult patients who weigh less than 40kg should receive 

an oral dose of 100mg every 12hours. Treatment duration is a 

minimum of 14 days and for at least seven days following 


Note: Voriconazole tablets should be taken at least one hour 

before or one hour following a meal. Switching between IV and 

oral is appropriate when necessary. 

Children: 

Microsize: 10-20mg/kg/day in single or 2 divided doses 

Ultramicrosize: >2 years: 5-10mg/kg/day in single or 2 divided 

doses 

Adults: 

Microsize: 500-1000mg/day in single or divided doses 

Ultramicrosize: 330-375mg/day in single or divided doses; doses up 

to 750mg/day have been used for infections more difficult to 

eradicate such as tinea unguium 

Duration of therapy: 

Tinea corporis: 2-4 weeks 

Tinea capitis: 4-6 weeks or longer 

Tinea pedis: 4-8 weeks 

Tinea unguium: 3-6 months or longer 

Note: The efficiency of GI absorption of griseofulvin ultramicrosize is 1.5 times 

that of conventional microsized griseofulvin. This factor permits the oral intake of 2/3 

as much ultramicrosize as the microsize form, but there is no evidence that this 

confers any significant clinical difference in regard to safety and efficacy. 

63


In studies where patients experienced nephrotoxicity while receiving conventional amphotericin 

B, and a lipid formulation of amphotericin B was substituted, serum creatinine concentrations 

23, 24 

generally declined during therapy with the lipid-based or liposomal formulations. 

Table 12. Special Dosing Considerations for the Antifungal Agents 23-25 

Drug Renal Dosing Hepatic 

Dosing 

Pediatric Use 


No 

Deoxycholate 


Cholesteryl 



Lipid Complex 


Liposomal 

Caspofungin 

Acetate 

Yes (Alternate 

daily dosing at 

1.5mg/kg/day); 

hydration and 

sodium repletion 

may decrease the 

risk of 

nephrotoxicity 

Not established by 

adequate wellcontrolled 

trials. 

No No No unusual adverse 

events have been 

reported with use in 

children (50ml/min = 

100% of usual 

daily dose and 

Itraconazole 

40ml/min., Q24 

hours with Cr. Cl. 

of 10-20ml/min, 

and Q24-48 hours 

or longer with Cr. 

Cl

Terbinafine 

Voriconazole 

Griseofulvin 

Ultramicrosize 

Griseofulvin 

Microsize 

Clearance of terbinafine may be 

decreased (by 50%) by patients with 

renal impairment or in those with 

preexisting liver disease. 

Terbinafine has not been adequately 

studied in this population, therefore, 

the manufacturer does not 

recommend use in either population. 

In moderatesevere 

renal 

failure, IV 

voriconazole 

should be used 

only when clearly 

needed due to 

accumulation of 

the IV vehicle; no 

adjustment is 

needed for the 

oral formulation 

In mildmoderate 

hepatic 

disease, the 

usual IV or 

oral loading 

dose should be 

used, 

however, the 

IV and oral 

maintenance 

doses should 

be decreased 

by 50% 

No dose adjustments are discussed 

in the manufacturers labeling, 

however, griseofulvin is 

contraindicated in patients with 

porphyria and hepatocellular failure. 

The safety and 

efficacy of 

terbinafine has not 

been established in 

pediatric patients 

(

VIII. Comparative Effectiveness of the Antifungal Agents 

The available lipid formulations of amphotericin B represent advancement in drug delivery technology. Clinical experience has primarily been in patients either 

refractory to or intolerance of conventional amphotericin B deoxycholate. 28 The lipid-based products have not demonstrated superior efficacy when 

prospectively compared with traditional amphotericin B in the treatment of documented infections. In some patients with life-threatening mycosis who failed 

treatment with, or were intolerant to, amphotericin B, the lipid formulations have been effective. 27 

When used for empirical treatment of febrile neutropenia, amphotericin B liposomal (AmBisome) significantly reduced the incidence of proven emergent fungal 

infections but did not improve short-term survival rates, in comparison with traditional amphotericin B. 34 For these reasons, the lipid amphotericin B products 

can be restricted for use in those who are intolerant of or refractory to amphotericin B. 

Table 13. Additional Outcomes Evidence for the Antifungal Agents 

Study Design Entry Criteria Sample Treatment 

Regimen 

Miller CB, et 

al. 35 

Fleming RV, 

et al. 36 

Retrospective 

analysis 

Randomized, 

double blind 

study 

• Adult hematopoietic 

stem cell transplant 

recipients 

• Proven or probable 

invasive fungal 

infection 

• Transplantation 

between 1995-2000 

Patients with leukemia 

and suspected or 

documented mycosis 

- Amphotericin B 

deoxycholate vs. 

AmBisome 

vs. 

Abelcet 

n=75 ABLC or 

AmBisome at 3- 

5mg/kg/day 

Duration of 

Study 

Amphotericin B Studies 

Infection and 

response 

dependent 

10 days at 3 

mg/kg for 

ABLC and 15 

days at 4 mg/kg 

for AmBisome 

Results 

In assessing renal function based on medical records in adult hematopoietic stem 

cell transplant recipients with proven or probable invasive fungal infection: 

• Due to nephrotoxicity, 88% of patients treated with amphotericin B 

deoxycholate were switched to a lipid formulation of amphotericin B. 

• 53% of patients initiated on amphotericin B were switched within the 

first week of therapy. 

• Significantly more patients (71%) treated with amphotericin B 

experienced a 100% increase in serum creatinine from baseline 

compared to patients treated with either AmBisome (44%) or Abelcet 

(41.2%). 

• Statistical analysis showed that compared to patients initiated on 

AmBisome or Abelcet, the risk of nephrotoxicity, dialysis, and death 

were all increased for patients initiated on amphotericin B 

deoxycholate. 

In evaluating the efficacy of ABLC and AmBisome: 

• The overall response to therapy was 27/43 (63%) for ABLC and 15/39 

(39%) for AmBisome (p=0.03). 

• Response rates were approximately 30% in both groups for patients 

with documented fungal infections. 

• Acute, not dose-limiting infusion side effects were seen in 70% vs. 

36% (p=0.002), ABLC vs. AmBisome. 

• Severe initial infusion reactions, all leading to discontinuation, 

occurred in three cases (one with ABLC and two with AmBisome). 

• Increase of bilirubin > 1.5 times from baseline was 38% vs. 59%, 

67

Cagnoni PJ 37 

Subira SM, et 

al. 38 

Kontoyiannis 

DP, et al. 39 

Randomized, 

double blind, 

multicenter 

trial 

Randomized, 

controlled 

trial 

Meta-analysis 

of prospective 

studies 

• Patients with febrile 

neutropenia 

• Empiric antifungal 

therapy 

• Patients with 

hematologic 

malignancies and 

fever of unknown 

origin after 

chemotherapy or 

autologous stem cell 

transplantation 

• Empiric therapy 

n=414 Liposomal 


vs. conventional 


n=105 ABLC at 

1mg/kd/day or 

conventional 

amphotericin B at 

0.6mg/kg/day 

Adults with candidaemia - Fluconazole vs. 


Infection and 

response 

dependent 

Infection and 

response 

dependent 

ABLC vs. AmBisome (p=0.05). 

• ABLC and AmBisome were equally effective for the treatment of 

suspected or documented fungal infections. 

• While, acute infusion-toxicity was greater with ABLC, infusion 

toxicity requiring discontinuation was similar for both drugs. 

• AmBisome was better tolerated than ABLC but was associated with 

mild abnormalities in liver function tests at the end of therapy. 

Using a composite end-point, liposomal amphotericin B and conventional 

amphotericin B were found to be equivalent in overall efficacy. Other findings 

included: 

• The liposomal amphotericin B treatment group had fewer proven 

fungal infections, fewer infusion-related side effects, and less 

nephrotoxicity. 

• Authors commented on findings of a randomized, double-blind study 

comparing liposomal amphotericin B at 3 or 5 mg/kg/day with 

amphotericin B lipid complex (ABLC) at 5mg/kg/day as empiric 

therapy in patients with febrile neutropenia. Liposomal amphotericin B 

was associated with less toxicity than ABLC, both in terms of infusionrelated 

reactions and nephrotoxicity. 

• In the previously mentioned study, the incidence of study drug 

discontinuation due to toxicity was: liposomal amphotericin B 

3mg/kg/day 14%; liposomal amphotericin B 5mg/kg/day 15%; and 

ABLC 42% (p

Johansen HK, 

et al. 40 

Meta-analysis 

of 16 trials, 

looking at the 

effect of 

morbidity and 

mortality 

Patients with cancer, 

complicated with 

neutropenia 

n=3,760 

Fluconazole vs. 


and microbiological failure according to all Candida species (OR, 0.99; 

CI, 0.78-1.26). 

• A trend favoring amphotericin B was seen in mycological eradication 

of non-albicans Candida species (OR, 0.70; CI, 0.47-1.06). 

• Amphotericin B was more toxic than fluconazole (OR, 2.94; CI, 2.14- 

4.4). 

• Summary: fluconazole is as efficacious as and less toxic than 

amphotericin B in stable, not severely immunosuppressed candidaemic 

patients at low risk for death. However, fluconazole may be less 

effective than amphotericin B in candidaemias caused by some nonalbicans 

Candida species. 

- Sixteen trials were included for comparative analysis: 

• In three large 3-armed trials, results for amphotericin B were combined 

with results for nystatin in a "polyene" group. Because nystatin is an 

ineffective drug in these circumstances, this approach creates a bias in 

favor of fluconazole. Furthermore, most patients were randomized to 

oral amphotericin B, which is poorly absorbed and poorly documented. 

It was unclear whether there was overlap among the "polyene" trials. 

• There were no significant differences in effect between fluconazole and 

amphotericin B, but the confidence intervals were wide. 

• More patients dropped out of the study when they received 

amphotericin B, but as none of the trials were blinded, decisions on 

premature interruption of therapy could have been biased. 

• Furthermore, amphotericin B was rarely given under optimal 

circumstances, with premedication to reduce infusion-related toxicity, 

slow infusion, and with potassium and magnesium supplements to 

prevent nephrotoxicity. 

• Summary: Amphotericin B has been disfavored in several trials due to 

design or analysis. Since intravenous amphotericin B is the only 

antifungal agent for which there is good evidence suggesting an effect 

on mortality, consideration should be given for its use. 

Bowden R, et 

al. 41 

Randomized, 

double-blind, 

multicenter 

trial 

Invasive aspergillosis n=174 Amphotec 

6mg/kg/day vs. 

conventional 

amphotericin B 1- 

1.5mg/kg/day 

Infection and 

response 

dependent 

In comparing the effects of amphotericin B colloidal dispersion (Amphotec, 

ABCD) to conventional amphotericin B (AmB) in the treatment of invasive 

aspergillosis: 

• For evaluable patients in the ABCD and AmB treatment groups, 

respective rates of therapeutic response (52% vs. 51%; p=1.0), 

mortality (36% vs. 45%; p=.4), and death due to fungal infection (32% 

vs. 26%; p=.7) were similar. 

• Renal toxicity was lower (25% vs. 49%; p=.002) and the median time 

69

Barrett JP, et 

al. 42 Meta-analysis Literature search of 

Medline, Embase, 

Biological Abstracts, 

Aidsline, Cancerlit, CRD 

database, Cochrane 

Controlled Trials 

Register, and other 

databases. 

Wingard JR, 

et al. 43 

Clark AD, et 

al. 44 

Randomized, 

double-blind 

comparative 

trial 

Retrospective 

analysis 

Neutropenic patients 

with unresolved fever 

after 3 days of 

antibacterial therapy 

• Single-center, 5- 

year use of 


8 publications 

n=244 ABLC 


liposomal 


(L Amph) at 3 

and 5mg/kg/day 

- AmBisome vs. 

Abelcet 

to onset of nephrotoxicity was longer (301 vs. 22 days; p

Linder N, et 

al. 45 

Kartsonis 

NA, et al. 46 

Cesaro S, et 

al. 47 

Colombo 

AL, et al. 48 

Comparative 

study 

Prospective 

study 

Prospective 

study 

Randomized, 

double blind, 

• Focus on 

indications, 

efficacy, and 

toxicity 

Infants in the neonatal 

intensive care unit from 

1996-2000 with candida 

bloodstream infections 


mucosal or invasive 

candida infections 

• Refractory or 

intolerant to 

amphotericin B or 

lipid amphotericin B 

• Invasive mycosis, as 

maintenance or 

rescue therapy, for 

refractory infection 

not responsive to 

liposomal 

amphotericin B or 

fluconazole 

• Diagnosis of 

patients included: 

leukemia, 

myelodysplastic 

syndrome, and 

Hodgkin’s 

n=56 Conventional 

amphotericin B, 

liposomal 


(LamB), and 


colloidal 

dispersion 

(ABCD) 

n=37 Caspofungin 

n=10 Caspofungin and 

liposomal 


followed by 

voriconazole 

lymphoma 

Invasive candidiasis n=239 Caspofungin vs. 


If blood cultures 

were + more 

than 10 days 

with clinical 

signs of fungal 

infection, a 

second 

antifungal was 

initiated. 

Caspofungin 

Infection and 

response 

dependent 

Combination 

therapy with 

caspofungin and 

liposomal 


was given for a 

median of 17 

days (range 6- 

40). 

Voriconazole 

was given for a 

mean of 75 days 

(range 42-194) 

4.8mg/kg/day. 

• Nephrotoxicity and electrolyte abnormalities were similar in both 

groups. 

• Rigors and febrile episodes were more common with Abelcet. 

In comparing conventional amphotericin B, liposomal amphotericin B, and 

amphotericin B colloidal dispersion: 

• No differences in mortality were found between the three groups. 

• Sterilization of the blood was achieved with amphotericin B in 67.6% 

of patients, LamB in 83.3%, and ABCD in 57.1%, when used as 

monotherapy; with the addition of a second antifungal agent, success 

rates were 100%, 83.3%, and 92.8%, respectively. 

• There were no differences between the groups in the time to resolution 

of fungaemia. 

• No patients had immediate local or systemic adverse events and none 

showed deterioration in renal function. 

In evaluating caspofungin in patients who are refractory to treatment with >/= 1 

antifungal agent: 

• A favorable response was noted in 82% (14/17) of patients with 

esophageal candidiasis, 100% (4/4) with oropharyngeal candidiasis, and 

87% (13/15) with invasive candidiasis. 

• Caspofungin was generally well tolerated; one serious drug-related 

adverse event was reported. 

In evaluating the safety and efficacy of caspofungin and liposomal amphotericin 

B, followed by voriconazole: 

• Among the nine patients with proven or probable mycosis, one was not 

evaluated because of early death caused by massive hemoptysis whilst 

in the remaining eight patients, the response was classified as complete, 

stable and failure in four, three, and one patients, respectively. 

• Complete response was also observed in patients with possible 

mycosis. 

• Voriconazole was well tolerated although some drug interactions were 

observed during treatment with methotrexate and digoxin. 

• Overall, a favorable response to antifungal treatment (including the 

case of possible mycosis) was obtained in 8 of 10 patients. 

In comparing caspofungin with amphotericin B for invasive candidiasis: 

• In the USA and Canada, Candida glabrata was the second most 

71

international 

study 

Mora-Duarte Double blind, 

J, et al. 49 randomized 

trial 

Galgiani JN, 

et al. 50 

Randomized, 

double blind, 

placebo 

controlled, 

multicenter 

trial 

Primary treatment of 

invasive candidiasis, 

with a subgroup of 

patients with candidemia 

Soft tissue, or skeletal 

coccidioidal infections 

n=239 Caspofungin vs. 


Infection and 

response 

dependent 

Infection and 

response 

dependent 

Oral Fluconazole, Itraconazole, Terbinafine and Ketoconazole 

n=198 Fluconazole 

400mg QD, 

itraconazole 

200mg BID, or 

Placebo 

commonly isolated pathogen (18%). In contrast, Candida parapsilosis 

and Candida tropicalis accounted for 55% of cases in Latin America. 

• Outcomes were comparable for patients treated with caspofungin (74% 

overall; 64% and 80% for infections due to Candida albicans and nonalbicans 

species) and amphotericin B (62% overall; 58% and 68% for 

infections due to Candida albicans and non- albicans species), and 

were generally similar across continents. 

In studying the efficacy of caspofungin and amphotericin B: 

• A modified intention-to-treat analysis showed that the efficacy of 

caspofungin was similar to that of amphotericin B, with successful 

outcomes in 73.4 % of the patients treated with caspofungin and in 

61.7% of those treated with amphotericin B (difference after 

adjustment for APACHE II score and neutropenic status, 12.7 

percentage points; 95.6% confidence interval, -0.7 to 26.0). 

• An analysis of patients who met prespecified criteria for evaluation 

showed that caspofungin was superior, with a favorable response in 

80.7%of patients, as compared with 64.9%of those who received 

amphotericin B (difference, 15.4 percentage points; 95.6 percent 

confidence interval, 1.1 to 29.7). 

• Caspofungin was as effective as amphotericin B in patients who had 

candidemia, with a favorable response in 71.7% and 62.8% of patients, 

respectively (difference, 10.0 percentage points; 95.0 percent 

confidence interval, -4.5 to 24.5). 

• There were significantly fewer drug-related adverse events in the 

caspofungin group than in the amphotericin B group. 

• Summary: Caspofungin is at least as effective as amphotericin B for 

the treatment of invasive candidiasis and, more specifically, 

candidemia. 

Primary Endpoint 

• Response to therapy defined as a 50% reduction in baseline 

abnormalities during the first eight months of therapy. 

Efficacy: Fluconazole = Itraconazole 

• 50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 

eight months of treatment with fluconazole and itraconazole, 

respectively (difference, 13 percentage points [95% CI, -2 to 28 

percentage points]; p=0.08). 

• Patients with skeletal infections responded twice as frequently to 

itraconazole as to fluconazole. 

• By month 12, 57% of patients had responded to fluconazole and 72% 

72

Evans EGV, 

et al. 51 

Randomized, 

double blind, 

parallel group, 

Multicenter 

• 18-75 years of age 

• Clinical and 

mycological 

diagnosis of 

dermatophyte 

onychomycosis of 

the toenail 

n=496 Terbinafine 

250mg QD for 12 

weeks (T 12 

group), 

terbinafine 

250mg QD for 16 

weeks (T 16 

group), 

itraconazole 

400mg QD for 

one week Q 4 

weeks for 12 

weeks (I 3 group), 

or 

itraconazole 

400mg QD for 

one week Q 4 

weeks for 16 

weeks (I 4 group) 

had responded to itraconazole (difference, 15 percentage points [CI 

,0.003 to 30 percentage points]; p=0.05). 

• Neither fluconazole nor itraconazole showed statistically superior 

efficacy in nonmeningeal coccidioidomycosis. 

• Relapse rates after discontinuation of therapy did not differ 

significantly between groups (28% after fluconazole treatment and 18% 

after itraconazole treatment). 

Safety: Fluconazole = Itraconazole 

• Serious adverse events occurred in 8 of 97 fluconazole-treated patients 

(8% [CI, 4% to 16%] ) and 6 of 101 itraconazole treated patients (6% 

[CI, 2% to 12%] (p>0.2). 

• Three adverse events may have been caused by a study drug: elevated 

liver enzyme levels (one itraconazole treated patient), hypokalemia 

(one itraconazole treated patient), and vomiting (one fluconazole 

treated patient). 

• Six patients treated with fluconazole and two treated with itraconazole 

were withdrawn from the study because of rash, dry skin, and 

gastrointestinal symptoms (fluconazole) , or difficulty concentrating 

(itraconazole). 

72 weeks Primary Endpoint 

• Assessment of mycological cure at week 72, defined as negative results 

on microscopy and culture of samples from the target toenail. 

Efficacy: Terbinafine > Itraconazole 

• At week 72 the mycological cure rates were 75.7% (81/107) in the T 12 

group and 80.8 (80/99) in the T 16 group compared with 38.3% (41/107) 

in the I 3 group and 49.1% (53/108) in the I 4 group. 

• All comparisons (T 12 vs. I 3 , T 12 vs. I 4 , T 16 vs. I 3 T 16 vs. I 4 ) showed 

higher cure rates in the terbinafine groups (all p

Brautigam Randomized, 

M, et al. 52 double blind, 


Multicenter 

study 

Ally R, et 

al. 53 

Randomized, 

double blind, 


multicenter 

• 18 years of age or 

older 

• Diagnosis of distal 

subungual or 

proximal 

onychomycosis and 

growth of 

dermatophytes in a 

mycological culture 

up to 12 weeks after 

the start of 

treatment 

• 18 to 75 years of 

age 

• Immunocompromised 

• Male or nonpregnant 

female 


esophagitis based 

on clinical 

symptoms with or 

without 

concomitant 

oropharyngeal 

candidiasis 

n=170 Terbinafine 

250mg QD 

vs. 

itraconazole 

200mg QD 

n=391 Voriconazole 

200mg bid + 

placebo or 

Day 1: 

fluconazole 

400mg + placebo, 

Day 2 onward: 

fluconazole 

200mg + placebo 

52 weeks: 

12 weeks of 

active drug; 40 

weeks of follow 

up 

recorded in the terbinafine or itraconazole groups. 

• Most common adverse events: nausea, headache, upper respiratory tract 

infection, chest infection, back pain, flu-like symptoms, bronchitis and 

fever. 

Primary Endpoints 

• Mycological cure (negative results on microscopy and culture) and 

clinical improvement (length and area of unaffected nail) at week 52 or 

at discontinuation of treatment. 

Efficacy: Terbinafine > Itraconazole 

• Mycological cure rates were 81% (70 out of 86) for terbinafine and 

63% (53 out of 84) for itraconazole (p

Oude Lashof 

AM, et al. 54 

Gupta AK, 

et al. 55 

Multicenter, 

randomized, 

comparative 

study 

Cumulative 

meta-analysis 

of 36 

(Esophageal 

candidiasis was 

confirmed by 

esophagoscopy, 

plus positive 

microscopy and 

mycological 

culture from a 

brush biopsy or 

tissue biopsy of 

esophageal 

lesions.) 


oropharyngeal 

candidiasis 

• Non-neutropenic 

cancer patients 

Dermatophyte toenail 

onychomycosis 

n=279 Fluconazole vs. 

itraconazole 

- Terbinafine, 

itraconazole, 

fluconazole, and 

• Of the patients treated with voriconazole, 94.8% (n=108) exhibited 

endoscopically proven cure, compared with 90.1% (n=127) in the 

fluconazole group. 

• Voriconazole (200mg BID) is at least as effective as fluconazole 

(200mg QD) in the treatment of microbiologically and histologically 

proven esophageal candidiasis in immunocompromised patients, 

including those with severe AIDS and a baseline CD4 count of 3 times the upper limit of the normal range in aspartate 

transaminase (20% vs. 8%), alanine transaminase (11% vs. 7%) and 

alkaline phosphatase (10% vs. 8%) were more frequently observed in 

the voriconazole group than in the fluconazole group. 

• Seven patients (3.5%) in the voriconazole group and 2 patients (1.1%) 

taking fluconazole discontinued because of lab abnormalities. 

- In evaluating the efficacy, safety, and tolerance of fluconazole and itraconazole in 

patients with oropharyngeal candidiasis: 

• The clinical cure rate was 74% for fluconazole and 62% for 

itraconazole (p=0.04, 95% Confidence Interval (CI): 0.5-23.3%). 

• The mycological cure rate was 80% for fluconazole and 68% for 

itraconazole (p=0.03, 95% CI: 1.2-22.6%). 

• The safety and tolerance profile of both drugs were comparable. 

• Summary: In patients with cancer and oropharyngeal candidiasis, 

fluconazole has a significantly better clinical and mycological cure rate 

All studies 

included in the 

meta-analysis 

compared with itraconazole. 

In reviewing the relevant studies with the oral antifungals for the treatment of 

onychomycosis: 

• The change in efficacy of mycological cure rates from the first trial to 

75

Marr KA, et 

al. 56 

Shikanai- 

Yasuda MA, 

et al. 57 

randomized 

controlled 

trials 

Randomized 

trial 

Randomized 

trial 

Patients receiving 

allogeneic stem cell 

transplants. 

Patients with active 

paracoccidioidomycosis 

griseofulvin 


400mg/day 

vs. 

itraconazole oral 

solution 2.5mg/kg 

TID vs. 

intravenous 

itraconazole 

200mg QD 

n=28 Itraconazole 50- 

100mg day, 

ketoconazole 

200-400 mg day, 

or 

sulfadiazine 100- 

had to include 

standard dosing, 

duration and 

follow-up 

180 days post 

stem cell 

transplant, or 

until 4 weeks 

after 

discontinuation 

of graft-versushost 

disease 

therapy 

the overall cumulative meta-average for each drug comparator is as 

follows (with 95% confidence interval): terbinafine, 78 +/- 6% (n = 2 

studies, 79 patients) to 76 +/- 3% (n = 18 studies, 993 patients) (p = 

0.68); itraconazole pulse, 75 +/- 10% (n = 1 study, 20 patients) to 63 

+/- 7% (n = 6 studies, 318 patients) (p = 0.25); itraconazole 

continuous, 63 +/- 5% (n = 1 study, 84 patients) to 59 +/- 5% (n = 7 

studies, 1131 patients) (p = 0.47); fluconazole, 53 +/- 6% (n = 1 study, 

72 patients) to 48 +/- 5% (n = 3 studies, 131 patients) (P = 0.50); and 

griseofulvin, 55 +/- 8% (n = 2 studies, 109 patients) to 60 +/- 6% (n = 

3 studies, 167 patients) (p = 0.41). 

• The cumulative meta-analytical average of mycological cure rates 

when comparing RCTs vs. open studies was: terbinafine, 76 +/- 3% (n 

= 18 studies, 993 patients) vs. 83 +/- 12% (n = 2 studies, 391 patients) 

(p = 0.0028); itraconazole pulse, 63 +/- 7% (n = 6 studies, 318 

patients) vs. 84 +/- 9% (n = 3 studies, 194 patients) (p = 0.0001); and 

fluconazole, 48 +/- 5% (n = 3 studies, 131 patients) vs. 79 +/- 3% (n = 

3 studies, 208 patients) (p = 0.0001). 

In evaluating fluconazole and itraconazole in the prevention of invasive mold 

infections: 

• More patients in the itraconazole arm developed hepatotoxicities, and 

more patients were discontinued from itraconazole because of 

toxicities or gastrointestinal (GI) intolerance (36% versus 16%, p 

Bhogal CS, 

et al. 58 

Shang H, et 

al. 59 

Bernhardt J, 

et al. 60 

Randomized 

trial 

Double blind, 

randomized, 

multi-center 

study 

In vitro 

efficacy of 

voriconazole 

and 

fluconazole on 

multilayered 

esophageal 

epithelium 


moderate to 

extensive pityriasis 

versicolor 

• Confirmation of the 

disease by KOH and 

Wood’s lamp 

examination 

Patients with deep and 

shallow fungal infections 

• Esophageal 

epithelium was 

infected with 

Candida albicans 

(SC5314) 

• The fluconazole 

group was also 

exposed to other 

clinical strains of 

150mg/kg/day up 

to 6grams/day 

n=180 Ketoconazole 

200mg QD 

(Category II) x 10 

days, 

ketoconazole 

400mg single 

dose (Category I), 

fluconazole 

400mg single 

dose (Category 

III), or 

fluconazole 

150mg per week 

for 4 weeks 

(Category IV) 

Follow-up was 

done at 2 and 4 

weeks, and then 

at 3, 6, and 12 

months after 

treatment 

n=222 Fluconazole 200-400mg QD x 1-8 

weeks, fluconazole 150mg single 

dose, ketoconazole 400mg QD for 1- 

8 weeks for fungal disease and 5 

days in patients with fungal vaginitis 

- Fluconazole 

vs. 

voriconazole 

Voriconazole 

• The test of the hypothesis that the drugs reduced antibody levels up to 

ten months of treatment showed a p value of p=0.0001 for itraconazole, 

0.017 for ketoconazole, and 0.0012 for sulfadiazine, a reduction that 

was similar for each group. 

• Summary: This study did not show superiority of any one regimen 

over the others in the clinical and serological responses of patients with 

moderately severe disease. 

In evaluating single vs. multiple doses of ketoconazole and fluconazole for the 

treatment of pityriasis versicolor: 

• After four weeks of treatment, clinical cure was observed in 66.6% 

(Category I), 73.3% (Category II), 80% (Category III) and 59.9% 

(Category IV) of patients. 

• Mycological cure after four weeks of treatment was observed in 53.3% 

(Category I), 73.3% (Category II), 82.2% (Category III) and 64.4% 

(Category IV) of patients. 

• After twelve months of follow-up, maximum relapses were observed 

with Category I. No relapse was seen in Category III patients. The time 

period of relapse varied from three to ten months. 

• Summary: Single dose 400 mg oral fluconazole provides the best 

clinical as well as mycological cure rate with no relapse during twelve 

months of follow-up. 

In comparing the cure and eradication rates of fluconazole vs. ketoconazole in the 

treatment of various fungal infections: 

• The cure rate in the fluconazole group was 81.3% (52/64), while the 

cure rate in group B was 58% (35/60) (p0.05). 

• There were mild and transient vomiting, nausea, and anorexia in the 

study. In the ketoconazole group, there was one case of ALT elevation 

in each group (p

Lipozencic Double blind, 

J, et al. 61 randomized, 

parallel-group, 

multi-center, 

durationfinding 

study 

Candida. distinct. Fluconazole was more effective against clinical strains of C. 

albicans than against the type strain. 

Griseofulvin 

Pediatric patients with 

tinea capitis 

n=134 Terbinafine for either 6, 8, 10, or 12 

weeks, vs. 12 weeks of high-dose 

griseofulvin 

In evaluating the efficacy of terbinafine vs. high-dose griseofulvin for 

tinea capitis: 

• Effective treatment was observed at the end of the study in 62% of 

patients treated with terbinafine for six weeks and in 63% treated for 8 

weeks. Mycological cure was obtained in 59% and 57%, respectively, 

and clinical cure in 76% and 80%. 

• In the griseofulvin group, effective treatment was 88%, mycological 

cure was 76% and clinical cure 96%. However, these high rates were 

believed to be due to the high dosage of this drug and the prolonged 

course of treatment. 

• Complete cure was observed at the end of study in 62% patients 

treated with terbinafine for 6 weeks, in 60% treated for 8 weeks and in 

84% patients treated with griseofulvin for 12 weeks. 

Wingfield 

AB, et al. 62 

Randomized 

trial 

• Age 12-76 

• Diagnosis of tinea 

imbricata 

Miscellaneous 

n=59 Griseofulvin 500mg BID for 4 

weeks, terbinafine 250mg QD for 4 

weeks, itraconazole 200mg BID for 1 

week, or fluconazole 200mg once 

weekly for 4 weeks 

In evaluating the efficacy of griseofulvin, terbinafine, itraconazole, and 

fluconazole in the treatment of tinea imbricata: 

• Significant remission was achieved in the terbinafine and griseofulvin 

groups, lasting up to eight weeks after cessation of therapy. 

• The fluconazole group experienced no significant remission, and 

remission was of short duration in the itraconazole group. 

• No adverse events were reported, and non-compliance with 

medications or follow-up was the only reason for removal from the 

study. 

• Summary: Griseofulvin and terbinafine are effective in the treatment 

of TI. The decision of whether to treat at all and which medication to 

choose depends greatly on the extent of involvement, the social 

situation, and the availability of resources such as laboratory testing 

and follow-up. 

78

Gupta AK, 

et al. 63 

Pfaller MA, 

et al. 64 

Prospective, 

comparative, 

single-blinded, 

randomized, 

parallel-group 

study 

Susceptibility 

testing of 

isolates of 

Candida 

glabrata by 

geographical 

location 

Moderate to severe 

onychomycosis of the 

toenails caused by S. 

brevicaulis 

601 invasive isolates of 

Candida glabrata 

n=59 Griseofulvin 600mg BID for 12 

months, ketoconazole 200mg QD for 

4 months, itraconazole pulse for 3 

pulses with each pulse at a dose of 

200mg BID for 1 week with 3 weeks 

off between pulses, fluconazole 

150mg QD for 12 weeks, or 

terbinafine 250mg QD for 12 weeks 

- Amphotericin B, 

flucytosine, 

fluconazole, 

voriconazole, and 

caspofungin 

In comparing the efficacy and tolerability of 5 different oral antifungal agents in 

the treatment of S. brevicaulis onychomycosis: 

• At month 12 after the start of treatment, the response was: 

griseofulvin, CC 3/11, MC 0/11, CC + MC 0/11; ketoconazole, CC 

10/12, MC 8/12, CC + MC 8/12; itraconazole, CC 12/12, MC 12/12, 

CC + MC 12/12; terbinafine, CC 12/12, MC 11/12, CC + MC 11/12, 

and fluconazole, CC 8/12, MC 8/12, CC + MC 8/12. CC is clinical 

cure and MC is mycological cure. 

• Adverse effects consisted of: griseofulvin, gastro-intestinal symptoms, 

allergic reaction, photodermatitis, hepatic and renal dysfunction in 11 

patients with discontinuation of treatment in three patients; 

ketoconazole, hepatic dysfunction but no symptomatic changes in two 

patients; itraconazole, nausea and vomiting in two patients; 

terbinafine, taste disturbance in two patients, nausea in three patients, 

and fluconazole, severe gastro-intestinal events in five patients. None 

of the patients receiving ketoconazole, itraconazole, terbinafine or 

fluconazole discontinued treatment. 

• Summary: Itraconazole and terbinafine demonstrate efficacy against 

some cases of S. brevicaulis toe onychomycosis. These agents also 

appear to be safe in the course of therapy for toe onychomycosis. 

Griseofulvin is ineffective against toe onychomycosis caused by S. 

brevicaulis. Ketoconazole is not recommended for toe onychomycosis 

given its potential for adverse effects, particularly with the availability 

of the newer antifungal agents. 

- In evaluating the susceptibilities of 601 invasive isolates of Candida glabrata to 5 

antifungal agents: 

• Caspofungin (MIC at which 90% of isolates tested are susceptible 

[MIC(90)], 0.12 microg/ml; 100% of strains are susceptible [S] at a 

MIC of

Silling, et 

al. 65 

Prospective 

study 

Patients with neutropenia 

secondary to 

hematological 

malignancies 


vs. 


plus flucytosine 

If no response 

to fluconazole 

after day 7, 

patients were 

switched to the 

amphotericin 

B/flucytosine 

group 

In comparing the efficacy and tolerability of fluconazole (FCA) to that of 

amphotericin B plus flucytosine (ABF) in neutropenic patients: 

• Overall in 44/51 (86.2%) of the fluconazole and 37/47 (78.8%) of the 

amphotericin B/flucytosine group defervescence was observed. 

• 46 patients (21 FCA, 25 ABF) developed radiological signs of 

pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 

20/25 ABF patients, and another 10 of 15 initially not responding 

patients showed regression when switched to ABF, 5 of these had 

highly suspected aspergillosis. 

• Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. 

• Summary: Fluconazole and amphotericin B/flucytosine seem to be 

equally effective. In view of its lower toxicity fluconazole may be 

preferred as first line empiric antifungal agent, but in case of 

nonresponse, pneumonia or aspergillosis it may be replaced by 

amphotericin B combined with flucytosine. 

80


Dose Simplification: A majority of the antifungals in this class are dosed once or twice daily. 

The exceptions to this include flucytosine (Q6 hours) and nystatin (Q6-Q8 hours). Additionally, 

antifungals are indicated primarily for acute use and are routinely not continued as maintenance 

therapy. Injectable antifungal therapies are routinely given to hospitalized or skilled nursing 

patients with more severe disease, who are under direct supervision. 

Although no studies were found in a literature search of Medline or Ovid that specifically looked 

at compliance with antifungal therapies, one study reported one of the biggest problems associated 

with the treatment of onychomycosis with oral antifungal agents is compliance with long-term 

therapy. 66 

Stable Therapy: Patients started on one of the antifungals in this class should continue on that 

drug until completion of the course of therapy, unless the patient does not respond to the therapy 

or is intolerant due to adverse events. Choice of treatment should also coincide with identification 

of the fungus and susceptibility testing of the organism. Antifungal resistance should also be a 

consideration. Because antifungal therapy is acute and continuation is determined by positive 

response, switching between antifungal agents is directly related to treatment failure and drug 

intolerance. 

To evaluate antifungal drug resistance, 1,143 cases of Candida bloodstream infections were 

identified in the Baltimore, Maryland and Connecticut areas. 67 Candida albicans comprised 45% 

of the isolates, followed by C. glabrata (24%), C. parapsilosis (13%), and C. tropicalis (12%). 

Only 1.2% of C. albicans isolates were resistant to fluconazole (MIC, > or = 64 microg/ml), 

compared to 7% of C. glabrata isolates and 6% of C. tropicalis isolates. Only 0.9% of C. albicans 

isolates were resistant to itraconazole (MIC, > or = 1 micro g/ml), compared to 19.5% of C. 

glabrata isolates and 6% of C. tropicalis isolates. Only 4.3% of C. albicans isolates were resistant 

to flucytosine (MIC, > or = 32 microg/ml), compared to < 1% of C. parapsilosis and C. tropicalis 

isolates and no C. glabrata isolates. Another study evaluated the prevalence and fluconazole 

susceptibility of Candida species in healthcare workers and non-healthcare workers and found that 

there was no significant difference in prevalence or species of oropharyngeal Candida and 

fluconazole resistance was infrequent. 68 

The mechanism of fluconazole resistance to C. glabrata appears to involve cellular resistance and 

increased drug efflux as measured by decreased accumulation of fluconazole and increased 

abundance of transcripts from two drug transporters. 69 

One case report presented data of a successful treatment of fluconazole resistant Candida with the 

combination of fluconazole plus flucytosine. 70 The addition of flucytosine to the treatment 

regimen in this case showed an additive interaction of fluconazole and flucytosine. 

A study evaluated the in vitro activities of multiple antifungal therapies against non-albicans 

bloodstream yeast infections. 71 For amphotericin B, the end-point was defined as the minimal 

antifungal concentration that exerts 90% inhibition compared with the control well growth. For 

the azoles, the end-points were determined at 50% inhibition of growth. Amphotericin B is highly 

active with 97% of isolates inhibited by < or =1 microg ml(-1). Decreased susceptibility or 

resistance to fluconazole was the rule among C. krusei, which is intrinsically resistant to 

fluconazole. For C. glabrata isolates, resistance to fluconazole and itraconazole was measured in 

13% and 17% of the isolates respectively. Voriconazole was quite active in vitro against all the 

isolates with a MIC90% of < or =1 microg ml(-1). 

Multiple clinical studies support use of the lipid amphotericin B formulations after a trial of 

conventional amphotericin B, largely due to differences from significantly higher renal toxicity 

with conventional amphotericin B. One study suggested amphotericin B is more effective than 

fluconazole in candidemias caused by some non-albicans Candida species. 39 Additionally, 

caspofungin has been shown to be effective in patients refractory to other antifungal therapy, and 

in combination with other antifungals. Voriconazole is an oral option that may also be used in 

combination with other antifungal treatments.

Impact on Physician Visits: Multiple pharmacoeconomic studies have looked at the treatments 

for onychomycosis. However, data is reported in terms of cost-savings, not in physician visits, 

and therefore cannot be included in this review. This section is not relevant to the injectable 

medications likely given during hospitalizations. No further data was found in a literature search 

of Medline and Ovid pertaining to antifungal use and physician visits. 

IX. 

Conclusions 

1) The lipid amphotericin B formulations are indicated for use for various fungal infections and in 

most cases, when renal toxicities/impairment or adverse events preclude the use of conventional 

amphotericin B. Conventional amphotericin B is available in a generic formulation, while there is 

not a generic lipid amphotericin formulation available. While studies have shown little differences 

in efficacy between the lipid-based formulations and conventional amphotericin B, limited clinical 

studies have directly compared the lipid amphotericin B agents. Clinical evidence that is available 

indicates the lipid amphotericin B agents are comparatively effective for the treatment of 

suspected or documented fungal infections. The amphotericin B agents offer benefits to patients 

with life-threatening fungal infections. As a result, there is not a role for these agents in general 

use. Because of the limited use in outpatient treatment, the amphotericin B agents should be 

available for special needs/circumstances that require medical authorization through the prior 

authorization process. Therefore, the brand amphotericin B agents within the class reviewed are 

comparable to each other and to the generics in the class and offer no significant advantage over 

other alternatives in general use. 

2) Some clinical comparative data is available for the other antifungals in this class, focusing on 

comparative studies for specific indications. Clinical evidence suggests greater efficacy 

(mycological cure) of terbinafine compared with itraconazole in the treatment of onychomycosis. 

However, treatment of onychomycosis is cosmetic in most cases, and therapy should be reserved 

for patients who are predisposed to foot complications (e.g. patients with diabetes). This will 

allow patients who medically need these agents, to receive them. As a result, there is not a role for 

the antifungal oncyomycosis agents in general use. Additionally, the following antifungal agents 

are available in a generic formulation: fluconazole (oral and IV), ketoconazole, nystatin, and 

griseofulvin (ultramicrosize). Therefore, all brand products within the class reviewed are 

comparable to each other and to the generics in the class and offer no significant clinical 

advantage over other alternatives in general use. 

3) The remaining agents, caspofungin, flucytosine, IV itraconazole, and voriconazole have 

indications for serious, invasive infections, and use of voriconazole and caspofungin is indicated 

in those whose disease is refractory to, or who are intolerant to, other therapies. In life-threatening 

illness, combinations of these anti-fungals and other antifungals already mentioned may be used. 

As caspofungin and voriconazole are newer agents, little direct comparative efficacy data is 

available to evaluate their use. These drugs should be made available with medical justification 

through the prior authorization process. Therefore, the brands of caspofungin, flucytosine, IV 

itraconazole and voriconazole are comparable to each other and to the generics and OTC products 

in this class and offer no significant clinical advantage over other alternatives in general use. 


No brand antifungal is recommended for preferred status. 

82

References 

1. Merck & Co. Introduction to medical mycology. Whitehouse Station, New Jersey: North Wales 

Press, Inc; 2001. 

2. Pfizer. Diflucan® (fluconazole) prescribing information. New York (NY): 1998. 

3. Janssen Pharmaceutica, Inc. Sporanox® (itraconazole) prescribing information. Titusville (NJ): 

2002. 

4. Janssen Pharmaceutica, Inc. Nizoral® (ketoconazole) prescribing information. Titusville (NJ): 

1998. 

5. Novartis. Lamisil® (terbinafine) prescribing information. East Hanover (NJ): 2001. 

6. Pfizer. Vfend® (voriconazole) prescribing information. New York (NY): 2002. 

7. Clinical Pharmacology 2000. [cited 2002 Oct 9] http://cpip.gsm.com/2002. 

8. Lacey CF, Armstrong LL, Goldman MP, Lance LL. Drug information handbook. Hudson, Ohio: 

Lexi-Comp, Inc; 2001. 

9. Dismukes W. Introduction to antifungal drugs. Clin Infect Dis 2000;3: 653-657. 

10. Sobel JD for the mycoses study group. Practice guidelines for the treatment of fungal infections. 

Clin Infect Dis 2000; 30:652. 

11. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guidelines for the treatment of 

coccidioidomycosis. Clin Infect Dis 2000;30: 658-61. 

12. Kauffman CA, Hajjeh R & Chapman W. Practice guidelines for the management of patients with 

sporotrichosis. Clin Infect Dis 2000;30 684-87. 

13. Wheat J, Sarosi G, McKinsey D et al. Practice guidelines for the management of patients with 

histoplasmosis. Clin Infect Dis 2000;30: 688-95. 

14. Chapman SW, Bradsher RW, Campbell D et al. Practice guidelines for the management of 

patients with blastomycosis. Clin Infect Dis 2000;30: 679-83. 

15. Saag MS, Graybill RG, Larsen RA et al. Practice guidelines for the management of cryptococcal 

disease. Clin Infect Dis 2000;30: 710-18. 

16. Stevens DA, Kan VL, Judson MA et al. Practice guidelines for diseases caused by aspergillus. 

Clin Infect Dis 2000;30: 696-709. 

17. Rex JH, Walsh TJ, Sobel JD et al. Practice guidelines for the treatment of candidiasis. Clin Infect 

Dis 2000;30: 662-78. 

18. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis Jan 

15 2004;38(2):161-89. 

19. Pappas PG, Rex JH, sobel JD, et al. National Guideline Clearinghouse. Guidelines for the 

treatment of candidiasis. Available at: www.guideline.gov. Accessed July 26, 2004. 

20. Rodgers P, Bassler M. Treating Onychomycosis. Am Fam Physician Feb 15 2001;63(4):663-672. 

21. University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program. 

Recommendations for the management of onychomycosis in adults. Austin (TX):University of 

Texas at Austin, School of Nursing; May 16 2003: 16. 

22. University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program. National 

Guideline Clearinghouse. Recommendations for the management of onychomycosis in adults. 

Available at: www.guideline.gov. Accessed July 26, 2004. 






26. Bellman R, Egger P, Wiedermann CJ. Differences in pharmacokinetics of amphotericin B lipid 

formulations despite clinical equivalence. Clin Inf Dis 2003;36:1500-1501. 

27. Dupont B. Overview of the lipid formulations of amphotericin B. J Antimicrob Chemother 2002 

Feb;49 Suppl 1:31-6. 


29. Rosemurgy AS, Markowsky S, Goode SE, et al. Bioavailability of fluconazole in surgical 

intensive care unit patients: a study comparing routes of administration. J Trauma 

1995;39(3):445-447. 

30. Nicolau DP, Crowe H, Nightingale CH, et al. Bioavailability of fluconazole administered via a 

feeding tube in intensive care patients. J Antimicrob Chemother 1995;36(2):395-401. 

83

31. Pelz RK, Lipsett PA, Swoboda SM, et al. Enteral fluconazole is well absorbed in critically ill 

surgical patients. Surgery 2002;131:534-540. 

32. Buijk SLC, Gyssens IC, Mouton JW, et al. Pharmacokinetics of sequential intravenous and 

enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised 

gastro-intestinal function. Intensive Care Med;27:115-121. 

33. Tosti A, Piraccini BM, Iorizzo M, et al. Management of onychomycosis in children. Dermatol 

Clin 2003;21(3):507-509. 

34. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical 

efficacy and toxicities. Clin Infect Dis 1998 Sep;27(3):603-18. 

35. Miller CB, Waller EK, Klingemann HG, et al. Lipid formulations of amphotericin B preserve and 

stabilize renal function in HSCT recipients. Bone Marrow Transplant 2004 Mar;33(5):543-8. 

36. Fleming RV, Kantarjian HM, Husni R, et al. Comparison of amphotericin B lipid complex 

(ABLC) vs. AmBisome in the treatment of suspected or documented fungal infections in patients 

with leukemia. Leuk Lymphoma 2001 Feb;40(5-6):511-20. 

37. Cagnoni PJ. Liposomal amphotericin B versus conventional amphotericin B in the empirical 

treatment of persistently febrile neutropenic patients. Antimicrob chemother 2002 Feb;49 Suppl 

1:81-6. 

38. Subira M, Martino R, Gomez L, et al. Low-dose amphotericin B lipid complex vs. conventional 

amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic 

malignancies—a randomized, controlled trial. Eur J Haematol 2004 May;72(5):342-7. 

39. Kontoyiannis DP, Bodey GP, Mantzoros CS. Fluconazole vs. amphotericin B for the management 

of candidaemia in adults: a meta-analysis. Mycoses 2001:44(5):125-35. 

40. Johansen HK, Gotzsche PC. Amphotericin B versus fluconazole for controlling fungal infections 

in neutropenic cancer patients. Cochrane Database Syst Rev. 2002 (2):CD000239. 

41. Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of 

amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis 

in immunocompromised patients. Clin Infect Dis 2002 Aug 15;35(4):359-66. 

42. Barrett JP, Vardulaki KA, Conlon C, et al. A systematic review of the antifungal effectiveness 

and tolerability of amphotericin B formulations. Clin Ther 2003 May;25(50:1295-320. 

43. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial 

evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the 

empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin 

Infect Dis 2000 Nov;31(5):1155-63. 

44. Clark AD, McKendrick S, Tansey PJ, et al. A comparative analysis of lipid-complexed and 

liposomal amphotericin B preparations in haematological oncology. Br J Haematol 1998 

Oct;103(1):198-204. 

45. Linder N, Klinger G, Shalit I, et al. Treatment of candidaemia in premature infants: comparison 

of three amphotericin B preparations. J Antimicrob Chemother 2003 Oct;52(4):663-7. 

46. Kartsonis NA, Saah A, Lipka CJ, et al. Second-line therapy with caspofungin for mucosal or 

invasive candidiasis: results from the caspofungin compassionate-use study. J Antimicrob 

Chemother 2004 May;53(5):878-81. 

47. Cesaro S, Toffolutti T, Messina C, et al. Safety and efficacy of caspofungin and liposomal 

amphotericin B, followed by voriconazole in young patients affected by refractory invasive 

mycosis. Eur J Haematol 2004 Jul;73(1):50-5. 

48. Cololbo AL, Perfect J, DiNubile M, et al. Global distribution and outcomes for Candida species 

causing invasive candidiasis: results from an international randomized double-blind study of 

caspofungin versus amphotericin B for the treatment of invasive candidiasis. Eur J Clin Microbiol 

Infect Dis 2003 Aug;22(8):470-4. 

49. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for 

invasive candidiasis. N Engl J Med 2002 Dec 19;347(25):2020-9. 

50. Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole and itraconazole for 

progressive, nonmeningeal coccidioidomycosis. A randomized, double blind trial. Mycoses study 

group. Ann Intern Med 2000;133(9): 676-86. 

51. Evans EGV, Sigurgeirsson B for the LION study group. Double blind, randomized study of 

continuous terbinafine compared with intermittent itraconazole in treatment of toenail 

onychomycosis. British Medical Journal 1999;318: 1031-1035. 

84

52. Brautigam M, Nolting S, Schopf RE, Weidinger G. Randomized double blind comparison of 

terbinafine and itraconazole for treatment of toenail tinea infection. British Medical Journal 

1995;311: 919-922. 

53. Ally R, Schurmann D, Kreisel W, et al. A randomized, double blind, double-dummy, multicenter 

trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in 

immunocompromised patients. Clin Infect Dis 2001;33(9): 1447-54. 

54. Oude Lashof AM, De Bock R, Herbrecht R, et al. An open multicenter comparative study of the 

efficacy, safety, and tolerance of fluconazole and itraconazole in the treatment of cancer patients 

with oropharyngeal candidiasis. Eur J Cancer 2004 Jun;40(9):1314-9. 

55. Gupta AK, Ryder JE, Johnson AM, et al. Cumulative meta-analysis of systemic antifungal agents 

for the treatment of onychomycosis. Br J Dermatol 2004 Mar;150(3):537-44. 

56. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal 

infections in patients receiving allogeneic stem cell transplants. Blood 2004 Feb 15;103(4):1527- 

33. 

57. Shikanai-Yasuda MA, Benard G, Higaki Y, et al. Randomized trial with itraconazole, 

ketoconazole and sulfadiazine in paracoccidioidomycosis. Med Mycol 2002 Aug;40(4):411-7. 

58. Bhogal CS, Singal A, Baruah MC. Comparative efficacy of ketoconazole and fluconazole in the 

treatment of pityriasis versicolor: a one-year follow-up study. J Dermatol 2001 Oct;28(10):535-9. 

59. Shang H, Lu Y, Liang D. Fluconazole versus ketoconazole in systemic fungal infection: a 

double-blind randomized study. Zhonghua Nei Ke Za Zhi 1997 May;36(5):317-20. 

60. Bernhardt J, Bernhardt H, Knoke M, et al. Influence of voriconazole and fluconazole on 

reconstituted multilayered esophageal epithelium infected by Candida albicans. Mycoses 2004 

Aug;47(7):330-7. 

61. Lipozencic J, Skerlev M, Orofino-Costa R, et al. A randomized, double-blind, parallel-group, 

duration-finding study of oral terbinafine and open-label, high-dose griseofulvin in children with 

tinea capitis due to Microsporum species. Br J Dermatol 2002 May;146(5):816-23. 

62. Wingfield AB, Fernandez-Obregon AC, Wignall FS, et al. Treatment of tinea imbricata: a 

randomized clinical trial using griseofulvin, terbinafine, itraconazole, and fluconazole. Br J 

Dermatol 2004 Jan;150(1):119-26. 

63. Gupta AK, Gregurek-Novak T. Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin, 

and ketoconazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the 

toes. Dermatology 2001:202(3):235-8. 

64. Pfaller MA, Messer SA, Boyken L, et al. Geographic variation in the susceptibilities of invasive 

isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment 

from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin 

Microbiol 2004 Jul;42(7):3142-6. 

65. Silling G, Fegeler W, Roos N, et al. Early empiric antifungal therapy of infections in neutropenic 

patients comparing fluconazole with amphotericin B/flucytosine. Mycoses 1999;42 Suppl 2:101- 

4. 

66. Iozumi K, Hattori N, Adachi M, et al. Long-term follow-up study of onychomycosis: cure rate 

and dropout rate with oral antifungal treatments. J Dermatol 2001 Mar;28(3):128-36. 

67. Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida 

species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based 

active surveillance program. J Clin Microbiol 2004 Apr;42(4):1519-27. 

68. Klein JD, Levin S. Prevalence of fluconazole susceptibility of Candida species recovered from the 

oropharynx of healthcare workers and non healthcare workers. Infect Control Hosp Epidemiol 

2004 Apr;25(4):352-4. 

69. Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida 

glabrata during prophylaxis. Antimicrob Agents Chemother 2004 May;48(5):1773-7. 

70. Girmenia C, Venditti M, Martino P, et al. Fluconazole in combination with flucytosine in the 

treatment of fluconazole-resistant Candida infections. Diagn Microbiol Infect Dis 2003 

Jul;46(3):227-31. 

71. Swinne D, Watelle M, Van der Flaes M, et al. In vitro activities of voriconazole (UK-109, 496), 

fluconazole, itraconazole, and amphotericin B against 132 non-albicans bloodstream yeast isolates 

(CANARI study). Mycoses 2004 Jun;47(5-6):177-83. 

85

I. Overview 



Pharmacotherapy Review of the Cephalosporins 

AHFS 081206 


Cephalosporins are commonly used antibiotics in the ambulatory and hospital setting for both 

adults and children due to low toxicity and activity against various organisms. Twenty-five 

cephalosporins are currently available in the United States. Cephalosporins are grouped into 

"generations" according to spectrum of activity. First-generation cephalosporins are most active 

against gram-positive aerobes, while third-generation drugs are most active against gram-negative 

aerobes. 

All first generation oral cephalosporins are available as generic products. Only two of the oral 

second generation products are availably generically, cefaclor and cefuroxime. For the third 

generation oral agents, only the generic version of Vantin tablets are available. Another third 

generation cephalosporin, Suprax, was discontinued by the manufacturer. The future availability 

of Suprax is unclear. 

Based on microbiological spectrum and clinical indications, the brand name products do not offer 

additional benefit over the existing generics. Oral third generation agents are inactive against 

Enterobacter, Pseudomonas and most of the anaerobic organisms. Among the third generation 

oral agents, cefixime and ceftibuten are inactive against Staphylococci. Cefditoren is the newest 

addition to this class and has increased activity against gram-positive organisms. All of the oral 

third generation agents, except cefditoren, are available as suspensions. In clinical trials, third 

generation oral agents demonstrated marginal benefit in clinical outcomes when compared to oral 

first or second generation agents in the treatment of mild to moderate respiratory, urinary tract, 

skin and structure infections. However, third generation oral agents have improved 

microbiological eradication rates and organisms develop resistance at slower rates. This review 

encompasses all dosage forms and strengths. Table 1 lists the drugs included in this review. 

Table 1. Cephalosporins in this Review 

Generic Name Generation Formulation Example Brand Name (s) 

Cefadroxil First Tablet, Capsule, Oral Suspension Duricef* 

Cefazolin Injection Ancef*, Kefzol 

Cephalexin Tablet, Capsule, Oral Suspension Keflex*, Panixine 

Cephapirin Injection Cefadyl 

Cephradine 

Capsule, Oral Suspension, Injection 

Anspor*, Velosef* 

Cefaclor Second Tablet, Capsule, Oral Suspension Ceclor*, Ceclor CD, Raniclor 

Cefprozil Tablet, Oral Suspension Cefzil 

Cefamandole -- Mandol† 

Cefuroxime 

Tablet, Oral Suspension, Injection Ceftin*, Kefurox, Alti, Zinacef 

Cefdinir Third 

Capsule, Oral Suspension Omnicef 

Cefditoren Tablet Spectracef 

Cefepime Injection Maxipime 

Cefixime Tablet, Oral Suspension Suprax† 

Cefotaxime Injection Claforan*, Claforan Galaxy 

Cefpodoxime Tablet, Oral suspension Vantin* (tablets only generic) 

Ceftazidime Injection Ceptaz, Fortaz, Tazicef 

Ceftibuten Capsule, Oral Suspension Cedax 

Ceftizoxime Injection Cefizox 

Ceftriaxone 

Injection 

Rocephin 


†This product has been discontinued and is no longer marketed in the United States. 

86

II. 


The cephalosporins are indicated for a wide range of indications, as detailed in the following 

section. These drugs play an important role in the treatment guidelines for many infections 

diseases. Of importance are the updated (March 2004) treatment guidelines for the diagnosis and 

management of acute otitis media. The guidelines are supported by the American Academy of 

Pediatrics and American Academy of Family Physicians. 1 

The new guidelines for the treatment of otitis media, middle ear infections, and pain management 

associated with both, are based on the age of the child and other factors. Acute otitis media 

(AOM) is the most common bacterial illness in children and the one most commonly treated with 

antibiotics. 1 There has been significant increase in, and concern about antibacterial resistance of 

the organisms that cause AOM. Additionally, the number of office visits for otitis media and 

effusion (middle ear fluid, OME) have decreased over the past ten years from 25 million in 1990 

to just 16 million in 2000. However, the number of antibiotic prescriptions to treat acute otitis 

media has remained constant. 

Highlights from the updated guideline include the following recommendations: 

1) Accurately diagnose AOM and differentiate it from OME, which requires different 

management. 

2) Relieve pain, especially in the first 24 hours, with ibuprofen or acetaminophen. 

3) Minimize antibiotic side effects by giving parents of select children the option of fighting the 

infection on their own for 48-72 hours, then starting antibiotics if they do not improve. 

4) Prescribe initial antibiotics for children who are likely to benefit the most from treatment. 

5) Encourage families to prevent AOM by reducing risk factors. For babies and infants, these 

include breastfeeding for at least six months, avoiding “bottle propping,” and eliminating 

exposure to passive tobacco smoke. 

6) If antibiotic treatment is agreed upon, the clinician should prescribe amoxicillin for most 

children. 

The guidelines apply to an otherwise health child with no underlying conditions that would alter 

the natural course of AOM. These conditions include, but are not limited to, anatomic 

abnormalities such as cleft palate, genetic conditions such as Down syndrome, immune system 

disorders, and cochlear implants. Also excluded are children with a clinical recurrence of AOM 

within 30 days of AOM with underlying chronic OME. 

The following offer other considerations with the use of cephalosporins, with respect to 

indications and spectrum of activity: 

1. Only one indication, acute otitis media with effusion, has limited evidence for superior 

efficacy of one cephalosporin (cefuroxime) over another (cefaclor). 

2. Cephalexin is currently the only oral cephalosporin with FDA approval for bone infections 

caused by staphylococci or Proteus mirabilis. 

3. Cephalexin is currently the only cephalosporin with FDA approval for genitourinary tract 

infections including acute prostatitis caused by Escherichia coli, P. mirabilis and Klebsiella 

sp. 

4. Cefpodoxime is currently the only cephalosporin with FDA approval for ano-rectal infections. 

5. Cefuroxime is currently the only cephalosporin with FDA approval for Lyme disease. 

87

III. 

Comparative Indications of the Cephalosporins 

Table 2 lists the indications and organisms covered by the cephalosporin drugs. 

Table 2. Indications and Spectrum of the Cephalosporins 2-5 

Drug 

Indications 

Cefadroxil • Escherichia coli 

• impetigo 

• Klebsiella sp. 

• Moraxella catarrhalis 

• pharyngitis 

• Proteus mirabilis 

• skin and skin structure infections 

• Staphylococcus aureus (MSSA) 

• Staphylococcus epidermidis 

• Streptococcus pneumoniae 

• Streptococcus pyogenes (group A beta-hemolytic streptococci) 

• tonsillitis 

• urinary tract infection (UTI) 

Cefazolin 

Cephalexin 

• biliary tract infections 

• bone and joint infections 

• burn wound infection 

• endocarditis 

• Enterobacter sp. 

• epididymitis 

• Escherichia coli 

• Haemophilus influenzae (beta-lactamase negative) 

• Klebsiella pneumoniae 

• lower respiratory tract infections 

• pneumonia 

• prostatitis 


• Shigella sp. 




• Streptococcus agalactiae (group B streptococci) 


• surgical infection prophylaxis 











• upper respiratory tract infections 


• pneumonia 


• cystitis 






• otitis media 

•pharyngitis

Cephapirin • Respiratory tract infections (S. pneumoniae, Klebsiella species, H. 

influenzae, S. aureus, group A beta-hemolytic streptococci) 

• Skin infections (S. aureus, S. epidermidis, E. coli, P. mirabilis, 

Klebsiella species, group A beta-hemolytic streptococci) 

• Urinary tract infections (E. coli, Klebsiella species, P. mirabilis, S. 

aureus) 

• Septicemia (S. viridans, S. aureus, Klebsiella species, E. coli, group 

A beta-hemolytic streptococci) 

• Endocarditis (S. aureus, S. viridans) 

• Osteomyelitis (S. aureus, P. mirabilis, Klebsiella species, group A 

beta-hemolytic streptococci) 

Cephradine • Escherichia coli 






• pneumonia 












Cefaclor • Propionibacterium acnes 


• Providencia sp. 

• pyelonephritis 


• sinusitis 











• Bacteroides sp. 

• Citrobacter diversus 

• cystitis 



• Haemophilus influenzae (beta-lactamase positive) 




• Neisseria gonorrhoeae 


• Peptococcus sp. 

• Peptostreptococcus sp. 



• pneumonia 

89

Cefprozil 

Cefuroxime 


• Salmonella sp. 


• sinusitis 




• Staphylococcus saprophyticus 


• Streptococcus dysgalactiae 





• Vibrio sp. 

• Viridans streptococci 

• bronchitis 


• Clostridium perfringens 


• Fusobacterium sp. 









• pneumonia 

• Prevotella melaninogenica 

• Propionibacterium acnes 

• Actinomyces sp. 

• bacteremia 




• cellulitis 

• cervicitis 


• Citrobacter freundii 

• Clostridium sp. 

• Enterobacter aerogenes 


• Eubacterium sp. 


• gonorrhea 



• Haemophilus parainfluenzae 

• impetigo 



• Lactobacillus sp. 


• Lyme disease 

• meningitis 



• Neisseria meningitidis 

• osteomyelitis 



90



• pneumonia 

• proctitis 

• Propionibacterium sp. 


• Providencia stuartii 


• septicemia 


• sinusitis 









• urethritis 


• Veillonella sp. 

Cefdinir 

Cefditoren 

Cefepime 

• pneumonia 


• sinusitis 

























• pneumonia 






• Acinetobacter sp. 

• Aeromonas hydrophila 



• Citrobacter koseri 


91

• Enterobacter agglomerans 

• Enterobacter cloacae 



• febrile neutropenia 

• Gardnerella vaginalis 



• Hafnia alvei 

• intraabdominal infections 




• Morganella morganii 



• pneumonia 


• Proteus vulgaris 

• Providencia rettgeri 


• Pseudomonas aeruginosa 


• Serratia liquefaciens 

• Serratia marcescens 





• Streptococcus bovis 





• Yersinia enterocolitica 

Cefixime 

• Pasteurella multocida 


• pneumonia 

• proctitis 














• Citrobacter amalonaticus 



• gonorrhea 




• Klebsiella oxytoca 




92




Cefotaxime 

Cefpodoxime 





• Borrelia burgdorferi 


• Citrobacter sp. 


• Eikenella corrodens 

• endometritis 




• gonorrhea 

• gynecologic infections 








• Lyme disease 





• Neisseria meningitides 

• pelvic cellulitis 

• pelvic inflammatory disease (PID) 



• peritonitis 

• pneumonia 

• proctitis 


• Proteus inconstans 







• Serratia sp. 








• typhoid fever 



• ventriculitis 


• pneumonia 


93



• sinusitis 



• Staphylococcus saprophyticus 




• Streptococcus sp. 






• cystitis 


• gonorrhea 










• Peptostreptococcus magnus 


Ceftazidime 




• bronchiectasis 





• endometritis 


• Enterobacter agglomerans 




• febrile neutropenia 


• Haemophilus ducreyi 











• pelvic cellulitis 




• pneumonia 



94

Ceftibuten 

Ceftizoxime 
























• Aeromonas hydrophila 

• Bacteroides fragilis 


• Bifidobacterium sp. 




• Citrobacter sp. 

• Clostridium perfringens 


• Corynebacterium diphtheriae 







• gonorrhea 



• intraabdominal abscess 







• Moraxella sp. 










• pneumonia 




95

Ceftriaxone 

• Providencia sp. 



• Pseudomonas sp. 












• Streptococcus sp. 





• Acinetobacter calcoaceticus 



• Borrelia burgdorferi 


• chancroid 





• endocarditis 





• gonorrhea 

• gonorrhea prophylaxis 


• Haemophilus ducreyi 







• Lactobacillus sp. 












• pneumonia 

• Prevotella melaninogenica 

• proctitis 





96


















97

IV. 

Pharmacokinetic Parameters of the Cephalosporins 

The cephalosporins are usually bactericidal in action. Beta-lactam antibiotics, such as the 

penicillins and cephalosporins, bind to bacterial enzymes and inhibit mucopeptide synthesis in the 

bacterial cell wall. Table 3 lists the cephalosporin antibiotics and pharmacokinetic parameters for 

each. 

Table 3. Pharmacokinetic Parameters of the Cephalosporins 2-5 

Drug Bioavailability Protein 

Binding 

Metabolism 

Cefadroxil Completely and rapidly 20 No appreciable 

absorbed 

metabolism. 

Cefazolin Administered IV, not well 80-85% Not hepatically 

absorbed from the GI tract 

metabolized. 

Cephalexin Following a 250 or 500mg 10% Largely excreted 

oral dose of cephalexin, 

unchanged in the 

average peak serum 

urine. 

concentrations of 9 or 

15—18mcg/ml, 

respectively, are achieved 

within 1 hour and mean 

serum concentrations 

decline to 1.6 or 

3.4mcg/ml, respectively, 

at 3 hours post-dose. 

Active 

Metabolites 

Elimination Half-Life 

- 90% excreted 1-2 hours 

unchanged in urine. 

- Largely excreted 1-2 hours 


- Renal 1 hour 

Cephapirin - 44-50 - - 70% recovered 


Cephradine Rapidly and almost 8-17% >90% of absorbed - >90 of drug excreted 

completely absorbed from 

drug is excreted 


the GI tract. 


Cefaclor 

Readily absorbed from the 

GI tract. 

urine. 

25% Largely excreted 


urine. 

Cefprozil Readily absorbed from the 

GI tract. 

Cefuroxime Peak serum levels of 

cefuroxime sodium 

(parenteral) occur within 

15—60 minutes following 

an IM dose. Cefuroxime 

axetil is rapidly 

hydrolyzed in the 

intestinal mucosa, with 

37—52% of an oral dose 

reaching the systemic 

circulation as cefuroxime. 

Peak serum levels of 

cefuroxime after oral 

administration occur 

within 2 hours following 

an oral dose. 

Cefdinir 21% (300mg capsule) 60-70% Not appreciably 

16% (600mg capsule) 

metabolized. 

25% (susp.) 

Cefditoren 14% (fasting) 16% (lowfat 

88% Minimal 

meal) 

metabolism. 

Cefepime 100% of IM dose 20% 80% recovery of 

unchanged drug 8 

hours after a dose. 

- Largely excreted 


36% - - 60% excreted 


50% Largely excreted - Largely excreted 



urine. 

No 

Excretion is primarily 

renal. 

- Mainly excreted 

renally. 

- 80% excreted 


36 hours 

1.3 hours 

½-1 hour 

1.3 hours 

1-2 hours 

1.7 hours 

1.2 hours 

Cefixime 40-50% of oral dose 65% Over 10% of a - 10% excreted in bile. 3-4 hours 

2-2.3 

hours

Cefotaxime 

Cefpodoxime 

Ceftazidime 

Peak levels following 

parenteral administration 

occur within 30 minutes 

of an IM dose. 

Approximately 50% of the 

administered dose of 

cefpodoxime proxetil is 

absorbed systemically. 

Administered parenterally; 

not absorbed from the GI 

dose is excreted in 

bile. 

30-40% Metabolized 

hepatically. 

22-33% Minimal 

metabolism. 

tract. 

Ceftibuten 80% relative 65% Minimal 

metabolism. 

Ceftizoxime 

Ceftriaxone 

Following IM 

administration of 500mg 

or 1g of ceftizoxime, peak 

ceftizoxime serum 

concentrations of 13.7 

mcg/ml or 39 mcg/ml, 

respectively, occur within 

30—60 minutes. 

Administered parenterally; 

not absorbed from the GI 

tract. Peak serum 

concentrations of 

ceftriaxone occur within 

1.5—4 hours following an 

IM dose. 

Desacetylcefo 

taxime 

Largely excreted in 

urine. 

Drug and metabolite 

excreted in urine. 

- 29-33% excreted 


5-24% - - Largely excreted in the 

urine. 

Cisceftibuten, 

transceftibuten 

56% excreted in urine 

and 39% in feces. 

30% Not metabolized. - 80% excreted 

85-96% Small amount is 

metabolized to 

inactive 

metabolite. 


- 33-67% excreted in 

urine and feces. 

Drug: 1- 

1.5 hours. 

Metabolit 

e: 1.5-2 

hours 

3 hours 

1.5-2 

hours 

2-2.5 

hours 

1.7 hours 

5.5-11 

hours 

99

V. Drug Interactions of the Cephalosporins 

Table 4 lists drug interactions of the cephalosporin antibiotics. 

Table 4. Drug Interactions of the Cephalosporins 6 

Interacting Drug Significance Interaction Mechanism 

Amikacin Sulfate, 

Gentamicin, 

Kanamycin Sulfate, 

Neomycin 

Netilmicin Sulfate, 

Tobramycin 

2-Interaction may cause 

deterioration in a 

patient's clinical status; 

occurrence suspected, 

established or probable 

in well controlled 

Nephrotoxicity may be increased. 

Bactericidal activity against certain 

pathogens may be enhanced. 

Interaction appears more prominent 

with cephalothin and gentamicin than 

with other combinations. 

Unknown 

Anisindione, 

Dicumarol, Warfarin 

Sodium 

Ethanol 

Heparin 

Cimetidine, 

Famotidine, 

Nizatidine, Ranitidine 

Colistimethate 

studies. 







studies. 







studies. 


moderate-to-major 

effects; data are very 

limited. 




limited. 




limited. 

The anticoagulant effect of warfarin 

is increased. 

A disulfiram-like reaction manifested 

by flushing, tachycardia, 

bronchospasm, sweating, nausea and 

vomiting may occur when ethanol is 

ingested after a patient has taken a 

cephalosporin with the 

methyltetrazolethiol moiety. 

Increased risk of bleeding. 

Ranitidine decreases the 

bioavailability of certain 

cephalosporins. 

Coadministration of colistimethate 

and cephalothin sodium may increase 

the risk of renal dysfunction. 

Unknown 

Aldehyde dehydrogenase inhibition by 

methyltetrazolethiol moiety results in 

acetaldehyde accumulation. Occurrence 

and severity are unpredictable. Doseresponse 

relationships and length of 

enzyme inhibition are unknown. 

Several cephalosporins have caused 

coagulopathies. This might be additive 

with heparin. 

Unknown. Changes in gastric pH may 

affect drug absorption. 

Unknown. 

100

VI. 

Adverse Drug Events of the Cephalosporins 

Tables 5 a, b, and c compare adverse events by generation for the drugs in this class. 

Table 5a. Common Adverse Events (%) Reported for the Cephalosporins (First Generation) 

Adverse Event Cefadroxil Cefazolin Cephalexin Cephapirin Cephradine 


Information not 

Malaise 

available 


Edema 

Hypotension 

Hypertension 




Diarrhea 



Pseudomonas Colitis 



Seizures 

Fatigue 

Fever 

Headache 

Meningeal Signs 

Raised Intracranial 

Pressure 

Collapse 

Confusion 

Drowsiness 

Hepatic 


Hepatitis 

Jaundice 

Hepatic failure 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 


Alopecia 

Rash 

Pruritus 

a a 

a 

Hematologic 

Neutropenia 

Agranulocytosis 

a a a a 

Renal 

Abnormal kidney fxn 


Other 

Angioedema 

Nephritis 

Convulsions 

Stevens-Johnson Syndrome 

a 

a 

a- Reported, but percentages not available. 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

101

Table 5b. Common Adverse Events (%) Reported for the Cephalosporins (Second Generation) 

Adverse Event Cefaclor Cefprozil Cefuroxime 


Malaise 

a 


Edema 

Hypotension 

Hypertension 




Diarrhea 



Pseudomonas Colitis 



Fatigue 

Fever 

Headache 



Pressure 

Collapse 

Confusion 

Drowsiness 

a 

a 

a 

a 

a 

a 

1 

3.5/1 

2.5 

1 in 440 

1 in 220 

Hepatic 


Hepatitis 

Jaundice 


a a 


Alopecia 

Rash 

Pruritus 

Hematologic 

Neutropenia 

Leukopenia 


Renal 



Other 

Angioedema 

Convulsions/Seizures 

Stevens Johnson Syndrome 


a 

a 

a 

a 

a 

a 

a 

1 

a 

a 

a 

0.9 

a 

a 

a 

1 in 100 

1 in 750 

a 

a 

a 

102

Table 5c. Common Adverse Events (%) Reported for the Cephalosporins (Third Generation) 

Adverse Event Cefdinir Cefditoren Cefepime Cefixime Cefotaxime 


Malaise 

a 


Edema 

Hypotension 

Hypertension 




Diarrhea 



Pseudomonas colitis 



Fatigue 

Fever 

Headache 



Pressure 

Collapse 

Confusion 

Drowsiness 

Hepatic 


Hepatitis 

Jaundice 



Alopecia 

Rash 

Pruritus 

a 

a 

a 

0.3 

a 

a 

2 

a 

a 

a 

a 

a 

a 

a 

a 

a 

0.9 

a 

0.2 

a 

Hematologic 

Neutropenia 

Leukopenia 


a a 

Renal 



Other 

Angioedema 

Convulsions/Seizures 


a 

a 


a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

Xerostomia 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

a 

Uticaria 

a 

a 

103

Table 5c. (continued) Common Adverse Events (%) Reported for the Cephalosporins (Third Generation) 

Adverse Event Cefpodoxime Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone 


Malaise

VII. 

Dosing and Administration for the Cephalosporins 

Table 6 details dosing for the cephalosporin antibiotics. 

Table 6. Dosing for the Cephalosporins 4 


Cefadroxil Capsules: 500mg 

Tablets: 1gram 

Powder for oral 

suspension: 

125mg/5ml 

250mg/5ml 

500mg/5ml 

Cefazolin 

Cephalexin 

Powder for 

Injection: 

500mg, 1gm, 

10gm, 20gm 

Injection: 

500mg, 1gm 

Tablets/Capsules: 

250mg and 

500mg 

Oral suspension: 

125mg/5ml 

250mg/5ml 

Urinary tract infections: For uncomplicated lower urinary tract infection (e.g., cystitis), the usual 

dosage is 1 or 2 g/day in single or 2 divided doses. For all other urinary tract infections, the usual 

dosage is 2 g/day in 2 divided doses. Skin and skin structure infections: 1g/day in single or 2 

divided doses. Pharyngitis and tonsillitis: Group A B-hemolytic streptococci: 

1 g/day in single or 2 divided doses for 10 days. Urinary tract infections, skin and skin 

structure infections: 30mg/kg/day in divided doses every 12 hours. Pharyngitis, tonsillitis: 

30mg/kg/day in single or 2 divided doses. For B-hemolytic streptococcal infections, continue 

treatment for ≥10 days. Renal function impairment: Adjust dosage according to creatinine 

clearance rates to prevent drug accumulation. 

Initial adult dose: 1 g; the maintenance dose (based on creatinine clearance rate, ml/min/1.73 m 2 ) 

is 500mg at the intervals below: 

Cefadroxil Dosage in Renal Impairment 

Creatinine clearance (ml/min) 

Dosage interval (hours) 

0-10 36 

10-25 24 

25-50 12 

> 50 No adjustment 

Mild infections caused by susceptible gram-positive cocci: 250 to 500 mg every 8 hours. 

Moderate-to-severe infections: 500 mg to 1 g every 6 to 8 hours. Pneumococcal pneumonia: 

500 mg every 12 hours. Severe, life-threatening infections (e.g., endocarditis, septicemia): 

1 to 1.5 g every 6 hours. Rarely, 12 g/day have been used. Acute uncomplicated urinary tract 

infections: 1 g every 12 hours. 

Perioperative prophylaxis: Preoperative: 1 g IV or IM, 0.5 to 1 hour prior to surgery. 

Intraoperative (≥2 hours): 0.5 to 1 g IV or IM during surgery at appropriate intervals. 

Postoperative: 0.5 to 1 g IV or IM every 6 to 8 hours for 24 hours after surgery. Prophylactic 

administration may be continued for 3 to 5 days, especially where the occurrence of infection may 

be particularly devastating (e.g., open heart surgery, prosthetic arthroplasty). 

Mild-to-moderately severe infections: A total daily dosage of 25 to 50 mg/kg ( 10 to 20 mg/lb) 

in three or four equal doses. Severe infections: Total daily dosage may be increased to 100 mg/kg 

(45 mg/lb). 

Children: Do not exceed adult recommended doses. 

Mild-to-moderately severe infections: 

A total daily dosage of 25 to 50 mg/kg ( 10 to 20 mg/lb) in three or four equal doses. 

Severe infections: 

Total daily dosage may be increased to 100 mg/kg (45 mg/lb). 

Renal function impairment: 

All reduced dosage recommendations apply after an initial loading dose appropriate to the severity 

of the infection. 

Cefazolin Dosage in Renal Impairment 

Dose 

Serum creatinine 

(mg/dl) 

Ccr 

(ml/min) 

Mild-tomoderate 

infection 

(mg) 

Moderate-tosevere 

infection 

(mg) 

Dosage 

interval 

(hrs) 

≤1.5 ≥55 250 to 500 500 to 1000 6-8 

1.6-3 35-54 250 to 500 500 to 1000 ≥8 

3.1-4.5 11-34 125 to 250 250 to 500 12 

≥4.6 ≤10 125 to 250 250 to 500 18-24 

Adults: 1 to 4g/day in divided doses. Usual dose - 250mg every 6 hours. Streptococcal 

pharyngitis, skin and skin structure infections, uncomplicated cystitis in patients > 15 years - 

500mg every 12 hours. May need larger doses for more severe infections or less susceptible 

organisms. If dose is> 4g/day, use parenteral drugs. 

Children: Do not exceed adult recommended doses. 

Monohydrate: 25 to 50mg/kg/day in divided doses. For streptococcal pharyngitis in patients > 1 

year and for skin and skin structure infections, divide total daily dose and give every 12 hours. In 

severe infections, double the dose. 

Otitis media: 75 to 100mg/kg/day in 4 divided doses. 

B-hemolytic streptococcal infections: Continue treatment for at least 10 days 

105

Cephapirin 

Powder for 

injection: 

1gm 

Administered by IM or IV injection 

• Adults: 

o 

o 

o 

500mg – 1 gram every 4-6 hours IM or IV 

Serious infections: up to 12grams per day, generally by IV infusion 

Alternate dosing: 1-2g q 6 hr for 24 hr. 

In clients with impaired renal function, a dose of 7.5-15 mg/kg q 12 hr may 

be adequate. 

• Perioperative prophylaxis: 

o 

o 

Pre-op: 1-2grams IV or IM, 30 to 60 minutes pre-surgery 

Intra-operative: 1-2grams IV or IM during surgery 

Cephradine 

Cefaclor 

Capsules: 

250mg, 500mg 


125mg/5ml 

250mg/5ml 

Capsules: 

250mg, 500mg 

Extended-release 

tablets: 

375mg, 500mg 


125mg/5ml 

187mg/5ml 

250mg/5ml 

375mg/5ml 

o 

Post-operative: 1-2grams IV or IM every 6 hours for 24 hours post-op 

Children: 40-80mg/kg/day administered in 4 equal doses 

Adults: 

Skin, skin structures and respiratory tract infections (other than lobar pneumonia): 

Usual dose is 250mg every 6 hours or 500mg every 12 hours. 

For lobar pneumonia: 500mg every 6 hours or 1 g every 12 hours. 

For uncomplicated urinary tract infections: The usual dose is 500mg every 12hours. In more 

serious infections and prostatitis, 500mg every 6 hours or 1 g every 12hours. Severe or chronic 

infections may require larger doses (≤1g every 6 hours). 

Children: No adequate information is available on the efficacy of twice daily regimens in children 

< 9 months of age. For children ≥9 months, the usual dose is 25 to 50mg/kg/day, in equally divided 

doses every 6 or 12 hours. For otitis media caused by H. influenzae, 75 to 100mg/kg/day in equally 

divided doses every 6 or 12 hours is recommended; do not exceed 4 g/day. 

All patients, regardless of age and weight: Larger doses (≤1g four times/day) may be given for 

severe or chronic infections. 


Patients not on dialysis: Use the following initial dosage schedule as a guideline based on 

creatinine clearance. Further modification in the dosage schedule may be required because of 

individual variations in absorption. 

Cephradine Dosage in Renal Impairment 

Ccr (ml/min) Dose (mg) Time Interval (hours) 

> 20 500 6 

5 to 20 250 6 

< 5 250 12 

Patients on chronic, intermittent hemodialysis: 250 mg initially; repeat at 12 hours and after 36 

to 48 hours. Children may require dosage modification proportional to their weight and severity of 

infection. 

Adults: Usual dosage is 250mg every 8 hours. In severe infections or those caused by less 

susceptible organisms, dosage may be doubled. Acute bacterial exacerbations of chronic 

bronchitis: 500mg every 12 hours for 7 days. The effectiveness of the extended release tablets 

against B-lactamase producing H. influenzae has not been established. Secondary bacterial 

infection of acute bronchitis: 500mg every 12 hours for 7 days. The effectiveness of the 

extended release tablets against B-lactamase producing H. influenzae has not been established. 

Pharyngitis or tonsillitis: 375mg every 12 hours for 10 days. Uncomplicated skin and skin 

structure infections: 375mg every 12 hours for 7 to 10 days. The effectiveness of the extended 

release tablets against S. pyogenes has not been established. 

Children: Give 20mg/kg/day in divided doses every 8 hours. In more serious infections, such as 

otitis media and infections caused by less susceptible organisms, administer 40mg/kg/day, with a 

maximum dosage of 1g/day. Do not exceed adult recommended doses. 

Twice daily treatment option: 

For otitis media and pharyngitis, the total daily dosage may be divided and administered every 12 

hours. Storage / Stability: Refrigerate suspension after reconstitution; discard after 14 days. 

106

Cefprozil 

Tablets: 

250mg, 500mg 


125mg/5ml 

250mg/5ml 

Cefprozil Dosage and Duration 

Population/Infection Dosage (mg) Duration (days) 

Adults (≥13 years of age) 

Pharyngitis/Tonsillitis 500q 24 hrs 10 1 

Acute sinusitis (use higher dose for 

moderate-to-severe infections) 

Secondary bacterial infection of 

acute bronchitis and acute 

bacterial exacerbation of 

chronic bronchitis 

Uncomplicated skin and skin 

structure infections 

Children (2 to 12 years) 2 

250q 12 hrs or 

500q 12 hrs 

10 

500q 12 hrs 10 

250q 12 hrs, 

500q 24 hrs 

or 500q 12 hrs 

Pharyngitis/Tonsillitis 7.5 mg/kg q12 hrs 10 1 

Uncomplicated skin and skin 


Infants and children(6 months to 

12 years) 2 

10 

20 mg/kg q24 hrs 10 

Otitis media 15 mg/kg q12 hrs 10 

Acute sinusitis (use higher dose 

7.5 mg/kg q12 hrs or 

for moderate-to-severe infections) 

15 mg/kg q12 hrs 

1 For infections caused by S. pyogenes, administer for 10 days. 

2 Not to exceed adult recommended doses. 

10 

Cefuroxime 

Tablets: 

125mg, 250mg, 

500mg 


125mg/5ml 

250mg/5ml 

Powder for 

injection: 

750mg 


For creatinine clearance (Ccr) of 30 to 120ml/min, use standard dosage and dosing interval. For 

Ccr < 30 ml/min, use a dosage 50% of standard at the standard dosing interval. 

Oral : Tablets and suspension are NOT bioequivalent and are NOT substitutable on a mg/mg 

basis. Tablets: The tablets may be given without regard to meals. 

Dosage for Cefuroxime Axetil Tablets 

Adults (≥13 years) 

Population/Infection Dosage Duration (days) 

Pharyngitis/tonsillitis 250mg bid 10 

Acute bacterial exacerbations of chronic bronchitis 1 10 

Secondary bacterial infections of acute 

250 or 500mg bid 5-10 

bronchitis 

Uncomplicated skin and skin structure 

infections 

250 or 500mg bid 10 

Uncomplicated urinary tract infections 125 or 250mg bid 7 to 10 

Uncomplicated gonorrhea 1000mg once single dose 

Early Lyme disease 500mg bid 20 

Children who can swallow tablets whole 2 

Pharyngitis/tonsillitis 125mg bid 10 

Acute otitis media 250mg bid 10 

1 Safety and efficacy of drug administered < 10 days in patients with acute exacerbations of chronic 

bronchitis have not been established. 

2 Do not exceed adult recommended doses. 

Suspension: Must be administered with food. Shake well each time before using. The suspension 

may be administered to children ranging in age from 3 months to 12 years, according to dosages in 

the following table: 

Dosage for Cefuroxime Axetil Suspension 

Infection 

(infants and children, 

3 months to 12 years ) Dosage 

Daily maximum 

dose 

Duration 

(days) 

Pharyngitis/tonsillitis 20mg/kg/day divided bid 500 mg 10 

Acute otitis media 30mg/kg/day divided bid 1000 mg 10 

Impetigo 30mg/kg/day divided bid 1000 mg 10 

Renal function impairment: Because cefuroxime is renally eliminated, its half-life will be 

107

Cefdinir 

Capsule: 300mg 


125mg/5ml 

prolonged in patients with renal failure. 

Adults/Adolescents: The recommended dosage and duration of treatment for infections in adults 

and adolescents are described in the following chart; the total daily dose for all infections is 

600mg. Once-daily dosing for 10 days is as effective as twice-daily dosing. Once-daily dosing has 

not been studied in pneumonia or skin infections; therefore, administer twice daily in these 

infections. Capsules may be taken without regard to meals. 

Cefdinir Dosage in Adults and Adolescents (≥13 years of age) 

Type of infection Dosage Duration 

Community-acquired pneumonia 300mg q 12 hrs 10 days 

Acute exacerbations of chronic bronchitis 

Acute maxillary sinusitis 

Pharyngitis/Tonsillitis 

300mg q 12 hrs 

or 



or 



or 


10 days 

10 days 

10 days 

10 days 

5 to 10 days 

10 days 


300mg q 12 hrs 10 days 

infections 

Children (6 months through 12 years of age): 

The recommended dosage and duration of treatment for infections in pediatric patients are 

described in the following chart; the total daily dose for all infections is 14mg/kg, up to a 

maximum dose of 600mg/day. Once-daily dosing for 10 days is as effective as twice-daily dosing. 

Once-daily dosing has not been studied in skin infections; therefore, administer twice daily in this 

infection. Oral suspension may be administered without regard to meals. 

Cefdinir Dosage in Pediatric Patients (Age 6 Months Through 12 years) 

Acute bacterial otitis media 



Type of infection Dosage Duration 


infections 

7 mg/kg q 12 h 

or 

14 mg/kg q 24 h 


or 

14 mg/kg q 24 h 


or 

14 mg/kg q 24 h 

10 days 

10 days 

10 days 

10 days 

5 to 10 days 

10 days 

7 mg/kg q 12 h 10 days 

kg 

Cefdinir for Oral Suspension Pediatric Dosage Chart 

Weight 

lb 

125 mg/5 ml 

9 20 2.5 ml (½ tsp) q 12 h 

or 5 ml (1 tsp) q 24 h 

18 40 5 ml (1 tsp) q 12 h 

or 10 ml (2 tsp) q 24 h 

27 60 7.5 ml (1½ tsp) q 12 h 

or 15 ml (3 tsp) q 24 h 

36 80 10 ml (2 tsp) q 12 h 

or 20 ml (4 tsp) q 24 h 

≥43 1 95 12 ml (2½ tsp) q 12 h 

or 24 ml (5 tsp) q 24 h 

1 Pediatric patients who weigh ≥43 kg should receive the maximum daily dose of 600 mg. 


For adult patients with creatinine clearance < 30 ml/min, the dose of cefdinir should be 300 mg 

given once daily. Creatinine clearance is difficult to measure in outpatients. However, the 

following formula may be used to estimate creatinine clearance (Ccr) in adult patients. For 

estimates to be valid, serum creatinine levels should reflect steady-state levels of renal function. 

108

Cefditoren Tablets: 200mg Cefditoren Dosage and Administration 

in Adults and Adolescents ≥12 Years of Age 1 

Type of infection Dosage Duration (days) 

Acute bacterial exacerbation 400mg BID 

of chronic bronchitis 


10 

Uncomplicated skin and skin 200mg BID 


1 Take with meals. 

Renal impairment: No dose adjustment is necessary for patients with mild renal impairment(Ccr 

50 to 80mL/min/1.73 m 2 ). It is recommended that ≤200mg twice daily be administered to patients 

with moderate renal impairment (Ccr 30 to 49 mL/min/1.73 m 2 ) and 200mg every day be 

administered to patients with severe renal impairment (Ccr < 30mL/min/1.73 m 2 ). The appropriate 

dose in patients with end-stage renal disease has not been determined. 

Cefepime 

Powder for 

injection: 

500mg, 1gm, 

2gm 

Recommended Dosage Schedule for Cefepime 

Site and type of infection Dose Frequency 

Duration 

(days) 

Mild-to-moderate uncomplicated or complicated 0.5 to 1g IV/IM 2 Q12 hrs 7 to 10 

E. coli, K. pneumoniae, or P. mirabilis. 1 

urinary tract infections, including pyelonephritis, 

caused by 

Severe uncomplicated or complicated urinary tract 

2g IV Q12 hrs 10 

or K. pneumoniae. 1 

infections, including pyelonephritis, caused by E. coli 

Moderate-to-severe pneumonia caused by S. 

1 to 2g IV Q12 hrs 10 

pneumoniae, 1 Pseudomonas aeruginosa, Klebsiella 

pneumoniae, or Enterobacter sp. 

Moderate-to-severe uncomplicated skin and skin 


structure infections caused by S. aureus or S. pyogenes. 

Empiric therapy for febrile neutropenic patients. 2g IV Q8 hrs 7 3 

Complicated intra-abdominal infections (used in 

2g IV q12 hrs 7 to 10 

combination with metronidazole) caused by E. coli, 

viridans group streptococci, P. aeruginosa, K. 

pneumoniae, Enterobacter species, or B. fragilis. 

1 Including cases associated with concurrent bacteremia. 

2 IM route of administration is indicated only for mild-to-moderate, uncomplicated, or complicated UTIs 

caused by E. coli when the IM route is a more appropriate route of drug administration. 

3 Or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for > 7 

days, 

the need for continued antimicrobial therapy should be reevaluated frequently. 


In patients with impaired renal function (creatinine clearance ≤60 ml/min), adjust the dose of cefepime to 

compensate for the slower rate of renal elimination. The recommended initial dose should be the same as 

in patients with normal renal function. In patients undergoing hemodialysis, 68% of the total amount 

of 

Cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. A 

repeat dose, equivalent to the initial dose, should be given at the completion of each dialysis session. In 

elderly patients, adjust dosage and administration in the presence of renal insufficiency. In patients 

undergoing continuous ambulatory peritoneal dialysis, administer cefepime at normal recommended 

doses at a dosage interval of every 48 hours. 

Recommended Cefepime Maintenance Schedule in Patients 

with Renal Impairment 

Creatinine 

clearance 

(ml/min) 

> 60 

Recommended maintenance schedule 

500mg 

q 12 hrs 1 1g q 12 hrs 2g q 12 hrs 2g q 8 hrs 

30 to 60 500mg 1g q 24 hrs 2g q 24 hrs 2g q 12 hrs 

11 to 29 q 24 hrs 500mg q 24 hrs 1g q 24 hrs 2g q 24 hrs 

250mg 

250mg q 24 hrs 500mg q 24 hrs 1g q 24 hrs 

< 11 q 24 hrs 

1 Normal recommended dosing schedule. 

109

Cefixime 

Cefotaxime 

Powder for 

injection: 

500mg, 1gm, 

2gm 

Powder for 

injection: 

500mg, 1gm, 

2gm, 10gm 

Injection: 

1gm, 2gm 

Recommended Dosage Schedule for Cefepime 

Site and type of infection Dose Frequency 

Duration 

(days) 

Mild-to-moderate uncomplicated or complicated 

urinary tract infections, including pyelonephritis, 

caused by 

E. coli, K. pneumoniae, or P. mirabilis. 1 0.5 to 1g IV/IM 2 Q12 hrs 7 to 10 

Severe uncomplicated or complicated urinary tract 

infections, including pyelonephritis, caused by E. 

coli 

or K. pneumoniae. 1 2g IV Q12 hrs 10 

Moderate-to-severe pneumonia caused by S. 

pneumoniae, 1 Pseudomonas aeruginosa, Klebsiella 

pneumoniae, or Enterobacter sp. 

Moderate-to-severe uncomplicated skin and skin 

structure infections caused by S. aureus or S. 

pyogenes. 

1 to 2g IV Q12 hrs 10 


Empiric therapy for febrile neutropenic patients. 2g IV Q8 hrs 7 3 

Complicated intra-abdominal infections (used in 2g IV Q12 hrs 7 to 10 

combination with metronidazole) caused by E. 

coli, 

viridans group streptococci, P. aeruginosa, K. 

pneumoniae, Enterobacter species, or B. fragilis. 

1 Including cases associated with concurrent bacteremia. 

2 IM route of administration is indicated only for mild-to-moderate, uncomplicated, or complicated UTIs 

caused by E. coli when the IM route is a more appropriate route of drug administration. 

3 Or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for > 7 

days, the need for continued antimicrobial therapy should be reevaluated frequently. 

Renal function impairment: In patients with impaired renal function (creatinine clearance ≤60 

ml/min), 

adjust the dose of cefepime to compensate for the slower rate of renal elimination. The recommended 

initial dose should be the same as in patients with normal renal function. 

In patients undergoing hemodialysis, 68% of the total amount of cefepime present in the body at the 

start 

of dialysis will be removed during a 3-hour dialysis period. A repeat dose, equivalent to the initial dose, 

should be given at the completion of each dialysis session. In elderly patients, adjust dosage and 

administration in the presence of renal insufficiency. In patients undergoing continuous ambulatory 

peritoneal dialysis, administer cefepime at normal recommended doses at a dosage interval of every 48 

hours. 

Recommended Cefepime Maintenance Schedule in Patients 

with Renal Impairment 

Creatinine 

clearance 

(ml/min) 

> 60 

Recommended maintenance schedule 

500mg 

q 12 hrs 1 1g q 12 hrs 2g q 12 hrs 2g q 8 hrs 

30 to 60 500mg 1g q 24 hrs 2g q 24 hrs 2g q 12 hrs 

11 to 29 q 24 hrs 500mg q 24 hrs 1g q 24 hrs 2g q 24 hrs 

250mg 

< 11 q 24 hrs 

250mg q 24 hrs 500mg q 24 hrs 1g q 24 hrs 

1 Normal recommended dosing schedule. 

Adults: Administer IV or IM. The maximum daily dosage should not exceed 12 g. Determine dosage 

and route of administration by susceptibility of the causative organisms, severity of the infection and the 

patient's condition (see table for dosage guidelines). 

Cefotaxime Dosage Guidelines for Adults 

Daily 

Type of infection 

dosage (g) Frequency and route 

Gonococcal urethritis/cervicitis in males 

and females 0.5 0.5g IM (single dose) 

Rectal gonorrhea in females 0.5 0.5g IM (single dose) 

110

Cefpodoxime 

Ceftazidime 

Tablets: 

100mg, 200mg 

Granules for 

Suspension 

50mg/5ml 

100mg/5ml 

Powder for 

injection: 

500mg, 1gm 

2gm, 6gm 

Injection: 

1gm 

Rectal gonorrhea in males 1 1g IM (single dose) 

Uncomplicated infections 2 1g every 12 hours 

IM or IV 

Moderate-to-severe 3 to 6 1 to 2g every 8 hours 

IM or IV 

Infections commonly needing 

higher dosage (e.g., septicemia) 

6 to 8 2g every 6 to 

8 hours IV 

Life-threatening infections 12 2g every 4 hours IV 

Perioperative prophylaxis: 1 g IV or IM, 30 to 90 minutes prior to surgery. 

Cesarean section: Administer the first 1 g dose IV as soon as the umbilical cord is clamped. 

Administer the second and third doses as 1 g IV or IM at 6 and 12 hour intervals after the first dose. 

Pediatric: It is not necessary to differentiate between premature and normal gestational age infants. 

The following dosage recommendations may serve as a guide: 

Cefotaxime Dosage Guidelines in Pediatric Patients 

Age Weight (kg) Dosage schedule Route 

0 to 1 week -- 50 mg/kg every 12 hours IV 

1 to 4 weeks -- 50 mg/kg every 8 hours IV 

1 month to 12 years < 50 1 50 to 180 mg/kg/day IV or IM 

in 4 to 6 divided doses 2 

1 For children ≥50 kg, use adult dosage. Do not exceed adult recommended doses. 

2 Use higher doses for more severe or serious infections including meningitis. 

Renal function impairment: Determine dosage by degree of renal impairment, severity of 

infection and susceptibility of the causative organism. In patients with estimated creatinine clearances 

of < 20 ml/min/1.73 m 2 , reduce dosage by 50%. 

Administer tablets with food to enhance absorption. Administer oral suspension without regard to food. 

Dosage/Duration of Cefpodoxime 

Total daily 


dose 

Adults ≥13 years of age 

Dose 

frequency 

Duration 

Acute community-acquired pneumonia 400mg 200mg every 12 hrs 14 days 

Acute bacterial exacerbations of chronic bronchitis 

(tablets) 400mg 200mg every 12 hrs 10 days 

Uncomplicated gonorrhea(men and women) and 

rectal gonococcal infections (women) 200mg single dose 

Skin and skin structure 

Pharyngitis/tonsillitis 

800mg 

200mg 

400mg every 12 hrs 

100mg every 12 hrs 

7 to 14 

days 

5 to 10 

days 

Uncomplicated urinary tract infection 200mg 100mg every 12 hrs 7 days 

Children(age 5 months through 12 years): 1 

Acute otitis media 

Pharyngitis/tonsillitis 

10mg/kg/day 

(max 400 

mg/day) 

10mg/kg/day 

(max 200 

mg/day) 

10mg/kg every 24 hrs 

(max 400mg/dose)or 

5mg/kg every 12 hrs 

(max 200mg/dose) 

5mg/kg every 12hours 

(max 100 mg/dose) 

10 days 

5 to 10 

days 


Renal function impairment: For patients with severe renal impairment (creatinine clearance [Ccr]

Ceftibuten 

Capsule: 400mg 

Powder for oral 

suspension: 

90mg/5ml 

Uncomplicated pneumonia; mild skin 

and skin structure infections 

500mg to 1g IV or IM 

Q8 hrs 

Bone and joint infections 2g IV Q12 hrs 

Serious gynecological and intraabdominal 

infections 

Meningitis 

Very severe life-threatening infections, 

especially in immunocompromised 

patients 

Pseudomonal lung infections in 

cystic fibrosis patients w/normal 

renal function 1 

2g IV 

30 to 50mg/kg IV 

to a max 6g/day 

Q8 hrs 

Q8 hrs 

Neonates (0 to 4 weeks) 2 30mg/kg IV Q12 hrs 

Infants and children 

30 to 50mg/kg IV Q8 hrs 

(1 month to 12 years) 2 to 6g/day 3 

1 Although clinical improvement has been shown, bacteriological cures cannot be expected in patients 

with chronic respiratory disease and cystic fibrosis. 


3 Reserve the higher dose for immunocompromised children or children with cystic fibrosis or meningitis. 

Hepatic function impairment: No dosage adjustment is required. 

Renal function impairment: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular 

filtration. In patients with impaired renal function (GFR < 50 ml/min), reduce dosage to compensate 

for slower excretion. In patients with suspected renal insufficiency, give an initial loading dose of 1 g. 

Estimate GFR to determine the appropriate maintenance dose. 

Ceftibuten suspension must be administered ≥2 hours before or 1 hour after a meal. 

Ceftibuten Dosage and Duration 



Acute bacterial exacerbations of 

chronic bronchitis caused by 

H. influenzae, M. catarrhalis 

or Streptococcus pneumoniae 

Pharyngitis and tonsillitis caused by 

S. pyogenes 

Acute bacterial otitis media caused 

by H. influenzae, M. catarrhalis 

or S. pyogenes 

Children 1 

Pharyngitis and tonsillitis caused by S. pyogenes 

Acute bacterial otitis media caused 

by H. influenzae, M. catarrhalis 

or S. pyogenes 


Daily maximum 

dose 

Dose and 

frequency 

Duration 

400mg 400mg QD 10 days 

400mg 9mg/kg QD 10 days 

Ceftizoxime 

Powder for 

injection: 

500mg, 1gm 

2gm, 10gm 

Injection: 

1gm, 2gm 

Ceftibuten Oral Suspension 

Pediatric Dosage Chart 1 

Weight 

kg lb 90 mg/5 ml 180 mg/5 ml 

10 22 5 ml (1 tsp) QD 2.5 ml (1/2 tsp) QD 

20 44 10 ml (2 tsp) QD 5 ml (1 tsp) QD 

40 88 20 ml (4 tsp) QD 10 ml (2 tsp) QD 

1 Children > 45 kg should receive the maximum daily dose of 400 mg 

Adults: Usual dosage is 1 or 2 g every 8 to 12 hours. Individualize dosage. 

Ceftizoxime Dosage Guidelines in Adults 

Type of infection Daily dose (g) Frequency and route 

Uncomplicated urinary tract 1 500mg every 12 hours IM or IV 

PID 1 6 2g every 8 hours IV 

Other sites 2-3 1g every 8 to 12 hours IM or IV 

Severe or refractory 3-6 1g every 8 hours IM or IV 

112

Life-threatening 2 9-12 3 to 4g every 8 hours IV 

1 Dosages ≤2 g every 4 hours have been given. 

2 Divide 2 g IM doses and give in different large muscle masses. 

Urinary tract infections: Because of the serious nature of urinary tract infections caused 

by P. aeruginosa and because many strains of Pseudomonas species are only moderately 

susceptible to ceftizoxime, higher dosage is recommended. Institute other therapy if the response 

is not prompt. 

Gonorrhea, uncomplicated: 

A single 1g IM injection is the usual dose. 

Life-threatening infections: 

The IV route may be preferable for patients with bacterial septicemia, localized parenchymal abscesses 

(such as intra-abdominal abscess), peritonitis or other severe or life-threatening infections. In those 

patients with normal renal function, the IV dosage is 2 to 12 g/day. In conditions such as bacterial 

septicemia, 6 to 12 g/day IV may be given initially for several days, and the dosage gradually reduced 

according to clinical response and laboratory findings. 

Pediatric: Children (6 months): 50mg/kg every 6 to 8 hours. Dosage may be increased to 

200mg/kg/day. 

Do not exceed the maximum adult dose for serious infection. 

Renal function impairment: Requires modification of dosage. Following an initial loading dose of 

500mg 

to 1g IM or IV, use the maintenance dosing schedule in the following table. Determine further dosing by 

therapeutic monitoring, severity of the infection and susceptibility of the causative organisms. 

Ceftriaxone 

Powder for 

injection: 

250mg, 500mg, 

1gm 

2gm, 10gm 

Injection: 

1gm, 2gm 

Administer IV or IM. Continue for ≥2 days after signs and symptoms of infection have disappeared. 

Usual duration is 4 to 14 days; in complicated infections, longer therapy may be required. For 

S. pyogenes, continue for ≥10 days. 

Adults: Usual daily dose is 1 to 2g once a day (or in equally divided doses twice a day) depending 

on the type and severity of the infection. Do not exceed total daily dose of 4g. 

Uncomplicated gonococcal infections: Give a single IM dose of 250mg. 

Surgical prophylaxis: Give a single 1g dose IV 0.5 to 2 hours before surgery. 

Children: To treat serious infections other than meningitis, administer 50 to 75mg/kg/day 

(not to exceed 2 g) in divided doses every 12 hours. 

Meningitis: 100mg/kg/day (not to exceed 4g). Thereafter, a total daily dose of 100mg/kg/day 

(not to exceed 4g/day) is recommended. May give daily dose once per day or in equally divided 

doses every 12 hours. Usual duration is 7 to 14 days. 

Skin and skin structure infections: Give 50 to 75mg/kg once daily (or in equally divided doses twice 

daily), 

not to exceed 2g. 

Renal/hepatic function impairment: No dosage adjustment is necessary; however, monitor blood levels. 

In patients with both hepatic dysfunction and significant renal disease, the dose should not exceed 2g/day 

without closely monitoring serum concentrations. 

CDC recommended treatment schedules for chancroid, gonorrhea and acute pelvic inflammatory 

disease (PID) 

Chancroid (Haemophilus ducreyi infection): 250mg IM as a single dose. 

Gonococcal infections: 

Uncomplicated: 125mg IM in a single dose plus 1g azithromycin in single oral dose or 100mg 

doxycycline twice a day for 7 days. 

Conjunctivitis: 1g IM single dose. 

Disseminated: 1g IM or IV every 24 hours. 

Meningitis/Endocarditis: 1 to 2g IV every 12 hours for 10 to 14 days (meningitis) or for 4 weeks 

(endocarditis). 

Special Dosing Considerations: 

The pregnancy category is Category “B” for the cephalosporins. 7 Safety during pregnancy is not 

established. Use only when potential benefits outweigh potential hazards to the fetus. 

All cephalosporin require dosing adjustment in renal impaired patients. Reduce total daily dose in patients 

with transient or persistent reduction of urinary output caused by renal insufficiency, high and prolonged 

serum concentrations can occur in such patients from usual doses. 

113

Table 7. Special Dosing Considerations for the Cephalosporins 

Drug Pediatric Use Special consideration 

Cefadroxil Maximum dose: 2 grams/day Available in tablet, capsule, and oral suspension for 

flexible dosing/route of administration. 

Cefazolin Safety and efficacy of capsule and suspension in 

Parenteral only. 

children 

divided doses every 12 hours. 

pain of IM injections. Parenteral only. 

115

VIII. Comparative Effectiveness of the Cephalosporins 

Table 8 describes comparative clinical data for the cephalosporins. 

Table 8. Outcomes Evidence for the Cephalosporins 

Reference Study Design Entry Criteria N Treatment Regimen Duration 

of Study 

Upper Respiratory Infection 

Pessey at 

al. 8 

Randomized, 

open, 

multicenter 

• Aged 6-36 months 

with acute otitis media 

with effusion, 

diagnosed by 

tympanocentesis and 

microbiologic culture 

• No antimicrobial 

treatment in the past 72 

hours 

716 • Cefuroxime axetil 

30mg/kg/day in two 

divided doses for 5 days. 

• Amoxicillin/ 

clavulanate 40mg/kg/day 

in three divided doses for 

8 days 

• Amoxicillin/ 

clavulanate 40mg/kg/day 

in three divided doses for 

10 days 

TOC = 

Day 8 

LTFU = 

Day 28 

Results 

Primary Endpoint: 

• Clinical response at the posttreatment assessment. Patients 

were considered cured if the clinical signs and symptoms 

subsided within the treatment period (exclusive of middle ear 

effusion) and were absent at posttreatment and follow-up; 

bacteriologic cure was presumed in these patients. Failure was 

defined as lack of resolution of clinical signs and symptoms 

(exclusive of middle ear effusion) and relapse as the 

reappearance, after initial cure, of clinical signs or symptoms 

of the original infection up to 28 days posttreatment. 

• Safety was assessed from all reported adverse events. 

Efficacy: cefuroxime 5 days = amoxicillin/clavulanate 8 days = 

amoxicillin/clavulanate 10 days 

• Primary endpoint was measured as clinical signs and 

symptoms subsided within the treatment period. Patients were 

evaluated at day 1, 8, and 28. 

• 86% in cefuroxime 5 day group, 88% in 

amoxicillin/clavulanate 8 day group and 88% in 

amoxicillin/clavulanate 10 day group responded to the therapy. 

• There was no difference in efficacy measurement among the 3 

study groups. 

Safety: cefuroxime 5 days = amoxicillin/clavulanate 8 days > 

amoxicillin/clavulanate 10 days 

• The incidence of diarrhea was higher in 

amoxicillin/clavulanate 10 day group than in 

amoxicillin/clavulanate 8 day group and the cefuroxime group. 

Nemeth et Randomized, • Patients ≥ 13 years 919 • Cefdinir 600mg daily TOC = 4-9 Primary Endpoint:

al. 9 

Pichichero 

et al. 10 

open, 

double-mask, 

multicenter 

Randomized, 

observer-blind, 

multicenter 

of age with diagnosis 

of group A streptococci 

pharyngitis 

• Children aged 2 to 

17 years with signs and 

symptoms of acute 

tonsillopharyngitis 

• Children with 

positive throat culture 

for group A 

streptococcus were 

evaluated 

487 

(377 

were 

evalu 

ated) 

for 10 days 

• Cefdinir 300mg twice 

daily for 10 days 

• Penicillin V 250mg 

four times daily for 10 

days 

• Cefpodoxime 5mg/kg 

twice daily for 5 days 

• Cefpodoxime 

10mg/kg per day for 10 

days 

• Penicillin V 40mg/kg 

per day divided into 3 

doses for 10 days 

days 

LTFU = 

17-24 days 

Post 

therapy 

TOC = 

Day 3-17 

LTFU = 

Day 32-38 

Asmar et Randomized, • Patients aged 2 368 • Cefpodoxime TOC = Primary Endpoints: 

• Clinically cured – All signs and symptoms are absent or in 

satisfactory remission and no further antibacterial therapy is 

required at long term follow-up 

• Microbiologic eradication – Cultures are negative for group- 

A beta hemolytic streptococci 

Efficacy: cefdinir 600mg QD=cefdinir 300mg BID>penicillin 

• The clinical cure rates at the test of cure were 94.8% for the 

cefdinir 600mg QD group, 96.3% for the cefdinir 300mg BID 

group and 88.9% for the penicillin group. The clinical cure rates 

in both cefdinir groups were significantly better than the 

penicillin group. 

• The microbiology eradication rates were 91.4% for the 

cefdinir 600mg QD group, 91.7% for the cefdinir 300mg BID 

group and 83.4% for the penicillin group. Both cefdinir groups 

were superior to the penicillin group. 

Safety: both cefdinir groups < penicillin 

• Diarrhea was more common in the cefdinir groups. (P cefpodoxime 5 day≥ penicillin 

• The clinical response rate was higher in cefpodoxime 10 day 

group (96%) than the cefpodoxime 5 day group (94%) and 

penicillin group (91%). The results did not reach statistical 

significance. 

• The bacteriologic eradication rate for cefpodoxime 10 day 

group was 95%, cefpodoxime 5 day group was 90% and 

penicillin 78%. 

Safety: cefpodoxime 10 day= cefpodoxime 5 day=penicillin 

• There was no difference in adverse events between treatment 

groups. 

• The most common adverse event was GI distress. 

117

al. 11 

multicenter, 

investigatorblind 

Lower Respiratory Infection 

Fogarty et Prospective, 

al. 12 randomized, 

double-blind, 

multicenter, 

Parallel 

Paster, et 

al. 13 

Randomized, 

double-blind 

multicenter 

months to 17 years 

with a diagnosis of 

acute suppurative otitis 

media. 

• Chronic bronchitis 

defined as cough and 

sputum production for 

at least three 

consecutive months 

• Age ≥ 13 years 

• Absence of an 

infiltrate on chest X ray 

• Patients were at least 

13 years old with 

diagnosis of acute 

exacerbation of chronic 

(236 

were 

evaluated) 

10mg/kg once daily for 

10 days 

• Cefixime 8mg/kg 

once daily for 10 days 

548 • Cefprozil 500mg 

twice daily (median 

time 10 days) 

• Cefdinir 300mg 

twice daily (median time 

5 days) 

586 • Cefdinir 300mg twice 


• Loracarbef 400mg 


Day 12-15 

LTFU = 

Day 25-38 

Cefdinir 

pts were 

evaluated 

on days 12- 

16; 

Cefprozil 

pts were 

evaluated 

on days 17- 

21 

TOC = 

Day 12-19 

LTFU = 

Days 26-40 

• Clinical response rate 

• Bacteriologic eradication rate 

Efficacy: cefpodoxime = cefixime 

• The clinical response rates were 56% for cefpodoxime treated 

patients and 54% for cefixime patients. 

• At long-term follow-up, 17% of the patients in cefpodoxime 

group and 20% in cefixime group had a recurrent infection. 

Safety: cefpodoxime = cefixime 

• Drug related adverse events (diarrhea, diaper rash, vomiting) 

occurred in 23.3% of cefpodoxime-treated patients and 17.9% of 

cefixime-treated patients. (P=0.282). 

Primary Endpoints: 

• Overall clinical efficacy - Clinical cure was defined as 

absence or significant remission of all admission signs and 

symptoms. Failure was defined as lack of significant remission 

of signs and symptoms and/or the requirement for further 

antibiotic treatment. Recurrence was defined as worsening of 

signs and symptoms at the LTFU after cure at the TOC visit. 


• Occurrence of adverse events 

Efficacy: cefprozil = cefdinir 

• The clinical cure rate was similar in both groups: 80% cefdinir 

and 72% cefprozil, 95% CIs were between –1.6% and 18.3%. 

• The microbiological eradication of pathogen rates was 81% 

for cefdinir-treated patients and 84% for cefprozil-treated 

patients. 

Safety: cefprozil ≥ cefdinir 

• 34% cefdinir treated patients and 33% cefprozil treated 

patients experienced at least one adverse event. 

• 17% cefdinir patients versus 6% cefprozil patients reported 

diarrhea. (P

Drehobl, et 

al. 14 

Phillips, et 

al. 15 

Randomized, 

double-blind, 

multicenter 

Randomized, 

multicenter, 

observer-blind 

bronchitis Efficacy: cefdinir 300mg for 5 days = loracarbef 400mg for 7 

days 

• Clinical response was determined by absence of clinical signs 

and symptoms at days 12-19 and days 26-40. 

• The response rates were 86% in cefdinir group and 85% in 

loracarbef group. 

• The microbiology eradication rates were 88% for cefdinir 

group and 90% in loracarbef group. 

• Predominant pathogens were H. parainfluenzae, H. influenzae, 

M. Catarrhalis and S. aureus. 

Safety: cefdinir > loracarbef 

• Adverse event rates were 30% for cefdinir and 21% 

loracarbef. 

• The most common adverse events were diarrhea for both 

groups, nausea for cefdinir and headache for loracarbef. 

• Patients ≥ 13 years 

of age with a diagnosis 

of community-acquired 

pneumonia 

• Patients who 

received antibiotics 

within 7 days of 

enrollment were 

excluded. 

• Patients with signs or 

symptoms of acute 

bacterial exacerbation 

of COPD 

690 • Cefdinir 300mg twice 


• Cefaclor 500mg three 

times day for 10 days 

301 • Cefpodoxime 200mg 


• Cefaclor 250mg three 

times a day for 10 days 

TOC = 

6-14 days 

LTFU = 

21-35 days 

posttherapy 

TOC = 

Day 3-7 

posttherapy 

LTFU = 

4 weeks 




• Adverse events rate 

Efficacy: cefdinir = cefaclor 

• The clinical response (cure plus improvement) rates were 89% 

in the cefdinir group and 86% in the cefaclor group. 

• 78% of patients with isolated pathogens were evaluated for 

microbiologic eradication. The rates were 92% in the cefdinir 

group and 93% in cefaclor group. 

• The predominant pathogens were H. parainfluenzae, H. 

influenza, S. pneumonia and S. aureus. 

Safety: cefdinir ≥ cefaclor 

• The incidence of diarrhea was higher in the cefdinir group. 

• Other adverse events were similar in both groups. 





Efficacy: cefpodoxime = cefaclor 

• The bacteriologic eradication rates were similar in both 

119

Skin Structure Infection 

Tack, et Randomized, 

al. 16 double-mask, 

comparative, 

multicenter 

Tack, et 

al. 17 

Randomized, 

investigatorblind, 

multicenter 

• Patients aged 13 

years and older with a 

diagnosis of skin or 

structure infection 

including abscess, 

infected burn, 

carbuncle, cellulitis, 

infected dermatitis and 

trauma/surgical 

wounds. 

• Patients aged 6 

months to 12 years 


uncomplicated mild to 

moderate skin or skin 

structure infection 

warranting systemic 

antimicrobial therapy 

• Most common 

diagnoses were 

impetigo, infected 

dermatitis, wound 

infection and cellulitis 

952 • Cefdinir 300mg 


• Cephalexin 500mg 


days 

394 • Cefdinir 7mg/kg 


• Cephalexin 10mg/kg 


days 

posttherapy 

7-16 days 

posttherapy 

TOC = 

7-14 days 

LTFU = 

21-35 days 

posttherapy 

groups: 91% in cefpodoxime group and 92% in cefaclor group. 

• More bacterial isolates were susceptible in vitro to 

cefpodoxime (91%) than to cefaclor (84%). 

• The most common pretreatment isolates were H. influenzae, 

H. parainfluenzae and S. pneumoniae. 

Safety: cefpodoxime = cefaclor 

• Both treatments were well tolerated and had similar incidents 

of drug-related adverse events (cefpodoxime 11%, cefaclor 12%). 





Efficacy: cefdinir = cephalexin 

• In the efficacy-assessable patients (~ 44%), clinical response 

rates were 88% in the cefdinir treatment group and 87% in 

cephalexin group. 

• The eradication rates were 93% in cefdinir group and 89% in 

cephalexin group. 

Safety: cefdinir < cephalexin 

• More patients reported adverse events in cefdinir group. 

(26% vs. 16%). 





Efficacy: cefdinir = cephalexin 

• The clinical cure rates were 98.3% in the cefdinir group and 

93.8% in the cephalexin group. (P=0.056). 

• The microbiologic eradication rates were 99.4% in the 

cefdinir group and 97.4% in the cephalexin group. 

• The most common pathogens isolated were S. aureus and S. 

pyogenses. 

Safety: cefdinir = cephalexin 

• 16% of patients in the cefdinir group and 11% in the 

cephalexin group experienced adverse events. 

120

Stevens, et 

al. 18 

Randomized, 

double-blind, 

multicenter 

• Patients ≥ 12 years 

with acute, single site 

skin or skin-structure 

infections 

• Excluded patients 

with resistant 

pathogen. 

Uncomplicated Urinary Tract Infection (UTI) 

Leigh, et 

al. 19 

Randomized, 

double-blind 

parallel-group 

multicenter 

TOC= test of cure, LTFU=long term follow up. 

• Patents ≥ 13 years of 

age with symptoms of 

a urinary tract infection 

for more than 2 days 

• Patients who had a 

history of UTI, were 

hospitalized or were 

currently on other 

antibiotics were 

excluded 

371 

(271 

were 

evaluated) 

661 

(381 

were 

analyzed) 

• Cefpodoxime 400mg 

twice daily for 7-10 

days (matching cefaclor 

placebo) 

• Cefaclor 500mg 

three times daily for 7- 

10 days (with matching 

cefpodoxime placebo) 

• Cefdinir 100mg 


• Cefaclor 250mg 

three times daily for 5 

days 

TOC = 

Day 7-10 

LTFU = 

2-3 weeks 

after 

treatment 

TOC = 5-9 

days 

LTFU = 6- 

8 weeks 

posttherapy 

• The most common adverse event was diarrhea. 





Efficacy: cefpodoxime ≥ cefaclor 

• Both treatments were highly effective: 99% eradication rate 

and 86% cure rate. 

• Cefpodoxime had lower minimum inhibitor concentrations 

against the majority of Staphylococcus species than did cefaclor. 

• Cefaclor had a higher failure rate (4%) than cefpodoxime 

(1%). 

Safety: cefpodoxime = cefaclor 

• Both treatments were well tolerated. 





Efficacy: cefdinir = cefaclor 

• Clinical cure rates and microbiological eradication rates were 

equivalent (95% CI=-8.8% to 1.5% (cefdinir) and –1.8% to 15% 

(cefaclor)). 

• Resistance to cefaclor (6.7%) was significantly higher than 

cefdinir (3.7%). (P


Dose Simplification: The oral cephalosporins are typically dosed twice daily, with a few 

exceptions (e.g. cephalexin). A study by Kardas et al. looked at patient adherence in respiratory 

tract infections with ceftibuten and other antibiotics. 20 The goal of the study was to establish 

whether dosing frequency (1 vs. 2 or 3 times daily) and other factors influenced compliance. 

Patients were randomized to ceftibuten 400mg daily or another antibiotic of the physician’s choice 

with a frequency of BID or TID. Compliance was measured in 406 patients by a pill count. 

Overall compliance was 76.6% with 97.6% for ceftibuten, 66.0% for antibiotics with BID dosing 

and 23.5% for antibiotics with TID dosing. Using a logistic regression analysis with a stepwise 

variable selection, dosing frequency was found to be a major variable associated with patient 

compliance (p = 0.00000, odds ratio 0.09, 95% confidence interval 0.057-0.165). This study, 

however did not measure an effect on outcome of the disease (respiratory tract infection 

improvement). 

A study by Tsi, et al looked at the efficacy and safety of once daily cefpodoxime proxetil 

suspension and cefaclor TID in the treatment of acute otitis media in children. 21 Satisfactory 

clinical outcome, either cure or improvement, was achieved at the end of treatment in 90% of 

patients in the cefaclor group and 95% of patients in the cefpodoxime group (p > 0.05). Clinical 

recurrence was identified at the follow-up visits in one case of the cefaclor group (3%), and none 

in the cefpodoxime group (p > 0.05). These drugs were well tolerated by 14/21 (67%) in the 

cefpodoxime-treated group and 27/32 (84%) in the cefaclor-treated group. The incidence of 

adverse events was slightly higher in the cefpodoxime group than in the cefaclor group, however 

the difference did not reach statistical significance (p > 0.05). In this study, cefaclor administered 

three times daily was as effective and safe as cefpodoxime administered once daily in the 

treatment of acute otitis media in children. 

Additionally, a study by de Klerk et al evaluated the efficacy of cefrtiaxone 1g QD to that of 

standard antibiotic treatment for lower respiratory tract infections. 22 Standard treatment was given 

according to guidelines from the American Thoracic Society. The mean duration of therapy was 

7.4 days in both groups. The average duration of hospitalization was 15.0 days for ceftriaxone and 

15.9 days for patients on standard therapy. Overall cure and improvement rates at the end of 

treatment were 47 (90%) for patients given ceftriaxone and 37 (77%) for patients receiving 

standard therapy. Once daily therapy with ceftriaxone was as effective as standard therapy in the 

treatment of lower respiratory infections, in view of multiple daily dosing regimens of most 

standard therapies. 

A study comparing IM ceftriaxone and oral amoxicillin-clavulanate in otitis media showed that the 

failure rate was similar in both groups (4.6% and 4.7%), respectively. 23 No significant differences 

in both groups were found in the dynamics of resolution of acute symptomatology, otoscopy 

findings, relapse rate at 30 days or tympanographic evidence of middle ear effusion at the 

scheduled visits. Recurrence rates of acute otitis media between days 31 and 90 were observed 

significantly in more children treated with amoxicillin/clavulanate than with cefriaxone (25 our of 

84 (29.4%) versus 11 out of 81 (13.6%) (P=0.012). A single ceftriaxone IM injection is as 

efficient as a 10-day oral amoxicillin clavulanate course and may be considered in the treatment of 

otitis media when children are unable to tolerate or absorb oral drugs, or in children refusing or 

unable to take oral therapy. Ceftriaxone is also be an option when compliance is questionable. 

Stable Therapy: Resistance to cephalosporins, especially the first generation cephalosporins, is a 

growing concern. Although changing between cephalosporins is not recommended, a different 

cephalosporin may be initiated due to therapeutic failure. 

Impact on Physician Visits: A literature search did not reveal clinical data pertinent to 

cephalosporin use and physician visits.

IX. 

Conclusions 

Not all cephalosporins have been directly compared to all other cephalosporins for certain 

indications. The clinical efficacy data presented above is a representative selection of recent 

comparative trials. These studies have shown comparable efficacy of some of the cephalosporins 

for the treatment of uncomplicated urinary tract infections, skin structure infections, and upper and 

lower respiratory tract infections. A few studies have shown greater efficacy of cephalosporin 

agents compared to amoxicillin/clavulanate and penicillin. Clinical data also demonstrates similar 

safety profiles between the cephalosporins (particularly within generations). 

In looking at indications, cephalexin is currently the only oral cephalosporin approved for bone 

infections caused by staphylococci or Proteus mirabilis. Likewise, cephalexin is also the only oral 

cephalosporin approved for genitourinary tract infections including acute prostatitis caused by E. 

coli, P. mirabilis, and Klebsiella Sp. Cefuroxime is the only cephalosporin approved for Lyme 

disease. Both of these agents are available with as generic formulations. Additionally, at least one 

agent in each cephalosporin generation is available in a generic formulation. 

Therefore, all brand products within the class reviewed are comparable to each other and to the 

generics and OTC products in the class and offer no significant clinical advantage over other 

alternatives in general use. 


No brand cephalosporin is recommended for preferred status. 

123

References 

1. Diagnosis and Management of Otitis Media. American Academy of Pediatrics, American 

Academy of Family Physicians. March 2004. Available at: www.aap.org. Accessed September 30, 

2004. 






5. Clinical Pharmacology, 2004. Available on-line at: www.cp.gsm.com. Accessed September 21, 

2004. 




8. Pessey J, Gehanno P, Thoroddsen E et al. Short course therapy with cefuroxime axetil for acute 

otitis media: results of a randomized multicenter comparison with amoxicillin/clavulanate. Pediatr 

Infect Dis J. 1999;18(10):854-859 

9. Nemeth MA, McCarthy J, Gooch WM et al. Comparison of cefdinir and penicillin for the 

treatment of streptococcal pharyngitis. Clin Ther. 1999;21(11):1873-1881. 

10. Pichichero ME, Gooch WM, Rodriguez W et al. Effective short-course treatment of acute group A 

beta-hemolytic streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med. 1994;148:1053-1060 

11. Asmar BI, Dajani AS, Del Beccaro MA et al. Comparison of cefpodoxime proxetil and cefixime in 

the treatment of acute otitis media in infants and children. Pediatrics. 1994;94:847-52 

12. Fogarty CM, Bettis RB, Griffin TJ et al. Comparison of a 5 day regimen of cefdinir with a 10 day 

regimen of cefprozil for treatment of acute exacerbations of chronic bronchitis. J Antimicrob 

Chemother. 2000;45:851-858 

13. Paster ZR, McAdoo AM, Keyserling CH et al. A comparison of five-day regimen of cefdinir with a 

seven-day regime of loracarbef of the treatment of acute exacerbations of chronic bronchitis. Int J Clin 

Pract. 2000; 54(5):293-299 

14. Drehobl M, Bianchi P, Constance H et al. Comparison of cefdinir and cefaclor in the treatment of 

community-acquired pneumonia. Antimicrobial Agents Chemother. 1997;41(7):1579-1583 

15. Phillips H, Van Hook CJ, Butler T et al. A comparison of cefpodoxime proxetil and cefaclor in the 

treatment of acute exacerbation of COPD in adults. Chest. 1993;104(5):1387-92 

16. Tack KJ, Littlejohn TW, Maillous G et al. Cefdinir versus cephalexin for the treatment of skin and 

skin-structure infections. Clin Ther. 1998;20(2):244-256. 

17. Tack KJ, Keyserling CH, McCarty J et al. Study of use of cefdinir versus cephalexin for treatment 

of skin infections in pediatric patients. Antimicrobial Agents Chemothe.. 1997;41(4):739-742 

18. Stevens DL, Pien F, Drehobl M. Comparison of oral cefpodoxime proxetil and cefaclor in the 

treatment of skin and soft tissue infections. Diagn Microbiol Infect Dis. 1993;16(2):123-129 

19. Leigh AP, Nemeth MA, Keyserling CH et al. Cefdinir versus cefaclor in the treatment of 

uncomplicated urinary tract infection. Clin Ther. 2000;22(7):818-825. 

20. Kardas P, Ratajczyk-Pakaluska E. Patient adherence in respiratory tract infections: ceftibuten 

versus other antibiotics. Pol Merkuriusz Lek 2001 Jun;10(60):445-9. 

21. Tsai HY, Huang LM, Chiu HH, et al. Comparison of once daily cefpodoxime proxetil suspension 

and thrice daily cefaclor suspension in the treatment of acute otitis media in children,. J Microbiol 

Immunol Infect 1998 Sep;31(3):165-70. 

22. de Klerk GJ, can Steijn JH, Lobatto S, et al. A randomized, multicenter study of ceftriaxone 

versus standard therapy in the treatment of lower respiratory tract infections. Int J Antimicrob Agents 

1999 Jul;12(2):121-7. 

23. Varsano I, Volovitz B, Horev Z, et al. Intramuscular ceftriaxone compared with oral 

amoxicillin/clavulanate for treatment of acute otitis media in children. Eur J Pediatr 1997 

Nov;156(11):858-63. 

124



Pharmacotherapy Review of the Miscellaneous β-Lactam Antibiotics 

Single Entity Agents 

AHFS 081207 


I. Overview 

The β-lactam antibiotics can be classified into several groups according to their structural 

characteristics, but their unique structural feature is the presence of a four-membered β-lactam 

ring. The benefits of the β-lactam antibiotics have been known for 50 years and these antiinfectives 

continue to be beneficial due to their low toxicities and enhanced spectrum of activity. 

The nonpenicillin β-lactams exhibit a variable spectrum of antimicrobial activity and have a wide 

range of clinical uses. 1 

The carbapenems offer a broad antimicrobial spectrum, and meropenem has an improved safety 

profile compared with imipenem. Aztreonam is a useful alternative for patients with aerobic 

gram-negative infections who have allergies to the penicillins. 2 

Only a single agent, loracarbef, is available orally in this class, and only cefoxitin is available as a 

generic formulation. This review encompasses all dosage forms and strengths. Table 1 lists the 

drugs in this review. 

Table 1. Single Entity Miscellaneous β-Lactam Antibiotics in this Review 

Generic Name β-Lactam Formulation Example Brand Name 

Classification 

Aztreonam Monobactam Injection Azactam 

Cefotetan Cephamycin Injection Cefotan 

Cefoxitin Cephamycin Injection Mefoxitin* 

Ertapenem Carbapenem Injection Invanz 

Loracarbef Carbacephem Oral Lorabid 

Meropenem Carbapenem Injection Merrem 


II. Evidence Based Medicine and Current Treatment Guidelines 

The β-lactam antibiotics can be used for various infections. Because of this, an abundance of 

treatment guidelines are available that involve use of the β-lactam antibiotics. A review of some 

of the treatment guidelines and recommendations is highlighted in Table 2. Table 3 illustrates the 

spectrum of coverage for the drugs in this class. 

125

Table 2. Clinical Guidelines and Recommendations for the Miscellaneous β-Lactam Antibiotics 

Clinical Guideline 

Recommendation 

Hospital Pharmacist Consensus Reports: First-line treatment of patients with community-acquired 

The Antibiotic Selection for Community pneumonia (CAP) is oral azithromycin, with quinolone 

–Acquired Pneumonia Consensus Panel antibiotics as alternative first-line therapy. 

(The ASCAP Panel), 2002 3 

Severe CAP complicated by structural disease of the lung, and 

increased pseudomonas and polymicrobial infection, should 

be treated with cefepime plus levofloxacin plus/minus an 

aminoglycoside or ciprofloxacin plus an aminoglycoside plus 

azithromycin. Alternatively, CAP can be treated with 

ciprofloxacin plus cefepime plus azithromycin or a 

carbapenem plus azithromycin plus an aminoglycoside. 

Patients with severe pneumonia requiring ICU hospitalization 

may also be treated alternatively with a carbepenem plus an 

aminoglycoside plus azithromycin. 

Infectious Diseases Society of America: Initial empiric therapy involving drugs in this class for 

Guidelines for community-acquired suspected bacterial community-acquired pneumonia include: 

pneumonia in immunocompetent adults, • Inpatient, medical ward with no recent antibiotic 

2003 4 

therapy; give a quinolone alone or an advanced 

macrolide plus a β-lactam (cefotaxime, ceftriaxone, 

ampicillin-sulbactam, or ertapenem). 

• ICU, pseudomonas is not an issue; give a β-lactam 

plus either an advanced macrolide or a quinolone. 

• ICU, pseudomonas is an issue; give either (1) an 

antipseudomonal agent (piperacillin, piperacillintazobactam, 

imipenem, meropenem, or cefepime) 

plus ciprofloxacin or (2) an antipseudomonal agent 

plus an aminoglycoside plus a quinolone or a 

macrolide. 

• ICU, pseudomonas is an issue but patient has β- 

lactam allergy; give either (1) aztreonam plus 

levofloxacin or (2) aztreonam plus moxifloxacin or 

gatifloxacin, with or without an aminoglycoside. 

126

Table 3. Comparison of Bacterial Coverage of the Single Entity Miscellaneous β-Lactam Antibiotics 5 

Drug 

Spectrum 

Aztreonam The spectrum of aztreonam is limited to aerobic gram-negative bacteria; it has no 

gram-positive or anaerobic activity. Aztreonam may be used in place of an 

aminoglycoside since it is less nephrotoxic. 

Cefotetan 

Cefoxitin 

Ertapenem 

Gram-negative aerobes that are usually susceptible to aztreonam include: N. 

meningitidis, N. gonorrhoea, H. influenzae, Branhamella catarrhalis, Aeromonas 

hydrophila, Pasteurella multocida, and most Enterobactericeae (E.coli, Klebsiella, 

Citrobacter, Enterobacter, Morganella, Proteus, Providencia, Serratia, Salmonella, 

and Shigella). Aztreonam is often active against Pseudomonas aeruginosa, with 

potency slightly less than that of ceftazidime, although, as with all gram-negative 

organisms, specific susceptibility data should be considered. Anaerobes are not 

susceptible. 

Cefotetan differs from most other cephalosporins due to its activity against anaerobic 

organisms other than Bacteroides. It also has a somewhat longer half-life, allowing 

for twice-daily dosing. Cefotetan is active against most gram-positive bacteria other 

than enterococcus, although cefazolin, a first-generation agent, and cefmetazole, 

another second-generation cephamycin, are much more active against S. aureus than 

is cefotetan. 

Its gram-negative spectrum includes many Enterobacteriaceae, notably E. coli, 

Klebsiella, Proteus, and Providencia. Enterobacter, Serratia, and Pseudomonas are 

not susceptible. It also provides excellent coverage against N. gonorrhoeae and H. 

influenzae. Anaerobic coverage of cefotetan is similar to that of cefoxitin. Grampositive 

coverage includes nonpenicillinase- and penicillinase-producing 

Staphylococcus aureus (methicillin-resistant strains are resistant) and streptococci 

(except enterococci); however, its activity against these organisms is less than that of 

many other cephalosporins and penicillins. 

Cefoxitin has added stability against the β-lactamases, providing better resistance to 

certain gram-negative species. When it was marketed, cefoxitin was the first 

cephalosporin-like antibiotic to exhibit activity against anaerobes. Many institutions 

have substituted cefotetan for cefoxitin since their spectra of activity is extremely 

similar, and cefotetan can be dosed less frequently. In addition, cefoxitin has been 

found to be a potent inducer of β-lactamases. 

Cefoxitin possesses greater activity against gram-negative aerobes and anaerobes than 

currently available first-generation cephalosporins (at the time it became available). 

Due to its added stability against beta-lactamase-producing organisms, it is active 

against E. coli, Klebsiella, H. influenzae, Proteus, and Providencia. In addition, it 

provides excellent coverage against N. gonorrhoeae and is the drug of choice for the 

treatment of pelvic inflammatory disease (PID) due to N. gonorrhoeae. Cefoxitin has 

good activity against most gram-positive bacteria including nonpenicillinase- and 

penicillinase-producing Staphylococcus aureus (methicillin-resistant strains are not 

susceptible), streptococci (except enterococci), and many anaerobic bacteria 

(including B. fragilis). 

Ertapenem is highly stable against β-lactamases and has activity against a wide 

variety of gram-positive, gram-negative and anaerobic microorganisms, particularly 

the Enterobacteriaceae. 

The following organisms are generally considered susceptible to ertapenem in vitro 

and in clinical infections: Bacteroides distasonis; Bacteroides fragilis; Bacteroides 

ovatus; Bacteroides thetaiotaomicron; Bacteroides uniformis; Clostridium 

clostridioforme; Escherichia coli; Eubacterium lentum; Haemophilus influenzae 

(beta-lactamase negative); Klebsiella pneumoniae; Moraxella catarrhalis; 

Porphyromonas asaccharolytica; Prevotella bivia; Staphylococcus aureus (MSSA); 

Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae 

127

(penicillin susceptible strains); Streptococcus pyogenes (group A beta-hemolytic 

streptococci). Methicillin-resistant staphylococci and Enterococcus sp. are resistant 

to ertapenem. Limited in vitro activity has been demonstrated against Acinetobacter 

sp., Pseudomonas aeruginosa and Aeromonas sp. However, in vitro studies 

demonstrate that imipenem is three to ten times more potent against Acinetobacter sp. 

and Pseudomonas aeruginosa than ertapenem. 

Loracarbef 

Meropenem 

Note: On September 15, 2004, the FDA reported it had approved a supplemental new 

drug application for ertapenem for the addition of Staphylococcus epidermidis, 

Providencia rettgeri, Providencia stuartii, and Bacteroides vulgatus. 

The clinical utility and beta-lactamase stability of loracarbef is similar to that of the 

second-generation cephalosporins. Thus loracarbef's spectrum of activity includes 

pathogens frequently isolated in respiratory, urinary, skin, and soft-tissue infections. 

Gram-positive coverage includes Streptococcus pneumoniae; S. pyogenes; betahemolytic 

streptococci groups B, C, and G; Staphylococcus aureus (methicillinresistant 

strains are resistant); and Clostridium difficile. As with the cephalosporins, 

loracarbef is inactive against enterococci. Gram-negative coverage includes activity 

against E. coli, Neisseria gonorrhoeae, N. meningitidis, Haemophilus influenzae, 

Moraxella catarrhalis, Klebsiella pneumoniae, Helicobacter pylori, and P. mirabilis. 

In vitro susceptibility testing has shown variable results with different inoculum sizes 

of beta-lactamase-positive strains of H. influenzae, M. catarrhalis, Staphylococcus 

aureus, and E. coli. Inoculum size does not affect loracarbef's activity against 

β-lactamase-negative strains. 

The spectrum of activity of meropenem is very similar to imipenem although 

meropenem is more active against Enterobacteriaciae, Haemophilus influenzae, 

gonococcus, and Pseudomonas aeruginosa. 

128

III. 

Comparative Indications of the Single Entity Miscellaneous β-Lactam Antibiotics

Aztreonam 

✔ 

Complicated 

and noncomplicated, 

pyelonephritis 

and cystitis 

✔ 

Pneumonia 

and 

bronchitis 

Skin and 

Skin 

Structure 

Infections 

Table 4. FDA-Approved Indications for the Single Entity Misc. B-Lactams 5-8 

Drug UTI Lower 

RTI* 

Upper 

RTI* 

Septicemia 

Intra- 

Abdominal 

Infections 

Gynecologic 

Infections 

Surgery 

Concurrent 

Initial 

Therapy 

✔ ✔ ✔ ✔ ✔ ✔ 

With grampositive 

coverage 

Bone and 

Joint 

Infections 

Perioperative 

Prophylaxis 

Cefotetan ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ 

Caused by 

S. aureus 

Cefoxitin ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ 

Pneumonia 

and lung 

abscesses 

Ertapenem ✔ 

Complicated, 

including 


✔ 

Complicated 

✔ 

Complicated 

✔ 

Acute pelvic 

infections: 

postpartum 

endomyometritis 

and septic 

abortion 

Loracarbef 

✔ 

Uncomplicated 

cystitis and 


✔ 

Pneumonia 

and 

bronchitis 

✔ 

Otitis media, 

sinusitis, 

pharyngitis, 

tonsillitis 

✔ 

Uncomplicated 

Meropenem ✔ 

Complicated 

appendicitis 

and 

peritonitis 

*Respiratory Tract Infection 

Community- 

Acquired 

Pneumonia 

✔ 

With 

concurrent 

bacteremia 

Bacterial 

Meningitis 

✔ 

Pediatric 

patients ≥ 3 

months 

only

IV. 


Table 5. Pharmacokinetic Parameters of the Single Entity Miscellaneous β-Lactams 5-8 


Binding 

Metabolism 

Aztreonam Aztreonam is mainly Poorly absorbed from 56-60% 6-16% in the 

bactericidal and inhibits the GI tract 

liver 

the third and final stage 

of bacterial cell wall 

synthesis by 

preferentially binding to 

specific penicillinbinding 

proteins (PBPs) 

that are located inside the 

bacterial cell wall. 

Cefotetan 

Cefoxitin 

Ertapenem 

Cefotetan inhibits the 

third and final stage of 

bacterial cell wall 

synthesis by 





bacterial cell wall. The 

drug’s ability to interfere 

with PBP-mediated cell 

wall synthesis ultimately 

leads to cell lysis. Lysis 

is mediated by bacterial 

cell wall autolytic 

enzymes. 

Cefoxitin, a beta-lactam 

cephamycin similar to 

penicillins and 

cephalosporins, inhibits 



synthesis by 






Ertapenem exhibits 

bactericidal activity due 

inhibition of cell wall 

synthesis mediated via 

binding to penicillin 

binding proteins (PBPs). 

Ertapenem inhibits the 



synthesis by 






Poorly absorbed from 

the GI tract; peak levels 

occur in 1.5-3 hours 

following IM injection 

Peak levels occur in 

20-30 minutes following 

an IM dose 

75-90% No 1-10% of a 

dose is 

present in 

plasma and 

urine as an 

active 

tautomer of 

the drug 

50-80% 2% 

metabolized 

90% 95% Yes, 

hydrolysis 

Active Elimination Half-Life 

Metabolites 

No 60-70% Renal 1.7 hours 

No 

No 

Renal, 

49-81% of 

dose is 

excreted in 

urine 

Excreted 

unchanged in 

by the 

kidneys 

80% renal, 

10% feces 

3-4.5 

hours 

40-60 

minutes 

4.5 hours

Loracarbef 

Meropenem 

By preferentially binding 

to specific penicillinbinding 


located inside the 

bacterial cell wall, 

loracarbef inhibits the 



synthesis. 

Meropenem inhibits cell 

wall formation, 

facilitates bacterial cell 

lysis, and is mainly 

bactericidal. It inhibits 



synthesis by 






90% absorbed following 

oral administration; 

administration of tablets 

with food decreases the 

peak plasma 

concentrations by 

40-50% and delays time 

to peak concentrations 

by 30-60 minutes; the 

extent of absorption is 

about the same for both 

formulations, but the 

increased rate of 

absorption and resulting 

increases in peak serum 

concentrations from the 

suspension should be 

considered when 

substituting capsules for 

the suspension. The 

capsules should not be 

used in place of the 

suspension for otitis 

media. 

Mean peak plasma 

concentrations at the end 

of a 30-minute IV 

infusion of a single dose 

in normal volunteers are 

approximately 

23 mcg/ml (range 

14-26 mcg/ml) for the 

500 mg dose and 

49 mcg/ml (range 

39-58 mcg/ml) for the 1 

gram dose. 

25% No evidence 

of metabolism 

2% Minimally 

metabolized 

No Renal 1 hour 

No 

70% is 

excreted 

unchanged in 

the urine 

1.2 hours 


Table 6 lists the most significant drug-drug interactions for the drugs indexed by Drug Interactions 

Facts (cefotetan and cefoxitin). 9 Interactions for the other drugs in the class are described below. 

Table 6. Drug Interactions of the Single Entity Miscellaneous β-Lactams 9 


Cephalosporins 

(cefotetan) 

Level 2 Cefotetan and ethanol (or drugs 

that contain ethanol) 

Aldehyde dehydrogenase inhibition by methyltetrazolethiol 

results in acetaldehyde accumulation. Occurrence and severity 

are unpredictable. Dose-response and length of enzyme 

inhibition are unknown. A disulfiram-like reaction manifested 

by flushing, tachycardia, bronchospasm, sweating, nausea and 

vomiting may occur when ethanol is ingested after a patient has 

been on cefotetan, or other cephalosporins with the 

methyltetrazolethiol moiety (cefmandole, cefoperazone, 


(cefotetan and 

cefoxitin) 


(cefotetan and 

cefoxitin) 

Level 2 

Level 2 

Cefotetan, cefoxitin and 

aminoglycosides 

Cefotetan, cefoxitin and 

anticoagulants (anisindione, 

warfarin, dicumarol) 

cefonicid, ceforanide, and moxalactam). 

Mechanism is unknown. Nephrotoxicity may be 

increased. Bactericidal activity against certain pathogens 

may be enhanced. 

Mechanism is unknown. The anticoagulant effect of warfarin 

is increased. 

132

Aztreonam 8 

Precipitant 

drug 

Probenecid 

Furosemide 

Antibiotics 

(e.g., cefoxitin, 

imipenem) 

* 

Additional Drug-Drug Interactions for the Single Entity Miscellaneous β-Lactam Antibiotics 

Object drug * 

Aztreonam 

Aztreonam 

Description 

Concomitant administration causes clinically insignificant increases in 

aztreonam serum levels. 

Antibiotics may induce high levels of -lactamase in vitro in some gramnegative 

aerobes such as Enterobacter and Pseudomonas sp, resulting in 

antagonism to many -lactam antibiotics including aztreonam. Do not use - 

lactamase-inducing antibiotics concurrently with aztreonam. 

Aztreonam Aminoglycosides If an aminoglycoside is used concurrently with aztreonam, especially if high 

dosages of the former are used or if therapy is prolonged, monitor renal function 

because of potential nephrotoxicity and ototoxicity of aminoglycoside 

antibiotics. 

= Object drug increased. = Object drug decreased. 

Ertapenem 

When ertapenem is coadministered with probenecid (500mg by mouth every 6 hours), probenecid competes 

6, 7, 8 

for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem 

concentrations, probenecid increased the AUC by 25% and reduced the plasma and renal clearances by 

20% and 35%, respectively. The half-life increased from 4 to 4.8 hours. Because of the small effect on halflife, 

the coadministration with probenecid to extend the half-life of ertapenem is not recommended. 

In vitro studies indicate ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or 

vinblastine and ertapenem is not a substrate for P-glycoprotein-mediated transport. In vitro studies in human 

liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following six 

cytochrome P450 isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Drug interactions caused by inhibition of 

P-glycoprotein-mediated drug clearance or CYP-mediated drug clearance with the listed isoforms are 

unlikely. 

Other than with probenecid, no specific clinical drug interaction studies have been conducted. 

Loracarbef 

Probenecid: As with other β-lactam antibiotics, renal excretion of loracarbef is inhibited by probenecid and 

resulted in an approximate 80% increase in the AUC for loracarbef. 11 

Meropenem 

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of 

meropenem. 6-8 This led to statistically significant increases in the elimination half-life (38%) and in the extent 

of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not 

recommended. 

There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels 

(therapeutic range considered to be 50 to 100micrograms/ml total valproate). 

133

VI. Adverse Drug Events of the Single Entity Miscellaneous β-Lactam 

Antibiotics 

Table 7. Common Adverse Events (%) Reported for the Single Entity Misc. B-Lactam Antibiotics 6, 8 

Adverse Event Aztreonam Cefotetan Cefoxitin Ertapenem Loracarbef Meropenem 


Malaise

VII. 

Dosing and Administration for the Single Entity Miscellaneous β-Lactam 

Antibiotics 

Table 8. Dosing for the Single Entity Miscellaneous β-Lactam Antibiotics 


Aztreonam Powder for injection: 

500mg, 1g, and 2g 

Give IM or IV. Individualize dosage. 

Aztreonam Dosage Guide (Adults) 

Type of infection Dose 1 Frequency (hours) 

Urinary tract infection 500mg or 1g 8 or 12 

Moderately severe systemic infections 1 or 2g 8 or 12 

Severe systemic or life-threatening 

infections 

2g 6 or 8 

1 Maximum recommended dose is 8 g/day. 

Aztreonam Dosage Guide (Children) 

Type of infection Dose 1 Frequency (hours) 

Mild-to-moderate infections 30mg/kg 8 

Moderate-to-severe infections 30mg/kg 6 or 8 

1 Maximum recommended dose is 120mg/kg/day. 

Duration: 

Therapy duration depends on the severity of infection. Generally, continue 

aztreonam for ≥48 hours after the patient becomes asymptomatic or evidence 

of bacterial eradication has been obtained. Persistent infections may require 

treatment for several weeks. Do not use doses smaller than those indicated. 

Cefotetan 


1, 2, and 10g 

Injection: 1g/50ml 

and 2g/50ml 

Adults: 

The usual dosage is 1 or 2g IV or IM every 12 hours for 5 to 10 days. 

General Cefotetan Dosage Guidelines 

Type of Infection Daily Dose Frequency and Route 

Urinary tract 

1 to 4g 500mg every 12hrs IV or IM 

1 or 2g every 24hrs IV or IM 

1 or 2g every 12hrs IV or IM 

Skin/Skin structure 

Mild-to-moderate 2 

2g 

2g q 24hrs IV 

1g q 12hrs IV or IM 

Severe 4g 2g q 12 hrs IV 

Other Sites 2 to 4g 1 or 2g every 12hrs IV or IM 

Severe 4g 2g every 12hrs IV 

Life-threatening 6g 1 3g every 12hrs IV 

1 Maximum daily dosage should not exceed 6g. 

2 Klebsiella pneumoniae skin and skin structure infections should be treated with 1 or 2 g every 

12 hours IV or IM. 

Prophylaxis: 

To prevent postoperative infection in clean contaminated or potentially 

contaminated surgery in adults, give a single 1 or 2g IV dose 0.5 to 1 hour 

prior to surgery. In patients undergoing cesarean section, give the dose as 

soon as the umbilical cord is clamped. 

135

Cefoxitin 


1, 2, and 10g 

Injection: 1g/50ml 

and 2g/50ml 

Adults: 

The dosage range is 1 to 2g every 6 to 8 hours. Maintain antibiotic therapy 

for group A β-hemolytic streptococcal infections for ≥10 days to guard 

against the risk of rheumatic fever or glomerulonephritis. 

Cefoxitin Dosage Guidelines 

Type of infection Daily dosage Frequency and route 

Uncomplicated (pneumonia, 3 to 4g 1g every 6 to 8 hours IV 

urinary tract, cutaneous) 1 

Moderately severe or severe 6 to 8g 1g every 4 hours or 2g 

every 6 to 8 hours IV 

Infections commonly requiring 

higher dosage (e.g. gas 

gangrene) 

12g 

1 Including patients in whom bacteremia is absent or unlikely. 

2g every 4 hours or 3g 

every 6 hours IV 

Ertapenem 

Loracarbef 


1g 

Oral pulvules: 

200mg and 400mg 


100mg/5ml (100ml), 

200mg/5ml (100ml) 

strawberry bubble 

gum flavor 

Uncomplicated gonorrhea: 2g IM with 1g oral probenecid given concurrently 

or ≤30 minutes before cefoxitin. 

Prophylactic use, surgery: Administer 2g IV 30 to 60 minutes prior to surgery 

followed by 2g every 6 hours after the first dose for ≤24 hours. 

Prophylactic use, cesarean section: Administer 2g IV as soon as the umbilical 

cord is clamped. If a three-dose regimen is used, give the second and third 2g 

dose IV, 4 and 8 hours after the first dose. 

Prophylactic use, transurethral prostatectomy: administer 1g prior to surgery; 

1g every 8 hours for ≤5 days. 

Dose: 1g given once a day. 

Ertapenem may be administered by IV infusion for up to 14 days or IM 

injection for up to 7 days. When administered IV, infuse ertapenem over a 

period of 30 minutes. 

IM administration of ertapenem may be used as an alternative to IV 

administration in the treatment of those infections for which IM therapy is 

appropriate. 

Dosage/Duration of Loracarbef 

Population/Infection 

Dosage 

(mg) 

Duration 

(days) 


Lower respiratory tract 

Secondary bacterial infection of acute 200-400 q 12 hrs 7 

bronchitis 

Acute bacterial exacerbation of 

400 q 12 hrs 7 

chronic bronchitis 

Pneumonia 400 q 12 hrs 14 

Upper respiratory tract 

Pharyngitis/Tonsillitis 200 q 12 hrs 10 1 

Sinusitis 400 q 12 hrs 10 


136

Meropenem 


500mg, 1g, also Add- 

Vantage vials in 

500mg and 1g 

Uncomplicated 200 q 12 hrs 7 

Urinary tract 

Uncomplicated cystitis 200 q 24 hrs 7 

Uncomplicated pyelonephritis 400 q 12 hrs 14 

Infants and children(6 months to 12 

years) 2 

Upper respiratory tract 

Acute otitis media 3 




Impetigo 

30mg/kg/day in 

divided doses q 12 hrs 





1 In treatment of infections caused by S. pyogenes, administer for ≥10 days. 


3 Use suspension; it is more rapidly absorbed than capsules, resulting in higher peak plasma 

concentrations when given at the same dose. 

Weight 

10 

10 1 

Loracarbef Pediatric Suspension Dosage 

Daily dose 15mg/kg/day Daily dose 30mg/kg/day 

100mg/5 ml 

twice daily 

200mg/5ml 

twice daily 

100mg/5 ml 

twice daily 

7 

200mg/5ml 

twice daily 

lb kg ml tsp ml tsp ml tsp ml Tsp 

15 7 2.6 0.5 -- -- 5.2 1 2.6 0.5 

29 13 4.9 1 2.5 0.5 9.8 2 4.9 1 

44 20 7.5 1.5 3.8 0.75 -- -- 7.5 1.5 

57 26 9.8 2 4.9 1 -- -- 9.8 2 

Adults: 

1g by IV administration every 8 hours. Give over 15 to 30 minutes or as an 

IV bolus injection (5 to 20ml) over 3 to 5 minutes. 

Use in pediatric patients: 

For pediatric patients from ≥3 months of age, the dose is 20 or 40mg/kg 

every 8 hours (maximum dose is 2g every 8 hours), depending on the type of 

infection (intra-abdominal or meningitis). Administer pediatric patients 

weighing > 50kg 1g every 8 hours for intra-abdominal infections and 2g 

every 8 hours for meningitis. Give over 15 to 30 minutes or as an IV bolus 

injection (5 to 20 ml) over 3 to 5 minutes. 

Recommended Meropenem IV Dosage Schedule for Pediatrics with 

Normal Renal Function 

Type of infection Dose (mg/kg) Dosing interval 

Intra-abdominal 20 every 8 hours 

Meningitis 40 every 8 hours 

137


Table 9. Special Dosing Considerations for the Single Entity Miscellaneous β-Lactams 5-9 

Drug Renal Dosing Hepatic Pediatric Use Pregnancy Can Drug Be Crushed/Stability 

Dosing 

Category 

Aztreonam 

Yes 

Patients with Cr. Cl 

10-30ml/min 

reduce dose by 

50%, after 1 or 2g 

loading dose. 

No Children only; there is 

insufficient data 

regarding IM 

administration to 

pediatric patients or 

dosing in pediatric 

patients with renal 

impairment. 

B Use solutions for IV infusion at 

concentrations ≤2% w/v within 

48 hours following constitution if 

kept at controlled room temperature 

(15° to 30°C; 59° to 86°F) or within 

7 days if refrigerated (2°to 8°C; 36° 

to 46°F). 

Cefotetan 

Cefoxitin 

Ertapenem 

Yes 

Increase the 

frequency of 

administration. 

Yes 


≤50ml/min should 

have the frequency 

of administration 

increased. 

Yes 

Patients with a Cr. 

Cl ≤30ml/min and 

end-stage renal 

disease should 

receive a dose of 

500mg daily. 

No 

No 

No 

Safety and efficacy in 

children have not been 

established. 

Safety and efficacy of 

pediatric patients from 

birth to three months 

of age has not been 

established. In 

patients three months 

or older, higher doses 

of the drug have been 

associated with an 

increased incidence of 

eosinophilia and 

elevated SGOT. 


pediatric patients has 

not been established; 

use in patients under 

18 years of age is not 

recommended. 

B Cefotetan maintains potency for 24 

hours at room temperature (25°C; 

77°F), for 96 hours refrigerated 

(5°C; 40°F) and for 1 week frozen. 

After reconstitution and subsequent 

storage in disposable glass or plastic 

syringes, cefotetan is stable for 24 

hours at room temperature and 96 

hours refrigerated. 

B 

B 

Reconstituted vials maintain 

potency for six hours at room 

temperature or an additional 48 

hours under refrigeration. Further 

dilution maintains potency for an 

additional 18 hours at room 

temperature or an additional 48 

hours if refrigerated. 

Do not mix or co-infuse ertapenem 

with other medications. Do not use 

diluents containing dextrose. 

The reconstituted solution may be 

stored at room temperature and used 

within 6 hours or stored for 24 

hours under refrigeration and used 

within 4 hours after removal from 

refrigeration. Solutions should not 

be frozen. 

Loracarbef 

Yes 


between 10- 

49ml/min = ½ the 

recommended dose, 

Cr. Cl

Meropenem 

Yes 

Reduce dosage in 

patients with a Cr. 

Cl

VIII. Comparative Effectiveness of the Single Entity Miscellaneous β-Lactams 

Clinical trials confirm that multiple cephalosporins (cefprozil, cefpodoxime, cefixime, loracarbef, 

and ceftibuten) are as effective as traditional therapies for the management of acute otitis media, 

pharyngitis/tonsillitis, sinusitis, bronchitis, pneumonia, urinary tract infections, and skin and skinstructure 

infections. 12 Selection of a specific agent is influenced by susceptibility data and safety, 

as well as issues of compliance. Table 10 describes published, peer-reviewed trials of the drugs 

within this class. 

Table 10. Additional Outcomes Evidence for the Single Entity Miscellaneous β-Lactams 


Results 

Description 

General Comparative Class Studies 

In vitro study in 

multidrugresistant 

Ps. 

Seven 

strains of the 

bacteria 

aeruginosa 13 

All strains of Ps. 

Aeruginosa were 

resistant to piperacillin, 

The goal of this study was to examine the combined effects of antibiotic 

combinations by agar incorporation inhibitory tests and by time-kill tests on seven 

isolates of multidrug-resistant Ps. aeruginosa. Results indicated: 

meropenem, 

ceftazidime, 

cefoperazonesulbactam, 

• Among the two-drug combinations, the combination aztreonam and 

amikacin was the most effective, inhibiting proliferation in five of the 

seven strains. 

aztreonam, 

amikacin, and 

ciprofloxacin 

• Among the three-drug combinations, the combinations of piperacillin, 

ceftazidime and amikacin, and that of ceftazidime, aztreonam and amikacin 

were the most effective, inhibiting proliferation in all seven strains. 

• In the killing tests, the three-drug combination of ceftazidime, aztreonam 

and amikacin was the most effective. This three-drug combination had 

bacteriostatic effects on all seven strains 2, 4, 6 and 24 hours after drug 

addition, synergic effects on 2-3 strains and bactericidal effects on 

1-2 strains after 4, 6 and 24 hours. 

• Summary: The three-drug combination of ceftazidime, aztreonam and 

amikacin may be effective against P. aeruginosa resistant to all commonly 

used antipseudomonal drugs, and deserves further study. 

A surveillance 

study of 65 labs 

in the United 

States 14 - From 1998-2001 A surveillance study of 65 laboratories in the United States, looking at Pseudomonas 

aeruginosa and Acinetobacter baumannii showed: 

• Greater than 90% of isolates of Ps. aeruginosa from hospitalized patients 

were found to be susceptible to amikacin and piperacillin-tazobactam; 80 

to 90% of isolates to be susceptible to cefepime, ceftazidime, imipenem, 

and meropenem; and 70 to 80% of isolates to be susceptible to 

ciprofloxacin, gentamicin, levofloxacin, and ticarcillin-clavulanate. 

• From 1998 to 2001, decreases in antimicrobial susceptibility (percents) 

among non-intensive-care-unit (non-ICU) inpatients and ICU patients, 

respectively, were greatest for ciprofloxacin (6.1 and 6.5), levofloxacin 

(6.6 and 3.5), and ceftazidime (4.8 and 3.3). 

• Combined 1998 to 2001 results for A. baumannii isolated from non-ICU 

inpatients and ICU patients, respectively, demonstrated that >90% of 

isolates tested were susceptible to imipenem (96.5 and 96.6%) and 

meropenem (91.6 and 91.7%); fewer isolates from both non-ICU inpatients 

and ICU patients were susceptible to amikacin and ticarcillin-clavulanate 

(70 to 80% susceptible); and

Report from the 3,047 

MYSTIC 

bacterial 

Program 15 isolates 

collected in 

2002 from 

16 North 

America 

sites 

The Meropenem Yearly 

Susceptibility Test 

Information Collection 

Program 

The activity of meropenem and nine broad-spectrum antibiotics were assessed 

against 3,047 bacterial isolates: 

• The overall rank order of susceptibility of the 10 antimicrobial agents 

tested against Gram-negative isolates was: meropenem (98%) > imipenem 

(97%) > cefepime (95%) > tobramycin (93%) > piperacillin/tazobactam = 

gentamicin (92%) > ceftazidime (91%) > ciprofloxacin (87%) > aztreonam 

(86%) > ceftriaxone (74%). 

• The utility of meropenem against Pseudomonas aeruginosa isolates has 

increased steadily with a rise in percent susceptibility each year from 

78.2% in 1999 to a present rate of 93.1% susceptible. 

• The susceptibility for ciprofloxacin against the same P. aeruginosa isolates 

decreased from 82.9 to 72.3% susceptible over four years. 

• Carbapenem resistance remains rarely documented and these betalactamase-stable 

agents appear to be an alternative treatment option for 

serious community-acquired or nosocomial infections in high risk patient 

populations. 

Report from the 

SENTRY 

antimicrobial 

surveillance 

Program 16 

Report from the 

SENTRY 

antimicrobial 

surveillance 

Program 17 

Sustained 

activity and 

spectrum 

against 

Enterobacter 

spp. and 

Klebsiella 

spp. 

Geographic 

variations in 

activity 

against Ps. 

aeruginosa 

Meta-analysis of n=79 

randomized trials randomized 

of antibiotic clinical trials 

therapy in intraabdominal 

infections 18 

- In evaluating the rates and trend resistance to extended-spectrum beta-lactams and 

other antimicrobial agents to Enterobacter spp. and Klebsiella spp. isolated between 

1997 and 2000: 

• Among Enterobacter spp., resistance (MIC>or=32 mg/l) to aztreonam, 

ceftazidime and ceftriaxone ranged from 12.3 to 21.2% over the 4 years, 

whereas resistance in Klebsiella (MIC>or=2 mg/l) ranged from 5.9 to 

6.8%. 

• Carbapenems (imipenem, meropenem) and cefepime had excellent activity 

against both ceftazidime-susceptible and -resistant Enterobacter spp. and 

Klebsiella spp. (>99% susceptible), although the minimum inhibitory 

concentration values of cefepime were higher in ceftazidime-resistant 

isolates compared with ceftazidime-susceptible isolates. 

- In comparing the activities of cefepime and eight other β-lactams against 6,969 

isolates of Ps. aeruginosa collected during 1997-2000: 

• The beta-lactams exhibited a wide range of potency, with carbapenems 

most active (meropenem, 80-91% susceptible; imipenem, 76-88% 

susceptible). 

• Piperacillin/tazobactam was the most active penicillin (77-80% 

susceptible), and cefepime (67-83% susceptible) had an average 2% (range, 

0.7-3.5%) greater susceptibility rate than ceftazidime (66-80% susceptible) 

across all regions. 

• The rank order of beta-lactam activity according to percent resistant 

isolates in North American Ps. aeruginosa strains was: meropenem (4.8% 

resistant) > cefepime (6.8%) > imipenem (8.6%) > piperacillin/tazobactam 

(10.3%) > piperacillin (12.9%). Only 2.3% and 6.5% of isolates were 

resistant to amikacin or tobramycin, respectively, and nearly 16% of Ps. 

aeruginosa strains were resistant to ciprofloxacin. 

• Compared with other geographic regions, strains of P. aeruginosa remain 

most susceptible in North America. 

- In reviewing the published randomized studies looking at antibiotic use in intraabdominal 

infections: 

• Studies are limited due to a lack of disease severity stratification and a 

relatively small study population for most antibiotics. 

• The clinical success rate of the antibiotics studied in a larger population is 

comparable for gentamicin + clindamycin (80%), tobramycin + 

clindamycin (83%), meropenem (89%), imipenem (85%), aztreonam + 

clindamycin (89%), cefoxitin (88%), cefotetan (92%), moxalactam* (83%), 

cefotaxime + metronidazole (87%), ampicillin/sulbactam (87%). 

Piperacillin/tazobactam has in most studies a success rate of approximately 

90%. 

• The aggregated data on adverse events and clinical failure rate do not show 

a major advantage for any of these antibiotics. 

• The clinical success rate of the best-studied antibiotics is similar and the 

choice which antibiotic is used depends on the expected pathogens and the 

resistance rate in a clinical setting. 

141

Aztreonam Clinical Evidence 

In vitro synergy 

of aztreonam and 

quinolones 

40 strains of 

Ps. 

aeruginosa 

Broth microdilution was 

used to determine MICs 

Because aztreonam can be used in combination with other antibiotics to enhance 

antimicrobial spectrum and produce synergistic activity, the drug was studied in vitro 

with ciprofloxacin, gatifloxacin, levofloxacin, cefepime, ceftazidime, and imipenem: 

against gramnegative 

bacilli 19 

and Enterobacteriaceae 

• No antagonism or indeterminate interactions were identified between any 

of the combinations. 

• The overall rate of synergy or partial synergy for aztreonam with 

fluoroquinolone combinations was 63.4% versus P. aeruginosa, greatest 

for aztreonam with gatifloxacin (67.5%). 

• Aztreonam with ceftazidime or cefepime versus P. aeruginosa had 

75.0 - 85.0% partial or complete synergy rates, but aztreonam with 

imipenem showed dominant indifference (65.0%). 

• In contrast, aztreonam with imipenem was more likely to exhibit synergy 

(32.5%) when tested against Enterobacteriaceae. 

• Summary: Aztreonam, often used as an aminoglycoside substitute in 

antimicrobial combinations, continues to demonstrate enhanced, but 

variable drug activity interactions for contemporary antimicrobial 

combinations when tested against recent (2002) clinical isolates. 

The role of 

- reviewing the literature to determine the clinical efficacy of aztreonam: 

surgery patients 20 with the aminoglycosides. 

aztreonam in 

nosocomial 

pneumonia in 

• Numerous studies have documented that aztreonam’s effectiveness is equal 

of superior to that of other suitable antibiotics in the treatment of 

nosocomial pneumonia. 

critically ill 

• Aztreonam’s safety profile makes the drug especially attractive compared 

• Due to bacterial resistance with use of broader-spectrum alternatives, 

aztreonam is a sound choice as well for the treatment of nosocomial 

Cefepime vs. 

ticarcillin and 

clavulanate 

potassium plus 

aztreonam for 

febrile 

neutropenia 21 n=126 Open label, 

randomized, 

comparative trial 

Aztreonam vs. 

ampicillin, 

cotrimoxazole, 

minocycline, 

nalidixic acid, 

norfloxacin, 

ciprofloxacin, 

gentamicin, or 

ceftriaxone in the 

treatment of 

urinary tract 

infections 22 

Aztreonam plus 

clindamycin vs. 

tobramycin plus 

clindamycin for 

abdominal 

n=342 gramnegative 

isolates 

An in vitro study of the 

listed drugs’ efficacy on 

E. coli, Klebsiella 

pneumoniae, proteus 

species, and Ps. 

aeruginosa 

infections 23 n=70 The average length of 

treatment was 10 days 

(tobramycin and 

clindamycin group) and 

9 days (aztreonam and 

clindamycin group) 

pneumonia. 

In order to evaluate the efficacy of empiric applied cefepime (C) as monotherapy 

versus combination therapy consisting of ticarcillin and clavulanate potassium and 

aztreonam (T/A), patients were randomized to treatment: 

• Using afebrile status following 3 days of therapy as a primary endpoint, 

both regimens produced comparable clinical response rates (C = 55% vs. 

T/A = 61%). 

• Also, the use of vancomycin for resistant gram-positive infections and 

alteration of gram-negative infection coverage was similar in both groups 

(C = 40% vs. T/A = 47% and C = 29% vs. T/A = 24%). 

• Both treatment groups had similar needs for empirical antifungal therapy 

(C = 25% vs. T/A = 22%). 

• Treatment of febrile neutropenic patients with these two treatment 

regimens offers similar efficacy results. 

In evaluating the efficacy of aztreonam versus eight other antibiotic treatments for 

bacteria common to urinary tract infections: 

• Out of 342 isolates, 76.6% were E. coli, 14.3% were Klebsiella 

pneumoniae, 5.2 were proteus spp., and 3.8 were Ps. aeruginosa. 

• The aztreonam showed 78% sensitivity against gram-negative bacilli, 

which is better than norfloxacin, which showed 62.2% sensitivity. 

Patients with intraabdominal infections were randomly assigned in a double-blinded 

manner to receive tobramycin plus clindamycin (TM/C) or aztreonam plus 

clindamycin (AZ/C). Results indicated: 

• In approximately one-half of both groups, the source of infection was 

perforated colon or perforated appendix. 

• Clinical response to therapy did not differ, as 84% of the TM/C patients 

and 78% of the AZ/C patients had satisfactory clinical responses. 

• The two regimens differed in adverse effects, as an elevated PT/PTT was 

more frequently (p < 0.05) observed in AZ/C. All PT/PTT elevations 

responded to injections of vitamin K, and no serious bleeding occurred. 

• Choice between these regimens depends on differences in adverse effects, 

142

Randomized, 

comparative 

study of 

cefoxitin, 

cefotetan, and 

cefalotin* (1 st 

generation 

cephalosporin not 

available in the 

United States) 24 n=155 Randomized treatments 

included: Cefoxitin 3 x 

1g (14 subjects), 

Cefotetan 2 x 1g (43 

subjects), Cefalotin 3 x 

2g for 24 hours (27 

subjects), Cefalotin 3 x 

2g for 72 hours (41 

subjects) and a control 

group of 30 subjects 

without prophylaxis 

Retrospective 

analysis of 

antibiotic 

prophylaxis 

(cefotetan vs. 

cefoxitin) 

following 

cesarean section 25 n=385 Single doses of 

cefotetan 1g vs. 

cefoxitin 2g 

Randomized, 

double-blind, 

controlled study 

of ertapenem vs. 

piperacillintazobactam 

for 

skin/skin 

structure 

infections 26 n=146 Ertapenem 1g QD vs. 

piperacillin-tazobactam 

13.5g divided Q6H, 

duration infection 

dependent 

Randomized, 

double-blind 

study of 

ertapenem vs. 


for 

methicillinsusceptible 

Staphylococcal 

aureas in 

skin/skin 

structure 

infections 27 n=529 Ertapenem 1g QD vs. 


3.375g Q6H, duration 

infection dependent 

as both regimens appear equally effective for treatment of abdominal 

infections in conjunction with appropriate surgical intervention. 

Cefotetan and Cefoxitin Clinical Evidence 

In evaluating cefotetan, cefoxitin, and cefalotin efficacy in perioperative prophylaxis 

in abdominal gynecological prophylaxis: 

• No patients receiving any prophylaxis developed infectious complications, 

while such complications occurred in 10% of the control without 

prophylaxis. 

• Antibiotic prophylaxis effectively prevented the infectious complications 

and shortened the postoperative hospital stay. 

• Despite its narrower anti-bacterial spectrum cefalotin is not inferior in its 

efficacy to the second and the third-generation cephalosporins. 

• The longer 72-hour cefalotin scheme shows no advantages to the 24-hour 

frequency. 

In comparing single-dose antibiotic prophylaxis in various subpopulations based on 

risk factors for postsurgical infection following cesarean section: 

• Postsurgical infection rate was greater in non-elective cases, 7.4%, vs. 

elective cases, 3.0% (p =0.056) as was the rate of endometritis (3.2% vs. 

1.2%, p =0.185). 

• No differences were noted based on antibiotic regimen. 

• Postsurgical infection rate was greater for 28 cases at high risk for both 

surgical infection and endometritis (17.9%) when compared to all 357 

other cases (4.5%), p =0.003. No difference was noted for endometritis. 

• Of the 28 cases 28.6% of patients treated with cefoxitin and 7.1% of cases 

treated with cefotetan developed postsurgical infection (p =0.13). 

• Summary: Overall cefoxitin and cefotetan provided equivalent clinical 

outcome. A small subset of patients with multiple risk factors for infection 

may benefit from cefotetan. 

Ertapenem Clinical Evidence 

During a clinical trial of complicated skin/skin structure infections in patients who 

received outpatient antimicrobial therapy (OPAT) with either ertapenem or 

piperacillin-tazobactam: 

• In evaluable patients managed by OPAT, 45 (83.3%) of 54 treated with 

ertapenem and 41 (82.0%) of 50 treated with piperacillin-tazobactam were 

cured at the test of cure assessment 10-21 days post-therapy (OR 1.2 (95% 

CI, 0.4-3.2), p=0.78). 

• The safety profile of both drugs was generally similar; diarrhea was the 

most common adverse event in both groups. 

• Summary: Among patients who received OPAT, ertapenem 1g daily was 

as effective as piperacillin-tazobactam 3.375g Q6H. 

In this subset study, the efficacy of ertapenem was compared with piperacillintazobactam 

for the treatment of complicated skin/skin structure infections caused by 

methicillin-susceptible S. aureus (MSSA): 

• At the test of cure assessment 10-21 days post-therapy, 54 of 67 (80.6%) 

protocol evaluable patients in the ertapenem group and 55 of 68 (80.9%) in 

the piperacillin-tazobactam group were cured (odds ratio: 1.0 (95% 

confidence interval (CI): 0.4-2.4), p = 0.99). 

• In both treatment groups, cure rates were higher in patients with 

monomicrobial than polymicrobial infections, but the difference was not 

significant. 

• Summary: Therapy with ertapenem 1g daily was as effective as 

piperacillin-tazobactam 13.5g divided in four daily doses, in this subgroup 

analysis of patients with MSSA. 

Two randomized, 

double-blind, 

multicenter trial 

of ertapenem vs. 

ceftriaxone in 

UTI 28 n=480 Ertapenem 1g QD vs. 

ceftriaxone 1g QD; 

patients could switch to 

oral therapy after ≥3 

days of IV study 

therapy 

In treating complicated urinary tract infections in adults with ertapenem or 

ceftriaxone: 

• Ninety-six percent of these patients were switched to oral therapy, usually 

ciprofloxacin; the median (range) duration of parenteral and total therapy, 

respectively, was 4 (2-14) days and 13 (14-18) days for ertapenem and 4 

(2-14) days and 13 (3-17) days for ceftriaxone. 

• At the primary efficacy endpoint 5-9 days after treatment, 229 (89.5%) 

patients who received ertapenem and 204 (91.1%) patients who received 

143

ceftriaxone had a favorable microbiological response (95% confidence 

interval, -7.4 to 4.0), indicating that outcomes in the two treatment groups 

were equivalent. 

• Success rates in both treatment groups were similar when compared by 

stratum and severity of infection. 

• The frequency and severity of drug-related adverse events were generally 

similar in both treatment groups. 

Post-hoc analysis 

of data from three 

large randomized, 

double-blind 

trials of 

ertapenem vs. 


n=1,558 Ertapenem 1g QD vs. 


3.375g Q6H; duration 

infection dependent 

In vitro 

n=482 

susceptibility of strains of 

antibioticresistant 

urinary pathogens 

urinary 

pathogens to 

ertapenem and 12 

other antiibotics 30 

Susceptibility testing of 

identified pathogens to 

ertapenem, ampicillin, 

cefazolin, cefuroxime, 

cefotaxime, 

amoxicillin/clavulanate 

acid, 

piperacillin/tazobactam, 

imipenem, gentamicin, 

amikacin, fosfomycin, 

ciprofloxacin, and cotrimoxazole 

Prospective, 

randomized, 

double-blind 

multicenter 

comparison of 

ertapenem vs. 

ceftriaxone in 

CAP 31 n=364 Ertapenem 1g QD vs. 

ceftriaxone 1g QD; 

durations of parenteral 

and total therapy were 

5.5 and 11.5 days for 

ertapenem and 5.6 and 

11.7 for ceftriaxone 

In evaluating the efficacy of ertapenem versus piperacillin-tazobactam for the 

treatment of polymicrobial complicated intra-abdominal, complicated skin/skin 

structure infections, and acute pelvic infections: 

• At the test-of-cure assessment, there were no significant differences in 

outcomes between the two treatment groups for any of the three infections. 

• Cure rates (clinical and microbiological for intra-abdominal infection, 

clinical for skin/skin-structure and pelvic infections) in microbiologically 

evaluable patients for ertapenem and piperacillin-tazobactam, respectively, 

were 85.6% (154/180 evaluable patients) and 82.5% (127/154) for 

polymicrobial intra-abdominal infection, 80.3% (53/66) and 78.7% (48/61) 

for polymicrobial skin/skin-structure infection, and 95.7% (88/92) and 

92.6% (88/95) for polymicrobial pelvic infection. 

• Respective cure rates for all evaluable patients in the original trials were: 

83.6% and 80.4% for intra-abdominal, 83.9% and 85.3% for skin/skinstructure, 

and 93.9% and 91.5% for pelvic infections. 

• Summary: These data show that in the three trials, ertapenem 1g once a 

day was highly effective for the treatment of polymicrobial infections and 

as effective as piperacillin-tazobactam 3.375g every 6 hours. 

In testing the in vitro susceptibility of urinary pathogens to that of the drugs listed in 

the previous column: 

• The distribution of pathogens tested was as follows: Escherichia coli (n = 

315), Proteus mirabilis (n = 42), Klebsiella spp. (n = 14) and AmpCproducing 

Enterobacteriaceae (n = 111). 

• All the strains were susceptible to ertapenem, imipenem and amikacin. 

• The MIC(90) of ertapenem ranged from a minimum of 0.03mg/L for 

Proteus vulgaris and a maximum of 1mg/L for Enterobacter spp. 

Ertapenem was the most active of all drugs tested in all cases. 

• On comparing antibiotic resistance among ESBL-producing strains of E. 

coli (n = 35) and E. coli strains not producing ESBLs (n = 280), 

statistically significant differences were obtained for ciprofloxacin (P = 

0.002) and gentamicin (p = 0.011). 

• Regarding ertapenem, only a slight increase in MIC(50) was seen, the 

value being 0.015mg/L for strains not producing ESBLs versus 0.03mg/L 

for ESBL-producing strains. 

In order to compare the efficacy and safety of ertapenem and ceftriaxone for the 

treatment of hospitalized adult patients with serious community-acquired pneumonia 

(CAP) requiring IV therapy: 

• Streptococcus pneumoniae was the most frequently isolated pathogen in 

both treatment groups. 

• Cure rates were 92.2% for clinically evaluable patients in the ertapenem 

group and 93.6% for those in the ceftriaxone group (95% CI for the 

difference, adjusted for stratum, -8.6 to 5.7), fulfilling the criteria for 

statistical equivalence. 

• At completion of parenteral therapy, 94.7% of patients in the ertapenem 

group and 95.8% in the ceftriaxone group showed clinical improvement. 

• Infused vein complications (ertapenem, 3.4% [8/236]; ceftriaxone, 7.3% 

[9/123]) and elevated transaminase levels (ertapenem, 6.3% [13/207]; 

ceftriaxone, 7.1% [8/113]) were the most common adverse events in both 

groups. 

• Summary: In this study, ertapenem therapy, with an oral switch option, 

was as effective as ceftriaxone with the same oral switch option for 

treatment of CAP requiring initial parenteral therapy. The overall safety 

profiles of the two drugs were comparable. 

144

Randomized, 

double-blind, 

multicenter study 

comparing 

loracarbef vs. 

doxycycline for 

acute bacterial 

maxillary 

sinusitis 32 n=662 Loracarbef 400mg BID 

or doxycycline 200mg x 

1 followed by 100mg 

QD, for 10 days 

Loracarbef vs. 

cefaclor and 

norfloxacin in the 

treatment of 

uncomplicated 

pyelonephritis 33 n=245 Loracarbef 400mg BID 

vs. cefaclor 500mg 

TID, and loracarbef 

400mg BID vs. 

norfloxacin 400mg 

BID; treatment was 

continued for ≥14 days 

Randomized, 

double-blind, 

parallel study of 

loracarbef vs. 

penicillin V 34 n=344 Ten day therapy with 

loracarbef (200mg BID 

or 15mg/kg/day oral 

suspension in two 

divided doses up to a 

maximum of 

375mg/day) vs. 

penicillin V (250mg 

QID or 20mg/kg/day 

suspension in four 

divided doses up to a 

maximum of 

500mg/day) 

Randomized, n=214 

double-blind trial children 

of loracarbef vs. ages 6 

cefaclor in months to 12 

pediatric patients years 

with skin and 

skin structure 

infections 35 

Oral suspensions given 

for 7 days at 

15mg/kg/day in two 

divided doses for 

loracarbef and 

20mg/kg/day in three 

divided doses for 

cefaclor 

Loracarbef Clinical Evidence 

In evaluating the efficacy of loracarbef vs. doxycycline in the treatment of acute 

maxillary sinusitis: 

• Streptococcus pneumoniae and/or Haemophilus influenzae were isolated 

from approximately 75% of patients. 

• The clinical response rate (cure or improvement) was significantly higher 

for patients receiving loracarbef (98.2%) than for those who received 

doxycycline (92.2%). 

• There was no significant difference between the two groups with respect to 

bacteriological outcome, although more of the pre-treatment isolates were 

resistant to doxycycline (35 strains) than to loracarbef (five strains). 

• Adverse events related to the gastrointestinal tract occurred in 11.7% and 

10.6% of loracarbef- and doxycycline-treated patients respectively; therapy 

was terminated prematurely in ten patients in the loracarbef group and in 

nine in the doxycycline group. 

Because conventional oral antibiotics such as the sulfonamides and the 

aminopenicillin are limited by development of resistance, the therapeutic efficacy of 

loracarbef was compared with cefaclor and norfloxacin in two trials: 

• Escherichia coli was the causative pathogen in 85.0% of these patients. 

• Successful post therapy clinical and bacteriologic responses were similar 

for all three study drugs: 94.1 and 86.8%, 96.0 and 80.0%, 97.7 and 88.4% 

for loracarbef, cefaclor, and norfloxacin, respectively. 

• Late post therapy clinical responses were 87.4, 83.3, and 91.7% for the 

loracarbef, cefaclor, and norfloxacin groups, respectively. Bacteriologic 

responses for the three groups were 79.6, 60.0, and 88.9%. 

• The most frequent adverse effects (headache, diarrhea, and nausea) were 

experienced by three patients (2.5%) in the loracarbef group; headaches 

were noted in two (4.7%) cefaclor patients, and diarrhea was noted in three 

(7.0%) patients in the cefaclor group. Gastrointestinal events were noted in 

four patients (4.8%) in the norfloxacin group. 

• Summary: Loracarbef is comparable in efficacy and safety to both cefaclor 

and norfloxacin as oral therapy for uncomplicated pyelonephritis. 

In the treatment of Group A beta-hemolytic streptococcal (GABHS) pharyngitis and 

tonsillitis, therapeutic efficacy of loracarbef and penicillin V was evaluated: 

• Post-therapy clinical responses were similar for evaluable patients in both 

treatment groups: 97.4% of the loracarbef group (101/115 patients cured 

and 11/115 improved) and 96.0% of the penicillin group (101/124 patients 

cured and 18/124 improved). 

• A statistically significant difference in the pathogen elimination rate was 

noted between treatment groups: post-therapy throat cultures were negative 

for GABHS in 94.8% (109/115) of loracarbef-treated patients compared 

with 87.1% (108/124) of penicillin-treated patients (p = 0.040). 

• Loracarbef and penicillin V were comparable in terms of safety. 

• Summary: Loracarbef twice daily is more effective in eradicating GABHS 

than penicillin V four times daily, and the two drugs are comparable in 

safety. 

In comparing the safety and efficacy of loracarbef and cefaclor for the treatment of 

skin and skin structure infections in children: 

• Assessment 72 hours after completion of the 7-day course of treatment 

indicated a favorable clinical response plus eradication of the pretherapy 

pathogen in 97.3% of the 74 loracarbef-treated patients eligible for 

evaluation and 92.3% of 78 evaluable cefaclor-treated patients. 

• Favorable response rates at a second post treatment visit 10 to 14 days after 

the end of therapy were 95.6% in 68 evaluable loracarbef-treated patients 

and 86.2% in 65 treated with cefaclor. 

• The incidence of adverse reactions, including gastrointestinal effects, was 

low in both groups. 

• No statistical difference in clinical or bacteriologic efficacy or safety was 

detected between patients treated with loracarbef and cefaclor. 

145

In vitro activity 

and 

pharmacodynami 

cs of oral betalactam 

antibiotics 36 - MICs were determined 

for penicillin, 

amoxicillin, 

amoxicillin-clavulanic 

acid, cefprozil, 

cefuroxime, 

cefpodoxime, cefaclor, 

and loracarbef 

Two multicenter, 

randomized, 

single-masked, 

trial of loracarbef 

vs. clarithromycin 

in children with 

acute otitis 

media 37 n=334 Loracarbef 15mg/kg or 

clarithromycin 

7.5mg/kg orally BID for 

10 days 

Randomized, 

double-blind, 

multicenter trial 

of cefdinir vs. 

loracarbef for 

exacerbations of 

chronic 

bronchitis 38 n=586 Cefdinir 300mg BID for 

five days or loracarbef 

400mg BID for seven 

days 

In evaluating the frequency and reduced susceptibility to penicillin, and to compare 

the in vitro activity and pharmacodynamics of oral β-lactam antibiotics against 

clinical isolates of Streptococcus pneumoniae: 

• The frequency of penicillin nonsusceptible S. pneumoniae was 28.7%. 

• For 25 penicillin-intermediate isolates, amoxicillin and amoxicillinclavulanic 

acid were significantly more active than cefprozil, cefaclor, and 

loracarbef. 

• The T > MIC (average time above MIC) for amoxicillin and amoxicillinclavulanic 

acid, simulated at 13.3mg/kg every 8 hours, was significantly 

longer than that for all other beta-lactams. 

• Summary: Amoxicillin and amoxicillin-clavulanic acid have superior in 

vitro activity and longer T > MIC for penicillin-intermediate isolates than 

the other oral beta-lactams. 

In order to evaluate loracarbef with clarithromycin with regard to efficacy, 

tolerability, and patient acceptance, two studies were performed in children aged 6 

months to 3 years: 

• The combined results of these two studies showed that the efficacy and 

tolerability of loracarbef were comparable to those of clarithromycin. 

• Adverse events were reported by 46.4% of loracarbef patients and 41.0% 

of clarithromycin patients, with no statistically significant difference 

between groups. 

• In the intent-to-treat analysis, 57.9% of loracarbef patients were cured at 

the termination of the study, compared with 55.7% of clarithromycin 

patients. 

• Improvement was seen in 4.1% of loracarbef patients and 2.7% of 

clarithromycin patients. 

• Results of the patient acceptance survey showed a clear preference for 

loracarbef over clarithromycin. 

• Difficulties with administration of treatment were reported by 36.3% of 

clarithromycin caregivers, compared with 7.8% of loracarbef caregivers 

(p < 0.001). 

• A desire to stop treatment was reported by 23.8% of clarithromycin 

caregivers, compared with 7.8% of loracarbef caregivers (p < 0.001). 

• Taste and texture issues were most frequently cited as reasons for 

nonacceptance. 

In comparing the clinical efficacy of cefdinir versus loracarbef for the treatment of 

chronic bronchitis: 

• The clinical cure rates were 86% (138/160) and 85% (141/166) for the 

evaluable patients treated with cefdinir and loracarbef, respectively. 

• Respiratory tract pathogens were isolated from 457 (78%) of 586 

admission sputum specimens, with the predominant pathogens being 

Haemophilus parainfluenzae, H. influenzae, Moraxella catarrhalis and 

Staphylococcus aureus. 

• The microbiological eradication rates at the test-of-cure visit were 88% 

(193/219 pathogens) and 90% (227/251 pathogens) for the evaluable 

patients treated with cefdinir and loracarbef, respectively. 

• Adverse event rates while on treatment were 30% and 21% for cefdinirand 

loracarbef-treated patients, respectively. 

Blinded taste 

comparison of 

twelve common 

pediatric drugs 39 - - In evaluating the taste of twelve antimicrobial suspensions with regards to smell, 

texture, taste, aftertaste, and overall acceptance: 

• Overall, loracarbef scored highest but not significantly higher than Keflex, 

Suprax and Ceclor, all of which score higher than the other test drugs. 

• Cefzil and Augmentin scored just below this group of drugs and higher 

than all other test drugs. 

• Vantin was inferior to these drugs primarily because of its low score in 

aftertaste. It was ranked along with V-Cillin-K, Veetids, Sulfatrim and 

Pediazole, the lowest scoring group of drugs other than Dynapen, which 

scored lower than all other test drugs. 

• No difference overall was detected between the two penicillin VK 

suspensions evaluated, V-Cillin-K and Veetids. 

146

n=900 

Meropenem Clinical Evidence 

In vitro activity 

- To compare the in vitro activity of meropenem with that of other agents with a broadspectrum 

of meropenem 

and other broadspectrum 

antibiotics 40 isolates 

(including 

multiresistant, 

of antibacterial activity: 

• The potency and spectrum 

and anaerobes, were undoubtedly 

beta-lactamases. 

of the carbapenems, unequalled against aerobes 

influenced by their stability to serine 

grampositive 

aerobes, 

• Meropenem and imipenem exhibited essentially the same spectrum of 

activity but imipenem was often less potent, notably against Gram-negative 

aerobes, including Pseudomonas aeruginosa and Burkholderia cepacia. 

Enterobacteriaceae, 

and, to some extent, the newer cephalosporins (MIC90s 0.06--8mg/L) and 

• Conversely, the activity of the third-generation (MIC90s 0.016--64 mg/L) 

nonfermenters, 

many genera of Enterobacteriaceae because of chromosomally mediated 

the augmented penicillins (MIC90s 1 to >128mg/L) was unreliable against 

and 

enzymes or the, now commonplace, plasmid-mediated beta-lactamases. 

anaerobes 

• Ciprofloxacin had modest activity (MIC90s 1--64mg/L) against Grampositive 

aerobes, was potent against nutritionally fastidious species, had 

again variable activity against the Enterobacteriaceae (MIC90s 0.008-- 

4mg/L) and was inactive against many strains of Pseudomonas, 

Burkholderia and Acinetobacter, resulting in MIC90s of 4 to >128mg/L. 

• The aminoglycosides were impressive only against the Enterobacteriaceae, 

with amikacin alone active (MIC90s 2--8mg/L) against the 11 species 

tested. 

• Summary: The study suggests also that, judged on activity in vitro, 

meropenem or imipenem are the only monotherapy options for empirical 

antibacterial therapy of polymicrobic infections or when local 

epidemiology indicates the predominance of multiresistant 

Enterobacteriaceae. Instability to current and emerging beta-lactamases is 

progressively compromising the use of all other beta-lactam compounds. 

Stability of 

antipseudomonal 

β-lactams with 

portable 

elastomeric 

pumps 41 - Aztreonam (100 g/liter), 

piperacillin (128 g/liter, 

with tazobactam), 

azlocillin (128 g/liter), 

mezlocillin (128 

g/liter), ceftazidime 

The stability of antipseudomonal beta-lactams in concentrated solutions was 

examined in view of their potential administration by continuous infusion with 

external pumps in patients with cystic fibrosis: 

• Aztreonam, piperacillin /tazobactam, and azlocillin* remained 90% stable 

for up to more than 24 hours at 37 degrees C (mezlocillin was stable at 

degrees C but not at 37 degrees C). 

25 

(120 g/liter), 

cefpirome* (32 g/liter), 

and cefepime (50 

g/liter) 

• Ceftazidime, cefpirome*, and cefepime (50 g/liter) remained 90% stable 

for up to 24, 23.7, and 20.5 hours at 25 degrees C but only for 8, 7.25, and 

13 hours at 37 degrees C, respectively. The control of temperature 

therefore appears to be critical for all three cephalosporins that cannot be 

recommended for use in portable pumps carried under clothes for 

prolonged periods for reasons of stability. 

• Imipenem and meropenem were too unstable (10% degradation at 25 

degrees C after 3.5 and 5.15h, respectively) to be recommended for use by 

Meropenem vs. 

ceftazidime 

monotherapy for 

cancer patients 

with chemoinduced 

febrile 

neutropenia 42 n=99 Duration dependent on 

response and severity of 

neutropenia 

Randomized, 

controlled trial of 

meropenem 

versus imipenem/ 

cilastatin 43 n=182 Meropenem 500mg 

Q12 (or 1g Q12 if 

necessary) or 

imipenem/cilastatin 

500mg Q12 (or 1g Q12 

if necessary), for a 

duration of 7-14 days 

continuous infusion. 

Patients (hospitalized for fever > 38 degrees C and ANC ≤ 500/cmm) were 

prospectively treated with meropenem, while their outcome was compared to patients 

treated with ceftazidime for the same indication: 

• Duration of fever, duration of neutropenia, and number of patients with 

pyrexia of undetermined origin were also similar. 

• Therapeutic outcome was the same between the two groups. 

• Eighty-four percent of patients receiving meropenem and 79% receiving 

ceftazidime required no modification of the initially assigned therapeutic 

regimen. 

In evaluating the efficacy and safety of meropenem versus imipenem/cilastatin in 

patients with lower respiratory tract infections, urinary tract infections, and other 

infections: 

• The overall efficacy rates were 90% for the meropenem group and 87% for 

the imipenem/cilastatin group, and the bacterial eradication rates were 86% 

in both groups. 

• The adverse drug reaction rates were 9.7% and 8.6%, respectively. 

• The results showed that there were no statistical differences between these 

two groups (p > 0.05). 

147

Randomized, 


meropenem vs. 

imipenem in the 

prophylactic 

treatment of 

septic 

complications of 

acute 

pancreatitis 44 n=176 Meropenem 500mg TID 

vs. imipenem 500mg 

QID 

In vitro activity - Multidrug-resistant Ps. 

ciprofloxacin 45 

of combo therapy 

aeruginosa isolates 

with cefepime, 

were studied by the 

piperacillin/tazob 

time-kill method 

actam, or 

meropenem with 

In looking at the efficacy of meropenem and imipenem in the treatment of severe 

acute pancreatitis: 

• No difference was observed between patients treated with meropenem and 

those treated with imipenem in terms of incidence of pancreatic infection 

(11.4% versus 13.6%) and extrapancreatic infections (21.6% versus 23.9%) 

and clinical outcome. 

• Summary: Meropenem is as effective as imipenem in preventing septic 

complications of patients with severe acute pancreatitis. 

In order to determine the in vitro effects of combinations of meropenem, cefepime, 

and piperacillin-tazobactam with ciprofloxacin against multidrug-resistant Ps. 

aeruginosa: 

• The results show that both the combination of two β-lactams with 

ciprofloxacin and three β-lactams with ciprofloxacin against 4 of 5 

multidrug-resistant P. aeruginosa strains has no effect in vitro. 

• The combination of one β-lactam (meropenem, cefepime, and piperacillintazobactam) 

with ciprofloxacin has a synergistic effect against one strain of 

multidrug-resistant P. aeruginosa that is ciprofloxacin susceptible and 

resistant to meropenem, cefepime, and piperacillin-tazobactam. 

• None of the combinations had an antagonistic effect against these 

multidrug-resistant strains. 

Meropenem vs. n=54 

combination pediatric 

therapy with cancer 

ceftazidime plus patients 

amikacin for 

pediatric cancer 

patients with 

neutropenia 46 

Results of the 

Meropenem 

Yearly 


Test Information 

Collection 

(MYSTIC) 

Program 47 

n=2,874 

strains 

processed 

from 15 U.S. 

medical 

centers 

- In evaluating the febrile episodes in pediatric cancer patients treated with meropenem 

or ceftazidime plus amikacin as empirical therapy: 

• The success rate with unmodified therapy was not significantly different 

between the meropenem group (72%) and the ceftazidime-plus-amikacin 

group (57%). 

• The incidence of side effects was similar between the two groups and these 

side effects were reversible. 

• The clinical response rates in subgroups of documented infection and 

unexplained fever did not significantly differ between the two treatment 

groups. 

• Meropenem was significantly more effective than ceftazidime plus 

amikacin in children at high risks of developing severe infection who had 

profound neutropenia (absolute neutrophil count [ANC] < 100/mm 3 ), 

prolonged neutropenia (ANC < 500/mm 3 lasting for > 10 days), or 

clinically deteriorating shock (p=0.045). 

• Summary: As an empirical treatment, meropenem seems to be as effective 

and safe as ceftazidime plus amikacin for febrile episodes in children with 

cancer and neutropenia. Meropenem is more effective for pediatric cancer 

patients at the high risk of severe infection. 

- To monitor in vitro activity of meropenem and other broad-spectrum antimicrobial 

agents, in institutions where meropenem is the primary therapeutic carbapenem: 

• The meropenem MIC(90) values were 0.03mg/l for Citrobacter spp., 

Escherichia coli and Klebsiella spp.; 0.06mg/l for Proteus mirabilis and 

Serratia spp. and 0.12 mg/l for Enterobacter spp. This potency was 8 to 16- 

fold greater than that of imipenem. The meropenem spectrum of activity 

versus the Enterobacteriaceae was the broadest of all tested antimicrobial 

agents. 

• Only piperacillin/tazobactam (MIC(9), 64mg/l) and tobramycin (MIC(90), 

4mg/l) were active against more than 90.0% of Pseudomonas aeruginosa at 

the NCCLS susceptible breakpoint, and the carbapenems were the most 

active compounds against Acinetobacter spp. 

• However, Acinetobacter spp. isolates were resistant to all of the 

antimicrobial agents tested and the molecular typing results suggested that 

they were epidemiologically related. 

• Only ciprofloxacin and ceftazidime had significantly reduced activity 

against oxacillin-susceptible staphylococci (87.9-92.6% susceptible). 

• Summary: These 2001 US MYSTIC Program results demonstrated no 

significant decline in carbapenem susceptibility rates compared with the 

previously monitored years. Most apparent were the decreasing 

susceptibility rates for ciprofloxacin and ceftazidime against staphylococci. 

148

Randomized, 

multicenter, 

open-label study 

of meropenem vs. 

imipenem/ 

cilastatin for 

serious intensive 

care unit 

infections 48 n=178 - In comparing the efficacy and tolerability of meropenem and imipenem/cilastatin as 

empirical monotherapy in intensive care unit (ICU) patients with serious bacterial 

infections: 

• The overall satisfactory clinical response rate at the end of randomized 

treatment was 77.0% (67/87) with meropenem and 68.1% (62/91) with 

imipenem/cilastatin (difference 8.9%; 95% confidence interval -4.2% to 

21.9%; p = 0.185). 

• The two drugs produced similar satisfactory clinical response rates against 

lower respiratory infections: 68.3% (41/60) with meropenem versus 68.6% 

(35/51) with imipenem/cilastatin. 

• Meropenem appeared to be slightly more effective against intra-abdominal 

infections: 95.5% (21/22) versus 76.7% (23/30), respectively. 

• All five meropenem recipients with sepsis had a satisfactory clinical 

response, compared to 40.0% (4/10) of those who received 

imipenem/cilastatin. 

• The overall satisfactory bacteriologic response rate was 67.1% (49/73) with 

meropenem and 60.3% (44/73) with imipenem/cilastatin (difference 6.9%; 

95% confidence interval -8.7% to 22.4%; p = 0.389). 

• No incidences of drug-related nausea and vomiting were reported, but one 

probable drug-related seizure occurred in the imipenem/cilastatin group. 

• Summary: Meropenem is at least as efficacious (clinically and 

bacteriologically) as imipenem/cilastatin for the empirical monotherapy of 

serious bacterial infections in ICU patients, and it can therefore be 

The Meropenem 

Yearly 


Test Information 

Collection 

(MYSTIC) 

Program 49 

n=2,848 

isolates 

Antimicrobial activity 

of 11 broad-spectrum 

agents was assessed 

considered a useful option in this setting. 

In evaluating the spectrum of activity and potency of meropenem within medical 

centers where carbapenems are used for the treatment of serious infections: 

• The minimum inhibitory concentration (MIC) results demonstrate the 

continued high potency of meropenem against all monitored pathogens. 

• Against all gram-negative bacilli tested, the overall rank order of 

susceptibility was meropenem (96.3%) > imipenem (95.6%) > cefepime 

(93.7%) > tobramycin (91.9%) > piperacillin/tazobactam (90.2%) > 

ceftazidime (90.1%) > gentamicin (89.6%) > levofloxacin (82.8%) > 

ciprofloxacin (82.5%) > aztreonam (81.8%) > ceftriaxone (72.3%). 

Meropenem in n=62 

cystic fibrosis patients with 

patients with cystic 

resistant Ps. fibrosis 

aeruginosa 50 

*Product not approved in the United States. 

Meropenem 2g TID for 

14 days 

To assess the efficacy and safety of meropenem, administered on a compassionate 

basis in cystic fibrosis patients chronically infected with Ps. aeruginosa: 

• During treatment for P. aeruginosa the mean increase in pulmonary 

function (as a percentage of the predictive values) was 5.6% for FEV1 

(forced expiratory volume in the first second) and 8.6% for FVC (forced 

vital capacity). 

• C-reactive protein and erythrocyte sedimentation rate (ESR) and leukocyte 

count decreased significantly. 

• In courses administered for chronic infection with B. cepacia the post 

treatment FEV1 and FVC values were higher than the pre-treatment values, 

and all the inflammatory parameters decreased. 

• The geometric means of minimal inhibitory concentration (MICs) 

(microg/mL) for P. aeruginosa (B. cepacia) were: tobramycin 6 (59), 

ciprofloxacin 1.2 (9.7), piperacillin 49 (16.3), ceftazidime 26 (23), 

aztreonam 26 (35), imipenem 6.4 (not determined) and meropenem 5.1 

(4.8). 

• No statistically significant increase in the MICs of meropenem for either 

pathogen occurred during therapy. 

• Of the 124 courses, 115 were tolerated without any clinical complaint. The 

following side effects were observed: nausea (0.8%), itching (4%), rash 

(3.2%), and drug fever (1.6%). 

• Summary: Meropenem proved to be a valuable drug in the treatment of CF 

patients with chronic pulmonary infection with multiresistant P. 

aeruginosa and B. cepacia and with hypersensitivity reactions to other 

beta-lactam drugs. 

149


Dose Simplification: The drugs in this class are for serious bacterial infections. Most 

frequently, the IV therapies are given during hospitalization or via nursing care within extended 

care facilities. There are no alternative dosing options for most drugs in this class. Additionally, 

the only oral medication in this class, loracarbef, is given twice daily. Ertapenem (QD) has a less 

frequent dosing regimen compared to meropenem (Q8). A literature search did not reveal data 

that has looked at the impact of a less frequent dosing regimen and impact on the outcome of the 

infectious disease. 

Stable Therapy: Not applicable. Some studies presented above have addressed resistance with 

drugs in this class. 

Impact on Physician Visits: Due to the nature of the use of the drugs in this class, and to their 

indications, no published studies have evaluated the impact of use of these drugs on physician 

visits. A search of Medline and Ovid did not reveal data pertinent to this topic. 

IX. 

Conclusions 

The drugs in this class are indicated for use in conditions from septicemia, to intra-abdominal 

infections and meningitis. These drugs would not routinely be used as first-line therapies on an 

outpatient basis. Aztreonam may be an alternative to the use of aminoglycosides, especially for 

use against atypicals and in patients with allergies to other antibiotics with gram-negative 

coverage. Clinical studies have shown ertapenem to be comparable to piperacillin/tazobactam and 

ceftriaxone (depending on the use). Ertapenem does have once-daily dosing, where meropenem 

and imipenem/cilastatin are dosed more frequently. The most common use for cefotetan and 

cefoxitin is in surgery prophylaxis and abdominal or gynecological infections. Loracarbef has a 

spectrum of coverage similar to cefaclor, a 2 nd generation cephalosporin, which is available 

generically. 51 Studies have shown loracarbef to have similar efficacy compared to doxycycline, 

norfloxacin, clarithromycin, and cefdinir. Treatment with meropenem is an option for empiric 

therapy in polymicrobic infections or with multi-resistant organisms, and studies have shown 

meropenem to be comparable or as effective as imipenem/cilastatin. 

In most cases, the drugs in this class are given to hospitalized patients, due to the serious nature of 

the indications and their injectable availability (with the exception of loracarbef). It is not, 

however, out of the question that a recipient could be discharged from a hospital institution to an 

extended-care facility or home, where antibiotic therapy could be continued for the remainder of 

the treatment course. In the event this does occur, the patient should be allowed to continue 

therapy with the same antibiotic. 

Although there may be some clinical advantage to drugs in this class in special 

needs/circumstances, this would not be considered applicable in general use. Therefore, all brand 

products within the class reviewed are comparable to each other and to the generics in the class 

and offer no significant clinical advantage over other alternatives in general use. 


No brand single entity miscellaneous β-lactam antibiotic is recommended for preferred status. 

150



Pharmacotherapy Review of the Miscellaneous β-Lactam Antibiotics 

Combination Agents 

AHFS 081207 

I. Overview 

Imipenem is a beta-lactam antibiotic derived from thienamycin and was the first drug to be 

classified as a carbapenem antibiotic. It is the only combination miscellaneous β-lactam drug 

available. Cilastatin is added to imipenem as an inhibitor of dehydropeptidase-1, an enzyme 

found in the renal tubule border that metabolizes imipenem. 6 Without cilastatin, imipenem is 

rapidly metabolized and causes toxicity to the proximal tubule. Cilastatin itself has no 

antibacterial activity. Imipenem possesses several traits that make it an effective antibiotic 

including: a) more efficient penetration through the bacterial cell wall, b) resistance to bacterial 

enzymes, and c) affinity for all bacterial PBPs. Imipenem has a broader spectrum of activity than 

do many other β-lactam antibiotics. Clinically, the combination of imipenem-cilastatin is used to 

treat severe or resistant infections, especially those that are nosocomial in origin. The FDA 

approved imipenem-cilastatin in November 1985. There is no generic formulation available for 

imipenem/cilastatin. This review encompasses all dosage forms and strengths. 

Table 1. Combination Misc. B-Lactam Antibiotics in this Review 

Generic Name β-Lactam Classification Formulation Example Brand Name 

Imipenem/cilastatin Carbapenem Injection (IV and IM) Primaxin 

Table 2. Comparison of Bacterial Coverage of Imipenem/cilastatin 5 

Drug 

Spectrum 

Imipenem Cilastatin is added as an inhibitor of dehydropeptidase-1, an enzyme found in the 

renal tubule border that metabolizes imipenem. Without cilastatin, imipenem is 

rapidly metabolized and causes toxicity to the proximal tubule. Cilastatin itself has 

no antibacterial activity. Imipenem possesses several traits that make it an effective 

antibiotic including: a) more efficient penetration through the bacterial cell wall, b) 

resistance to bacterial enzymes, and c) affinity for all bacterial penicillin binding 

proteins (PBPs). Imipenem has a broader spectrum of activity than do many other 

β-lactam antibiotics. Clinically, the combination of imipenem-cilastatin is used to 

treat severe or resistant infections, especially those that are nosocomial in origin. 

Imipenem is active against a wide variety of organisms. The gram-positive 

organisms susceptible to imipenem include Enterococcus faecalis, group A, C, and 

G streptococci, Streptococcus pneumoniae, and group D enterococci as well as the 

penicillinase- and nonpenicillinase-producing staphylococci and Listeria 

monocytogenes. In vitro, imipenem is inactive against Enterococcus faecium. 

Activity against methicillin-resistant strains of staphylococci is variable but, it is 

recommended that these strains be reported as resistant to imipenem. Imipenem's 

gram-negative spectrum includes N. meningitidis, N. gonorrhoea, H. influenzae, 

Branhamella catarrhalis, Acinetobacter, Aeromonas hydrophila, Campylobacter 

jejuni, Pasteurella multocida, and most Enterobactericeae (E.coli, Klebsiella, 

Citrobacter, Eneterobacter, Morganella, Proteus, Providencia, Serratia, 

Salmonella, Shigella, and Yersinia). Imipenem has exceptional stability against β- 

lactamases. It is highly active against Enterobacteriaceae that are resistant to thirdgeneration 

cephalosporins. Also, imipenem exhibits good activity against 

Pseudomonas aeruginosa, similar to that of ceftazidime. However, imipenem is 

inactive in vitro against Xanthomonas (Pseudomonas) maltophillia and some strains 

of P. cepacia. The anaerobic spectrum of imipenem includes Bacteriodes fragilis, 

Clostridium perfringens, Clostridium tetani, and Peptococcus and 

Peptostreptococcus species. 

151

II. 

Indications of the Combination Miscellaneous β-Lactam Antibiotics 

Table 3. FDA-Approved Indications for the Combination Miscellaneous β-Lactams 5-8 

Drug UTI Lower 

RTI 

Gynecologic 

Infections 

Septicemia 

Imipenem/ 

Cilastatin 

✔ 

Complicated 

and 

uncomplicated 

Intraabdominal 

Infections 

* May use IM route for non life-threatening infections. 

Bone and 

Joint 

Infections 

Skin and 

Skin 

Structure 

Infections 

Endocarditis 

Polymicrobic 

Infections 

✔* ✔* ✔* ✔ ✔ ✔* ✔ ✔ 

III. 


Table 4. Pharmacokinetic Parameters of the Combination Miscellaneous β-Lactams 5-8 


Binding 


Metabolites 

Imipenem/ 

cilastatin 

Imipenem is mainly 

bactericidal. It inhibits the 



synthesis by preferentially 

binding to specific 

penicillin-binding proteins 

(PBPs) that are located 

inside the bacterial cell 

wall. 

Peak plasma 

levels occur in 

20 minutes 

following an 

IV dose 

20% 

imipenem 

and 40% 

cilastatin 

Cilastatin is 

metabolized 

by the 

kidneys 

Elimination 

- 70% of a 

dose of 

imipenem 

(when 

given with 

cilastatin) 

is excreted 

in urine, 

within 10 

hours 

Half- 

Life 

60 

minutes 

in 

normal 

renal 

function 

IV. 

Drug Interactions 

Table 5 lists the most significant drug drug-interactions (Level 1 and 2) for the drugs indexed by 

Drug Interactions Facts. 9 

Table 5. Drug Interactions of the Combination Miscellaneous β-Lactams 9 


Imipenem/cilastatin Level 2 Imipenem/cilastatin and 

cyclosporine 

This interaction may be the result of 

additive or synergistic toxicity. The 

CNS side effects of both agents may be 

increased. 

Other reported side effects for imipenem/cilastatin 8 : 

Imipenem-Cilastatin Drug Interactions 

Precipitant Drug Object Drug * Description 

Imipenem- 

Cilastatin 

Ganciclovir Generalized seizures have occurred with coadministration. Do not use concomitantly. 

Probenecid Imipenem Coadministration results in only minimal increases in imipenem levels and half-life; do 

not give probenecid concurrently. 

* 

= Object drug increased. 

152

V. Adverse Events of the Combination Miscellaneous β-Lactam Antibiotics 

Table 6. Common Adverse Events (%) Reported for the Combination Miscellaneous β-Lactams 6-8 

Adverse Event 


Malaise 


Vasodilation 

Hypotension 

Hypertension 

Transient ECG Changes 




Diarrhea 



Constipation 



Fatigue 

Fever 

Headache 


Raised Intracranial Pressure 

Collapse 

Confusion 

Drowsiness 

Insomnia 

Hepatic 


Hepatitis 

Jaundice 



Alopecia 

Rash 

Pruritus 

Erythema multiforme 

Hematologic 

Neutropenia 


Leukopenia 

Eosinophilia 

Anemia 

Thrombocytosis 

Bleeding events 

Imipenem/Cilastatin 

0.4 

VI. 

Dosage and Administration for the Combination Miscellaneous β-Lactam 

Antibiotics 

Table 7. Dosing for the Combination Misc. B-Lactam Antibiotics 5-8 

Drug Availability Dose/Frequency/Duration 

IV: 250mg and 500mg 

powder for injection, 

also available in Add- 

Vantage and Monovial 

vials; 

IM: 500mg and 750mg 

powder for injection 

Imipenem/ 

cilastatin 

IV : 

Give a 125, 250, or 500mg dose by IV infusion over 20 to 30 minutes. 

Infuse a 750mg or 1g dose over 40 to 60 minutes. If nausea develops, 

slow the infusion rate. 

Because of high antimicrobial activity, do not exceed 50mg/kg/day or 

4g/day, whichever is lower. There is no evidence that higher doses 

provide greater efficacy. 

Type or severity 

of infection 

Imipenem-Cilastatin IV Dosing Schedule for Adults 

with Normal Renal Function 

Fully susceptible 

organisms 1 

Total 

daily 

dose 

Moderately susceptible 

organisms, primarily 

some strains of 

P. aeruginosa 

Total 

daily 

dose 

Mild 250mg q 6 hr 1g 500mg q 6 hr 2g 

Moderate 

Severe, 

life-threatening 

Uncomplicated 

UTI 

500mg q 8 hr 

or 500mg q 6 hr 

1.5 or 

2g 

500mg q 6 hr 

or 1g q 8 hr 

500mg q 6 hr 2g 1g q 8 hr 

or 1g q 6 hr 

2 or 

3g 

3 or 

4g 

250mg q 6 hr 1g 250mg q 6 hr 1g 

Complicated 500mg q 6 hr 2g 500mg q 6 hr 2g 

UTI 

1 Including gram-positive and -negative aerobes and anaerobes 

IM : 

Total daily IM dosages > 1500mg/day are not recommended. 

Duration of therapy depends on the type and severity of the infection. 

Generally, continue for ≥2 days after signs and symptoms of infection 

have resolved. Safety and efficacy of treatment > 14 days have not been 

established. 

Administer by deep IM injection into a large muscle mass (such as the 

gluteal muscles or lateral part of the thigh) with a 21-gauge 2-inch needle. 

Aspiration is necessary to avoid inadvertent injection into a blood vessel. 

Imipenem-Cilastatin IM Dosage Guidelines in Adults 

Type/Location of 

infection Severity Dosage regimen 

Lower respiratory tract 


Gynecologic 

Mild/Moderate 500 or 750mg q12 hr 

depending 

on the severity of infection 

Intra-abdominal 

Mild/Moderate 750mg q 12 hr 

154

Children: 

In mild-to-moderate infections the recommended dose is 10 to 

15mg/kg every 6 hours. 

Pediatric Dosing Guidelines (≥3 months old) 

15 to 25mg/kg/dose every 6 hours 

≥3 months old (non-CNS infections) 

Maximum daily dose for fully susceptible organisms is 2g/day, and for 

infections with moderately susceptible organisms (primarily some strains 

of P. aeruginosa)is 4g/day (based on adult studies). 

Higher doses (≤90mg/kg/day in older children) have been used in 

cystic fibrosis patients. 

Pediatric Dosing Guidelines(≤3 months old) 

≤3 months old (weighing ≥1500g; non-CNS infections) 

< 1 week old: 25mg/kg every 12 hours 

1 to 4 weeks old: 25mg/kg every 8 hours 

4 weeks to 3 months old: 25mg/kg every 6 hours 

Give doses ≤500mg by IV infusion over 15 to 30 minutes. Give doses 

>500mg by IV infusion over 40 to 60 minutes. 

Imipenem-cilastatin IV is not recommended in pediatric patients with 

CNS infections because of the risk of seizures and in pediatric patients 

VII. 

Comparative Efficacy 

Imipenem/cilastatin can be compared with the other carbapenems, ertapenem and meropenem. 

Imipenem has stronger coverage for Enterococcus faecalis, Enterococcus faecium, and Y. 

enterocolitica as compared to ertapenem and meropenem. 51 Multiple studies presented in the 

single-entity review comparing meropenem and imipenem/cilastatin showed no statistically 

significant differences in clinical outcome between the two agents. Little data is available directly 

comparing imipenem/cilastatin with ertapenem. Table 9 describes additional comparative data for 

the carbapenems. 

Table 9. Additional Outcomes Evidence for the Combination Miscellaneous β-Lactams 

Study Sample Treatment/Duration Results 

Randomized study of 

carbapenems vs. 

standard therapy for 

CAP 52 n=204 Meropenem 500mg 

TID, 


500mg TID, 

In evaluating the carbapenems versus standard therapy for elderly hospitalized 

patients with community-acquired pneumonia: 

• A satisfactory clinical, bacteriological response was achieved 

respectively in 86.5% in meropenem; 86.3% in imipenem/cilastatin; 

clarithromycin 500mg + 

ceftriaxone 1g BID, 

clarithromycin 500mg + 

amikacin 250mg BID 

69% in ceftriaxone + clarithromycin and in 85.7% in clarithromycin + 

amikacin. 

• This study shows that treatment with either meropenem or imipenem is 

as efficacious as conventional therapy in the treatment of community 

Empiric carbapenem 

monotherapy in 

pediatric bone 

marrow recipients 53 n=32 Prospective analysis of 

meropenem patients and 

retrospective analysis of 


patients 

acquired pneumonia (CAP). 

To determine which carbapenem is the preferable empiric antibiotic 

monotherapy in pre-engrafted pediatric bone marrow transplant in terms of 

patient tolerance and therapeutic efficacy: 

• No differences were found in the number of culture proven or 

clinically suspected breakthrough bacterial infections or the need for 

concurrent additional antibiotics between the groups. 

• Our analysis found that patients who received meropenem 

experienced significantly less vomiting than those in the 

imipenem/cilastatin cohort. The statistical and clinical differences 

in the number of vomiting episodes between these groups impacted 

other aspects of patient care, antiemetic use, and TPN duration. 

Randomized, 


meropenem and 


for acute bacterial 

infections 54 n=112 Meropenem 500mg 

Q12 (or 1g Q12) vs. 


500mg Q12 (or 1g Q12) 

Randomized, 

n=144 

multicenter trial of patients 

meropenem vs. age 18- 

imipenem/cilastatin 94 years 

for communityacquired 

pneumonia 55 

Meropenem 1.5g daily 

vs. imipenem/cilastatin 

2g daily; the mean 

duration of treatment 

was 10 days for 

meropenem and 9.7 

days for 


In comparing the effectiveness of meropenem with imipenem for acute 

bacterial infections: 

• 42 of the 55 cases receiving meropenem and 41 of the 57 cases 

receiving imipenem/cilastatin were assessable for clinical efficacy. 

• The overall efficacy rate was 88.1% (37/42) for the meropenem 

group and 85.4% (35/41) for the imipenem/cilastatin group, whereas 

the bacterial eradication rate was 81.1% (30/37) and 84.2% (32/38), 

respectively. 47 (69.1%) of 68 strains isolated from patients 

produced beta-lactamase. 

• Adverse drug reaction was evaluated in 44 cases of the meropenem 

group and 41 cases of the imipenem/cilastatin group. The adverse 

drug reaction rate was 13.6% (6/44) and 12.2% (5/41), respectively. 

• The results showed that there were no statistical differences between 

these two groups (p > 0.05). 

In comparing the efficacy and safety of meropenem and imipenem/cilastatin in 

the hospital treatment of community-acquired pneumonia: 

• At the end of therapy, cure or improvement in signs and symptoms 

as a satisfactory clinical response was observed in 57 of 64 (89.1%) 

meropenem-treated patients and in 60 of 66 (90.9%) 

imipenem/cilastatin patients. 

• In patients who were followed up for weeks 2-4, the response was 

satisfactory (100%) for both treatments. 

• A satisfactory bacteriological response, defined as either presumed 

or confirmed eradication of all pathogens, was found in eight 

patients who had received meropenem and in 14 patients who had 

received imipenem/cilastatin. Response was considered satisfactory 

in 100% of the meropenem group and in 92.9% of the 

imipenem/cilastatin group and at follow-up, it was 100% for both 

treatments. 

156

• Drug-related adverse events were reported in three (4.2%) 

meropenem-treated patients and in eight (11.0%) 

imipenem/cilastatin-treated patients. 

• Summary: The clinical and bacteriological efficacy and tolerability 

of meropenem are similar to that of imipenem/cilastatin in the 

hospital treatment of community-acquired pneumonia. 


Dose Simplification: Imipenem/cilastatin is a potent antibiotic for serious bacterial infections. 

This medication would most likely be given during hospitalization or potentially through nursing 

care within an extended care facility. Meropenem (Q8) and ertapenem (QD) have less frequent 

dosing regimens as compared to imipenem, however, clinical data is not available that has 

evaluated the dosing frequency difference and outcome of the infectious disease. 

Stable Therapy: Not applicable. 

Impact on Physician Visits: A search of Medline and Ovid did not reveal data pertinent to 

medical resource utilization or the duration of hospitalization. 

VIII. Conclusion 

Clinical data suggests imipenem/cilastatin and meropenem are similar or comparable in efficacy 

and safety. Although ertapenem has a comparable spectrum of coverage, less clinical comparative 

data is available for ertapenem. 

Imipenem, like the single entity miscellaneous β-Lactams, would not routinely be used as first-line 

therapy on an outpatient basis. Imipenem/cilastatin is an agent that would not be considered 

applicable to general use in the population. Imipenem’s role is in the treatment of polymicrobic 

infections and other serious infections usually requiring hospitalization. Should therapy need to 

be continued beyond the hospital stay, imipenem/cilastatin should be available for the remainder 

of the course of therapy. 

Again, there may be some clinical advantage to the drugs within this combination class review in 

special needs/circumstances, but use of these agents would not be considered applicable in general 

use. Therefore, all brand products within the class reviewed are comparable to each other and to 

the generics in the class and offer no significant clinical advantage over other alternatives in 

general use. 

IX. 


No brand combination miscellaneous β-lactam antibiotic is recommended for preferred status. 

157

References 

1. Asbel LE, Levison ME. Cephalosporins, carbapenems, and monobactams. Infect Dis Clin North 

Am 2000 Jun;14(2):435-47. 

2. Lizasoain M, Noriega AR. Tolerance and safety of carbapenems: the use of meropenem. 

Enferm Infec Microbiol Clin 1997 Sep 15 Suppl 1:73-7. 

3. The ASCAP Panel Consensus Report, 2002. Community-acquired pneumonia (CAP) year 2002, 

antibiotic selection and patient management update. Available at: www.clinicalconsensusreports.com. 

Accessed September 15, 2004. 

4. Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of 

community-acquired pneumonia. Clin Inf Dis 2003 Dec 1;37:1405-33. 


2004. 









11. Lorabid ® [package insert]. Bristol, TN: Monarch Pharmaceuticals; September 2002. 

12. Schatz BS, Karavokiros KT, Taeubel MA, et al. Comparison of cefprozil, cefpodoxime, 

loracarbef, cefixime, and ceftibuten. Ann Pharmacother 1996 Mar;30(3):258-68. 

13. Oie S, Uematsu T, Sawa A, et al. In vitro effects of combinations of antipseudomonal agents 

against seven strains of multidrug-resistant Pseudomonas aeruginosa. J Antimicrob Chemother 2003 

Dec;52(6):911-4. 

14. Karlowsky JA, Draghi DC, Jones ME, et al. Surveillance for antimicrobial susceptibility among 

clinical isolates pf Pseudomonas aeruginosa and Acinetobacter baumannii from hospitalized patients in 

the United States, 1998 to 2001. Antimicro Agents Chemother 2003 May;47(5):1681-8. 

15. Rhomberg PR, Jones RN; MYSTIC Program (USA) Study Group. Antimicrobial spectrum of 

activity for meropenem and nine broad spectrum antimicrobials: report from the MYSTIC Program. 

Diagn Microbiol Infect Dis 2003 Sep;47(1):365-72. 

16. Jones RN, Biedenbach DJ, Gales AC. Sustained activity and spectrum of selected extendedspectrum 

B-lactams (carbapenems and cefepime) against Enterobacter spp. ESBL-producing 

Klebsiella spp.: report from the SENTRY antimicrobial surveillance program (USA, 1997-2000). 

17. Jones RN, Kirby JT, Beach ML, et al. Geographic variations in activity of broad-spectrum betalactams 

against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial 

Surveillance Program (1997-2000). Diagn Microbiol Infect Dis 2002 Jul;43(3):239-43. 

18. Holzheimer RG, Dralle H. Antibiotic therapy in intra-abdominal infections—a review on 

randomized clinical trials. Eur J Med Res 2001 Jul 30;6(7):277-91. 

19. Sader HS, Huynh HK, Jones RN. Contemporary in vitro synergy rates for aztreonam combined 

with newer fluoroquinolones and beta-lactams tested against gram-negative bacilli. Diagn Microbiol 

Infect Dis 2003 Nov;47(3):547-50. 

20. Boucher BA. Role of aztreonam in the treatment of nosocomial pneumonia in the critically ill 

surgical patient. Am J Surg 2000 Feb 1;179(2 Suppl 1):45-50. 

21. Fleming DR, Zeigler c, Baize T, et al. Cefepime versus ticarcillin and clavulanate potassium and 

aztreonam for febrile neutropenia therapy in high-dose chemotherapy patients. Am J Clin Oncol 2003 

Jun;26(3):285-8. 

22. Khan MT, Shah SH. Comparison of aztreonam against other antibiotics used in urinary tract 

infections. J Ayub Med Coll Abbottabad 2001 Oct-Dec;13(4):22-4. 

23. Ballow CH, Wels PB, Welage LS, et al. A double-blind, randomized comparison of aztreonam 

plus clindamycin with tobramycin plus clindamycin in abdominal infections. Am J Ther 1995 

Jun;2(6):373-377. 

24. Doganov N, Shtereva K, Dimitrov R. A comparative study of the efficacy of antibiotic 

prophylaxis with cephalosporins in operative gynecology. 

25. Gugino L, Cimino M, Wactawski-Wende J. Single-dose antibiotic prophylaxis during cesarean 

section. Prim Care Update Ob Gyns 1998 Jul 1;5(4):147-148. 

158

26. Gesser RM, McCarroll KA, Woods GL. Evaluation of outpatient treatment with ertapenem in a 

double-blind controlled clinical trial of complicated skin/skin structure infections. I Infect 2004 

Jan;48(1):32-8. 

27. Gesser RM, McCarroll KA, Woods GL. Efficacy of ertapenem against methicillin-susceptible 

Staphylococcus aureus in complicated skin/skin structure infections: results of a double-blind 

clinical trial versus piperacillin-tazobactam. Int J Antimicrob Agents 2004 Mar;23(3):235-9. 

28. Wells WG, Woods GL, Jiang Q, et al. Treatment of complicated urinary tract infection in adults: 

combined analysis of two randomized, double-blind, multicenter trials comparing ertapenem and 

ceftriaxone followed by appropriate oral therapy. J Antimicrob Chemother 2004 Jun;53 Suppl 

2:ii67-74. 

29. Solomkin J, Teppler H, Graham DR, et al. Treatment of polymicrobial infections: post hoc 

analysis of three trials comparing ertapenem and piperacillin-tazobactam. J Antimicrob 

Chemother 2004 Jun;53 Suppl 2:ii51-7. 

30. Alhambra A, Cuadros JA, Cacho J, et al. In vitro susceptibility of recent antibiotic-resistant 

urinary pathogens to ertapenem and 12 other antibiotics. J Antimicrob Chemother 2004 

Jun;53(6):1090-4. 

31. Vetter N, Cambronero-Hernandez E, Rohlf J, et al. A prospective, randomized, double-blind 

multicenter comparison of parenteral ertapenem and ceftriaxone for the treatment of hospitalized 

adults with community-acquired pneumonia. Clin Ther 2002 Nov;24(11):1770-85. 

32. Unnamed authors. Loracarbef versus doxycycline in the treatment of acute bacterial maxillary 

sinusitis. Scandinavian Study Group. J Antimicrob Chemother 1993 Jun;31(6):949-61. 

33. Hyslop DL, Bischoff W. Loracarbef (LY163892) versus cefaclor and norfloxacin in the treatment 

of uncomplicated pyelonephritis. Am J Med 1992 Jun 22;92(6A):86S-94S. 

34. Muller O, Spirer Z, Wettich K. Loracarbef versus penicillin V in the treatment of streptococcal 

pharyngitis and tonsillitis. Infection 1992 Sep-Oct;20(5):301-8. 

35. Hanfling MJ, Hausinger SA, Squires J. Loracarbef vs. cefaclor in pediatric skin and skin structure 

infections. Pediatr Infect Dis J 1992 Aug;11(8 Suppl):S27-30. 

36. Kays MB, Wood KK, Miles DO. In vitro activity and pharmacodynamics of oral beta-lactam 

antibiotics against Streptococcus pneumoniae from southeast Missouri. Pharmacotherapy 1999 

Nov;19(11):1308-14. 

37. Gooch WM 3 rd , Adelglass J, Kelsey DK, et al. Loracarbef versus clarithromycin in children with 

acute otitis media with effusion. Clin Ther 1999 Apr;21(4):711-22. 

38. Paster RZ, McAdoo MA, Keyserling CH, et al. A comparison of a five-day regimen of cefdinir 

with a seven-day regimen of loracarbef for the treatment of acute exacerbations of chronic 

bronchitis. Int J Clin Pract 2000 Jun;54(5):293-9. 

39. Demers DM, Chan DS, Bass JW. Antimicrobial drug suspensions: a blinded comparison of taste 

of twelve common pediatric drugs including cefixime, cefpodoxime, cefprozil and loracarbef. 

Pediatr Infect Dis J 1994 Feb;13(2):87-9. 

40. Greenhalgh JM, Edwards JR. A comparative study of the in vitro activity of meropenem and 

representatives of the major classes of broad-spectrum antibiotics. Clin Microbiol Infect 1997 

Feb;3 Suppl 4:S20-S31. 

41. Viaene E, Chanteux J, Servais H, et al. Comparative stability studies of antipseudomonal betalactams 

for potential administration through portable elastomeric pumps (home therapy for cystic 

fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents 

Chemother 2002 Aug;46(8):2327-32. 

42. Malik I, Shaharyar. Comparison of meropenem with ceftazidime as monotherapy of cancer 

patients with chemotherapy induced febrile neutropenia. J Pak Med Assoc 2002 Jan;52(1):15-8. 

43. Hou F, Li J, Wu G, et al. A randomized, controlled clinical trial of meropenem versus 

imipenem/cilastatin for the treatment of bacterial infections. Chin Med J (Engl) 2002 

Dec;115(12):1849-54. 

44. Manes G, Rabitti PG, Menchise A, et al. Prophylaxis with meropenem of septic complications in 

acute pancreatitis: a randomized, controlled trial versus imipenem. Pancreas 2003 

Nov;27(4):e79-83. 

45. Erdem I, Kucukercan M, Ceran N, et al. In vitro activity of combination therapy with cefepime, 

piperacillin/tazobactam, or meropenem with ciprofloxacin against multidrug resistant 

Pseudomonas aeruginosa strains. Chemotherapy 2003 Dec;49(6):294-7. 

159

46. Hung KC, Chiu HH, Tseng YC, et al. Monotherapy with meropenem versus combination therapy 

with ceftazidime plus amikacin as empirical therapy for neutropenia in children with malignancy. 

J Microbiol Immunol Infect 2003 Dec;36(4):254-9. 

47. Rhomberg PR, Jones RN, Sader HS, et al. Results from the meropenem yearly susceptibility test 

information (MYSTIC) Program: report of the 2001 data from United States medical centers. Int 

J Antimicrob Agents 2004 Jan;23(1):52-9. 

48. Verwaest C, Belgian Multicenter Study Group. Meropenem versus imipenem/cilastatin as 

empirical monotherapy for serious bacterial infections in the intensive care unit. Clin Microbiol 

Infect 2000 Jun;6(6):294-302. 

49. Rhomberg PR, Jones RN, Sader HS, et al. Antimicrobial resistance rates and clonality results 

from the meropenem yearly susceptibility test information collection (MYSTIC) Program: Report 

of the year five (2003). Diagn Microbiol Infect Dis 2004 Aug;49(4):273-81. 

50. Ciofu O, Jensen T, Pressler T, et al. Meropenem in cystic fibrosis patients infected with resistant 

Pseudomonas aeruginosa or Burkholderia cepacia and with hypersensitivity to beta-lactam 

antibiotics. Clin Microbiol infect 1996;2(2):91-98. 

51. Gilbert DN, Moellering RC, Eliopoulos GM, Sande MA. The Sanford guide to antimicrobial 

therapy. Thirty-Fourth Edition, 2004. Antimicrobial Therapy, Inc. Hyde Park, VT. 

52. Romanelli G, Cravarezza P, Pozzi A, et al. Carbapenems in the treatment of severe communityacquired 

pneumonia in hospitalized elderly patients: a comparative study against standard 

therapy. J Chemother 2002 Dec;14(6):609-17 

53. Nelson WK, Rayback PA, Quinones R, et al. Empiric carbapenem monotherapy in pediatric bone 

marrow transplant recipients. Ann Pharmacother 2002 Sep;36(9):1360-5. 

54. Hou F, Wu G, Zheng B. A randomized, controlled clinical trial of meropenem and 

imipenem/cilastatin in the treatment of acute bacterial infections. Zhonghua Nei Ke Za Zhi 2001 

Sep;40(9):589-93. 

55. Bartoloni A, Strohmeyer M, Corti G, et al. Multicenter randomized trial comparing meropenem 

(1.5g daily) and imipenem/cilastatin (2g daily) in the hospital treatment of community-acquired 

pneumonia. Drugs Exp Clin Res 1999;25(6):243-52. 

160

Pharmacotherapy Review of Chloramphenicol 

AHFS 081208 


I. Overview 

In 1947, chloramphenicol was isolated from Streptomyces venezuelae, and was approved by the 

FDA in 1950. Chloramphenicol is now available synthetically for therapeutic use. 1 It is marketed 

as an injection, but the drug is seldom used today due to its potential toxicity and the availability 

of other antibiotics. 

Chloramphenicol is a true broad-spectrum antibiotic. It is active against a wide range of grampositive 

and gram-negative bacteria, many anaerobic bacteria, Chlamydia, and Rickettsia. It is 

inactive against fungi. In vitro concentrations of 0.1—20 mcg/mL of chloramphenicol are 

generally effective against susceptible strains. 1 Since hematologic toxicity can be dose-related, 

peak serum concentrations above 25 mcg/ml are discouraged. 

Injectable chloramphenicol is available as a generic formulation. This review encompasses all 

dosage forms and strengths. Table 1 lists the drugs included in this review. 

Table 1. Antibiotics in this Review 


Chloramphenicol Sodium Succinate Injection Chloromycetin* 


II. 


Meningococcal Disease 

Chloramphenicol is an option for the treatment of meningococcal disease, including meningitis, 

according to the World Health Organization (WHO). 2 Chloramphenicol is a good choice, due to 

the drug’s ability to penetrate sufficiently into the cerebrospinal space. The WHO guidelines 

recommend either penicillin or ampicillin as the drug of choice, and ceftriaxone and cefotaxime as 

excellent alternatives. Although the intravenous route is recommended, clinical studies have 

shown the use of intramuscular chloramphenicol in oil to be as efficacious as intravenous 

ampicillin. Penetration of chloramphenicol into the cerebrospinal space has been reported to be 

good even after oral administration. 

Anthrax 

The antimicrobial susceptibility patterns of Bacillus anthracis isolates associated with the 

intentional exposures in 2001 were determined. 3 Isolates were susceptible to ciprofloxacin and 

doxycycline, the two drugs approved for post-exposure prophylaxis to B. anthracis. These strains 

were also susceptible to chloramphenicol, clindamycin, rifampin, vancomycin, and clarithromycin, 

but limited or no data exists regarding use of these agents in the treatment or prophylaxis of B. 

anthracis infections. To clarify, chloramphenicol is not formally FDA-approved for the treatment 

or prophylaxis of anthrax, it is an alternative therapy. 

As with all antibiotics, use of chloramphenicol is also dependent on the drug’s indications and 

spectrum of coverage. 

161

III. 

Indications of Chloramphenicol 

Chloramphenicol should not be used for the treatment of trivial infections, as a prophylactic agent 

to prevent bacterial infections, or when it is not indicated as in the treatment of colds, influenza, or 

throat infections. 4 Additionally, although not FDA-approved indications, chloramphenicol has 

been used in the following infections: Anthrax, Cholera, Melioidosis, Glanders, Burkholderia 

cepacia infections (Cystic fibrosis patients), Plague, Tularemia, Brucellosis, and Ehrlichiosis. 

Table 2. FDA-Approved Indications 4, 5 

Drug Serious Infections Acute Infections 

Chloramphenicol 

✔ 

Those for which less potentially dangerous drugs are 

ineffective or contraindicated caused by susceptible strains of 

Salmonella species; H. influenzae, specifically, meningeal 

infections; rickettsiae; lymphogranuloma-psittacosis group; 

various gram-negative bacteria causing bacteremia, meningitis 

or other serious gram-negative infections; infections involving 

anaerobic organisms, when Bacteroides fragilis is suspected; 

other susceptible organisms which have been demonstrated to 

be resistant to all other appropriate antimicrobial agents. 

If presumptive therapy is initiated, perform in vitro sensitivity 

tests concurrently, so that the drug may be discontinued if less 

potentially dangerous agents are indicated. 

✔ 

Those caused by S. typhi. 

Chloramphenicol is a drug of choice. 

In treatment of typhoid fever, some 

authorities recommend that 

chloramphenicol be used at 

therapeutic levels for 8 to 10 days 

after the patient becomes afebrile, to 

lessen the possibility of relapse. It is 

not recommended for the routine 

treatment of the typhoid “carrier 

state.” 

IV. Pharmacokinetic Parameters 

Chloramphenicol base is absorbed rapidly from the intestinal tract and is 75% to 90% 

bioavailable. In adults, at doses of 1g every 6 hours for 8 doses, the average peak serum level was 

11.2mcg/ml 1 hour after the first dose, and 18.4mcg/ml after the fifth 1g dose. Mean serum levels 

ranged from 8 to 14mcg/ml over the 48 hour period. 

Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are 

found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid 

(CSF). However, chloramphenicol enters the CSF, even in the absence of meningeal 

inflammation, appearing in concentrations 45% to 99% of those found in the blood. Measurable 

levels are also detected in pleural and ascitic fluids, saliva, milk, and in the aqueous and vitreous 

humors. 

Table 3. Pharmacokinetic Parameters of Chloramphenicol 4, 5 

Drug Mechanism of 

Action 

Bioavailability 

Protein 

Binding 


Metabolites 

Elimination 

Chloramphenicol Chloramphenicol 70-90% 60% Liver N o Total urinary 

binds to 50 S 

excretion 

ribosomal subunits of 

ranges from 

bacteria and interferes 

68-99% over 

with or inhibits protein 

3 days 

synthesis. In vitro, 

chloramphenicol 

exerts mainly a 

bacteriostatic effect on 

a wide range of gramnegative 

and grampositive 

bacteria. 

Half- 

Life 

4 hours


Table 4 lists the most significant (Level 2) drug-drug interactions for chloramphenicol. No level 1 

interactions have been documented with chloramphenicol and other drugs. 

Table 4. Drug Interactions of Chloramphenicol 6 


Chloramphenicol Level 2 

Delayed, moderate, 

Chloramphenicol and 

sulfonylureas 

suspected 

possible hypoglycemia. 

Level 2 


suspected 

Level 2 


suspected 

Level 2 


suspected 


anticoagulants 


hydantoins 


iron salts (ferrous 

fumerate, ferrous 

gluconate, ferrous 

sulfate, iron dextran, etc.) 

Reduction in sulfonylurea hepatic clearance by chloramphenicol 

leading to sulfonylurea accumulation (proposed mechanism), and 

Possible inhibition of hepatic metabolism of oral 

anticoagulants, causing the anticoagulant action of oral 

anticoagulants to be enhanced by chloramphenicol. 

Alteration in phenytoin metabolism can lead to increased serum 

phenytoin concentrations with potential toxicity. 

Chloramphenicol concentrations may also change. 

Decreased iron clearance and erythropoiesis due to direct bone 

marrow toxicity from chloramphenicol, resulting in increased 

serum iron levels. 

Additional less severe (Level 3 and Level 4) drug-drug interactions have been documented with 

chloramphenicol and include the following drugs 6 : 

• Vitamin B12 (Level 3)- The hematologic effects of vitamin B12 in patients with 

pernicious anemia may be decreased by concurrent administration of chloramphenicol. 

• Barbiturates (Level 4)- The metabolism of chloramphenicol may be increased and the 

barbiturate metabolism decreased. The efficacy of chloramphenicol may be reduced 

while the effects of the barbiturate are enhanced. The effects can persist for days after 

the barbiturate is withdrawn. 

• Penicillins (Level 4)- Mechanism is not fully understood. Synergistic effects may 

develop in the treatment of certain microorganisms, but antagonism has also been 

reported in animal studies. 

• Cyclophosphamide (Level 4)- Thought to result from inhibition of the hepatic 

microsomal enzyme system by chloramphenicol. The interaction may result in a 

decreased or delayed activation of cyclophosphamide. It is unclear at this time if a 

significant decrease in the effect of cyclophosphamide would result from this interaction. 

• Cyclosporine (Level 4)- Mechanism is unknown. Trough plasma concentrations of 

cyclosporine may be elevated, increasing the likelihood of adverse effects (e.g. 

nephrotoxicity). 

• Tacrolimus (Level 4)- Inhibition of hepatic metabolism of tacrolimus is suspected in this 

interaction. Tacrolimus concentrations may be elevated, increasing the risk of toxicity. 

• Rifampin (Level 4)- Chloramphenicol metabolism may be increased due to induction of 

hepatic microsomal enzymes by rifampin. Chloramphenicol serum levels progressively 

decrease, possibly leading to decreased anti-infective action. The effects could continue 

for days after rifampin is withdrawn. 

163

VI. 

Adverse Drug Events 

Chloramphenicol use is associated with a black box warning with the following important 

prescribing information. 

1, 4, 5 

Black Box Warning 

Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia and 

granulocytopenia) occur after Chloramphenicol administration. Aplastic anemia, which later 

terminated in leukemia, has been reported. Blood dyscrasias have occurred after both short-term 

and prolonged therapy. Chloramphenicol must not be used when less potentially dangerous agents 

are effective. It must not be used to treat trivial infections (e.g., influenza, colds, throat 

infections), infections other than indicated, or as prophylaxis for bacterial infections. 

It is essential that adequate blood studies be performed during treatment. While blood studies may 

detect early peripheral blood changes, such as leukopenia, reticulocytopenia or granulocytopenia 

before they become irreversible, such studies cannot be relied upon to detect bone marrow 

depression prior to development of aplastic anemia. To facilitate appropriate studies and 

observation, patients should be hospitalized. 

Blood Dyscrasias 

Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia and 

granulocytopenia) occur. 5 An irreversible type of marrow depression leading to aplastic anemia 

with a high rate of mortality is characterized by the appearance of bone marrow aplasia or 

hypoplasia weeks or months after therapy. Peripherally, pancytopenia is most often observed, but 

only one or two of the three major cell types (erythrocytes, leukocytes and platelets) may be 

depressed. This complication appears unrelated to administration route. One estimate, based on 

149 cases, stated that the route was oral in 83%, parenteral in 14% and rectal in 3%. Several cases 

of aplastic anemia have been associated even with chloramphenicol ophthalmic ointment. 

A dose-related reversible type of bone marrow depression may occur and is associated with 

sustained serum levels at peak ≥25mcg/ml, trough ≥10mcg/ml. This type of marrow depression is 

characterized by vacuolization of the erythroid cells, a decrease in red cell iron uptake, an increase 

in circulating serum iron with saturation of iron-binding globulin (usually within 6 to 10 days) and 

reduction of reticulocytes (usually within 5 to 7 days)and leukopenia; it responds promptly to 

withdrawal of the drug. 

Table 5 lists the common adverse events for chloramphenicol. 

164

Table 5. Common Adverse Events (%) Reported for Chloramphenicol 6 

Adverse Event 



Malaise 


Edema 

Hypotension 

Hypertension 




Diarrhea 

Glossitis/stomatitis 




Fatigue 

Fever 

Headache 


Raised Intracranial Pressure 

Collapse 

Confusion 

Drowsiness 

Mild Depression 

Hepatic 


Hepatitis 

Jaundice 



Alopecia 

Rash 

Pruritus 

Hematologic 

Neutropenia 


Bone marrow depression 

Aplastic anemia (later as leukemia) 

Renal 



Other 

Angioedema 

Convulsions 

Optic and peripheral neuritis 

Gray syndrome* 

✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

1:40,000 cases 

✔ Adverse event reported; specific percentages not available. 

*Toxic reactions including fatalities (approximately 40%) have occurred in premature infants and newborns; the signs and 

symptoms associated with these reactions have been referred to as the “gray syndrome”. 

✔ 

✔ 

✔ 

165

VII. 

Dosing and Administration 

1, 4, 5 

Table 6. Dosing for Chloramphenicol 



Powder for Injection: 

1g (100mg/ml when 

reconstituted) vials 

Therapeutic concentrations should be maintained as follows: Peak 10 to 20mcg/ml; 

trough 5 to 10mcg/ml. 

Monitoring: 

It is important to monitor serum levels because of the variability of 

chloramphenicol's pharmacokinetics. Monitor serum concentrations weekly; monitor 

more often in patients with hepatic dysfunction, in therapy >2 weeks or with 

potentially interacting drugs. 

Adults: 

50mg/kg/day in divided doses every 6 hours for typhoid fever and rickettsial 

infections. Exceptional infections (e.g., meningitis, brain abscess) due to moderately 

resistant organisms may require dosage up to 100mg/kg/day to achieve blood levels 

inhibiting the pathogen; decrease high doses as soon as possible. 

Children: 

50 to 75mg/kg/day in divided doses every 6 hours are recommended for most 

indications. For meningitis, 50 to 100mg/kg/day in divided doses every 6 hours has 

been recommended. 

Newborns: 

(See Gray syndrome under Adverse Reactions.) 25mg/kg/day in 4 doses every 6 

hours usually produces and maintains adequate concentrations in blood and tissues. 

Give increased dosage demanded by severe infections only to maintain the blood 

concentration within an effective range. After the first 2 weeks of life, full-term 

infants ordinarily receive up to 50mg/kg/day in 4 doses every 6 hours. 

• Neonates (2kg): 

25mg/kg once daily. 

• Neonates over 7 days (>2kg): 

50mg/kg/day in divided doses every 12 hours. 

These dosage recommendations are extremely important because blood concentration 

in all premature and full-term infants


1, 5, 7 

Table 7. Special Dosing Considerations for Chloramphenicol 

Drug 

Hepatic Pediatric Use 


Renal 

Dosing 

Dosing 

Yes 

Impaired metabolic 

processes require that 

doses be adjusted based 

on drug concentration in 

the blood. An initial 

loading dose of 1g 

followed by 500mg every 

6 hours has been 

recommended in 

impaired hepatic 

function. 

Yes 

See adverse 

event section for 

warning on Gray 

syndrome 

Pregnancy 

Category 

C 

Can Drug Be Crushed/Stability 

Following reconstitution, 

chloramphenicol at 100mg/ml is 

stable for 30 days at room 

temperature. 

VIII. 

Comparative Effectiveness 

Since chloramphenicol is an older antibiotic, limited recent clinical comparable data is available. 

Table 8 describes clinical studies that have recently looked at the efficacy and place-in-therapy of 

chloramphenicol. 

Table 8. Additional Outcomes Evidence for Chloramphenicol 


Duration 

Third generation 

cephalosporins 

vs. conventional 

antibiotics for 

acute bacterial 

meningitis 8 

Meta-analysis 

of 18 trials 

and 993 

patients 

Criteria for trials 

included 

randomized, 

controlled studies 

comparing 

ceftriaxone or 

cefotaxime with 

conventional 

antibiotics 

Treatment of 

Rickettsia with 

five different 

antibiotic 

regimens 9 n=87 Doxycycline, 

chloramphenicol, 

ciprofloxacin, 

doxycycline plus 

chloramphenicol, 

and doxycycline 

167 

Results 

The goal of this study was to determine the effectiveness and safety of the third 

generation cephalosporins versus conventional treatment with 

penicillin/ampicillin-chloramphenicol in patients with community-acquired 

acute bacterial meningitis: 

• There was no heterogeneity of results among the studies in any 

outcome except diarrhea. 

• There was no statistically significant difference between the groups 

in the risk of death (risk difference -1%; 95% confidence interval 

(CI) -4% to +3%), risk of deafness (risk difference -4%; 95% CI - 

9% to +1%), or risk of treatment failure (risk difference -2%; 95% 

CI -5% to +2%). 

• There was a significant decrease in the risk of culture positivity of 

CSF after 10-48 hours (risk difference -6%; 95% CI -11% to 0%) 

and statistically significant increase in the risk of diarrhea between 

the groups (risk difference +8%; 95% CI +3% to +13%) with the 

third generation cephalosporins. 

• The risks of neutropenia and skin rash were not significantly 

different between the two groups. 

• All the studies were conducted in the 1980’s except two, which 

were conducted in 1993 and 1996. 

• Summary: Although the review shows no clinically important 

difference between ceftriaxone or cefotaxime and conventional 

antibiotics, the studies were done decades ago and may not apply 

to current routine practice. However, in situations where 

ceftriaxone or cefotaxime are not available or affordable, 

ampicillin-chloramphenicol combination may be used as an 

alternative. 

In examining the clinical effectiveness of five different antibiotic regimens for 

infection with Rickettsia, in terms of duration of fever: 

• The mean time to defervescence was 2.9 days for doxycycline, 4.0 

days for chloramphenicol, and 4.2 days for ciprofloxacin. 

• In patients receiving combinations of doxycycline plus 

chloramphenicol and doxycycline plus ciprofloxacin, fever subsided in

Resistance to 


among 

vancomycin 

resistant 

enterococcal 

(VRE) 

infections 10 

All VRE 

isolates were 

analyzed for 

susceptibility 

profiles 

plus ciprofloxacin 

10-year study 

period (1991- 

2000) 

3.4 and 4.0 days, respectively. 

• The outcome was favorable in all patients, and no deaths or relapses 

were observed within two months. 

In evaluating the antimicrobial susceptibility profiles of all VRE blood isolates 

from 1991-2000, and to look at hospital use of specific antibiotics and antibiotic 

classes and chloramphenicol resistant vancomycin-resistant enterococcal (CR- 

VRE) prevalence: 

• Chloramphenicol is effective when VRE isolates are susceptible to this 

agent. 

• During the 10-year study period, the prevalence of CR-VRE increased 

from 0 to 11% ( p< 0.001, trend). 

• CR-VRE prevalence was correlated only with chloramphenicol use 

(p=0.05) and quinolone use (p= 0.01). 

• If these trends continue, dependence on newer, more expensive agents 

will increase. The correlation between both chloramphenicol use and 

quinolone use and the prevalence of CR-VRE suggests that efforts to 

preserve the utility of chloramphenicol in VRE infections may depend 

- 

on optimizing the use of these agents. 

In vitro postantibiotic 

effect 

Two stains of 

Bacillus 

- In investigating the in vitro post-antibiotic effect (PAE) of 19 antibacterial 

agents against two strains of Bacillus anthracis: 

of 19 drugs/drug 

classes on 

Bacillus 

anthracis 11 

anthracis 

were used 

• The PAE was determined by calculating the time required for the 

viable counts of antibiotic-exposed bacteria (at concentrations of 10x 

MIC and exposure for 2h) at 37 degrees C to increase by 1 log10 

above the counts observed immediately after antibiotic removal 

compared with the corresponding time for controls not exposed to 

antibiotics. 

• The PAEs of the fluoroquinolones (ciprofloxacin, ofloxacin, 

levofloxacin, moxifloxacin and garenoxacin*) were 2-5h. 

• The macrolide (erythromycin, clarithromycin and telithromycin) PAEs 

were 1-4h and that of clindamycin was 2h. 

• The PAEs induced by tetracycline and minocycline were 1-3h. 

• The PAEs induced by the beta-lactams (penicillin G, amoxicillin and 

ceftriaxone), vancomycin, linezolid, and chloramphenicol were 1-2h. 

The PAE induced by rifampicin was 4-5h. 

• Quinupristin/dalfopristin had the longest PAE, lasting for 7-8h. 

• These results indicate that the PAE is unrelated to the MIC but may be 

related to the rapidity of bacterial kill. These observations may bear 

importance on treatment regimens of human anthrax. 

Chloramphenicol n=101 In evaluating the trends in prevalence of chloramphenicol resistance in VRE 

quinolone use 12 

resistance in VRE 

bacteremia: 

blood isolates from 1991-2002 to identify risk factors for chloramphenicol 

resistance among isolates: 

impact of prior 

• During the review period, the annual prevalence of 


vs. rifampin for 

Streptococcus 

pneumoniae- 

A group of 

107 isolates 

of S. 

pneumoniae 

The min. 

inhibitory 

concentration 

(MIC) and min. 

chloramphenicol-resistant VRE increased from 0% to 12% (p < 

.001, chi-square test for trend). 

• Independent risk factors for chloramphenicol-resistant VRE were 

prior chloramphenicol use (odds ratio [OR], 10.9; 95% confidence 

interval [CI95], 1.72-68.91; P = .01) and prior fluoroquinolone use 

(OR, 4.74; CI95, 1.15-19.42; p = 0.03). 

• Chloramphenicol-resistant VRE isolates were more likely to be 

susceptible to beta-lactams and resistant to tetracycline than were 

chloramphenicol-susceptible VRE isolates. 

• Significant increases in the prevalence of chloramphenicolresistant 

VRE may limit the future utility of chloramphenicol in 

the treatment of VRE infections, and close monitoring of 

susceptibility trends should continue. The association between 

fluoroquinolone use and chloramphenicol-resistant VRE, 

reflecting possible co-selection of resistance, suggests that recent 

dramatic increases in fluoroquinolone use may have broader 

implications than previously recognized. 

In evaluating the minimal inhibitory concentration and minimal bactericidal 

concentration for chloramphenicol and rifampin in strains of S. pneumoniae: 

• Chloramphenicol resistance was found in 21% of the 107 isolates. 

• In the group susceptible to penicillin, 11% were resistant to 

168

induced 

meningitis and 

systemic 

infections 13 

from children 

under 5 

*Not available in the United States. 

bacterial 

concentration 

(MBC) for 


and rifampin were 

obtained 

chloramphenicol, and in the group resistant to penicillin, 28% were 

resistant to chloramphenicol as well. 

• MBC was found >4microg/ml in 28% of the isolates susceptible to 

penicillin and in 60% of the resistant isolates. 

• No isolates were found resistant to rifampin. 

• However, 2 penicillin resistant isolates showed CBM >1microg/ml to 

rifampin, and one with CIM = 1microg/ml had a MBC to rifampicin of 

16microg/ml. 

• Meningitis isolates showed higher CIM and CBM than the group of 

total isolates. 

• These data suggest that chloramphenicol is not recommended for 

invasive infections caused by S. pneumoniae in Colombia. Rifampin 

is a more effective therapy in combination with other antibiotics for 

treatment of this kind of infections. Further studies are necessary to 

clarify the significance of low levels of MBC to rifampin found in 

some strains, since this may affect the efficacy of therapies that 

include this antibiotic. 


Dose Simplification: Since chloramphenicol is only available in a single formulation, there isn’t 

another agent or dosage formulation for which chloramphenicol can be compared to for dose 

simplification. Therefore, dose simplification does not apply to this particular class. 


Impact on Physician Visits: A literature search of Medline and Ovid did not reveal clinical data 

pertinent to physician visits or hospitalizations with chloramphenicol. 

IX. 

Conclusions 

Use of chloramphenicol should be reserved for serious infections or infections resistant to other 

therapies. Use is likely limited to hospitalized patients, where intravenous therapy can be given 

and monitored appropriately. Because of the black box warning associated with chloramphenicol 

use, and due to the fact that the drug should not be used for trivial infections, there is not a role for 

the use of chloramphenicol in general use. Chloramphenicol should be available for special 

needs/circumstances that require medical justification through the prior authorization process. 


generics in the class and offer no significant clinical advantage over other alternatives in general 

use. 


No brand of chloramphenicol is recommended for preferred status. 

169

References 


2004. 

2. World Health Organization. Control of epidemic meningococcal disease. WHO practical 

guidelines. 2 nd edition. Available at: www.who.int/emc. Accessed September 21, 2004. 

3. Centers for Disease Control. Health Advisory. Antimicrobial susceptibility of Bacillus anthracis 

isolates associated with intentional distribution in Florida, New Jersey, New York, Pennsylvania, 

Virginia, and Washington, D.C., September-October, 2001. Available at: www.cdc.gov. 








8. Prasad K, Singhal T, Jain N, et al. Third generation cephalosporins versus conventional 

antibiotics in treating acute bacterial meningitis. Cochrane Database Syst Rev 

2004;(2):CD001832. 

9. Gikas A, Doukakis S, Pediaditis J, et al. comparison of the effectiveness of five different 

antibiotic regimens on infection with Rickettsia typhi: therapeutic data from 87 cases. Am J Trop 

Med Hyg 2004 May;70(5):576-9. 

10. Lautenbach E, Gould CV, LaRosa LA, et al. Emergence of resistance to chloramphenicol among 

vancomycin resistant enterococcal (VRE) bloodstream isolates. Int J Antimicrob Agents 2004 

Feb;23(2):200-3. 

11. Athamna A, Athmana M, Medlej B, et al. In vitro post-antibiotic effect of fluoroquinolones, 

macrolides, beta-lactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, 

quinupristin/dalfopristin and rifampin on Bacillus anthracis. J Antimicrob Chemother 2004 

Apr;53(4):609-15. 

12. Gould CV, Fishman NO, Nachamkin I, et al. Chloramphenicol resistance in vancomycin – 

resistant enterococcal bacteremia: impact of prior fluoroquinolone use. Infect Control Hosp 

Epidemiol 2004 Feb;25(2):138-45. 

13. Hernandez M, Mejia GI, Trujillo H, et al. Effectiveness of the antibiotics chloramphenicol and 

rifampin in the treatment of Streptococcus pneumoniae-induced meningitis and systemic 

infections. Biomedica 2003 Dec;23(4):456-61. 

170

I. Overview 



Pharmacotherapy Review of the Single Entity Penicillins 

AHFS 081216 


Penicillins are natural or semisynthetic antibiotics produced or derived from Penicilium fungus. 1 

The drugs are ß-lactam antibiotics structurally and chemically related to cephalosporins and 

cephamycins. Currently available penicillins can be divided into four groups primarily based on 

their spectrum of activity: 

o Natural Penicillins 

o Penicillinase-Resistant Penicillins 

o Aminopenicillines 

o Extended-Spectrum Penicillins 

NATURAL PENICILLINS 

• Penicillin G 

• Penicillin V 

Natural penicillins are produced by fermentation of mutant strains of Penicillium chrysogenum. 

Several natural penicillins have been produced, however, only penicillin G and Penicillin V are 

currently available. Natural penicillins are active in vitro against many gram-positive cocci 

including nonpenicillinase-producing Staphylococcus aureus and S. epidermidis, Streptococcus 

pneumoniae, groups A, B, C, G, H, K and L streptococci, viridians streptococci and certain strains 

of enterococci. Natural penicillins are hydrolyzed by staphylococcal penicillinases and are 

inactive against penicillinase-producing strains of S. aureus and S. epidermidis. 

Natural penicillins are also active against gram-negative cocci and some gram-negative bacilli. 

These pathogens include; Neisseria meningitides and most strains of nonpenicillinase-producing 

N. gonorrhoeae. The drugs are active in vitro against some gram-negative stains of Haemophilus 

influenzae, Pasteurella multocida, and Spiillum minus. The drugs are also active against most 

spirochets, including Treponema pallidum, T. pertenue, leptospira, Borrelia recurrentis, and B. 

burgdorferi, the causative pathogen of Lyme disease. 1 

PENICILLINASE-RESISTANT PENICILLINS 

• Dicloxacillin 

• Nafcillin 

• Oxacillin 

Penicillinase-resistant penicillins are stable against hydrolysis of most staphylococcal 

penicillinases, including S. aureus and S. epidermidis that are resistant to natural penicillins, 

aminopenicillins, and extended-spectrum penicillins. They have some activity against gramnegative 

bacteria and spirochetes, although they are less active against these organisms than 

natural penicillins. 1 

171

AMINOPENICILLINS 

• Amoxicillin 

• Ampicillin 

Aminopenicillins have enhanced activity against gram-negative bacteria compared with natural 

penicillins and penicillinase-resistant penicillins. Aminopenicillins are generally active against 

gram-positive aerobic bacilli. Similar to natural penicillins and extended-spectrum penicillins, 

aminopenicillins are readily hydrolyzed by staphylococcal penicillinases and are inactive against 

penicillinase-producing strains of S. aureus and S. epidermidis. 

Aminopenicillins are generally active in vitro against gram-negative cocci and bacilli as well as 

anaerobic bacteria. Also, aminopenicillins are active versus Enterobacteriaceae including some 

strains of E. coli, Proteus mirabilis, Salmonella, and Shigella. 

Clavulanic acid and sulbactam can inhibit certain ß-lactamases that generally inactivate 

aminopenicillins. Combination of amoxicillin and clavulanate potassium and combinations of 

ampicillin and sulbactam sodium are active against many ß-lactamase-producing organisms that 

are resistant of aminopenicillins alone. 1 

EXTENDED-SPECTRUM PENICILLINS 

• Piperacillin 

• Ticarcillin 

• Carbenicillin 

• Mezlocillin 

Extended-Spectrum Penicillins have a wider spectra that the aforementioned agents. They are 

more active against gram-negative aerobic and gram-negative anaerobic bacilli than 

aminopenicillins. The use of extended-spectrum penicillins are limited to treatment of serious 

infections caused by gram-negative bacilli and mixed aerobic-anaerobic bacterial infections. 

In vitro, they are generally active gram-positive and gram-negative cocci. Like natural penicillins 

and aminopenicillins, extended-spectrum penicillins are hydrolyzed by penicillinases and are 

therefore inactive against penicillinase-producing strains of S. aureus and S. epidermidis. The 

drugs are also active against strains of Enterobacteriaceae and certain strains of Pseudomonas. 

This review encompasses all dosage forms and strengths of the single entity penicillins. Table 1 

lists the drugs included in this review. 

172

Table 1. Single Entity Penicillins in this Review 1,2 

Generic Name Formulation Example Brand Name (s) 

Natural Penicillins 

Penicillin G (sodium and Sterile Suspension, Injection Bicillin LA, Bicillin CR *Pfizerpen, 

procaine) 

Wycillin 

Penicillin V 

Solution, Tables, Film-Coated *Penicillin VK, *Ledercillin VK, 

Tablets 

*Veetids 

Penicillinase-Resistant Penicillins 

Dicloxacillin Suspension, Capsules *Dynapen 

Nafcillin Injection *Nallpen, *Unipen 

Oxacillin Solution, Capsules, Injection *Bactocill 

Aminopenicillins 

Amoxicillin 

Chewable Tablets, Capsules, *Trimox, *Amoxil, Dispermox 

Suspension, Film-Coated Tablets 

Ampicillin Capsules, Injection, Suspension *Principen, Totacillin-N 

Extended-Spectrum Penicillins 

Carbenicillin Film-Coated Tablets Geocillin 

Piperacillin Injection *Pipracil 

Ticarcillin Injection Ticar 


II. Evidence Based Medicine and Current Treatment Guidelines 1,3 

Penicillins continue to be the drugs of choice or alternatives for a variety of microorganisms. 

Methicillin is the drug of choice for sensitive strains of Staphylococcal infections. The 

aminopencillins are also used first-line for Enterococcus species, particular urinary tract infections 

caused by Enterococcus faecalis. Sensitive strains for Streptococcal infection including, 

pneumoniae, viridans group and groups A, B, C, G are generally treated empirically with 

Penicillin G or ampicillin. Clostridium perfringens is also treated with Penicillin G in 

combination with clindamycin. Anthrax (Bacillus anthracis) can also be alternatively treated with 

doses of Penicillin G or Amoxicillin. 4 

Gram-negative microorganisms such as Escherichia coli, Acinetobacter spp. and Pseudomonas 

aeruginosa are initially treated with combination penicillins such as amoxicillin/clavulanate, 

ampicillin/sulbactam or piperacillin/tazobactam. In the case of Pseudomonas aeruginosa, 

penicillins are usually combined with other antibiotics. Drugs of choice for Pasteurella multocida 

and Proteus mirabilis are Penicillin G and Ampicillin, respectively. Treponema pallidum, the 

causative microorganism responsible for Neurosyphilis, is treated with Penicillin G. 

Pneumonia 

Community acquired pneumonia can be caused by various microorganisms. 

Amoxicillin/clavulanate is considered an alternative option for the treatment on non-hospitalized 

community acquired pneumonia. Patients hospitalized with severe community-acquired 

pneumonia are treated empirically with ß-lactam inhibitors in combination with a fluoroquinolone 

or a macrolide. Nosocomial pneumonia is usually a mixed infection with anaerobic activity. 

Combination agents such as ticarcillin/clavulanate and piperacillin/tazobactam are generally given 

in combination with other agents, particularly when pseudomonas is suspected. 

Urinary Tract Infection 

ß-lactams such as amoxicillin or ampicillin are usually considered alternatives for uncomplicated 

cystitis. These agents are categorized as a Pregnancy Category B and can be therefore used in 

pregnancy. Extended-spectrum penicillins are administered for 14-day treatment of complicated 

urinary tract infections. 

173

Skin & Soft Tissue Infections 

Acute Cellulitis and Erysipelas caused by S. pyogens or S. aureus are generally treated with antistaphylococcal 

penicillins (nafcillin, oxacillin, or dicloxacillin). Necrotizing fasciitis due to mixed 

microorganisms, including anaerobes is empirically treated with ß-lactam inhibitor combinations. 

Diabetic foot infections are generally polymicrobial involving two to six different 

microorganisms. This infection requires broad coverage with ß-lactam inhibitors combination 

agents like piperacillin/tazobactam. 

Endocarditis Prophylaxis 

Endocarditis is a result of bacterial vegetation in the heart valves. Usual suspects include grampositive 

organisms such as Streptococci, S. aureus, Enterococci and coagulase-negative 

staphylococci. Amoxicillin is the drug of choice for prophylaxis. For patients unable to take oral 

medications, ampicillin is an alternative in either IM or IV formulation. 

Bacterial Meningitis 

Several penicillins are listed as drugs of choice for several pathogens responsible for bacterial 

meningitis. Penicillin G in combination with rifampin is indicated for meningitis caused by N. 

meningitides. Ampicillin and oxacillin are indicated for L. monocytogenes and methicillinsensitive 

S. aureus, respectively. 

Otitis Media 

Initial cases of otitis media in children can be treated with standard doses of amoxicillin. High 

doses of amoxicillin (80-100mg/kg/day) are used for treatment failures or recurrent episodes. 

Amoxicillin/clavulanate is also a treatment regimen for cases of otitis media. 

174

III. 

Susceptibility of the Single Entity Penicillins 

Table 2. Organisms Generally Susceptible to Single Entity Penicillins In Vitro 2 

Organisms Natural Penicillins Penicillinase-Resistant Penicillins Aminopenicillins Extended-Spectrum Penicillins 

Gram- 

Penicillin Penicillin Cloxacillin∞ Dicloxacillin Nafcillin Oxacillin Amoxicillin Ampicillin Carbenicillin Mezlocillin† Piperacillin Ticarcillin 

✔ = Generally 

Positive 

G V 

Susceptible 

Staphylococci 

✔* ✔* ✔ ✔ ✔ ✔ ✔* ✔* ✔* ✔* ✔* 

Staphylococcus 

aureus 


Epidermidis 

Streptococci 

Streptococcus 

Pneumoniae 

Beta-hemolytic 

streptococci 

Enterococcus 

faecalis 

Streptococcus 

viridans 

Corynebaacterium 

diphtheriae 

Bacillus anthracis 

✔ ✔ ✔ ✔ ✔ ✔ ✔* ✔* ✔* ✔* 

✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ 

✔ ✔ 

Streptococcus 

agalactiae 

Streptococcus 

pyogens 

Erysipelothrix 

✔ 

rhusiopathiae 

Listeria 

✔ ✔ 

monocytogenes 

* Non-penicillinase producing 

† Mezlocillin has been discontinued in the United States and is not being reviewed with this class. 

∞ Cloxacillin is no longer available in the United States and is not listed in the Alabama Medicaid drug file. It is not included in this review. 

175

Table 2. Continued…Organisms Generally Susceptible to Single Entity Penicillins In Vitro 2 

Organisms Natural Penicillins Penicillinase-Resistant Penicillins Aminopenicillins Extended-Spectrum Penicillins 

Gram- 



Negative 

G V 

Susceptible 


✔ ✔ ✔ ✔ ✔ ✔ ✔ 

Haemophilus 

influenzae 

✔ ✔ ✔ ✔ ✔ ✔ 

Haemophilus 

parainfluenzae 

✔ 

Eikenella 

corrodens 

Bacteroides 

melaninogenicus 

Klebsiella sp. 

✔ ✔ ✔ 

Neisseria 

gonorrhoeae 

Neisseria 

meningitides 

Proteus mirabilis 


Shigella sp. 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ 

Morganella 

morganii 

✔ ✔ ✔ ✔ 

Proteus vulgaris 

✔ ✔ ✔ ✔ 

Providencia 

stuartii 



✔ ✔ ✔ ✔ ✔ 

✔ 

Pseudomonas 

aeruginosa 

✔ ✔ ✔ ✔ 

Serratia sp. 

✔ ✔ ✔ ✔ 

Acinetobacter sp. 

✔ ✔ ✔ 

Streptobacillus 

moniliformis 

✔ ✔ 


176

Table 2. Continued…Organisms Generally Susceptible to Single Entity Penicillins In Vitro 2 

Anaerobic 



G V 

Susceptible 

Clostridium sp. 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

Peptococcus sp. 

Peptostreptococcus 

sp. 

Bacteroides sp. 

Fusobacterium sp. 

Eubacterium sp. 

Treponema 

pallidum 

Actinomyces bovis 

✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ 

✔ ✔ 

✔ ✔ ✔ 

Veillonella sp. 

✔ ✔ ✔ 

† Mezlocillin has been discontinued in the United States and is not being reviewed with this class. 


177

III. 

Indications of the Single Entity Penicillins 

Table 3. FDA Approved Indications of the Single Entity Penicillins 

Drug Meningococ 

cal 

Meningitis 

Septicemia Actinomycosis Clostridial 

Infections 

Fusospirochetal 

Infections 

Rat 

Bite 

Fever 

Listeria 

Infections 

Penicillin G X X X X X X X Endocarditis, Pasteurella 

inf., Erysipeloid, 

Diphtheria, Anthrax, 

streptococcal inf., 

empyema, pneumonia, 

pericarditis, syphilis, 

neurosyphilis, disseminated 

gonococcal inf. 

Penicillin V X Staphylococcal, 

streptococcal, and 

pneumococcal inf., to 

prevent recurrence 

following rheumatic fever 

or chorea. 

Dicloxacillin 

Nafcillin 

Oxacillin 

Amoxicillin 

Ampicillin 

X 

Injection only 

X 

Injection 

only 

Other 

Treatment of infections 

caused by penicillinaseproducing 

staphylococci. 



staphylococci 

that have demonstrated 

susceptibility to the drug. 



staphylococci. 

Ear, nose and throat inf., 

GU tract, skin and skin 

structure inf., lower RTI, 

and acute uncomplicated 

gonorrhea. 

Endocarditis, RTI inf., GI 

and GI inf. 

Carbenicillin 

UTI, prostatitis, and other 


susceptible inf. 

Piperacillin X Mixed infections caused by 

susceptible inf., intraabdominal 

inf., UTI, GYN 

inf., lower RTI, skin and 

skin structure inf., bone and 

joint inf., gonococcal inf., 

streptococcal inf., 

prophylaxis for surgical 

procedures. 

Ticarcillin X Skin and skin structure inf., 

acute and chromic RTI 

including P. aeruginosa, 

Proteus sp, and E. coli. 

Also GU inf., and inf. 

Caused by susceptible 

anaerobic bacteria.

IV. 

Pharmacokinetic Parameters of the Single Entity Penicillins 

Table 3 lists the pharmacokinetic parameters of the single entity penicillin antibiotics. Penicillins 

inhibit the biosynthesis of cell wall mucopeptide. 

Table 4. Pharmacokinetic Parameters of the Single Entity Penicillins 2, 5 

Drug Acid Stable Penicillanaseresistant 

% Protein 

Binding 

Elimination May be taken 

with meals 

NATURAL PENICILLINS 

Penicillin G No No 60 Renal IM/IV use 

Penicillin V No No 80 Renal Yes 

PENICILLINASE-RESISTANT 

Dicloxacillin Yes Yes 98 Renal No 

Nafcillin Yes Yes 87-90 Hepatic No 

Oxacillin Yes Yes 94 Hepatic No 

AMINOPENICLLINS 

Amoxicillin Yes No 20 Renal Yes 

Ampicillin Yes No 20 Renal No 

EXTENDED-SPECTRUM 

Carbenicillin Yes No 50 Renal No 

Piperacillin IM/IV use No 16 Renal IM/IV use 

Ticarcillin IM/IV use No 45 Renal IM/IV use 

V. Drug Interactions of the Single Entity Penicillins 

Table 5. Drug Interactions of the Single Entity Penicillins 6 


Penicillins 

Level 1 (delayed, major, 

Tetracyclines impair the bacteriocidal effects of 

Tetracyclines 

suspected) 

penicillins. 

Penicillins, Level 2 (delayed, 

Should not be used in same solution as penicillins 

Aminoglycosides, parenteral 

parenteral moderate, possible) 

may inactivate certain aminoglycosides. 

Penicillins, Level 2 (delayed, major, 

IV doses of penicillins can increase bleeding by 

Anticoagulants 

parenteral suspected) 

prolonging bleeding times. 

Penicillins, oral 


moderate, suspected) 

Beta blockers 

Ampicillin may reduce the bioavailablility of atenolol. 

Some reports of anaphylactic reactions potentiated by 

beta-blockers. 

Ampicillin 


Rate of skin rash is potentiated by concomitant use with 

Allopurinol 


allopurinol 

Penicillin G 

Level 2 (delayed, minor, 

These drugs compete with penicillin G for renal tubular 

Diuretics, aspirin, sulfonamides 

suspected) 

secretion and may prolong penicillin half-life. 

Penicillins 


Oral contraceptives 

Oral contraceptive efficacy may be reduced and 

Penicillins, 

parenteral 

Nafcillin 

Penicillins 

Penicillins 





possible) 


moderate, possible 


possible) 

Heparin 

Cyclosporin 


Erythromycin 

increased bleeding may occur. 

Increased risk of bleeding may occur. 

Nafcillin may cause subtherapeutic cyclosporine levels. 

Antagonistic effects reported in animal studies. 

Clinical studies have demonstrated both antagonistic 

and synergistic effects. 

Other interactions (per manufacturers labeling): 5-6 

• Penicillins and NSAIDs: Since NSAIDs are highly protein bound; they can theoretically 

be displaced from binding sites by penicillins. 

• Penicillins and Colestipol: Serum concentrations of penicillins are reportedly decreased if 

Colestipol is given simultaneously. 

179

• Penicillins (e.g., amoxicillin, carbenicillin, mezlocillin) and Methotrexate: Concomitant 

use of these agents may decrease the clearance of methotrexate, but inhibiting renal 

tubular secretion of the drug. 

• Ticarcillin and lithium: Because of high sodium content in commercially available 

ticarcillin, lithium’s renal elimination can be displaced resulting in toxicity. Patients 

receiving lithium with extended-spectrum penicillins should be closely monitored. 

VI. 

Adverse Drug Events of the Single Entity Penicillins 

Table 6. Common Adverse Events Overview for Single Entity Penicillins 4-6 

Ticarcillin 

Piperacillin 

Carbenicillin 

Ampicillin 

Amoxicillin 

Oxacillin 

Nafcillin 

Dicloxacillin 

Penicillin G, V 

Local 

Phlebitis + - ++ + - - - 4% 3% 


Fever 

Rash 

Photosensitivity 

Anaphylaxis 

Serum Sickness 

Hematologic 

Neutropenia 

Eosinophilia 


↑ PT/PTT 

+ 

3% 

- 

R 

4% 

R 

+ 

R 

R 

+ 

4% 

- 

- 

- 

- 

+ 

- 

- 

+ 

4% 

- 

R 

- 

+ 

22% 

R 

+ 

+ 

4% 

- 

R 

R 

22% 

R 

- 

+ 

5% 

- 

- 

- 

+ 

2% 

R 

+ 

+ 

5% 

- 

R 

- 

+ 

22% 

R 

+ 

+ 

- 

- 

+ 

- 

+ 

+ 

+ 

+ 

+ 

1% 

- 

- 

- 

6% 

+ 

+ 

+ 

+ 

3% 

- 

+ 

+ 

- 

+ 

R 

+ 

GI 

Nausea/Vomiting 

Diarrhea 

C. difficile colitis 

- 

- 

- 

+ 

+ 

R 

- 

- 

R 

- 

- 

R 

2% 

5% 

R 

2% 

10% 

R 

+ 

+ 

R 

+ 

2% 

+ 

+ 

3% 

+ 

Hepatic 



CNS 

Headache 

Confusion 

Seizures 

Special Senses 

Ototoxicity 

Vestibular 

R 

- 

R 

R 

R 

- 

- 

R 

- 

- 

- 

- 

- 

- 

Renal 

↑ BUN, Cr R - - - R R + - - 

Cardiac 

Dysrhythmias R - - - - - - - - 

+ = Occurs, incidence not available; ++ = Significant adverse reaction; R = Rare, defined as < 1% 

- 

- 

R 

R 

- 

- 

- 

+ 

- 

R 

R 

+ 

- 

- 

R 

- 

- 

- 

- 

- 

- 

R 

- 

R 

R 

R 

- 

- 

+ 

- 

+ 

- 

+ 

- 

- 

+ 

- 

R 

R 

- 

- 

- 

- 

- 

R 

R 

R 

- 

- 

180

VII. 

Dosing and Administration for the Single Entity Penicillins 

Table 7. Dosing for the Single Entity Penicillins 4-6 

Drug Usual Adult Dose Comments, Adverse-Reactions 

Natural Penicillins 

Benzathine Pen G 

600,000-1.2 million u IM Q -4 

weeks 

Hoignes syndrome--An immediate, but transient 

neurological reaction with bizarre behavior can occur from 

the use of benzathine Pen G or procaine Pen G. 

Penicillin G 

Low: 600,000-1.2 million u/d IM 

High: > 20million u QD IV 

Penicillin V 

250-500mg BID, TID, QID before 

meals and bedtime 

Penicillinase-Resistant Penicillins 

Dicloxacillin 

125-500mg PO Q6h AC 

Acute hemorrhagic cystitis reported from high blood levels. 

Nafcillin 

Oxacillin 

1-2g IV/IM Q4h 

1-2g IV/IM Q4h 

Extravasations can result in tissue necrosis. 

Reversible neutropenia (over 10% with >21 day therapy). 

Hepatic dysfunction with greater than 12g/day. 


Amoxicillin 

Ampicillin 

500mg PO Q8h or 875mg Q12h 

250-500mg PO Q6h 

A maculopapular rash occurs, but not a true PCN allergy. 


Mezlocillin 

3g IV Q4h 

1.85mEq Na/g 

Piperacillin 

Ticarcillin 

3-4g IV Q4-6h 

UTI: 2g IV Q6h 

3g IV Q4-6h 

Interferes with platelet function, may prolong bleeding 

times. 


Table 8. Special Dosing Considerations for the Single Entity Penicillins 4-6 

Drug Half-life (Normal/ESRD) hr Adjusted for Renal Failure 

Estimated CrCl ml/min 

Natural Penicillins >50-90 10-50


Amoxicillin/Ampicillin 

1.0/5-20: 1.0/7-20 

q8h/q6h 

q8-12h/q6-12h 

q24h/q12-24h 

Amoxicillin/clavulanate 

1.3/1.0:5-20/4.0 

500/125mg q8h 

250-500mg AM 

component q12h 

250-500mg AM 

component q24h 

Ampicillin/sulbactam 

1.0/1.0:9.0/10.0 

q6h 

q8-12h 

q24h 


Mezlocillin 

1.1/2.6-5.4 

q4-6h 

q6-8h 

q8h 

Piperacillin 

1.0/3.3-5.1 

q4-6h 

q6-8h 

q8h 

Piperacillin/tazobactam 

1.0(P)/1.0(T)/3.0(P)4.0(T) 

3.375g q6h 

2.25g q6h 

2.25g q8h 

Ticarcillin 

1.2/13 

1-2g q4h 

1-2g q8h 

1-2g q12h 

Ticarcillin/clavulanate 

1.0(T)/1.0(C)/13(T)4(C) 

3.1g q4h 

2.0g q4-6h 

2.0g q12h 

182

VIII. Comparative Effectiveness of the Single Entity Penicillins 

Table 8 describes the clinical studies for the single entity penicillin. 

Table 9. Outcomes Evidence for the Single Entity Penicillin Antibiotics 

Study Sample Design Results 

High-dose vs. standarddose 

-- 3 year, randomized, 

acute otitis media 7 amoxicillin for 

double-blind 

trial 

Amoxicillin vs. 

azithromycin for C. 

trachomatis in 

pregnancy before 33 

weeks gestation 8 n=39 Randomized, 

single-blind trial 

Single additional dose n=292 Randomized, 

chorioamnionitis 9 

of ampicillin plus 

controlled trial 

gentamicin vs. 

continued therapy in 

Ampicillin vs. cefotetan 

vs. ampicillin/sulbactam 

for prevention of post- 

Cesarean 

endomyometritis 10 n=298 Prospective, 

randomized, 

double-blind trial 

Nafcillin vs. 

vancomycin for 

staphylococcal 

endocarditis 11 n=56 Retrospective 

review 

Oxacillin/dicloxacillin 

vs. linezolid for 

complicated skin and 

soft tissue infections 12 n=819 Multicenter, 

randomized, 


Oxacillin or 

vancomycin plus 

gentamicin vs. 

ciprofloxacin plus 

rifampin for 

staphylococcal 

endocarditis in injection 

drug users 13 n=85 Prospective, 

randomized, nonblinded 

trial 

Pediatric patients received either high-dose (80 to 

90mg/kg/day) or standard-dose (40 to 45mg/kg/day) 

for 3 to 4 days. 

• Absolute difference of antibiotic failure rate 

between the two groups was nonsignificant 

(95% CI, -1.5 to 3.4%; p=0.78). 

• Mean duration of illness was similar (3 ± 2 

days). 

Patients received amoxicillin 500mg TID for 7 days 

or a single dose of azithromycin 1g. 

• No statistically significant differences in 

side effects, compliance, or efficacy. 

Patients received ampicillin 2g every 6 hours and 

gentamicin 1.5mg/kg every 8 hours when 

chorioamnionitis was diagnosed. After delivery, they 

received either only 1 additional dose or continued 

therapy until afebrile and asymptomatic for 24 hours. 

• Failure rate was 3.5% in the continued 

therapy group vs. 4.6% in the single 

additional dose group (p=0.639). 

All patients received single-dose antibiotic 

prophylaxis following umbilical cord clamping. 

• Frequency of endomyometritis was 4% in 

the ampicillin/sulbactam group, 4.2% in the 

cefotetan group, and 5.9% in the ampicillin 

group. 

In patients with methicillin-sensitive Staphylococcus 

aureus infection: 

• Complete response rate was 74% in the 

nafcillin group vs. 50% in the vancomycin 

group (p=0.12). 

• Mortality rate was 22% in the nafcillin 

group vs. 28% in the vancomycin group 

(p=0.73). 

Patients received oxacillin 2g IV every 6 hours 

followed by dicloxacillin 500mg PO every 6 hours or 

linezolid 600mg IV every 12 hours. 

• Clinical cure rate was 64.9% in the 

oxacillin/dicloxacillin group vs. 69.8% in 

the linezolid group (p=0.141). 

Patients received ciprofloxacin 750mg BID plus 

rifampin 300mg BID (oral arm), or oxacillin 2g every 

4 hours or vancomycin 1g every 12 hours plus 

gentamicin 2mg/kg every 8 hours for the first 5 days 

(IV arm). They received 28 days of therapy. 

• Observed cure rate was 95% in the oral arm 

and 88% in the IV arm (p=0.6). 

• Drug toxicity was observed in 2.8% of the

oral arm and in 61.5% of the IV arm 

(p

IX. 

Conclusions 

The single entity penicillins have been useful antibiotics for many types of infections, for many 

years. Although resistance is an issue with some drugs in this class, the penicillin antibiotics 

remain safe and effective for the first-line treatment of many bacterial organisms in adults and 

children. All oral, single entity natural penicillins, penicillinase-resistant penicillins, and 

aminopenicillins in this class are available in generic formulations and are available to recipients. 

The extended spectrum penicillins (one oral agent and two injectables) may have a use for more 

serious infections requiring hospitalization, but their use is not applicable to the general 

population. The extended spectrum penicillins should be available for special 

needs/circumstances that require medical justification through the prior authorization program. 

Therefore, all brand products within the class are comparable to each other and to the generics and 

OTC products in the class and offer no significant clinical advantage over other alternatives in 

general use. 


No brand single entity penicillin is recommended for preferred status. 

185

I. Overview 

Pharmacotherapy Review of the Penicillin Antibiotics 

Combination Agents 

AHFS 081216 

Several penicillin agents such as amoxicillin, ampicillin, piperacillin and ticarcillin are available in 

fixed combinations with ß-lactam inhibitors (Clavulanic acid, Sulbactam, Tazobactam). These 

combinations act synergistically to expand the spectrum of activity against many strains of ß- 

lactamase producing microorganisms. 1 

This review encompasses all dosage forms and strengths. Table 1 lists the drugs included in this review. 

Table 1. Combination Penicillin Antibiotics in this Review 2 


Amoxicillin/Clavulanate Suspension, Tablets, 

Chewable Tablets, Filmcoated 

Augmentin*, Augmentin 

ES-600, Augmentin XR 

Tablets 

Ampicillin/Sulbactam Injection (IV, IM) Unasyn* 

Piperacillin/Tazobactam Injection (IV) Zosyn 

Ticarcillin/Clavulanate Injection (IV) Timentin 


Table 2. Comparison of Bacterial Coverage of the Combination Penicillins 2 

Gram-Positive 

Amoxicillin/ Ampicillin/ Piperacillin/ 

✔ = Generally Susceptible 

Clavulanate Sulbactam Tazobactam 

Staphylococci 

Staphylococcus aureus 


epidermidis 

Streptococci 

Streptococcus 

Pneumoniae 

Beta-hemolytic streptococci 

Enterococcus faecalis 

Streptococcus viridans 

Corynebaacterium 

diphtheriae 

Bacillus anthracis 

Streptococcus agalactiae 

Streptococcus pyogens 

Ticarcillin/ 

Clavulanate 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ 

✔ 

Gram- 

Negative 

Erysipelothrix 

rhusiopathiae 

Listeria monocytogenes 


Haemophilus influenzae 

Eikenella corrodens 

Bacteroides 

melaninogenicus 

✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ 

186

Anaerobic 

Klebsiella sp. 

Neisseria gonorrhoeae 

Neisseria meningitides 

Proteus mirabilis 


Shigella sp. 

Morganella morganii 

Proteus vulgaris 

Providencia stuartii 



Pseudomonas aeruginosa 

Serratia sp. 

Acinetobacter sp. 

Streptobacillus 

moniliformis 


Susceptible 

Clostridium sp. 

Peptococcus sp. 

Peptostreptococcus sp. 

Bacteroides sp. 

Fusobacterium sp. 


Treponema pallidum 

Actinomyces bovis 

Veillonella sp. 

✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ 

✔ 

✔ ✔ ✔ 

✔ ✔ ✔ 

✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ 

Amoxicillin/ 

Clavulanate 

✔ 

✔ 

Ampicillin/ 

Sulbactam 

✔ 

✔ 

✔ 

Piperacillin/ 

Tazobactam 

✔ 

✔ 

✔ 

✔ 

Ticarcillin/ 

Clavulanate 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ 

✔ ✔ ✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

✔ 

187

II. 

Indications of the Combination Penicillin Antibiotics 

Table 3. FDA-Approved Indications for the Combination Penicillins 2 

Drug 

UTI 

Lower RTI 

Intraabdominal 

Infections 

Gynecologic 

Infections 

Septicemia 

Bone and Joint 

Infections 

Skin and Skin 

Structure 

Infections 

Endometriosis/ 

PID 

CAP 

Nosocomial 

Pneumonia 

Otitis Media/ 

Sinusitis 

Appendicitis 

Amoxicillin/ 

Clavulanate 

Ampicillin/ 

Sulbactam 

Piperacillin/ 

Tazobactam 

Ticarcillin/ 

Clavulanate 

* Augmentin XR 

✔ ✔ ✔ ✔ ✔ ✔ * ✔ 

✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ 

✔ ✔ ✔ ✔ ✔ ✔ ✔ 

III. 

Pharmacokinetic Parameters of the Combination Penicillins 

Table 4. Pharmacokinetic Parameters of the Combination Penicillins 1-5 

Drug Mechanism of Bioavailability Protein Metabolism Elimination Half-Life 

Action 

Binding 

Amoxicillin/ 

Clavulanate 

Ampicillin/ 

Sulbactam 

Piperacillin/ 

Tazobactam 

Amoxicillin 

inhibits cell wall 

synthesis by 


penicillin-binding 




Clavulanic 

inhibits β- 

lactamases that 

inactivate 

penicillins 

Ampicillin inhibits 

cell wall synthesis 

by binding to 


proteins 

(PBPs) located 

inside the bacterial 

cell wall. 

Sulbactam 

inhibits β- 


inactivate 

penicillins 

Piperacillin 

inhibits cell wall 

synthesis by 



75% 

Peak 

concentrations 

occur in 1-2.5 

hours 

Peak serum 


are obtained 

immediately 

following IV 

infusion. Peak 

serum 


when given 

IM are 

obtained 

within 30-40 

minutes. 

Both 

bioavailability 

and peak 


are dose 

17% 

amoxicillin 

and 25% 

clavulanic 

Ampicillin: 

28% 

Sulbactam: 

38% 

Piperacillin: 

26%-33% 

Tazobactam 

: 31%-32% 

188 

Clavulanic 

acid is 

metabolized 

hepatically 

Piperacillin: 

6%-9%, 

Tazobactam: 

26% 

80% of a dose 

of amoxicillin is 

excreted 

unchanged in 

urine; 

clavulanic 30%- 

40% 

- 75%-80% of 

both drugs are 

excreted 

unchanged in 

the urine within 

8 hours after 

administration 

Piperacillin: 

50%-70% 

unchanged in 

the urine, 10%- 

20% eliminated 

1.2 hours in 

normal renal 

function 

Ampicillin: 

1-1.8 hours 

Sulbactam: 

1-1.3 hours 

in patients 

with normal 

renal 

function. 

Piperacillin: 

1hour, 

metabolite: 

1-1.5 hours. 

Tazobactam:

Ticarcillin/ 

Clavulanate 




Tazobactam 

inhibits β- 


inactivate 

penicillins 

Ticarcillin inhibits 


synthesis by 






Clavulanic 

inhibits β- 


inactivate 

penicillins 

proportional 

Peak serum 


are obtained 

immediately 

following IV 

infusion. 

Ticarcillin: 

45%-65% 

Clavulanic: 

9%-30% 

Clavulanic 

acid is 

metabolized 

hepatically 

in bile. 

Tazobactam: 

found in the 

urine in 24 

hours, with 

26% as active 

metabolite 

45% excreted 

unchanged in 

the urine. 60%- 

90% of 

ticarcillin 

excreted 

unchanged in 

the urine 

0.7-0.9 

hours 

Clavulanate: 

66-90 

minutes, 

Ticarcillin: 

66-72 

minutes in 

patients with 

normal renal 

function. 

IV. 

Drug Interactions of the Combination Penicillins 

Table 5 lists the most significant drug drug-interactions (Level 1 and 2) for the drugs indexed by 

Drug Interactions Facts. 2,6 

Table 5. Drug Interactions of the Combination Penicillins 2,6 


Penicillins 

Level 1 

Tetracyclines impair the bacteriocidal effects 

Tetracyclines 

of penicillins. 

Level 2 

Should not be used in same solution as 

Penicillins, parenteral 

Aminoglycosides, parenteral penicillins may inactivate certain 

aminoglycosides. 

Penicillins, parenteral 

Level 2 

IV doses of penicillins can increase bleeding 

Anticoagulants 

by prolonging bleeding times. 

Level 2 

Ampicillin may reduce the bioavailability of 

Penicillins, oral 

Beta blockers atenolol. Some reports of anaphylactic 

reactions potentiated by beta-blockers. 

Ampicillin 

Level 2 

Rate of skin rash is potentiated by 

Allopurinol 

concomitant use with allopurinol 

Table 6. Other Reported Drug Interactions of the Combination Penicillins 6 

Precipitant 

Drug 

Parenteral 

penicillins 

Object Drug * 

Heparin 

Penicillin Drug Interactions 

Description 

Heparin with high-dose penicillins may increase risk of bleeding. 

Probenecid Penicillin Coadministration results in increases in penicillin levels and half-life; do not give 

probenecid concurrently. 

Penicillin 

Neuromuscular 

blockers 

Increase duration of blockade 

* 

= Object drug increased. 

189

V. Adverse Events of the Combination Penicillins Antibiotics 

Table 7. Common Adverse Events (%) Reported for the Combination Penicllins 4 

Amoxicillin/ 

Clavulanate 

Ampicillin/ 

Sulbactam 

Piperacillin/ 

Tazobactam 

Ticarcillin/ 

Clavulanate 

Local 

Phlebitis - 3% 1% - 


Fever 

Rash 

Photosensitivity 

Anaphylaxis 

Serum Sickness 

Hematologic 

Neutropenia 

Eosinophilia 


↑ PT/PTT 

+ 

3% 

- 

R 

- 

+ 

+ 

R 

- 

+ 

2% 

- 

- 

+ 

+ 

22% 

R 

- 

2% 

4% 

- 

- 

+ 

+ 

+ 

+ 

+ 

+ 

2% 

- 

+ 

+ 

+ 

5% 

R 

+ 

GI 

Nausea/Vomiting 

Diarrhea 

C. difficile colitis 

3% 

9% 

+ 

+ 

2% 

+ 

7% 

11% 

+ 

1% 

1% 

+ 

Hepatic 



CNS 

Headache 

Confusion 

Seizures 


Ototoxicity 

Vestibular 

+ 

- 

+ 

- 

R 

- 

- 

Renal 

↑ BUN, Cr - R - - 

Cardiac 

Dysrhythmias - - - - 

+ = Occurs, incidence not available; ++ = Significant adverse reaction; R = Rare, defined as < 1% 

6% 

- 

R 

R 

- 

- 

- 

+ 

- 

8% 

R 

R 

- 

- 

+ 

- 

R 

R 

+ 

- 

- 

190

VI. 

Dosage and Administration for the Combination Penicillin Antibiotics 

Table 8. Dosing for the Combination Penicillin Antibiotics 2,5 


Amoxicillin/ 

clavulanate 

Tablets: 250mg/125mg, 

500mg /125mg, 875mg/125mg. 

Adults: 

One 500mg tablet Q12h or 250mg tablet Q8h 

Extended Release tablets: 

1000mg/62.5mg (scored and 

unscored tablets) 

Chewable Tablets: 

125mg/31.25mg, 

250mg/28.5mg, 400mg/57mg. 

Oral Suspension (per 5ml): 

125mg/31.25mg, 

200mg/28.5mg, 250mg/62.5mg, 

400mg/57mg, 600mg/42.9mg 

(Augmentin ES-600) 

Suspension: 

125mg/5ml or 250mg/5ml in place of 500mg tablet or 

200mg/5ml or 400mg/5ml suspension in place of 

875mg 

tablet. 

Severe infections and respiratory tract infections: 

One 875mg tablet every 12 hours or 500mg tablet every 8 hours 

Children: 

Less than 3 months of age: 

30mg/kg/day divided every 12 hours, based on amoxicillin 

component. 

3 months of age or older: 

Refer to table below. 250mg table should not be used until 

child weighs 40kg or more 

40kg or more: 

Dose according to adult recommendations 

Amoxicillin/Clavulanate Dosing Regimen in Children > 3 months 

of age 

Dosing Regimen 

Infection 

200mg/5ml or 

400mg/5ml (Q 12h) 

OM 1 , sinusitis, 45mg/kg/day 

LRTI 2 , severe 

infections 

Less severe 25mg/kg/day 

infections 

1 

Otitis Media 

2 

Lower Respiratory Tract Infection 

125mg/5ml or 

250mg/5ml (Q 8h) 

40mg/kg/day 

20mg/kg/day 

Augmentin ES-600mg 

Augmentin ES-600mg (Pediatric patients 3 months and older) 

Body Weight (kg) 

Volume of Augmentin ES-600 

8 90mg/kg/day 

12 3ml twice daily 

16 4.5mg twice daily 


24 7.5mg twice daily 


32 10.5ml twice daily 

36 13.5ml twice daily 

Pediatric patients weighing 40kg or more: 

Experience with Augmentin ES-600 not available 

191

Augmentin XR: 

Augmentin XR Dosing 

Indication Dose Duration 

Sinusitis 2 tablets Q 12h 10 days 

Communityacquired 

2 tablets Q 12h 7 – 10 days 

Pneumonia 

Ampicillin/ 

Sulbactam 

Piperacillin/ 

Tazobactam 

Ticarcillin/ 

Clavulanate 


1.5g (1g ampicillin/0.5g 

sulbactam in vials and ADD- 

Vantage vials) 

3g (2g ampicillin/1g sulbactam 

in vials and ADD-Vantage 

vials) 

15g (10g ampicillin/5g 

sulbactam in bulk package) 

Powder for Injection 

(lyophilized): 

2.25g (2g piperacillin/0.25g 

tazobactam in vials and ADD- 

Vantage vials-4.69mEq sodium) 

3.375g (3g piperacillin/0.375mg 

tazobactam- 7.04mEq sodium) 





Injection: 

2.25g/50ml (2g 

piperacillin/0.25g tazobactam- 

5.7mEq sodium) 

3.375g/50ml (3g 

piperacillin/0.375g tazobactam 

8.6mEq sodium) 

4.5g/100ml (4g piperacillin/0.5g 



3g ticarcillin and 0.1g clavulanic 

acid. In piggyback bottles, 

ADD-Vantage vials and 31g 

bulk packages 

Injection, solution: 

3g ticarcillin and 0.1g clavulanic 

acid. In 100ml premixed, frozen 

Galaxy plastic containers. 

Given IV or IM 

Adults: 

1.5mg – 3mg every 6 hours. Do not exceed 4g/day 

Children 40kg or more: 

Dose according to adult recommendations 

Adults: 

Administer by IV infusion over 30 minutes. The usual total 

daily dose for adults is 3.375g every 6 hours totaling 13.5g for 

7-10 days. 

Nosocomial Pneumonia: 

Start with 4.5g every 6 hours plus an aminoglycoside. The 

recommended total daily dose is 18g for 7-14 days. Continue 

aminoglycoside in patients where P. aeruginosa is isolated. 

Administer by IV infusion over 30minutes. Usual duration is 

approximately 10-14 days. 

Adults: 

Systemic and Gynecological Infections 

Urinary 

Infections 

Moderate Severe 

Adults > 60kg 3.1g every 4-6h 200mg/kg/day 

every 6hrs 

Adults < 60kg 

300mg/kg/ 

day every 

4hrs 

200-300mg/kg/day every 4-6 hours 

192

Children: 

Dosing Guidelines for Children > 3 Months of age 

Mild to Moderate 

Infection 

Severe Infections 

> 60kg 3.1g every 6h 3.1g every 4h 

< 60kg 200-300mg/kg/day 

every 6h 

300mg/kg/day every 

4h 


Table 9. Special Dosing considerations for the Combination Penicillins 2,5 

Drug Renal 

Dosing 

Hepatic 

dosing 

Pediatric Use Pregnancy 

Category 

Amoxicillin/ 

Doses provided in B 

clavulanate 

previous section. 

Ampicillin/ 

sulbactam 

Piperacillin/ 

tazobactam 

Ticarcillin/ 

clavulanate 

No, unless 

severe 

impairment 

(CrCl


plus ciprofloxacin vs. 

gentamicin plus 

piperacillin/tazobactam 

for low-risk febrile 

neutropenia 19 n=126 Prospective, 

randomized, 


Study conducted in 

the UK. 


vs. telithromycin for 

acute maxillary 

sinusitis 20 n=434 Assessed 17 to 24 

days post-therapy, 

multicenter, 

randomized, 


Pharmacokinetically 

enhanced 


(Augmentin XR) for 

respiratory tract 

infections caused by S. 

pneumoniae 21 n=427 Pooled analysis of 

nine clinical 

studies 


vs. clindamycin ± 

cephalosporin for 

aspiration pneumonia 

and lung abscess 22 n=70 Open-label, 

multicenter, 

prospective, 

randomized, 



Germany. 


vs. cefuroxime for 

serious skin and skin 

structure infections in 

pediatrics 23 n=98 Open-label, 

multicenter, 

prospective, 

randomized trial 

Ciprofloxacin plus 

piperacillin vs. 

tobramycin plus 

piperacillin for empiric 

therapy of febrile 

neutropenia 24 n=471 Multicenter, 

randomized, 

double-blind, 


194 

Patients received amoxicillin/clavulanate 500/175mg 

every 8 hours plus ciprofloxacin 750mg BID for 5 

days (oral arm) or gentamicin 80mg every 8 hours 

plus piperacillin/tazobactam 4.5 g every 8 hours (IV 

arm) until hospital discharge. 

• Initial treatment was successful without 

antibiotic modification in 90% of IV arm 

vs. 84.8% in the oral arm (p=0.55). 

• Median patient stay was 4 days in the IV 

arm vs. 2 days in the oral arm (p


vs. ertapenem for 

complicated skin and 

skin structure infections 

caused by MSSA 25 n=135 Assessed 10 to 21 

days post-therapy, 

randomized, 

double-blind, 


Piperacillin/tazobactam n=316 Assessed 2 to 4 

pelvic infections 26 therapy, 

vs. ertapenem for acute 

weeks post- 

multicenter, 

randomized, 

double-blind, 



vs. ciprofloxacin plus 

amoxicillin ± 

metronidazole for 

infections after liver 

transplantation 27 n=217 3 month, 

prospective, 



London. 


plus tobramycin vs. 

ceftazidime plus 

tobramycin for 

nosocomial lower 

respiratory tract 

infection 28 n=136 Open-label, 

multicenter, 

randomized, 



plus amikacin vs. 

ceftazidime plus 

amikacin for ventilatorassociated 

pneumonia 29 n=115 Open-label, 

multicenter, 

randomized, 



France. 

195 

in the tobramycin/piperacillin group (95% 

CI, -2.2 to 6.4%). 

• Fevers resolved faster in the 

ciprofloxacin/piperacillin group vs. the 

tobramycin/piperacillin group (5 vs. 6 days, 

respectively; p=0.005). 

• No significant differences in adverse events 

or toxicity (p=0.083). 

Patients received ertapenem 1g daily or 

piperacillin/tazobactam 3.375g every 6 hours. 

• Use of ertapenem resulted in cure rate of 

80.6% compared to 80.9% in the 

piperacillin/tazobactam group (p=0.99). 

Patients received ertapenem 1g daily or 

piperacillin/tazobactam 3.375g every 6 hours. 

• Median duration of therapy was 4 days. 

• Most common pathogen was E. coli. 

• Use of ertapenem resulted in a cure rate of 

93.9% compared to 91.5% in the 

piperacillin/tazobactam group (95% CI, -4 

to 8.8%). 

Patients received piperacillin/tazobactam or 

ciprofloxacin/amoxicillin for the first 3 months after 

liver transplant. Patients in the 

ciprofloxacin/amoxicillin group also received 

metronidazole if anaerobic infection was suspected. 

• At 72 hours, overall response rate was 

66.1% in the piperacillin/tazobactam group 

vs. 60% in the ciprofloxacin/amoxicillin 

group (p=0.399). 

• At end-of-study, successful clinical 

outcome rate was 58.9% in the 

piperacillin/tazobactam group vs. 50.5% in 

the ciprofloxacin/amoxicillin group 

(p=0.222). 

Patients received piperacillin/tazobactam 3.375g 

every 4 hours or ceftazidime 2g every 8 hours. All 

patients received tobramycin 5mg/kg/day divided 

every 8 hours. 

• Clinical success rate was 74% in the 

piperacillin/tazobactam group vs. 50% in 

the ceftazidime group (p=0.006). 

• Eradication rate of baseline pathogen was 

66% in the piperacillin/tazobactam group 

vs. 38% in the ceftazidime group (p=0.003). 

• Mortality rate in the piperacillin/tazobactam 

group was 7.7% vs. 17% in the ceftazidime 

group (p=0.03). 

Patients received piperacillin/tazobactam 4.5g QID 

or ceftazidime 1g QID. All patients received 

amikacin 7.5mg/kg BID. 

• Bacteriologically confirmed infections 

included polymicrobial (37%) and 

involving P. aeruginosa (32%). 

• Clinical cure rate was 51% with 

piperacillin/tazobactam vs. 36% with 

ceftazidime (95% CI, -0.2 to 30.2%).


plus aztreonam vs. 

cefepime for febrile 

neutropenia in high-dose 

chemotherapy patients 30 n=126 Open-label, 



vs. Imipenem/cilistatin 

for gangrenous and 

perforated appendicitis 31 n=137 Randomized, 

double-blind, 


• Twenty-eight day mortality rate was 16% 

with piperacillin/tazobactam vs. 20% with 

ceftazidime (p=0.55). 

• Bacteriologic failure rate was 33% with 

piperacillin/tazobactam vs. 51% with 

ceftazidime (p=0.05). 

Patients received ticarcillin/clavulanate 3.1g every 6 

hours plus aztreonam 1g every 8 hours or cefepime 

2g every 8 hours for 72 hours. 

• Clinical response rates were similar in the 

two groups (55% for cefepime and 61% for 

ticarcillin/clavulanate plus aztreonam). 

Patients received ticarcillin/clavulanate 3.1g every 6 

hours or imipenem/cilistatin 500mg every 6 hours for 

3 to 5 days. 

• Clinical success rate was 96.9% in the 

ticarcillin/clavulanate group vs. 95.9% in 

the imipenem/cilastatin group (p=0.99). 

• Bacteriologic success rate was 100% in the 

ticarcillin/clavulanate group vs. 98.4% in 

the imipenem/cilastatin group (p=0.99). 

• Adverse event rate was similar in both 

groups (p=0.31). 


Dose Simplification: In most cases, the penicillins in this class are given in divided doses 

depending on the infection being treated. Literature search of Medline/PubMed revealed no 

clinical trials available comparing the efficacy of amoxicillin/clavulanate dosed three times daily 

and the enhanced formulations dosed twice daily. 


Impact on Physician Visits: A search of Medline and Ovid did not reveal data pertinent to 

medical resource utilization or the duration of hospitalization. 

VIII. Conclusion 

Amoxicillin/clavulanate is the only combination penicillin antibiotic in this class with use that is 

applicable to the general population. It is recommended as a first or second-line agent for several 

different infections (acute otitis media, sinusitis, community-acquired pneumonia). A generic 

formulation is available for amoxicillin/clavulanate (Augmentin), but generic formulations are not 

available for Augmentin XR or Augmentin ES-600. Augmentin XR has limited indications versus 

regular Augmentin, with similar efficacy. Additionally, only regular Augmentin is available in 

solid and liquid dosage formulations. 

The other combination penicillins in this class (ampicillin/sulbactam, piperacillin/tazobactam, and 

ticarcillin/clavulanate) are injections for use in more serious infections typically requiring 

hospitalization. These drugs should be available for special needs/circumstances that require 

medical justification through the prior authorization program. 

Therefore, all brand products within the class are comparable to each other and to the generics and 

OTC products in the class and offer no significant clinical advantage over other alternatives in 

general use. 

IX. 


No brand combination penicillin antibiotic is recommended for preferred status. 

196

References 


Society of Health-System Pharmacists. Bethesda. 2004 


3. Abate BJ, Barriere SL. Antimicrobial Regimen Selection. In: Pharmacotherapy. A 

Pathophysiologic Approach, Fifth Edition. Dipiro JT, Talbert RL, Yee GC, et al. Eds. McGraw- 

Hill. New York. 2002. Pg. 1817-29. 

4. Gilbert DN, Moellering, RC, Sande MA. The Sanford Guide to Antimicrobial Therapy 34 th 

Edition. Hyde Park, Vermont. 2004. 




7. Garrison GD, Sorum PC, Hior W, Miller MM. High-dose versus standard-dose amoxicillin for 

acute otitis media. Ann Pharmacother. 2004;38(1):158-60. 

8. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus 

amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 

2001;9(4):197-202. 

9. Edwards RK, Duff P. Single additional dose postpartum therapy for women with 

chorioamnionitis. Obstet Gynecol. 2003;102(5 Pt 1):957-61. 

10. Spinnato JA, Youkilis B, Cook VD, et al. Antibiotic prophylaxis at Cesarean delivery. J Matern 

Fetal Med. 2000;9(6):348-50. 

11. Gentry CA, Rodvold KA, Novak RM, Hershow RC, Naderer OJ. Retrospective evaluation of 

therapies for Staphylococcus aureus endocarditis. Pharmacotherapy. 1997;17(5):990-7. 

12. Stevens DL, Smith LG, Bruss JB, et al. Randomized comparison of linezolid (PNU-100766) 

versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. 

Antimicrob Agents Chemother. 2000;44(12):3408-13. 

13. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of right-sided staphylococcal 

endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. 

Am J Med. 1996;101(1):68-76. 

14. Bland ML, Vermillion ST, Soper DE. Late third-trimester treatment of rectovaginal group B 

streptococci with benzathine penicillin G. Am J Obstet Gynecol. 2000;183(2):372-6. 

15. Hook EW, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of 

azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis. 

2002;29(8):486-90. 

16. Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic 

syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD 

AIDS. 2004;15(5):328-32. 

17. Curtin-Wirt C, Casey JR, Murray PC, et al. Efficacy of penicillin vs. amoxicillin in children with 

group A beta hemolytic streptococcal tonsillopharyngitis. Clin Pediatr (Phila). 2003;42(3):219- 

25. 

18. Lode H, Magyar P, Muir JF, et al. Once-daily oral gatifloxacin vs. three-times-daily co-amoxiclav 

in the treatment of patients with community-acquired pneumonia. ClinMicrobiol Infect. 

2004;10(6):512-20. 

19. Innes HE, Smith DB, O’Reilly SM, et al. Oral antibiotics with early hospital discharge compared 

with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a 

prospective randomized controlled single centre study. Br J Cancer. 2003;89(1):43-9. 

20. Luterman M, Tellier G, Lasko B, Leroy B. Efficacy and tolerability of telithromycin for 5 or 10 

days vs. amoxicillin/clavulanic acid for 10 days in acute maxillary sinusitis. Ear Nose Throat J. 

2003;82(8):576-80. 

21. File TM Jr., Jacobs MR, Poole MD, et al. Outcome of treatment of respiratory tract infections due 

to Streptococcus pneumoniae, including drug-resistant strains, with pharmacokinetically enhanced 

amoxicillin/clavulanate. Int J Antimicrob Agents. 2002;20(4):235-47. 

22. Allewelt M, Schuler P, Bolcskei PL, Mauch H, Lode H, Study Group on Aspiration Pneumonia. 

Ampicillin + sulbactam vs. clindamycin ± cephalosporin for the treatment of aspiration pneumonia 

and primary lung abscess. Clin Microbiol Infect. 2004;10(2):163-70. 

197

23. Azimi PH, Barson WJ, Janner D, Swanson R, UNASYN Pediatric Study Group. Efficacy and 

safety of ampicillin/sulbactam and cefuroxime in the treatment of serious skin and skin structure 

infections in pediatric patients. 

24. Peacock JE, Herrington DA, Wade JC, et al. Ciprofloxacin plus piperacillin compared with 

tobramycin plus piperacillin as empirical therapy in febril neutropenic patients. A randomized, 

double-blind trial. Ann Intern Med. 2002;137(2):77-87. 

25. Gesser RM, McCarroll KA, Woods GL. Efficacy of ertapenem against methicillin-susceptible 

Staphylococcus aureus in complicated skin/skin structure infections: results of a double-blind 

clinical trial versus piperacillin-tazobactam. Int J Antimicrob Agents. 2004;23(3):235-9. 

26. Roy S, Higareda I, Angel-Muller E, Protocol 023 Study Group. Ertapenem once a day versus 

piperacillin-tazobactam every 6 hours for treatment of acute pelvic infections: a prospective, 

multicenter, randomized, double-blind study. Infect Dis Obstet Gynecol. 2003;11(1):27-37. 

27. Philpott-Howard J, Burroughs A, Fisher N, et al. Piperacillin-tazobactam versus ciprofloxacin 

plus amoxicillin in the treatment of infective episodes after liver transplantation. J Antimicrob 

Chemother. 2003;52(6):993-1000. 

28. Joshi M, Bernstein J, Solomkin J, Wester BA, Kuye O, Piperacillin/tazobactam Nosocomial 

Pneumonia Study Group. Piperacillin/tazobactam plus tobramycin versus ceftazidime plus 

tobramycin for the treatment of patients with nosocomial lower respiratory tract infection. J 

Antimicrob Chemother. 1999;43(3):389-97. 

29. Brun-Buisson C, Sollet JP, Schweich H, Briere S, Petit C, VAP Study Group. Treatment of 

ventilator-associated pneumonia with piperacillin-tazobactam/amikacin versus 

ceftazidime/amikacin: a multicenter, randomized controlled trial. Clin Infect Dis. 

1998;26(2):346-54. 

30. Fleming DR, Ziegler C, Baize T, Mudd L, Goldsmith GH, Herzig RH. Cefepime versus ticarcillin 

and clavulanate potassium and aztreonam for febrile neutropenia therapy in high-dose 

chemotherapy patients. Am J Clin Oncol. 2003;26(3):285-8. 

31. Allo MD, Bennion RS, Kathir K, et al. Ticarcillin/clavulanate versus imipenem/cilistatin for the 

treatment of infections associated with gangrenous and perforated appendicitis. Am Surg. 

1999;65(2):99-104. 

198



Pharmacotherapy Review of the Tetracyclines 

AHFS 081224 


I. Overview 

Tetracyclines have been used for the treatment of a wide variety of gram-positive and gramnegative 

bacterial infections since the 1950s. They are important for the treatment of and 

prophylaxis against infections with bacteria that could be used in biological weapons. Bacterial 

resistance to tetracycline was identified shortly after the introduction of therapy. In contrast, 

tetracycline resistance has not yet been described in protozoa or other eukaryotic organisms. 10 

The tetracyclines were discovered in the 1940s, and because they had few major side effects, 

(except in young children and pregnant women) therapeutic use began in the 1950s. At the same 

time, tetracyclines were found to be useful growth promoters in animals and have been extensively 

used in agriculture in North America since the 1950s. Only a limited number of derivatives are 

currently used. Tetracyclines are broad-spectrum agents, with activity against both gram-positive 

and gram-negative bacteria and intracellular chlamydiae, mycoplasmas, and rickettsiae. More 

recently, tetracyclines have been used against eukaryotic protozoan parasites and for the treatment 

of a variety of noninfectious conditions, often at subtherapeutic levels (e.g., for acne) and over 

extend time periods. Shortly after the introduction of tetracycline therapy, the first tetracyclineresistant 

bacterial pathogen was identified. Since then, tetracycline-resistant bacterial pathogens 

have continued to be identified, limiting the tetracyclines’ effectiveness in the treatment of 

bacterial disease. 10 

That being said, the tetracyclines still play an important role in the treatment of infectious 

diseases. These drugs are well absorbed orally and are available generically. They have also 

become preferred therapy for some relatively new infectious diseases. Doxycycline is the 

preferred agent for rickettsial tick borne diseases and early Lyme disease. 25, 11, 12 Minocycline has 

been used to treat MRSA and MRSE infections. 25 

This review encompasses all dosage forms and strengths. Table 1 lists the drugs included in this 

review. 

Table 1. Tetracyclines in this Review 


Tetracycline Capsules/Oral suspension *Sumycin, Achromycin V, Emtet-500 

Oxytetracycline Parenteral Injection Terramycin 

Doxycycline Tablets, Capsules, Injection, Powder for oral 

suspension, Syrup 

*Vibramycin, Vibra-Tabs, Doryx, Adoxa, ED 

Doxy Caps, Monodox, Periostat 

Minocycline Tablets, Capsules, Powder for oral suspension, 

*Minocin, Dynacin 

injection 

Demeclocycline Tablets *Declomycin 

*Generic Formulation Available. 

199

II. Evidence Based Medicine and Current Treatment Guidelines 

This category encompasses hundreds of possible treatment algorithms because of the 

numerous organisms and infectious diseases that are covered by these drugs. Many 

documented treatment protocols and dosage recommendations from a variety of reputable 

sources exist. These treatment guidelines can change frequently as resistant strains of 

organisms appear. Guidelines are available with the most up-to-date information from the 

CDC, 37 Facts and Comparison drug monographs, 9 the various medications prescribing 

information for treatment protocols on specific disease states, 1-8 and review articles based on 

14, 15,24,27,34,35 

accepted practices. Examples of therapy guidelines that include use of 

tetracyclines are presented here: 

Lyme Disease 

For the treatment of early Lyme disease, administration of doxycycline (100mg BID) or 

amoxicillin (500mg TID) for 14-21 days is recommended for early localized or early 

disseminated Lyme disease associated with erythema migrans, in the absence of neurological 

involvement or third-degree atrioventricular heat block (A-I). Doxycycline has the advantage 

of being efficacious for the treatment of human granulocytic ehrlichiosis or babesiosis. 

Doxycycline is also useful in the treatment of Lyme arthritis. 

Sexually Transmitted Diseases 

Epididymitis is often caused by C. trachomatis or N. gonorhoeae in sexually active men aged 

35 years, men who have recently undergone urinary tract instrumentation or surgery, 

and men who have anatomical abnormalities of the urinary tract. 

Empiric therapy is indicated before culture results become available. For infections most 

likely caused by gonococcal or chlamydial infection, the CDC recommended regimen is: 

• Ceftriaxone 250mg IM in a single dose 

PLUS 

• Doxycycline 100mg orally BID for 10 days 

For epididymitis most likely caused by enteric organisms, for patients allergic to 

cephalosporins and/or tetracyclines, or for epididymitis in patients aged >35 years, the 

recommended regimen is: 

• Ofloxacin 300mg orally BID for 10 days 

OR 

• Levofloxacin 500mg orally QD for 10 days 

III. Comparative Indications of the Tetracycline Antibiotics 

Table 2. FDA-approved indications for the Tetracycline antibiotics, unlabeled uses, and susceptible 

organisms and describes the major organisms under each indication. 9 

✔ =Organisms Generally Susceptible to Tetracyclines 1 but not FDA-approved and unlabeled uses. 

✔✔=FDA-approved indications 

Category or 

Disease Organism Demeclocycline Doxycycline Minocycline Oxytetracycline Tetracycline 

Gram-positive Actinomyces sp. ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Alpha-hemolytic 

streptococci(Viridans 

group) 

200 

✔ ✔ ✔



Category or 


Bacillus anthracis ✔✔ ✔ ✔✔ ✔✔ ✔✔ 

Clostridium sp. ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Enterococcus 

faecalis 2 , 3 ✔ ✔ ✔ ✔ 

E. faecium ✔ ✔ ✔ 

Listeria 

monocytogenes 

✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Propionibacterium 

acnes 

✔✔ ✔✔ ✔✔ 


aureus 4 ✔✔ ✔ ✔✔ ✔✔ 

Streptococcus 

pneumoniae 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

S. pyogenes 2 , 5 ✔✔ ✔ ✔ ✔✔ ✔✔ 

Treponema pallidum ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

T. pertenue ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Gram-negative 

Acinetobacter sp. 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Bacteroides sp. 2 ✔✔ ✔ ✔ ✔✔ ✔✔ 

Bartonella 

bacilliformis 

✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Borrelia recurrentis ✔✔ ✔✔ ✔✔ ✔✔ ✔ 

Brucella sp. ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Calymmatobacterium 

granulomatis 

✔✔ ✔✔ ✔ ✔✔ ✔✔ 

Campylobacter fetus ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Enterobacter 

aerogenes 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔ 

Escherichia coli 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Francisella tularensis ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Fusobacterium 

fusiform 

✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Haemophilus ducreyi ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

H. influenzae 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔ 

Klebsiella sp. 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Neisseria gonorrhoeae ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

N. meningitides ✔ ✔ 

201



Category or 


Shigella sp. 2 ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Vibrio cholerae ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Yersinia pestis ✔✔ ✔ ✔✔ ✔✔ ✔✔ 

Balantidium coli ✔ ✔ ✔ 

Chlamydia psittaci ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

C. trachomatis ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Entamoeba sp. ✔ ✔ ✔ ✔ ✔ 

Miscellaneous 

Mycobacterium 

marinum 

Mycoplasma 

pneumoniae 

Plasmodium 

falciparum 6 

✔ 

✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

✔✔ 

Rickettsiae sp. ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Acute intestinal 

amebiasis 

Ureaplasma 

urealyticum 

✔✔ ✔✔ ✔✔ 

Entamoeba histolytica ✔✔ ✔✔ ✔✔ ✔✔ ✔✔ 

Severe Acne ✔✔ ✔✔ ✔✔ 

Anthrax, 

including 

inhalational 

anthrax 

Malaria 

prophylaxis 

Treatment of 

asymptomatic 

meningococcal 

carriers 

Periodontitis 

Gonococcal 

Arthritis, early 

Lyme disease, 

malaria, ocular 

rosacea 

Peptic ulcers, 

adjunctive 

therapy 

✔✔ 

Plasmodium 

✔✔ 

falciparum 

N. meningitides ✔✔ 

Helicobacter pylori 

✔ 

✔ 

202



Category or 


Malaria, pleural 

malignant 

effusions, 

nocardiosis, 

ocular rosacea, 

treatment of 

traveler’s 

diarrhea, 

prophylaxis of 

pneumothorax, 

✔ 

Lyme Disease Lyme borreliosis ✔ 

STD (syphilis, 

✔ 

chlamydia, PID, 

epididymitis, 

sexual assault 

prophylaxis 

Rheumatoid 

✔ 

arthritis-early 

treatment 

Gallbladder E. coli ✔ 

infections 

Nocardiosis, 

✔ 

chronic 

malignant pleural 

effusion 

Syndrome of 

✔ 

inappropriate 

antidiuretic 

hormone 

(SIADH) 

Peptic ulcers H. Pylori ✔ ✔✔ 

1 Cross-resistance of these organisms to tetracyclines is common. 

2 Because many strains of gram-negative micro-organisms have been shown to be resistant to tetracyclines, culture and susceptibility 

testing are recommended. 

3 Up to 74% of Enterococcus faecalis have been found to be resistant to tetracyclines. 

4 Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections. 

5 Up to 44% of Streptococcus pyogenes have been found to be resistant to tetracycline drugs. 

6 Doxycycline has been found to be active against the asexual erythrocytic form of Plasmodium falciparum but not against the 

gametocytes of P. falciparum. 

IV. Pharmacokinetic Parameters 1-9 

Tetracyclines are adequately, but incompletely, absorbed from the GI tract. The percentage 

absorbed when taken on an empty stomach is lowest for oxytetracycline, demeclocycline, and 

tetracycline, and highest for doxycycline and minocycline. The extent of absorption is usually 

decreased by the presence of divalent and trivalent cations, and to a variable degree by milk or 

food (see Drug Interactions). Tetracyclines are bound to plasma proteins in varying degrees. 

203

Penetration of the tetracyclines into most body fluids and tissues is excellent. Tetracyclines are 

distributed in varying amounts into bile, liver, lung, kidney, prostate, urine, CSF, synovial fluid, 

mucosa of the maxillary sinus, brain, sputum, and bone. Inflammation of the meninges is not 

required for passage into the CSF, but concentrations may increase in the presence of inflamed 

meninges. Tetracyclines cross the placenta and enter the fetal circulation and amniotic fluid. 

The tetracyclines are concentrated in the bile by the liver. They are excreted in the urine and feces 

at high concentrations in a biologically active form. Because renal clearance of tetracyclines is by 

glomerular filtration, excretion is significantly affected by the state of renal function. The renal 

clearance of demeclocycline has been shown to be about half of that of tetracycline. The urinary 

and fecal recovery of minocycline is one-half to one-third that of other tetracyclines, and 

minocycline also appears to undergo some metabolism, largely to 9-hydroxyminocycline. 

Doxycycline appears to be excreted extensively by the digestive tract. 

Table 4. Pharmacokinetic Parameters of the Tetracycline Agents 1-9 

* nd = no data. 

1 300 mg single oral dose. 

2 200 mg single oral dose. 

3 200 mg administered IV over 2 hours. 

4 Single oral dose of two 100 mg pellet-filled capsules. 

Protein 

binding 

(%) 

Serum 

half-life 

(h) 

Excreted 

in 

urine (%) 

Tetracyclines 

Absorption 

(%) C max (mcg/mL) T max (h) 

Demeclocycline 60 to 80 1.5 to 1.7 1 3 to 4 1 35 to 90 16 nd * 

Doxycycline 90 to 100 2.6 (hyclate) 2 2 (hyclate) 2 80 to 95 to 22 40 

3.6 (IV) 3 

3.61(monohydrate) 2 2.6(monohydrate) 2 

Minocycline 90 to 100 2.1 to 5.1 4 1 to 4 75 11 to 22 5 to 10 

(oral) 

15 to 23 

(IV) 

Oxytetracycline 60 to 80 nd 2 to 4 20 to 40 6 to 12 10 to 35 

Tetracycline 60 to 80 nd 2 to 4 20 to 65 6 to 12 20 to 55 

204


Table 5. Drug Interactions of the Tetracycline Agents 1- 9 

Precipitant drug Object drug * Description 

Antacids 

(containing 

aluminum, calcium 

or magnesium 

salts) 

Iron salts 

Zinc salts 

Tetracyclines 

Tetracyclines administered with aluminum, calcium, magnesium, 

iron, or zinc salts form an insoluble chelate, thereby decreasing 

the absorption and serum levels of the tetracycline. Administer 

tetracyclines at least 2 hours before or after these agents. 

Barbiturates Doxycycline Barbiturates increase the hepatic metabolism of doxycycline, 

therefore decreasing doxycycline’s half-life and serum levels. 

Adjust doxycycline dose as needed. Consider using an 

alternative tetracycline. 

Bismuth salts Tetracyclines Coadministration of bismuth salts in liquid formulations may 

decrease the serum levels of tetracyclines. Give the bismuth salt 

2 hours after the tetracycline. 

Carbamazepine Doxycycline Carbamazepine may decrease the half-life and serum levels of 

doxycycline due to increased hepatic metabolism. Adjust 

doxycycline dose as needed. Consider using an alternative 

tetracycline. 

Cholestyramine 

Colestipol 

Phenytoin 

Rifamycins 

Urinary alkalinizers 

(e.g., sodium 

lactate, potassium 

citrate) 

Tetracyclines 

Tetracyclines 

Tetracyclines 

Doxycycline 

Tetracyclines 

Anticoagulants, 

oral 

Contraceptives, 

oral 

Coadministration may decrease or delay the absorption of 

tetracyclines, therefore decreasing the serum concentrations. 

Adjust the tetracycline dose if needed. 

Phenytoin and rifamycins appear to induce the metabolism of 

doxycycline, causing the half-life to be significantly decreased. 

Increased doxycycline dosage may be needed. 

Coadministration may result in increased excretion of the 

tetracyclines and decreased serum levels. Separate 

administration by 3 to 4 hours; however, this may not be 

effective and an increase in tetracycline dose may be necessary if 

the pH of the urine remains increased. 

The action of oral anticoagulants may be increased because of 

the elimination of vitamin K-producing gut bacteria by 

tetracyclines. Monitor coagulation parameters and adjust 

anticoagulant dose as needed. 

Tetracyclines may interfere with the enterohepatic recirculation 

of certain contraceptive steroids, leading to reduced efficacy. 

Although infrequently reported, contraceptive failure is possible. 

Tetracyclines Digoxin Coadministration may result in increased serum levels of digoxin 

in a small subset of patients ( 10%). Monitor digoxin levels and 

signs of toxicity. 

Tetracyclines Insulin The ability of insulin to produce hypoglycemia may be 

potentiated. In diabetic patients, monitor blood glucose 

concentrations closely and tailor the insulin regimen as needed. 

Tetracyclines Isotretinoin Isotretinoin use has been associated with a number of cases of 

pseudotumor cerebri, some of which involved coadministration 

of tetracyclines. Therefore, avoid concomitant use. 

Tetracyclines Methoxyflurane Coadministration may enhance the risk for renal toxicity; deaths 

have been reported. Do not coadminister. If possible seek 

alternative agents. 

Tetracyclines Penicillins The bacteriostatic action of tetracyclines may interfere with the 

205

Precipitant drug Object drug * Description 

bactericidal activity of penicillins. Consider avoiding this 

combination if at all possible. 

Tetracyclines Theophyllines The incidence of adverse reactions to theophyllines may be 

increased. Monitor theophylline levels and adjust dose as 

needed. 

* 

= Object drug increased. = Object drug decreased. 

Drug / Food Interactions: 1-9 

The administration of demeclocycline, oxytetracycline, and tetracycline with milk and dairy 

products forms poorly absorbed chelates. A number of studies have reported the serum levels of 

these tetracyclines, when administered with milk products, to be 50% to 80% lower. Administer 

the interacting tetracyclines at least 2 hours before or after meals. The inhibitory effect of food 

and milk on the absorption of doxycycline and minocycline is considerably less than that observed 

with the other tetracycline derivatives. These two drugs are often administered without regard to 

meals; but the potential risk of decreased drug efficacy must be weighed against the benefit of 

treating the infection. The administration of doxycycline with a high-fat meal has been shown to 

delay the time to peak plasma concentrations by an average 1 hour 20 minutes. Peak plasma 

concentrations of doxycycline were also decreased by up to 20% with simultaneous ingestion of 

dairy products or a high-fat, high-protein meal. The peak plasma concentration of minocycline 

was slightly decreased and delayed by 1 hour when administered with food, compared to dosing 

under fasting conditions. 

VI. Adverse Drug Events of the Tetracycline Agents 

ADRs are possible with all agents in the class unless specified. 

Table 6. Common Adverse Events Reported for the Tetracycline Agents 1-9 

Category 

Adverse Event 

ORAL 

CNS 

Dermatologic 

GI 

Dizziness, headache, bulging fontanel, pseudotumor cerebri, convulsions, hypesthesia, 

paresthesia, sedation, vertigo, myasthenic syndrome (demeclocycline; rare). 

Maculopapular and erythematous rashes, photosensitivity, fixed drug eruptions, balanitis, 

erythema multiforme, Stevens-Johnson syndrome, skin and mucus membrane pigmentation, 

alopecia, erythema nodosum, hyperpigmentation of the nails, pruritus, toxic epidermal 

necrolysis, vasculitis; exfoliative dermatitis (rare). 

Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions 

(with monilial overgrowth) in the anogenital region, esophageal ulcerations, pancreatitis, 

dyspepsia, stomatitis, enamel hypoplasia, pseudomembranous colitis, esophagitis, bulky loose 

stools, sore throat, black hairy tongue, hoarseness (tetracycline). 

Due to oral minocycline and doxycycline’ s virtually complete absorption, side effects of the 

lower bowel, particularly diarrhea, have been infrequent. 

Hematologic 

Hepatic 


Anemia, hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia 

Increased liver enzymes, hepatic toxicity, hyperbilirubinemia, hepatic cholestasis; hepatic 

failure, hepatitis (rare). 

Urticaria, angioneurotic edema, pericarditis, anaphylaxis, anaphylactoid purpura, systemic lupus 

erythematous exacerbation, polyarthralgia, pulmonary infiltrates with eosinophilia. 

Musculoskeletal 

Arthralgia, arthritis, bone discoloration, myalgia, joint stiffness and swelling. 

206

Renal 

Respiratory 

Category 

Miscellaneous 

PARENTERAL 

CNS 

Dermatologic 

GI 

Hematologic 

Hepatic 



Renal 

Respiratory 

Miscellaneous 

Adverse Event 

Dose-related increase in BUN, acute renal failure, interstitial nephritis, nephrogenic diabetes 

insipidus (demeclocycline). 

Cough, dyspnea, bronchospasm, asthma exacerbation. 

Brown-black microscopic discoloration of thyroid glands (prolonged therapy), tooth 

discoloration, lupus-like syndrome, fever, secretion discoloration, vulvovaginitis, tinnitus, 

decreased hearing, serum sickness-like syndrome. 

Headache, convulsions, dizziness, hypesthesia, paresthesia, sedation, vertigo, bulging fontanels, 

pseudotumor cerebri 

Maculopapular and erythematous rashes, photosensitivity, alopecia, erythema nodosum, 

hyperpigmentation of the nails, pruritus, toxic epidermal necrolysis, vasculitis, fixed drug 

eruptions, balanitis, erythema multiforme, Stevens-Johnson syndrome, skin and mucus 

membrane pigmentation, injection site erythema and injection site pain, exfoliative dermatitis 

(rare). 

Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions 

(with monilial overgrowth) in the anogenital region, dyspepsia, stomatitis, enamel hypoplasia, 

pseudomembranous colitis, pancreatitis. 

Hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, leukopenia, 

pancytopenia. 

Hyperbilirubinemia, hepatic cholestasis, increased liver enzymes, jaundice, hepatitis, liver failure 

Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of 

systemic lupus erythematous, myocarditis, pulmonary infiltrates. 

Arthralgia, arthritis, bone discoloration, myalgia, joint stiffness and swelling, polyarthralgia 

Dose-related increase in BUN; interstitial nephritis, acute renal failure(minocycline). 

Cough, dyspnea, bronchospasm, asthma exacerbation 

Brown-black microscopic discoloration of thyroid glands (prolonged therapy);tooth 

discoloration, vulvovaginitis, tinnitus, hypersensitivity syndrome (cutaneous reaction, 

eosinophilia, and one or more of the following: Hepatitis, pneumonitis, nephritis, myocarditis, 

pericarditis, fever, lymphadenopathy), lupus-like syndrome, serum sickness-like syndrome, 

fever, secretion discoloration 

Warnings 1-9 

Malaria prophylaxis (doxycycline only): 

Doxycycline offers substantial but not complete suppression of the asexual stages of Plasmodium 

strains. It does not suppress P. falciparum's sexual blood stage gametocytes and therefore patients 

completing this prophylactic regimen may still transmit the infection to mosquitos outside 

endemic areas. Advise patients taking doxycycline for malaria prophylaxis of when prophylaxis 

should begin and end; that no present-day antimalarial, including doxycycline, guarantees 

protection against malaria; and to avoid being bitten by mosquitos by wearing protective clothing, 

using effective insect-repellent, mosquito nets, etc. 

Pseudomembranous colitis: 

Treatment with antibacterial agents alters the normal flora of the colon and may permit 

overgrowth of clostridia. Pseudomembranous colitis has been reported with nearly all 

antibacterial agents and may range in severity from mild to life-threatening. It is important to 

consider this diagnosis in patients who present with diarrhea following subsequent administration 

of antibacterial agents. Once the diagnosis is established, initiate therapeutic measures. Mild cases 

usually respond to discontinuation of the drug. Moderate to severe cases may require management 

with fluids, electrolytes, protein supplementation, and treatment with an antibacterial agent 

effective against Clostridium difficile colitis. 

207

Parenteral therapy: 

Reserve for situations in which oral therapy is not indicated. Institute oral therapy as soon as 

possible. If given IV over prolonged periods, thrombophlebitis may result. IM use produces 

lower blood levels than recommended oral dosages. If high blood levels are needed rapidly, 

administer IV. 

Nephrogenic diabetes insipidus: 

Administration of demeclocycline has resulted in appearance of the diabetes insipidus syndrome 

(e.g., polyuria, polydipsia, weakness) in some patients on long-term therapy. The syndrome has 

been shown to be nephrogenic, dose-dependent, and reversible upon discontinuation of therapy. 

Hypersensitivity reactions: 

Sensitivity reactions are more likely to occur on patients with a history of allergy, asthma, hay 

fever, or urticaria. Use tetracyclines with caution in these patients. Cross-sensitivity among the 

tetracyclines is extremely common. 


Use tetracyclines with caution in patients with impaired renal function. 

If renal impairment exists, even usual doses may lead to excessive systemic accumulation of the 

tetracyclines (with the exception of doxycycline) and possible liver toxicity. Use lower than usual 

doses; if therapy is prolonged, drug serum level determinations may be advisable. Concurrent use 

of tetracycline and methoxyflurane has resulted in fatal renal toxicity. 

The antianabolic action of tetracyclines may cause an increase in blood urea nitrogen. In 

significantly impaired renal function, higher serum tetracycline levels may lead to azotemia, 

hyperphosphatemia, and acidosis. This does not seem to occur with doxycycline. 

Hepatic function impairment: 

Use tetracyclines with caution in patients with impaired liver function. 

In the presence of renal dysfunction, and particularly in pregnancy, IV tetracycline more than 2 

g/day has been associated with death secondary to liver failure. When need for intensive treatment 

outweighs its potential dangers (especially during pregnancy or in known or suspected renal and 

liver impairment), monitor renal and liver function tests. Serum tetracycline concentrations should 

not exceed 15 mcg/mL. Do not prescribe other potentially hepatotoxic drugs concomitantly. 

Hepatotoxicity has been reported with minocycline; therefore, minocycline should be used with 

caution in patients with hepatic dysfunction and in conjunction with other hepatotoxic drugs. 

The hazard of liver toxicity is of particular importance in parenteral administration to pregnant or 

postpartum patients with pyelonephritis. 

Carcinogenesis: 

There has been evidence of oncogenic activity in studies with oxytetracycline (adrenal and 

pituitary tumors) in rats and minocycline (thyroid tumors) in rats and dogs. 

Mutagenesis: 

Tetracycline and oxytetracycline have produced positive mutagenic results in mammalian cell 

assays in vitro. 

Fertility impairment: 

Minocycline has been shown to impair fertility in male rats. 

Pregnancy: 

Category D. Tetracyclines readily cross the placenta and are found in fetal tissues and can have 

toxic effects on the developing fetus (retardation of skeletal development). Evidence of 

embryotoxicity has also been noted in animals treated early in pregnancy. 

208

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of 

infants with no congenital anomalies) shows a weak but marginally statistically significant 

association with total malformations and use of doxycycline any time during pregnancy. Sixtythree 

(0.19%) of the controls and 56 (0.3%) of the cases were treated with doxycycline. This 

association was not seen when the analysis was confined to maternal treatment during the period 

of organogenesis with the exception of a marginal relationship with neural tube defect based on 

only two exposed cases. 

Lactation: 

Tetracyclines are excreted in breast milk. Milk:plasma ratios vary between 0.25 and 1.5. Because 

of the potential for serious adverse reactions, decide whether to discontinue nursing or discontinue 

the drug. 

Children: 

Generally, do not use tetracyclines in children under eight years of age (except for anthrax, 

including inhalational) due to adverse effects on teeth and bones, unless other drugs are not likely 

to be effective or are contraindicated. 

Teeth: 

The use of tetracyclines during the period of tooth development (from the last half of pregnancy 

through 8 years of age) may cause permanent discoloration (yellow, gray, brown) of teeth. This 

adverse reaction is more common during long-term use of the drugs, but has been observed 

following repeated short-term courses. Enamel hypoplasia has also been reported. 

Bone: 

Tetracyclines form a stable calcium complex in any bone-forming tissue. Decreased fibula growth 

rate occurred in premature infants given 25 mg/kg oral tetracycline every 6 hours. This was 

reversible when the drug was discontinued. 

Photosensitivity: 

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some 

individuals taking tetracyclines. Advise patients who are apt to be exposed to direct sunlight or 

ultraviolet light that this reaction can occur with tetracycline drugs, and discontinue treatment at 

the first evidence of skin erythema. 

Exaggerated sunburn reactions are characterized by severe burns of exposed surfaces, resulting 

from direct exposure to sunlight during therapy with moderate or large doses. Phototoxic 

reactions are most frequent with demeclocycline, and occur less frequently with the other 

tetracyclines. 

209

VII. 

Dosing and Administration for the Tetracycline Agents 

Table 7. Dosing for the Tetracycline Agents 5-7 


Tetracycline 

Capsules: 250mg 

Capsules: 500mg 

Oral Suspension:125mg/5mL 

Take with plenty of fluids. Food and some dairy products interfere with the absorption of 

tetracycline. 

Adults: 

Usual dose: 1 to 2g/day in 2 or 4 equal doses. 

Oxytetracycline 

Doxycycline 

Minocycline 

Injection:50mg/mL with 2% lidocaine 

125mg/mL with 2% lidocaine 

Lidocaine is included in this formulation not as a therapeutic agent, but 

to decrease the pain associated with intramuscular injection. 

Tablets: 100mg (as hyclate) 

Capsules: 50mg (as hyclate) 

Capsules: 100mg (as hyclate) 

Capsules, coated pellets: 75mg (as hyclate) 

100mg (as hyclate) 

Tablets: 50mg (as monohydrate) 

Tablets: 75mg (as monohydrate) 

100mg (as monohydrate) 

Capsules: 50mg (as monohydrate) 

100mg (as monohydrate) 

Powder for Oral Suspension: 25mg (as monohydrate) per 

5mL when reconstituted 

Syrup: 50mg (as calcium) per 5mL 

Powder for Injection, lyophilized: 100mg (as hyclate) 

Powder for Injection, lyophilized: 200mg (as hyclate) 

Tablets: 50mg (as HCl) 

75mg (as HCl) 

100mg (as HCl) 

Capsules: 50mg (as HCl) 


See package insert for dosing on specific diseases. 

The usual daily dose is 250mg administered IM once every 24 hours or 300mg given in divided 

doses at 8 to 12 hour intervals. 

Oral: 

When used in streptococcal infections, continue therapy for 10 days. Take with plenty of 

water. Absorption and peak plasma levels may be reduced when administered with meals 

or with dairy products, including milk. 

Adults: 

Usual dose: 

200 mg on the first day of treatment (100mg every 12 hours); follow with a maintenance 

dose of 100mg/day. The maintenance dose may be administered as a single dose or as 50 

mg every 12 hours. 

More severe infections (particularly chronic urinary tract infections): 

100mg every 12 hours. 


Oral: 

May be taken with or without food. Take with plenty of fluids. 

Adults: 

Usual dosage:



Capsules, pellet filled: 50mg (as HCl) 

100mg (as HCl) 

Oral suspension:50mg (as HCl)/5 mL 

Powder for injection, cryodesiccated: 100mg 

200mg initially, followed by 100mg every 12 hours. If more frequent doses are preferred, give 100 

or 200mg initially; follow with 50mg, 4 times/day. 


Demeclocycline 150mg and 300mg tablets Take with plenty of fluids. Foods and some dairy products interfere with absorption; take 

demeclocycline at least 1 hour before or 2 hours after meals or dairy products. 

Adults: 

Daily dose: 

4 divided doses of 150mg each or 2 divided doses of 300mg each. 

Gonorrhea patients sensitive to penicillin: 

Initially, 600mg; follow with 300mg every 12 hours for 4 days to a total of 3 g. 

Streptococcal infections: 

Treat streptococcal infections for at least 10 days. 

Concomitant therapy: 

Absorption is impaired by antacids containing aluminum, calcium, or magnesium, and by 

preparations containing iron. Take demeclocycline at least 1 hour before or 2 hours after 

these products. 

211


Table 8. Special Dosing Considerations for the Tetracycline Agents 1- 9 

Drug Renal Dosing Hepatic Dosing Pediatric Use Pregnancy 

Category 

Tetracycline 

Decrease recommended 

dosages and/or extend dosing 

intervals in patients with renal 

impairment. 

Children (over 8 years of age): 

Daily dose is 10 to 20mg/lb (25 to 

50mg/kg) in 4 equally divided doses. 

D 

Can Drug Be 

Crushed 

Yes 

Oxytetracycline 


Decrease recommended dosage 

and/or extend dosing intervals 

in patients with renal 

impairment. 


15 to 25mg/kg, up to a maximum of 

250mg per single daily IM injection. 

Dosage may be divided and given at 8 

to 12 hour intervals. 

D 

N/A 

Doxycycline Children (over 8 years of age): 

100lb or less (less than 45kg): 

2mg/lb (4.4 mg/kg) divided into 

2 doses on the first day of treatment; 

follow with 1mg/lb (2.2mg/kg) given 

as a single daily dose or divided into 2 

doses on subsequent days. 

More severe infections: 

Up to 2mg/lb (4.4mg/kg) may be used. 

For children over 100lb (45kg): 

Use the usual adult dose. 

D 

Yes 

Minocycline 

Decrease the recommended dosage 

and/or increase the dosing 

intervals in patients with renal 

impairment. Do not exceed 

200mg Minocin in 24 hours in 

patients with renal impairment 


Initially, 4mg/kg; follow with 2mg/kg 

every 12 hours. 

D 

Yes 

212

Drug Renal Dosing Hepatic Dosing Pediatric Use Pregnancy 

Category 

Demeclocycline Renal/Hepatic function 

Renal/Hepatic function Children (over 8 years of age): 

D 

impairment: 

impairment: 

Usual daily dose: 

Administer tetracyclines 

Administer tetracyclines 

3 to 6mg/lb (6.6 to 13.2mg/kg), 

cautiously with renal or hepatic cautiously with renal or 

depending upon the severity of 

impairment; reduce the 

hepatic impairment; reduce the disease, divided into 2 or 4 

recommended dosage and/or the recommended dosage 

doses. 

extend the dosing interval. and/or extend the dosing 

interval. 

Can Drug Be 

Crushed 

Yes 

213

VIII. 

Comparative Effectiveness of the Tetracycline Agents* 

Table 9. Additional Outcomes Evidence for the Tetracyclines 


Duration 

Wormser n=180 Ten days of 

al. 12 

GP, et 

oral 

doxycycline, 

with or without 

a single 

intravenous 

dose of 

ceftriaxone, or 

20 days of oral 

doxycycline 

Results 

A randomized, double-blind, placebo-controlled trial of patients with early 

Lyme Disease. 

• At all time points, the complete response rate was similar for 

the three treatment groups in both on-study and intention-totreat 

analyses. 

• There were no significant differences in the results of 

neurocognitive testing among the three treatment groups and a 

separate control group without Lyme disease. 

• Diarrhea occurred significantly more often in the doxycyclineceftriaxone 

group (35%) than in either of the other two groups. 

Tilley 

BC, et 

al. 13 n=219 A double-blind, 

randomized, 

multicenter, 48- 

week trial of 

oral 

minocycline 

(200mg/d) or 

placebo. 

CONCLUSION: Extending treatment with doxycycline from 10 to 20 days 

or adding one dose of ceftriaxone to the beginning of a 10-day course of 

doxycycline did not enhance therapeutic efficacy in patients with erythema 

migrans. Regardless of regimen, objective evidence of treatment failure was 

extremely rare. 

219 patients with active rheumatoid arthritis participated in a 48 week, 

double-blind, placebo-controlled trial (MIRA trial). 

• 109 and 110 patients were randomly assigned to receive 

minocycline and placebo, respectively. At entry, demographic, 

clinical, and laboratory measurements were similar in both 

groups. Most patients had mild to moderate disease activity and 

some evidence of destructive disease. 

• At the week 48 visit, 79% of the minocycline group and 78% of 

the placebo group continued to receive the study medication. 

At 48 weeks, more patients in the minocycline group than in the 

placebo group showed improvement in joint swelling (54% and 

39%) and joint tenderness (56% and 41%) (p < 0.023 for both 

comparisons). The minocycline group also showed greater 

improvement in hematocrit, erythrocyte sedimentation rate, 

platelet count, and IgM rheumatoid factor levels (all P values < 

0.001), and more patients receiving minocycline had laboratory 

values within normal ranges at 48 weeks. 

• For the remaining outcomes, P values ranged from 0.04 to 0.76, 

all greater than the critical value of 0.005 (Bonferroni 

adjustment for multiple comparisons). The frequency of 

reported side effects was similar in both groups, and no serious 

toxicity occurred. 

CONCLUSION: Minocycline was safe and effective for patients with mild 

to moderate rheumatoid arthritis. Its mechanisms of action remain to be 

determined. 

214


Results 

Duration 

Stone M, 

et al. 26 

535-metaanalysis 

1966-2002 The purpose of this analysis was to compare the effectiveness of tetracycline 

antibiotics versus control (placebo or conventional treatment) in rheumatoid 

arthritis. 

• Tetracyclines, when administered for > 3 months, were associated 

with a significant reduction in disease activity in RA as follows: for 

TJC, standardized mean difference (SMD) = -0.39, 95% CI -0.74, - 

0.05; and for acute phase reactants, ESR, SMD = -8.96, 95% CI - 

14.51, -3.42. The treatment effect was more marked in the subgroup 

of patients with disease duration < 1 year who were seropositive. 

• There was no absolute increased risk of adverse events associated 

with tetracyclines: absolute risk difference = 0.10, 95% confidence 

interval (CI) -0.01, 0.21. No beneficial effect was seen on 

radiological progression of disease: for erosions, SMD = 0.17, 95% 

CI -0.29, 0.64. 

• In addition, subgroup analysis excluding trials with doxycycline 

showed that minocycline alone had a greater effect on reduction of 

disease activity: for TJC, SMD = -0.69, 95% CI -0.89, -0.49; and 

for ESR, SMD = -10.14, 95% CI -14.72, -5.57. 

Maesen 

FP, et 

al. 28 n=41 Doxycycline or 

minocycline 

100mg BID for 

seven days 

Kovacs N=103 Minocycline or 

al. 30 10 days 

GT, et 

doxycycline for 

CONCLUSION: Tetracyclines, in particular minocycline, were associated 

with a clinically significant improvement in disease activity in RA with no 

absolute increased risk of side effects. Unfortunately, the information 

available was inadequate to allow a detailed analysis of individual side 

effects in the studies. Further research is warranted to compare these agents 

to newer disease modifying drugs for comparable safety, efficacy, and costeffectiveness. 

This double-blind comparative clinical trial observed patients admitted to the 

hospital because of acute purulent exacerbations of chronic respiratory 

disease. 

• Bacteriological and clinical assessment before and immediately after 

treatment showed no significant differences between the 

doxycycline and the minocycline groups, nor did further evaluation 

after seven days follow-up. 

• Pharmacokinetic studies showed that the Cmax and 0-11 h AUC 

values in blood were higher for doxycycline, whereas the sputum 

Cmax was, on average, higher for minocycline because of the 

greater penetration of the latter. 

• The MIC values for the two antibiotics differed slightly, usually, but 

not always, in favor of minocycline. 

• Problems were experienced with both agents in the eradication of 

Haemophilus influenzae. 

CONCLUSION: The net clinical results with the two drugs were identical. 

One hundred and three women were found to have Chl. trachomatis infection 

of the cervix and were invited to participate in a clinical trial of minocycline 

and doxycycline for the treatment of chlamydial infection. 

• A 10-day course of either drug resulted in a negative result of a 

chlamydial culture for all patients at the follow-up assessment, 

which occurred between 11 days to 12 weeks after the therapy. 

• Minocycline appeared to have a slight advantage with respect to the 

resolution of the gynecological symptoms that were associated with 

the chlamydial infection. 

215


Duration 

Ramano 

wski b, et 

al. 31 N=253 Minocycline 

100mg nightly 

or doxycycline 

100mg BID for 

7 days 

Results 

CONCLUSION: Minocycline and doxycycline showed equal effectiveness 

in the eradication of mycoplasmas in over 80% of the treated patients. 

The objective in this randomized, double-blind trial was to compare the 

efficacy and tolerability of minocycline versus doxycycline in the treatment 

of nongonococcal urethritis and mucopurulent cervicitis. 

• 151 men and 102 women with nongonococcal urethritis, 

mucopurulent cervicitis or whose sexual partner had either condition 

or a positive culture for Chlamydia trachomatis. 

• The proportion with urethritis or cervicitis did not differ by 

treatment group at any follow-up visit (P > 0.08). Unprotected 

sexual contact did not affect clinical or microbiological cure rates. 

• Adverse effects occurred more frequently in the doxycycline group 

(men: 43% versus 26%; P = 0.05; women: 62% versus 35%; P = 

0.009). Although the proportion with dizziness did not differ by 

drug administered (P = 0.1), dizziness was reported more often by 

women (11% versus 3%). 

Shapiro Various Retrospective 

L, et al. 19 literature 

review 

Langevit 

z P, et 

al. 20 Review Minocycline 

given for 

various times 

and dosages in 

three double- 

CONCLUSION: Minocycline, 100mg nightly, was as effective as 

doxycycline, 100mg twice daily, each given for seven days in the treatment 

of nongonococcal urethritis and mucopurulent cervicitis. Vomiting and 

gastrointestinal upset occurred more frequently in the doxycycline group. 

Background: Because minocycline can cause serious adverse events, 

including hypersensitivity syndrome reaction (HSR), serum sickness-like 

reaction (SSLR), and drug-induced lupus, a follow-up study based on a 

retrospective review of our Drug Safety Clinic and the Health Protection 

Branch databases and a literature review was conducted to determine if 

similar rare events are associated with tetracycline and doxycycline. Cases 

of isolated single organ dysfunction (SOD) attributable to the use of these 

antibiotics also were identified. 

• Nineteen cases of HSR due to minocycline, two due to tetracycline, 

and one due to doxycycline were identified. Eleven cases of SSLR 

due to minocycline, three due to tetracycline, and two due to 

doxycycline were identified. All 33 cases of drug-induced lupus 

were attributable to minocycline. Forty cases of SOD from 

minocycline, 37 cases from tetracycline, and six from doxycycline 

were detected. Hypersensitivity syndrome reaction, SSLR, and 

SOD occur on average within four weeks of therapy, whereas 

minocycline-induced lupus occurs on average two years after the 

initiation of therapy. 

CONCLUSION: Early serious events occurring during the course of 

tetracycline antibiotic treatment include HSR, SSLR, and SOD. Druginduced 

lupus, which occurs late in the course of therapy, is reported only 

with minocycline. We theorize that minocycline metabolism may account 

for the increased frequency of serious adverse events with this drug. 

Review of three double-blind studies giving minocycline to patients with 

rheumatoid arthritis. 

• The antirheumatic effect of minocycline can be related to its 

immunomodulatory and anti-inflammatory, rather than to its 

antibacterial properties. Its efficacy in rheumatoid arthritis has been 

216


Duration 

blind studies 

Results 

reported in two open trials and in three double-blind controlled 

studies. 

• The first two double-blind studies, one in The Netherlands and one 

in the US, were performed in patients with advanced disease. Both 

studies showed a modest, but statistically significant improvement 

in the clinical parameters of disease activity and in the erythrocyte 

sedimentation rate in the minocycline-treated patients. 

• The US study also reported that patients in the minocycline group 

developed fewer types of erosion than those in the placebo group. 

This finding supports the role of minocycline as a disease modifying 

agent. 

• The common adverse effects of minocycline reported in these two 

studies included gastrointestinal adverse effects, dizziness, rash, and 

headaches. Less common adverse effects were intracranial 

hypertension, pneumonitis, persistent skin and mucosal 

hyperpigmentation, lupus-like syndrome and acute hepatic injury. 

• The third double-blind study enrolled only seropositive rheumatoid 

arthritis patients with early disease (less than one year duration), and 

showed very encouraging results of significant improvement in the 

disease activity parameters in the minocycline treated group of 

patients. The same authors later reported that about half of these 

patients were in or near remission after three years of follow up. No 

adverse effects were reported in this study. 

CONCLUSION: Summarizing the data of these three double-blind studies, 

we may conclude that minocycline may be beneficial in patients with 

rheumatoid arthritis, especially when given early in the disease course or in 

patients with a mild disease. 

*Table 9 is an all-inclusive listing of evidence from clinical studies with tetracyclines. Some studies (Haider et al.) have been included due to other FDA 

approved indications of these agents. 


Dose Simplification: Limited clinical studies have evaluated the impact of the dosing frequency with 

tetracyclines, especially with respect to impact on the outcome of disease. One study by Dunbar-Jacob et 

al. evaluated compliance to oral therapies for pelvic inflammatory disease. 38 In the randomized trial, study 

subjects took an average of 70% of prescribed doses, took the two daily prescribed doses of doxycycline 

for less than half of their outpatient days, took an unscheduled drug holiday for almost 25% of their 

outpatient days, and took only 16.9% of their doses within the optimal timing interval. These disturbing 

rates of adherence, even after hospitalization, suggest the need for education and antibiotic regimens 

involving shorter courses and longer dosing intervals, however, no conclusion on outcome of the diseasae 

was made. Another study by Lee et al. looked at the effectiveness of an enhanced compliance program for 

Helicobacter pylori therapy (treatment with bismuth subsalicylate, metronidazole, and tetracycline). 39 The 

enhanced group received medication counseling from a pharmacist, along with a medication calendar and a 

mini pillbox. There was no statistically significant difference between the groups in the number of patients 

taking more than 60% of the medications. However, there was a statistically significant difference in the 

number of patients taking more than 90% of the medications (67% of the control group vs. 89% of the 

enhanced compliance group; p

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal clinical literature 

relevant to use of the tetracycline agents and their impact on physician visits. 

IX. 

Conclusions 

Since these medications are prescribed mostly because of sensitivity of organisms, all agents have a place 

in the treatment of infectious diseases. Several agents have specific uses for non-infectious disease states, 

such as demeclocycline for hyponatremia, and do not have appropriate substitutes as outlined in the 

comparison of efficacy studies listed above. Adverse reactions with the agents in this class are also 

comparable. Additionally, generic formulations are available for all oral tetracyclines in this class. 

Therefore, all brand products within the class reviewed are comparable to each other and to the generics 

and offer no significant clinical advantage over other alternatives in general use. 


No brand tetracycline is recommended for preferred status. 

218

References 

1. Bristol-Myers Squibb Company. Sumycin Syrup prescribing information. Princeton (NJ). May 2002. 

2. Bristol-Myers Squibb Company. Sumycin Tablets prescribing information. Princeton (NJ). July 2002. 

3. Roerig Pfizer. Terramycin Intramuscular Solution prescribing information. New York (NY). September 

2003. 

4. Roerig Pfizer. Vibramycin for Injection prescribing information. New York (NY). November 2001. 

5. Roerig Pfizer. Vibramycin and Vibra-Tabs prescribing information. New York (NY).September 2003. 

6. Lederle Pharmaceutical Division of American Cyanamid Company. Minocin Capsules prescribing 

information. Pearl River (NY). October 2003. 

7. Medicis. Dynacin prescribing information. Scottsdale (AZ). April 2003. 

8. Lederle Pharmaceutical Division of American Cyanamid Company. Declomycin Tablet prescribing 

information. Pearl River (NY). June 2003. 

9. Drug Facts and Comparisons 2004. Antiviral Agents [cited 2004 September 17] http://www.efactsweb.com 

10. Roberts MC. Tetracycline therapy: update. Clin Infect Dis. 2003 Feb 15;36(4):462-7. Epub 2003 Jan 28. 

11. Mullegger RR. Dermatological manifestations of Lyme borreliosis. Eur J Dermatol. 2004 Sep- 

Oct;12(5):296-309. 

12. Wormser GP, Ramanathan R, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, 

double-blind, placebo-controlled trial. Ann Intern Med. 2003 May 6;138(9):697-704. 

13. Tilley BC, Alarcon GS, et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebocontrolled 

trial. MIRA Trial Group. 

14. Goh KP. Management of hyponatremia. Am Fam Physician. 2004 May 15;69(10):2387-94. 

15. Goulden V. Guidelines for the management of acne vulgaris in adolescents. Pediat Drugs. 2003;5(5):301- 

13. 

16. Garner SE, Eady EA, Popescu C, Newton J, Le WA. Minocycline for acne vulgaris: efficacy and safety. 

Cochrane Database Syst Rev. 2003;(1):CD002086. 

17. Haider A, Shaw J. Treatment of Acne Vulgaris. JAMA 2004 August 11;292(6):reprint. 

18. Saikali, Zeina, Sing, Gurmit. Doxycycline and other tetracyclines in the treatment of bone metastasis. 

Anti-Cancer Drugs. 2003 November;14(10):773-778. 

19. Shaprio L, Knowles S, Shear N. Comparative safety of tetracycline, minocycline and doxycycline. 

Archives of Dermatology. October 1997;133(10):1224-1230. 

20. Langevitz P, Livneh A, Bank I, Pras M. Benefits and Risks of minocycline in rheumatoid arthritis. Drug 

Safety 2000;22(5):405-414. 

21. Eichenfield A. Minocycline and autoimmunity. Current opinion in pediatrics. October 1999;11(5):477. 

22. O’Dell J, Paulsen G, Haire C, et al. Treatment of early seropositive rheumatoid arthritis with minocycline: 

Four year follow up of a double blind, placebo controlled trial. Arthritis and Rheumatism. 1999 

August;42(8):1691-1695. 

23. O’Dell J, Haire C, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: 

Results of randomized, double-blind, placebo-controlled trial. Arthritis and Rheumatis. 1997 

May;40(5):842-848. 

24. Smilack JD. The tetracyclines. Mayo Clin Proc. 1999 July;74(7):727-9. 

25. Klein NC, Cunha BA. New uses of older antibiotics. Med Clin North Am. 2001 Jan;85(1):125-32. 

26. Stone M, Fortin PR, Pacheco-Tena C, Inman RD. Should tetracycline treatment be used more extensively 

for rheumatoid arthritis Mataanalysis demonstrates clinical benefit with reduction in disease activity. J 

Rheumatol. 2003 Oct;30(10):2112-22. 

27. Kinzie BJ. Management of the syndrom of inappropriate secretion of antidiuretic hormone. Clin Pharm. 

1987 Aug;6(8):625-33. 

28. Maesen FP, Davies BI, vanden Bergh JJ. Doxycycline and minocycline in the treatment of respiratory 

infections: a double-blind, comparative clinical, microbiological and pharmacokinetic study. J Antimicrob 

Chemother. 1989 Jan;23(1):123-9. 

29. Forrest JC, Cox M, Hon C, Morrison G, Bia N, Singer I. Superiority of democlocycline over lithium in the 

treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978 Jan 

26;298(4):173-7. 

30. Kovacs GT, et al. A prospective single-blind trial of minocycline and doxycycline in the treatment of 

genital chalmydia trachomatis infection in women. Med J Aust. 1989 May 1;150(9):483-5. 

219

31. Romanowski B, et al. Minocycline compared with doxycycline in the treatment of nongonococcal urethritis 

and mucopurulent cervicitis. Ann of Int Med. 1993 July:119(1):16-22. 

32. Cunha B. Minocycline versus doxycycline in the treatment of Lyme neuroborreliosis. Clin Inf Diseases. 

200;30:237-238. 

33. Hanes PJ, Purvis JP. Local anti-infective therapy: pharmacological agents. A systematic review. Ann 

Periodontol. 2003 Dec;8(1):79-98. 

34. Klein NC, Cunha BA. Tetracyclines. Med Clin North Am. 1995 Jul;79(4(:789-801. 

35. Barza M, Schiefe RT. Antimicrobial spectrum, pharmacology and therapeutic use of antibiotics. Part 1: 

tetracyclines. Am J Hosp Pharm. 1977 Jan;24(1):49-57. 

36. Sum PE, Sum JW, Projan SJ. Recent developments in tetracycline antibiotics. Curr Pharm Des. 1998 

Apr;4(2):119-32. 

37. CDC. www.cdc.gov. Accessed 9/20/04. 

38. Dunbar-Jacob J, Sereika SM, foley SM, et al. Adherence to oral therapies in pelvic inflammatory disease. 

J Womens Health (Larchmt) 2004 Apr;13(3):285-91. 

39. Lee M, Kemp JA, Canning A, et al. A randomized controlled trial of an enhanced patient compliance 

program for Helicobacter pylori therapy. Arch Int Med 1999 Oct 25;159(19):2312-6. 

220



Pharmacotherapy Review of Nucleoside and Nucleotide Antiviral Agents 

AHFS 081832 


I. Overview 

Herpesviruses 

There are eight identified human herpesviruses (HHVs) which are divided into three groups: 

• the alpha-herpesviruses (e.g., herpes simplex virus types 1 and 2 [HSV-1 and HSV-2] 

and varicella-zoster) 

• beta-herpesviruses (e.g., cytomegalovirus, HHV-6, and HHV-7) 

• gamma-herpesviruses (e.g., Epstein-Barr virus, Kaposi’s sarcoma-associated herpes 

virus, and HHV-8) 1 

The HHVs are all structurally similar with an internal core containing viral DNA, a capsid, 

and a lipid envelope. However, the HHVs are distinct with respect to their biologic and 

epidemiologic characteristics. 

Herpes Simplex Virus (HSV-1 and HSV-2) 

Herpes simplex virus infection can produce a multitude of illnesses including mucocutaneous infections, 

central nervous system infections, and infections of visceral organs. The two most common cutaneous 

manifestations of HSV are orolabial and genital lesions. The HSV-1 strain is most often associated with 

oropharyngeal disease and HSV-2 is most often associated with genital disease; however, both viruses can 

cause clinically indistinguishable infections in either of these anatomic areas. Genital herpes is one of the 

most common viral sexually transmitted diseases in the world, and it is estimated that at least 45 million 

people in the United States have genital HSV infection. 2 The most frequent mode of transmission is 

through direct contact of mucus membranes or abraded skin with infected secretions (e.g., oral, genital, 

mucosal) of someone who is shedding the virus. Initial infection may result in clinical manifestations (e.g., 

lesions), but is often subclinical and asymptomatic, which may represent the most common source of 

transmission. 1,2 After viral inoculation, HSV replicates and spreads to peripheral sensory nerves. The virus 

remains latent in sensory or autonomic nerve root ganglia, with a lifelong potential for reactivation and 

recurrence. The factors involved in maintaining latency have not been fully elucidated; however, immune 

function and emotional and physical stressors appear to play an important role in reactivation of the virus. 

Additionally, immunocompromised patients often have more frequent and more severe episodes of 

reactivation. A diagnosis of HSV infection can often be made based on the presence of characteristic 

vesicular lesions; however, laboratory testing is necessary for confirmation. Herpes simplex virus can be 

isolated in a tissue culture or detected by the presence of HSV antigens or DNA in lesion samples. 

Varicella-Zoster Virus 

Another HHV, varicella-zoster virus (VZV) is responsible for two diseases: chickenpox and herpes zoster. 3 

Chickenpox, the primary infection, is highly contagious and is assumed to spread via the respiratory route. 

However, chickenpox is normally a benign disease characterized by a generalized exanthematous rash, 

low-grade fever, and malaise. Over 90% of chickenpox cases occur in children under the age of 13, and 

patients are contagious from approximately 48 hours before vesicles begin to form until all the vesicles 

have crusted. Mortality associated with chickenpox occurs in less than 2 out of every 100,000 cases; 

however, adults often have a more severe disease and risk of mortality is increased more than 15-fold. A 

live, attenuated virus vaccine for the prevention of chickenpox is available and recommended for normal 

children and in susceptible adults. After primary infection with chickenpox, VZV becomes latent within 

the dorsal root ganglia. Reactivation of VZV occurs sporadically and results in a herpes zoster infection 

(e.g., shingles), which is characterized by a unilateral vesicular eruption with a dermatomal distribution. 

Herpes zoster most commonly affects elderly patients; however, it can occur at any age and will occur in 

221

approximately 20% of the population at some point. Neuritis, ophthalmic complications, and postherpetic 

neuralgia are some of the most significant manifestations of herpes zoster. The mechanism responsible for 

reactivation is not known, but is likely dependent on both virus and host factors. Immunocompromised 

patients have a greater incidence of both chickenpox and shingles and often have greater disease severity as 

a result of infection. The diagnosis of both chickenpox and shingles is usually based on a history and 

physical examination; however, in unclear cases, VZV can be isolated from a tissue culture or serum 

antibody assays can be utilized. 

Cytomegalovirus 

Although cytomegalovirus (CMV) is highly prevalent, reaching 60% to 70% in urban cities of the United 

States, it rarely produces symptoms in patients with normal immune function. 4 Cytomegalovirus is the 

most common opportunistic pathogen in immunocompromised patients and produces the most severe 

symptoms in transplant patients. Similar to the other herpesviruses, CMV can become latent after primary 

infection. As with the other herpes viruses, the mechanism responsible for reactivation is unknown, but can 

occur as a result of immunosuppression, occurrence of other illness, or the use of chemotherapeutic 

medications. A diagnosis of CMV almost always requires laboratory confirmation and is based on growth 

of the virus from body fluids or the isolation of viral antigens or viral DNA. Complications of CMV 

infection include interstitial pneumonia, hepatitis, Guillain-Barre Syndrome, meningoencephalitis, 

myocarditis, colitis and esophageal ulcers, thrombocytopenia, hemolytic anemia, and skin eruptions. In 

patients with AIDS, CMV retinitis is the most common form of CMV disease, usually reported when the 

CD 4 cell count is less than 50 cells/mm 3 , and can lead to blindness. 

Chronic Hepatitis 

Chronic Hepatitis B 

An estimated 350 million people are chronically infected with Hepatitis B virus (HBV) worldwide, with 

1.25 million cases in the United States. 5,6 Hepatitis B infection can be self-limited or a chronic disease. 

Men who have sex with men, intravenous drug users, and people with multiple sex partners have an 

increased prevalence of HBV infection. Transmission of HBV occurs by percutaneous or mucous 

membrane exposure to infected body fluids, and sexual transmission among adults accounts for most cases 

in the United States. The development of chronic HBV infection following acute exposure is estimated at 

90% in newborns of mothers positive for hepatitis B e antigen (HBeAg), 25% to 30% in infants and 

children under the age of five, and less than 10% in adults. Individuals with compromised immune function 

are also at an increased risk of developing chronic HBV infection following acute exposure. Patients with 

chronic HBV are more likely to develop cirrhosis, hepatic decompensation, and hepatocellular carcinoma 

(HCC), although only 15% to 40% will develop serious manifestations during their lifetime. Additional 

risk factors for the development of HCC in patients with chronic HCV infection include male gender, 

family history of HCC, increased age, presence of HBeAg, history of reversions from anti-Hbe to HBeAg, 

cirrhosis, and coinfection with HCV. 

Chronic Hepatitis C 

Current estimates suggest that more than 2.7 million Americans have chronic HCV infection. 7,8 Studies 

indicate that 55% to 85% of persons who contract acute HCV will develop a chronic HCV infection. 

Younger age, female gender, and normal immune function are some factors that have been identified which 

may increase the likelihood of clearing an acute HCV infection. Chronic HCV infection is diagnosed by 

the detection of HCV RNA in the blood for at least six months. The most serious sequelae of HCV include 

liver fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC), with an estimated 5% 

to 20% of patients developing cirrhosis over a period of 20 years. Hepatitis C virus represents the leading 

cause of death from liver disease in the United States. There are six genotypes of HCV, and in the United 

States genotype 1 accounts for 70% to 75% of HCV infections. Genotype 1 has also been associated with 

lower response to therapy. Transmission of HCV primarily occurs through contact with infected blood or 

blood products. Intravenous drug use is the leading route of transmission in the United States; however, 

blood transfusions prior to 1992, solid organ transplants from infected donors, occupational exposure to 

infected blood, birth to an HCV-positive mother, and multiple sexual partners are also potential sources of 

exposure. The goal of treatment is to prevent long-term complications of HCV infection, for which 

222

suppression of HCV RNA is used as a surrogate marker. Infection is considered eradicated when there is a 

sustained virologic response, defined as the absence of HCV RNA in serum at the end of treatment and six 

months post-therapy. 

Complications of chronic HBV or HCV may take decades to appear; therefore, virologic suppression or 

clearance and normalization of liver enzymes are often used to guide therapy and are used as surrogate 

markers for decreased risk of cirrhosis, HCC, or death. 

Respiratory Syncytial Virus 

Respiratory Syncytial Virus (RSV) is a common childhood disease, and almost all children will have been 

exposed to RSV by the age of two. 9 It is estimated that RSV infections account for 100,000 

hospitalizations in the United States each year. Most patients with RSV will experience only mild common 

cold symptoms; however, in vulnerable patients, RSV can progress to the lower respiratory tract causing 

bronchiolitis or pneumonia, with an increased risk of morbidity and mortality. Palivizumab (Synagis ® ) is a 

monoclonal antibody that is used to prevent the development of lower respiratory tract infection from RSV 

in high-risk infants (eg, premature, immunocompromised). Symptoms of RSV lower respiratory tract 

infection include tachypnea, wheezing, rales, hypoxemia, and apnea. Immunofluorescence or enzyme 

immunoassay rapid detection tests should be used to confirm a diagnosis of RSV infection. Patients with 

upper respiratory tract infections typically only require symptomatic therapy (eg, hydration, treatment of 

fever, management of nasal congestion). Treatment options for RSV lower respiratory infection include 

intravenous hydration, oxygen supplementation, bronchodilators, aerosolized ribavirin, and mucolytic 

therapy. Additionally, in the face of respiratory failure, corticosteroids, mechanical ventilation, and 

exogenous surfactant are considerations. 

The antiviral nucleoside and nucleotide analogs included in this review are summarized in Table 1. This 

review encompasses all systemic dosage forms and strengths. 

Table 1. Antiviral Nucleosides and Nucleotides in this Review 


Ganciclovir Oral Capsule, Powder for Injection Cytovene ® *, Cytovene ® -IV 

Valganciclovir Oral Tablet Valcyte 

Acyclovir Oral Tablet, Oral Capsule, Oral Suspension, 

Zovirax ® * 

Powder for Injection, Solution for Injection 

Famciclovir Oral Tablet Famvir ® 

Valacyclovir Oral Caplet Valtrex ® 

Cidofovir Solution for Injection Vistide ® 

Ribavirin Oral Capsule, Oral Tablet, Powder for Aerosol Rebetol ® *, Copegus ® , Virazole ® , Ribasphere ® 

Reconstitution 

Adefovir Oral Tablet Hepsera ® 

*Generic oral formulation available. 

223

II. 

Current Treatment Guidelines 

Herpes Simplex Virus 

The Centers for Disease Control and Prevention (CDC) have made recommendations for the management 

of genital herpes. 10 These recommendations are summarized in Table 2. 

Table 2. Centers for Disease Control and Prevention Treatment Guidelines for Genital 

Herpes Simplex Virus Infections* 10 

• Systemic antiviral medications partially control the signs and symptoms of herpes episodes 

when used to treat first clinical episodes and recurrent episodes, or when used as daily 

suppressive therapy. 

• Topical antiviral agents confer minimal clinical benefit, and the use of these medications is 

not recommended. 

• Initial episode: one of the following regimens. 

Acyclovir 400mg orally TID for 7-10 days 

Acyclovir 200mg orally five times daily for 7-10 days 

Famciclovir 250mg orally TID for 7-10 days 

Valacyclovir 1000mg BID for 7-10 days 

Treatment may be extended if healing is incomplete after 10 days 

• Recurrent episodes: one of the following regimens. 

Acyclovir 400mg orally TID for 5 days 

Acyclovir 200mg orally five times daily for 5 days 

Acyclovir 800mg orally BID for 5 days 

Famciclovir 125mg orally BID for 5 days 

Valacyclovir 500mg orally BID for 3-5 days 

Valacyclovir 1000mg orally QD for 5 days 

• Suppressive therapy for recurrent genital herpes: one of the following regimens. 

Acyclovir 400mg orally BID 

Famciclovir 250mg orally BID 

Valacyclovir 500mg orally QD 

Valacyclovir 1000mg orally QD 

• Severe disease: Intravenous acyclovir therapy should be provided for patients with severe 

disease or complications that require hospitalization, such as disseminated infection, 

pneumonitis, hepatitis, or complications of the central nervous system. The recommended 

regimen is intravenous acyclovir 5-10mg/kg body weight every 8 hours for 2-7 days or until 

clinical improvement is seen. 

• Treatment of Patients with HIV: one of the following regimens. 

Acyclovir 400mg TID for 5-10 days 

Acyclovir 200mg five times daily for 5-10 days 

Famciclovir 500mg BID for 5-10 days 

Valacyclovir 1000mg BID for 5-10 days 

• Suppressive Therapy in Patients with HIV: one of the following regimens. 

Acyclovir 400-800mg BID to TID 

Famciclovir 500mg BID 

Valacyclovir 500mg BID 

• Counseling of infected patients and their sex partners is critical to the management of genital 

herpes. Counseling should help patients cope with the infection and prevent sexual and 

perinatal transmission. The misconception that herpes simplex virus causes cancer should be 

dispelled, because the role of herpes virus in cervical cancer is at most that of a cofactor, not a 

primary etiologic agent. 

*TID indicates three times daily; BID, twice daily; QD, once daily. 

224

Varicella-Zoster Virus 

The American Academy of Pediatrics (AAP) does not recommend the use of oral acyclovir for treatment of 

varicella in otherwise healthy children. 11 Oral acyclovir should be considered for otherwise healthy 

patients at an increased risk for moderate to severe varicella infection, including people over 12 years of 

age, people with chronic cutaneous or pulmonary disorders, people receiving long-term salicylate therapy, 

and people receiving short, intermittent, or aerosolized courses of corticosteroids. Intravenous acyclovir is 

recommended for immunocompromised patients. The AAP does not have a recommendation regarding 

famciclovir and valacyclovir because pediatric formulations are not available and data on the use of these 

medications are lacking. No formal treatment guidelines for the management of herpes zoster infections 

were identified. 12 However, goals of therapy should include acceleration of healing, limitation of the 

intensity and duration of acute and chronic pain, and reduction of complications. For immunocompromised 

patients and those at an increased risk of more severe disease, treatment objectives should also include 

reducing the risk of VZV dissemination. Acyclovir, valacyclovir, and famciclovir have demonstrated 

benefit with respect to these treatment goals and are specifically indicated for the treatment of herpes 

zoster. 13-15 


The United States Public Health Service in conjunction with the Infectious Disease Society of 

America (IDSA) has established guidelines for the prevention of opportunistic infections among 

HIV-infected patients. 16 For primary prevention of disease, these guidelines recommend consideration of 

prophylaxis with oral ganciclovir in HIV-infected adults and adolescents who are CMV-positive and have a 

CD 4 cell count

Table 3. American Association for the Study of Liver Diseases Recommendations for the Treatment 

of Chronic Hepatitis B Infection 5,6 * 

Presence of 

HBeAg 

Presence of 

HBV DNA† ALT Level Recommended Treatment 

Yes Yes ≤2 x ULN Observation only. Consider treatment when ALT becomes elevated. 

Yes Yes >2 x ULN • IFN-α for 16 weeks OR 

• Lamivudine for minimum of 1 year, continue 3-6 months after 

HBeAg seroconversion OR 

• Adefovir for minimum of 1 year 

• If nonresponder with IFN-α or contraindication, use lamivudine or 

adefovir 

• Adefovir in patients with lamivudine resistance. 

No Yes >2 x ULN IFN-α, lamivudine, or adefovir can be used; however, IFN-α or adefovir 

is preferred due to need for long-term therapy. 

• IFN-α for 16 weeks OR 

• Adefovir for minimum of 1 year OR 

• Lamivudine for minimum of 1 year, continue 3-6 months after 

HBeAg seroconversion 

• If nonresponder with IFN-α or contraindication, use lamivudine or 

adefovir 

• Adefovir in patients with lamivudine resistance. 

No No ≤ x ULN Observation only. 

Yes or No Yes Cirrhosis • Compensated cirrhosis: lamivudine or adefovir 

• Decompensated cirrhosis: lamivudine or adefovir; refer for liver 

transplant; IFN-α is contraindicated. 

Yes or No No Cirrhosis • Compensated: observation only. 

• Decompensated: refer for liver transplant. 

*HBeAg indicates hepatitis B e antigen; HBV, hepatitis B virus; ALT, alanine aminotransferase; ULN, upper limit of normal; IFN-α, 

interferon-alfa. 

†Presence indicates HBV DNA >10 5 copies/mL, which was arbitrarily chosen. 

Interferon, ribavirin, or a combination of interferon and ribavirin are indicated for the treatment of chronic 

HCV infection. 7 Recent guidelines issued by the American Association for the Study of Liver Diseases for 

the treatment of chronic HCV infection recommend initiation of therapy in patients 18 years of age and 

older, who have abnormal ALT levels, liver biopsy demonstrating significant fibrosis, compensated liver 

disease, and acceptable hematological and biochemical indices (e.g., hemoglobin >13g/dL for men and 

>12g/dL for women, creatinine 75kg. 

Genotype-2 or Genotype-3 HCV Infection 

• Peginterferon plus ribavirin for 24 weeks 

• Ribavirin dose = 800mg 

Genotypes 4, 5, and 6 HCV Infection 

• Insufficient data to provide recommendations 

Respiratory Syncytial Virus 

Recommendations by the AAP for treatment of RSV state that primary treatment is supportive and should 

include hydration, monitoring of respiratory status, supplemental oxygen, and mechanical ventilation if 

necessary. 21 Although aerosolized ribavirin has demonstrated good in vitro activity against RSV, an 

inconsistent demonstration of clinical benefit has been observed in placebo-controlled trials. Therefore, 

the AAP does not generally recommend the use of aerosolized ribavirin for treatment of RSV infection. In 

addition to conflicting results from clinical trials, the cost of aerosolized ribavirin as well as concerns about 

226

potential toxic effects to exposed health care professionals, have contributed to this recommendation. The 

AAP states that decisions regarding administration of aerosolized ribavirin should be made based on 

individual clinical circumstances. 

227

III. Comparative Indications of the Antiviral Nucleosides and Nucleotides 

Table 4 lists the FDA-approved indications for the antiviral agents included in this review. 

Table 4. FDA-Approved Indications for the Nucleoside and Nucleotide Agents* 13-15,17,18,20,22-27 

Drug 

CMV 

Retinitis 

Prevention 

of CMV 

Disease 

Mucocutaneous 

HSV Infections 

Initial 

Genital 

Herpes 

Episodes 

Recurrent 

Genital 

Herpes 

Episodes 

Chronic 

Suppression 

of Recurrent 

Genital 

Herpes 

HSV 

Encephalitis 

Herpes 

Zoster 

(Shingles) 

Chickenpox 

Chronic 

Hepatitis 

C 

Chronic 

Hepatit 

s B 

Lower 

Respiratory 

Infection 

caused by 

RSV 

Oral Ganciclovir X†‡ X† 

IV Ganciclovir X§ X║ 

Valganciclovir X X║ 

Cidofovir X 

Oral Acyclovir X X X X X 

IV Acyclovir X§ X** X X§ X§ 

Famciclovir X†† X** X** X 

Valacyclovir X X** X** X**†† X 

Oral Ribavirin X‡‡ 

Aerosolized 

Ribavirin X 

Adefovir X 

*CMV indicates cytomegalovirus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; IV, intravenous. Boxes marked with "X" designate an indication approved by the Food and Drug Administration. 

†In immunocompromised patients, including patients with advanced HIV infection or transplant patients. 

‡For maintenance treatment in patients with stable retinitis following induction therapy. 

§In immunocompromised patients. 

║In transplant recipients. 

In patients with AIDS. 

**In patients with normal immune function. 

††In patients with HIV. 

‡‡Interferon must be given with ribavirin. Rebetol ® is indicated in combination with interferon alfa-2b, recombinant or peginterferon alfa-2b, recombinant. Copegus ® is indicated in combination with peginterferon 

alfa-2a only. 

228

IV. 

Pharmacokinetic Parameters of the Antiviral Nucleosides and Nucleotides 

Table 5 lists the pharmacokinetic parameters and mechanisms of action of these antiviral agents. 

Table 5. Pharmacokinetic Parameters of Antiviral Nucleoside and Nucleotide Agents 13-15,17,18,20,22-27 

Drug 

Mechanism of 

Action Bioavailability 

Protein 

Binding Metabolism 

Active 

Metabolites Elimination 

Ganciclovir Synthetic Poorly 1%-2% CMV-encoded 

guanine absorbed 

protein kinase 

nucleoside orally (5% 

and other 

analog. fasting, 6%- 

cellular kinases 

Converted by a 9% with 

CMV encoded food). 

protein kinase to Intravenous 

ganciclovir formulation 

monophosphate, available. 

that is further 

phosphorylated 

to ganciclovir 

triphosphate by 

cellular kinases. 

The ganciclovir 

triphosphate 

inhibits viral 

DNA synthesis 

and replication of 

herpes viruses 

either by 

competitive 

inhibition of 

DNA 

polymerases or 

direct 

incorporation 

into viral DNA. 

Valganciclovir 

Cidofovir 

Prodrug of 

ganciclovir. 

Rapidly 

converted to 

ganciclovir by 

intestinal and 

hepatic esterases. 

Nucleotide 

analog that 

suppresses CMV 

replication by 

inhibition of viral 

DNA syntheses. 

Cidofovir is 


into active 

cidofovir 

diphosphate that 

inhibits DNA 

polymerase and 

incorporates into 

viral DNA. 

60% with food 1%-2% Intestinal and 

hepatic 

esterases (once 

converted to 

ganciclovir, 

also undergoes 

metabolism by 

CMV encoded 

protein kinase 

and other 

cellular kinases) 

Intravenous 

formulation 

only. 

Half- 

Life 

Yes Renal Oral: 

4.8 

hours 

IV: 3.5 

hours 

Yes Renal 4.1 

hours 

Acyclovir 

Famciclovir 

Valacyclovir 

Ribavirin 

Synthetic purine 

nucleoside 

analog. 

Converted by 

thymidine kinase 

encoded by HSV 

and VZV into 

acyclovir 

monophosphate 

that is further 


by other enzymes 

into acyclovir 

triphosphate. 

Acyclovir 

triphosphate 


DNA replication 

by competitive 

inhibition of viral 

DNA 

polymerase, 

incorporation 

into viral DNA, 

and inactivation 

of viral DNA 

polymerase. 

Rapid 

biotransformation 

to penciclovir, 

which is 


by thymidine 

kinase to 

penciclovir 

monophosphate, 

that is then 

converted to 

penciclovir 

triphosphate. 

Penciclovir 

triphosphate 


DNA synthesis 

and replication 

via competitive 

inhibition of 

HSV-2 

polymerase. 

Prodrug of 

acyclovir. 

Rapidly 

converted to 

acyclovir by 

first-pass 

intestinal and/or 

hepatic 

metabolism. 

Unknown. May 

act as an analog 

of guanosine or 

10%-20%, 

which 

decreases with 

increasing 

doses. 

Intravenous 

formulation 

also available. 

9%-33% Thymidine 

kinase and other 

enzymes 

77%

Adefovir 

xanthosine. 

Nucleotide 

analog that 

inhibits HBV 

DNA polymerase 

via competitive 

inhibition of 

binding site and 

incorporation 

into viral DNA. 

Phosphorylated 

into active 

adefovir 

diphosphate. 

is absorbed 

systemically. 

deribosylation/ 

amide 

hydrolysis 

59% ≤4% Phosphorylation 

by cellular 

kinases. 

urine; 12% 

of oral dose 

is excreted 

in feces. 

Aerosol: 

9.5 

hours 

Yes Renal 7.5 

hours 

231

V. Drug Interactions of the Antiviral Nucleosides and Nucleotides 

Drug interactions identified for the nucleoside and nucleotide antiviral medications in this review are 

summarized below. 

Table 6. Drug Interactions of the Antiviral Nucleoside and Nucleotide Agents 28 


Ganciclovir Level 3 Ganciclovir and didanosine Mechanism is unknown. Didanosine concentrations 

are increased during coadministration with 

ganciclovir, possibly resulting in didanosine 

toxicity. Because both ganciclovir and didanosine 

are partially eliminated via renal secretion, this 

interaction could be the result of competitive 

inhibition of renal secretion. 

Ganciclovir Level 1 Ganciclovir and zidovudine Mechanism is unknown. Combination therapy 

with ganciclovir and zidovudine in the 

treatment of cytomegalovirus disease 

increases hematological toxicity. The toxicity 

appears to be related to combined 

pharmacodynamic effects rather than to a 

pharmacokinetic interaction. This 

combination should be avoided until 

additional information is available. 

Acyclovir Level 4 Acyclovir and cimetidine Cimetidine reduces the rate but not extent of 

conversion of valcyclovir to acyclovir. Acyclovir 

renal clearance is reduced by concomitant 

administration of cimetidine. Cimetidine moderately 

increases acyclovir concentrations; however, the 

clinical significance of this interaction is probably 

limited. 

Acyclovir Level 4 Acyclovir and probenecid Acyclovir renal clearance is reduced by 

concomitant probenacid administration. Probenacid 

increases acyclovir concentrations moderately; 

however, the clinical significance of this interaction 

is probably limited. 

Acyclovir Level 4 Acyclovir and zidovudine Mechanism is unknown. A single case of severe 

lethargy and fatigue has been reported following the 

coadministration of acyclovir and zidovudine. 

Acyclovir does not appear to affect zidovudine 

concentrations. 

Famciclovir Level 4 Famciclovir and digoxin Mechanism is unknown. Famciclovir administration 

produces a small increase in digoxin peak plasma 

concentrations; however, this change is not likely to 

enhance patient response to digoxin. 

Ribavirin Level 3 Ribavirin and warfarin Mechanism is unknown. One patient on warfarin 

developed reduced anticoagulant effect when 

ribavirin was added. Although a causal relationship 

was evident in this case, it is not known how often 

other patients would be similarly affected. 

Anticoagulant effect should be monitored if 

ribavirin is initiated, discontinued, or changed with 

respect to dosage. 

*Level 1 indicates an interaction where risks always outweigh benefit of therapy and combination should be avoided; Level 2, use combination only under 

special circumstances; Level 3, take action as necessary to reduce risk; Level 4, risk of adverse outcomes appears small and no action is needed. 

232

Other interactions (per manufacturers labeling): 

Ganciclovir 17 

• Ganciclovir and probenecid = Probenecid 500mg every 6 hours increased ganciclovir (1000mg 

every 8 hours) area under the concentration-time curve (AUC) 53% ± 91% (range, -14% to 

299%). Renal clearance of ganciclovir decreased 22 ± 20% (range, -54% to –4%) indicating an 

interaction involving competition for renal tubular secretion. 

• Ganciclovir and imipenem-cilastatin = Generalized seizures have been reported in patients who 

received concomitant ganciclovir and imipenem-cilastatin. These drugs should not be used 

concomitantly unless the potential benefits outweigh the risks. 

• It is possible that drugs that inhibit replication of rapidly dividing cells may have additive toxicity 

when administered with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, 

vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole, or other 

nucleoside analogues, should be considered for concomitant use with ganciclovir only if the 

potential benefits outweigh the potential risks. 

Valganciclovir 20 

• No in vivo evaluations of drug-drug interactions were conducted with valganciclovir. However, 

because it is a prodrug of ganciclovir and is rapidly and extensively converted, interactions 

associated with ganciclovir would be expected with valganciclovir. 

Valacyclovir 21 

• Valacyclovir and cimetidine = A single dose of cimetidine 800mg with valacyclovir 1000mg 

increased the AUC and maximum plasma concentration (C max ) of acyclovir by 32% and 8%, 

respectively. This effect is not thought to be clinically significant in patients with normal renal 

function. 

• Valacyclovir and probenacid = A single dose of probenecid 1000mg with valacyclovir 1000mg 

increased the AUC and maximum plasma concentration (C max ) of acyclovir by 49% and 22%, 

respectively. This effect is not thought to be clinically significant in patients with normal renal 

function. 

Famciclovir 15 

• Concomitant use of famciclovir and probenecid or other drugs significantly eliminated by active 

renal tubular secretion may result in increased plasma concentrations of penciclovir. 

Cidofovir 18 

• Cidofovir and probenecid = Concomitant administration of cidofovir and probenacid reduced the 

amount of cidofovir excreted unchanged in the urine to 70% to 85% of the dose. The renal 

clearance of cidofovir was reduced to a level consistent with creatinine clearance, indicating that 

probenecid blocks active renal tubular secretion of cidofovir. Probenecid must be administered 

with each cidofovir dose to minimize the risk of potential nephrotoxicity. 

• Cidofovir and nephrotoxic agents = Concomitant administration of cidofovir and agents with 

nephrotoxic potential is contraindicated. 

Adefovir 27 

• Adefovir and ibuprofen = Ibuprofen 800mg TID increased adefovir C max by 33% and AUC by 

23%. This interaction appears to be due to higher oral bioavailability, not a reduction in renal 

clearance of adefovir. 

Ribavirin 24,25 

• Ribavirin and didansoine = Exposure to didanosine is increased from concomitant administration 

with ribavirin, which could cause or worsen clinical toxicities. Coadministration of ribavirin and 

didanosine is not recommended. 

233

• Ribavirin and stavudine = Ribavirin has been shown in vitro to inhibit phosphorylation of 

stavudine, which could lead to decreased antiretroviral activity. Concomitant use of these 

medications should be used with caution. 

• Ribavirin and zidovudine = Ribavirin has been shown in vitro to inhibit phosphorylation of 

zidovudine, which could lead to decreased antiretroviral activity. Concomitant use of these 

medications should be used with caution. 

VI. 

Adverse Drug Events of the Nucleoside and Nucleotide Antiviral Agents 

Acyclovir, Valacyclovir, Famciclovir 

Adverse events for oral acyclovir, intravenous acyclovir, famciclovir, and valacylovir have been relatively 

similar in comparative clinical trials. Because valacyclovir is rapidly converted to acyclovir in vivo, a 

similar adverse event profile would be expected for these medications. Renal failure, in some cases 

resulting in death, has been observed with acyclovir and valacyclovir therapy. 13,14 Concomitant use of 

other nephrotoxic drugs, preexisting renal disease, and dehydration make renal impairment with acyclovir 

more likely. Intravenous acyclovir must be given over at least one hour to reduce the risk of renal tubular 

damage. 13 Thrombotic thrombocytopenic pupura/hemolytic uremic syndrome, which has resulted in death, 

has also occurred in immunocompromised patients receiving acyclovir and valacyclovir therapy. 13,14 

Additionally, approximately 1% of patients receiving intravenous acyclovir have experienced 

encephalopathic changes characterized by lethargy, obtundation, tremors, confusion, hallucinations, 

agitation, seizures, or coma. 13 The manufacturer recommends that acyclovir be used with caution in 

patients with underlying neurologic abnormalities or serious renal, hepatic, or electrolyte abnormalities, or 

significant hypoxia. Acute renal failure has also been reported in patients receiving famciclovir. 15 

Ganciclovir, Valganciclovir, Cidofovir 

In clinical trials comparing oral ganciclovir to intravenous ganciclovir, subjects treated with intravenous 

ganciclovir experienced lower minimum absolute neutrophil counts and hemoglobin levels, consistent with 

more neutropenia and anemia, compared to subjects treated with oral ganciclovir. 21 Retinal detachment has 

been reported in subjects with CMV retinitis, both before and after initiation of ganciclovir. 17 The 

relationship between retinal detachment and treatment with ganciclovir is unknown. The safety profiles of 

ganciclovir and valganciclovir have been similar in comparative clinical trials, which would be expected 

because valganciclovir is a prodrug of ganciclovir. Granulocytopenia (neutropenia), anemia, and 

thrombocytopenia have been observed in patients receiving ganciclovir or valganciclovir therapy 17,20 ; 

therefore, the manufacturer does not recommend the use of ganciclovir or valganciclovir in patients with an 

absolute neutrophil count

Adefovir 

Severe acute exacerbation of hepatitis has been reported in patients who have discontinued adefovir therapy 

for chronic HBV. 27 Nephrotoxicity, lactic acidosis, and severe hepatomegaly with steatosis, including fatal 

cases, have also been reported in patients receiving adefovir. 

Aerosolized Ribavirin 

Sudden deterioration of respiratory function has been associated with initiation of aerosolized ribavirin in 

infants. 26 Respiratory function needs to be carefully monitored during ribavirin therapy. Administration of 

aerosolized ribavirin to mechanically ventilated patients should only be undertaken by health care 

professionals experienced with this mode of administration and the specific ventilator being used. 

Attention must be paid to procedures that have been shown to minimize the accumulation of drug 

precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary 

pressure. Additionally, ribavirin is teratogenic and studies have shown that the drug can disperse into 

surrounding bedside area, placing caretakers at risk. Other adverse events associated with aerosolized 

ribavirin include deaths during or shortly after treatment, some possibly related to ribavirin and some 

attributed to ribavirin precipitation in mechanical ventilation systems. Pulmonary and cardiovascular 

complications, anemia, rash, conjunctivitis, seizures, and asthenia have also been observed with aerosolized 

ribavirin therapy. 

Adverse events observed in clinical trials with these medications are listed in Table 7. However, this list 

may not include every adverse event reported in all clinical trials with these drugs. Additionally, as many 

of these agents are used in various patient populations (e.g., transplant recipients, HIV-infected individuals) 

and for different disease processes, adverse event percentages are often different between the respective 

studies depending on the patient population. Where noted, some percentages in the following Table may 

reflect an average of adverse event incidences from various trials. Please refer to the manufacturer labeling 

for additional safety information regarding specific disease states and treatment groups. 

235

Table 7. Common Adverse Events (%) Reported for the Antiviral Nucleosides and Nucleotides 13-15,17,18,20,22,23,27 

Adverse Event Ganciclovir* Valganciclovir† Cidofovir Acyclovir*‡ Famciclovir‡ Valacyclovir‡ Adefovir 


Malaise 

Fever 

Chills 


Edema 

Hypotension 

Hypertension 

Gastrointestinal 


Nausea 

Vomiting 

Diarrhea 

Anorexia 

Flatulence 



Depression 

Headache 

Neuropathy 

Paresthesia 

Insomnia 

Tremor 

Migraine 

Seizures 

Hepatic 

Increased LFTs 

Hepatitis 

Elevated total bilirubin 



Alopecia 

Rash 

Pruritus 

Sweating 

Injection site reaction 

Urticaria 

Hematologic 

Neutropenia 

Leukopenia 

Anemia 



Thrombocytosis 

Leukocytosis 

Neutrophilia 

Hemolytic anemia 

Genitourinary 

Increased SCr/BUN 

Acute renal failure 

Hematuria 

Dysmenorrhea 

Proteinuria 

Other 

Infection 

Sepsis 

Pneumonia 

Vitreous disorder 

Catheter-related infection 

Retinal detachment 

Graft rejection 

Decreased serum HCO 3 

Decreased intraocular pressure 

Uveitis 

Dyspnea 

 

38/48 

7/10 

 

 

 

17/19 

26/25 

13/13 

41/44 

15/14 

6/3 

 

 

 

8/9 

6/10 

 

 

 

31/13 58 

22 

 

 

-/18 

15/- 

30/23 

21/16 

41/30 

 

 

22/22 

9/- 

8/- 

16/20 

-/28 

 

 

 

 

69 

7 

26 

23 

 

 

 

30 

 

 

 

 

 

 

 

 

15/10 

6/5 

11/12 

 

 

17/38 

29/41 

19/25 

6/6 

 

 

 

9/13 

4/15 

6/8 

6/4 

4/9 

8/11 

 

-/14 

27/- 

26/- 

6/- 

 

15/- 

-/24 

27 

30 

 

 

43 

 

24 

 

24 

 

 

88 

28 

9 

16 

24 

11 

23 

11.5/- 5.2 

3.3/7║ 

3.3/7║ 

2.8/- 

VII. 

Dosing and Administration of the Antiviral Nucleosides and Nucleotides 

Table 6. Dosing for the Antiviral Nucleoside and Nucleotide Agents 13-15,17,18,20,22-27 


Ganciclovir 250mg oral capsule; 

500mg oral capsule 

Dosing depends on indication. Capsules should be taken with food. 

500mg/10mL vial 

ganciclovir sodium for 

injection 

Treatment of CMV Retinitis 

Induction: 

• IV: 5mg/kg (at a constant rate over 1 hour) every 12 hours for 14-21 days. 

• Capsules are not indicated for induction. 

Maintenance: 

• IV: 5mg/kg (at a constant rate over 1 hour) QD, 7 days per week, or 6mg/kg 

QD, 5 days per week OR 

• Oral: 1000mg TID with food, or 500mg 6 times daily every 3 hours with 

food, during waking hours. 

Prevention of CMV Disease in Patients with Advanced HIV 

1000mg orally TID with food. 

Prevention of CMV Disease in Transplant Recipients 

• IV: initial dose of 5mg/kg (at a constant rate over 1 hour) every 12 hours for 

7-14 days, followed by 5mg/kg QD, 7 days per week or 6mg/kg QD, 5 days 

per week. 

• Oral: 1000mg TID with food. 

• Duration of treatment in transplant recipients depends on the duration and 

degree of immunosuppression. 

Other Notes: 

Ganciclovir should not be administered to a patient with an absolute neutrophil 

count

Acyclovir 

Famciclovir 

200mg capsule; 

400mg capsule; 

800mg capsule 

200mg/5mL suspension 

500mg/10mL and 

1000mg/10mL vials of 

acyclovir sodium for 

injection 

125mg tablets; 

250mg tablets; 

500mg tablets 

3 hours prior to cidofovir, and 1000mg at 2 and again at 8 hours after 

completion of cidofovir infusion). 

• Cidofovir is contraindicated in patients with a creatinine clearance 

≤55mL/min. 

Dosing depends on indication. 

Herpes Zoster 

• Oral: 800mg every 4 hours, 5 times daily for 7-10 days. 

Genital Herpes 

Initial episode: 

• Oral: 200mg every 4 hours, 5 times daily for 10 days OR 

• IV: 5mg/kg (at a constant rate over 1 hour), every 8 hours for 5 days. 

Chronic suppression for recurrent disease: 

• Oral: 400mg BID for up to 12 months, followed by re-evaluation. Other 

regimens have included doses ranging from 200 mg TID to 200mg 5 times 

daily. 

Intermittant therapy: 

• Oral: 200mg every 4 hours, 5 times daily for 5 days. Therapy should be 

initiated at the earliest sign of symptom of recurrence. 

Treatment of Chickenpox 

Therapy should be initiated at the earliest sign or symptom of chickenpox as 

there is no information about the efficacy of therapy initiated more than 24 hours 

after onset of signs and symptoms. 

Children: 

• Oral: 20mg/kg/dose QID for 5 days. Children over 40kg should receive the 

adult dose. 

Adults: 

• Oral: 800mg QID for 5 days. 

Immunocompromised children: 

• IV: 20mg/kg/dose (at a constant rate over 1 hour) every 8 hours for 7 days. 

Immunocompromised adults: 


Mucosal and Cutaneous HSV Infections in Immunocompromised Patients 

Adults: 


Pediatrics: 


Herpes Simplex Encephalitis 

Adults: 


Pediatrics: 


Neonatal HSV Infections (birth to 3 months): 


Doses of 15mg/kg or 20mg/kg at the same frequency have also been used; 

however, the safety and efficacy of these doses are not known. 

Dosage depends on indication. 

Herpes Zoster 

• 500mg every 8 hours for 7 days. 

238

Valacyclovir 

Ribavirin 

500mg caplets; 

1000mg caplets 

200mg tablet; 

200mg capsule 

• Therapy should be initiated as soon as herpes zoster is diagnosed, as no data 

are available on efficacy of treatment started greater than 72 hours after 

onset of rash. 


Recurrent genital herpes: 

• 125mg BID for 5 days. 

• Therapy should be initiated at the first sign or symptom if medical 

management is indicated, as efficacy has not been established when 

treatment is initiated more than 6 hours after onset of symptoms or lesions. 

Suppression of recurrent genital herpes: 

• 250mg BID for 5 days for up to 1 year. 

• The safety and efficacy of famciclovir therapy beyond 1 year of treatment 

have not been established. 

Recurrent Orolabial or Genital Herpes in HIV-Infected Patients 


Dosage depends on indication. 

Herpes Zoster 

• 1000mg TID for 7 days. 

• Therapy should be initiated at earliest sign or symptom of herpes zoster, and 

is most effective when started within 48 hours of the onset of zoster rash. 

There are no data available on efficacy of treatment initiated greater than 

72 hours after onset of rash. 


Initial episodes: 


• Therapy is most effective when initiated within 48 hours of the onset of 

signs and symptoms. There are no data on the efficacy of treatment when 

initiated more than 72 hours after the onset of signs and symptoms. 

Recurrent episodes: 


• Therapy should be initiated at the first sign or symptom of an episode if 

medical management is indicated. There are no data on the efficacy of 

treatment when initiated more than 24 hours after the onset of signs or 

symptoms. 

Suppression of recurrent genital herpes: 

• 1000mg QD. 

• 500mg QD is an alternative for patients with 9 or fewer recurrences per year. 

Suppression of recurrent genital herpes in HIV-infected patients: 

• Patients with CD 4 cell count ≥100 cells/mm 3 may receive 500mg BID. 

Reduction of transmission: 

• 500mg QD for the source partner is recommended for reduction of 

transmission of genital herpes in patients with a history of 9 or fewer 

recurrences per year. 

Herpes Labialis (cold sores) 

• 2000mg BID for 1 day. 

• Therapy should be initiated at earliest symptom of a cold sore, as there are 

no data on the effectiveness of treatment initiated after the development of 

clinical signs of a cold sore (e.g., papules, vesicles, or ulcer). 

*Monotherapy is not effective for the treatment of chronic HCV infection. 

Ribavirin must be used in combination with interferon therapy. The safety 

239

40mg/mL oral solution 

6grams lyophilized 

ribavirin powder for 

reconstitution and 

inhalation 

and efficacy of ribavirin tablets (Copegus ® ) have only been established when 

used in combination with pegylated interferon alfa-2a, recombinant. The safety 

and efficacy of ribavirin capsules and oral solution (Rebetol ® ) have been 

established when used in combination with interferon alfa-2b or pegylated 

interferon alfa-2b. 

Treatment of Chronic Hepatitis C with Ribavirin (Copegus ® ) plus pegylated 

interferon alfa-2a, recombinant 

Genotypes 1 and 4: 

• 75kg should receive ribavirin 600mg (3 capsules) QAM and 600mg 

(3 capsules) QPM daily with interferon alfa-2b. 

• The recommended duration of treatment for previously untreated patients is 

24-48 weeks. In patients who relapse following non-pegylated interferon 

monotherapy, the recommended duration of treatment is 24 weeks. 

Pediatrics 

• 15mg/kg/day divided into an AM and PM dose. 

• The recommended duration of therapy is 48 weeks for pediatric patients with 

genotype 1, and 24 weeks for pediatric patients with genotype 2/3. 

Treatment of Chronic Hepatitis C with Ribavirin (Rebetol ® ) plus pegylated 

interferon alfa-2b, recombinant 

Adults: 

• Ribavirin 400mg (2 capsules) QAM and 400mg (2 capsules) QPM with 

peginterferon alfa-2b. 

Other Notes Regarding Oral Ribavirin 

• A dosage reduction to 600mg daily (200mg in the morning, two 200mg 

tablets in the evening) is recommended for certain decreases in hemoglobin 

(e.g.,

Adefovir 10mg tablet Chronic Hepatitis B Infection 

• 10mg QD. 

• The optimal duration of therapy is unknown. 

*Dosages listed in this table are based on normal renal function. Dosages should be adjusted according to manufacturer recommendations for patients 

with impaired renal function. 


Table 7. Special Dosing Considerations for the Nucleoside and Nucleotide Antiviral Agents 13-15,17,18,20,22-27 

Drug Renal Hepatic 

Pediatric Use 

Pregnancy Can Drug Be Crushed 

Dosing Dosing 

Category 

Ganciclovir Yes No The safety and efficacy of gancicloivr 

in pediatric patients have not been 

established. Use of ganciclovir in this 

patient population warrants extreme 

caution due to the probability of 

long-term carcinogenicity and 

reproductive toxicity. Administration 

should be undertaken only after 

careful evaluation and only if the 

potential benefits of treatment 

outweigh the risks. 

C According to the package insert, 

ganciclovir capsules should not be 

opened or crushed. The 

manufacturer reports no data are 

available regarding opening 

capsules or use as an oral 

suspension. 

Valganciclovir Yes No Safety and efficacy in pediatric 

patients have not been established. 

Acyclovir Yes No Safety and efficacy of oral 

formulations of acyclovir in pediatric 

patients under 2 years of age have not 

been established. The intravenous 

formulation is FDA-approved for the 

treatment of neonatal HSV infection; 

dosing recommendations are 

available. 

Valacyclovir Yes No Safety and efficacy in prepubertal 

pediatric patients have not been 

established. 

Famciclovir Yes No Safety and efficacy in children under 

the age of 18 years have not been 

established. 

Cidofovir Yes No Safety and efficacy in children have 

not been established. Use of cidofovir 

C 

B 

B 

B 

C 

According to the package insert, 

valganciclovir tablets should not be 

broken or crushed. However, 

information is available from the 

manufacturer regarding the 

preparation of an extemporaneous 

oral liquid prepared from 

valganciclovir tablets. 

The manufacturer reports no data 

are available regarding opening 

capsules or crushing tablets as an 

oral suspension formulation is 

available. 

The manufacturer reports that 

caplets are scored and can be 

broken. The pharmacokinetics of 

crushed tablets have not been 

specifically evaluated. However, 

information on the preparation of 

an extemporaneous suspension 

from 500 mg tablets is available 

from the manufacturer and has 

been evaluated for formulation, 

stability, sterility, and palatability. 

The manufacturer reports that there 

is no information regarding 

splitting or crushing famciclovir 

tablets. 

Intravenous solution is only 

formulation currently available. 

241

in children with AIDS warrants 

extreme caution due to the risk of 

long-term carcinogenicity and 

reproductive toxicity. Administration 

should only be undertaken after 

careful evaluation and only if the 

potential benefits of treatment 

outweigh the risks. 

Ribavirin Yes* No Ribavirin capsules and oral solution 

are indicated in patients 3 years of age 

and older. Importantly, however, 

suicidal ideation or attempts occurred 

more frequently among pediatric 

patients, primarily adolescents, 

compared to adult patients during 

treatment and off-therapy follow-up. 

Safety and efficacy of ribavirin tablets 

(ie, Copegus ® ) in pediatric patients 

under the age of 18 years have not 

been established. 

Adefovir Yes No Safety and efficacy in pediatric 

patients have not been established. 

*Ribavirin should not be used in patients with a creatinine clearance less than 50 mL/min. 

X 

C 

According to the manufacturers, no 

information is available regarding 

crushing of ribavirin tablets (ie, 

Copegus ® ) or opening of ribavirin 

capsules (ie, Rebetol ® ). An oral 

solution formulation is available. 

According to the manufacturer, 

there is no data available regarding 

crushing or splitting adefovir 

tablets. 

242

VIII. 

Comparative Effectiveness of the Antiviral Nucleosides and Nucleotides 

Table 8. Outcomes Evidence for the Antiherpetic Agents 

Study Sample 

Size 

Treatment/ 

Duration 

Shafran 

SD, et al 29 n=559 Famciclovir 750mg 

QD versus famciclovir 

500mg BID versus 

famciclovir 250mg 

TID versus acyclovir 

800mg 5 times daily 

for 7 days 

Warkentin 

DI, et al 30 n=151 Valacyclovir 500mg 

BID versus 

valacyclovir 250mg 

BID versus acyclovir 

400mg TID 

Shen MC, n=55 Famciclovir 250mg 

et al 31 TID versus acyclovir 


Lin WR, 

et al 32 n=57 Valacyclovir 1000mg 



for 7 days 

Tyring S, 

et al 33 n=148 Famciclovir 500mg 



for 10 days 

243 

Results 

In comparing various doses of famciclovir to acyclovir for the treatment of herpes 

zoster in immunocompetent adults: 

• No significant differences between treatment groups with respect to time to full 

crusting, loss of vesicles/ulcers/crusts, cessation of new lesion formation, 50% 

reduction in area of affected skin, and resolution of acute pain. 

• There were no significant differences in the frequency of adverse events between 

treatment groups. 

• Agents had comparable efficacy in healing cutaneous herpes zoster. 

In comparing valacyclovir 500 mg BID (n=48), valacyclovir 250mg BID (n=52), and 

acyclovir 400mg TID (n=51) for HSV prophylaxis in neurtopenic patients, where 

therapies were given for the duration of neutropenia: 

• The absence of HSV infection was similar among the treatment groups: 

acyclovir 96%, valacyclovir 500mg 95%, valacyclovir 250mg 100% (P=0.08). 

• The overall rates of adverse events were similar in the 3 treatment groups. 

In comparing famcilovir (n=27) to acyclovir (n=28) for the treatment of acute, 

uncomplicated herpes zoster in immunocompetent adults: 

• Treatment was initiated within 72 hours of onset of the zoster rash and was 

continued for 7 days. 

• Famciclovir and acyclovir had comparable efficacy with respect to healing 

cutaneous lesions (indicated by time to full crusting), resolution of acute pain, 

loss of vesicles, and loss of crusts. 

• Constipation, hematuria, and glycosuria were the most commonly reported 

adverse events. Famciclovir had a more favorable adverse event profile than 

acyclovir. 

In comparing valacyclovir (n=32) to acyclovir (n=25) for the treatment of acute, 

uncomplicated herpes zoster: 

• Patients presenting with herpes zoster within 72 hours after onset of zoster rash 

were included. 

• Valacyclovir significantly shortened the time necessary for resolution of herpes 

zoster associated pain compared to acyclovir. 

• There were no significant differences between groups with respect to frequency 

or severity of adverse events. 

• The authors concluded that valacyclovir accelerates the resolution of herpes 

zoster pain with a simpler dosing schedule, while maintaining a similar safety 

profile as acyclovir. 

In comparing famciclovir to acyclovir for the treatment of herpes zoster in 

immunocompromised patients 12 years of age or older: 

• Famciclovir and acyclovir were comparable with respect to the number of 

patients reporting new lesion formation while on therapy (77% versus 73%, 

respectively). 

• There were no differences between treatment regimens in time to cessation of 

new lesion formation, full crusting, complete healing of lesions, or resolution of 

acute pain. 

• The adverse event profile was comparable between treatment groups. 

Chosidow 

O, et al 34 n=204 Famciclovir 125mg 


In comparing famciclovir to acyclovir for the treatment of recurrent genital herpes 

infection: 

200mg 5 times daily • Mean healing time was 5.1 days with famciclovir and 5.4 days with acyclovir 

for 5 days 

(P=0.82). 

• No difference was observed in the proportion of patients having complete 

healing on different days of evaluation. Additionally, there was no difference in 

the duration until the complete resolution of all symptoms. 

• The adverse event profile was comparable between treatment groups. 

• Famciclovir and acyclovir had comparable safety and efficacy in the treatment of 

recurrent genital herpes. 

Romanow n=293 Famciclovir 500mg In comparing famcilovir to acyclovir for the treatment of mucocutaneous HSV

ski B, et 

al 35 



for 7 days 

Tyring 

SK, et al 36 n=1,250 Valacyclovir 1000mg 



versus placebo for 

5 days 

Fife KH, 

et al 37 n=643 Valacyclovir 1000mg 



for 10 days 

Bodswort 

h NJ, et 

al 38 n=739 Valacyclovir 500mg 



for 5 days 

Tyring 

SK, et al 39 n=597 Valacyclovir 1000mg 

TID versus 

famciclovir 500mg 

TID for 7 days 

infection in HIV-infected patients: 

• Patients initiated therapy within 48 hours of the first appearance of lesions. 

• Famciclovir and acyclovir were comparable with respect to prevention of new 

lesion formation (new lesions in 16.7% and 13.3% of patients, respectively). 

• Famciclovir and acyclovir treatment groups were also comparable in time to 

complete healing (median 7 days in each group), cessation of viral shedding 

(median of 2 days), and loss of lesion-associated symptoms (median 4 days). 

• The incidence of adverse events was comparable between treatment groups. 

• Famciclovir and acyclovir are equally safe and effective for the treatment of 

mucocutaneous infections in HIV-infected patients; however, famciclovir has a 

more convenient dosing schedule. 

In comparing valacyclovir, acyclovir, and placebo for the treatment of recurrent 

genital herpes infections: 

• Valacyclovir and acyclovir were significantly more effective than placebo in 

accelerating resolution of herpes episodes, time to lesion healing, and resolution 

of pain. 

• Valacyclovir and acyclovir demonstrated comparable efficacy with respect to the 

above parameters. 

• The incidence of adverse events did not differ among the 3 treatment groups. 

In comparing valacyclovir to acyclovir for the treatment of adults with a first episode 

of genital herpes: 

• Valacyclovir and acyclovir were comparable with respect to duration of viral 

shedding, time to healing, duration of pain, and time to resolution of all 

symptoms. 

• Adverse events were comparable between treatment groups. Overall, adverse 

events were infrequent and mild in severity. 

In comparing valacyclovir to acyclovir for the treatment of immunocompetent adults 

with recurrent genital herpes infections: 

• Valacyclovir and acyclovir were comparable with respect to duration of signs 

and symptoms (including lesion healing and pain). 

• Cessation of viral shedding was rapid and comparable between treatment groups. 

• Adverse events were infrequent and generally mild in severity. Incidence of 

adverse events was similar between treatment groups. 

In comparing valacyclovir to famciclovir for the treatment of immunocompetent 

adults, ages 50 years and older, with herpes zoster: 

• Patients were required to present within 72 hours of rash onset for inclusion. 

• The valacyclovir and famciclovir groups were comparable with respect to 

resolution of zoster-associated pain, rash healing, and analyses of postherpetic 

neuralgia. 

• Safety profiles of valacyclovir and famciclovir were similar; headache and 

nausea were the most common adverse events. 

• Valacyclovir was comparable to famciclovir treatment in accelerating the 

resolution of zoster-associated pain and postherpetic neuralgia. 

244

Table 9. Outcomes Evidence for the Treatment or Prevention of Cytomegalovirus 

Study Sample 

Size 

Treatment/ 

Duration 

Results 

Paya C, et 

al. 40 n=364 Valganciclovir 900mg 

QD versus oral 

ganciclovir 1000mg 

TID 

Szer, et 

al. 41 n=58 Oral ganciclovir 

3000mg QD versus IV 

ganciclovir 5mg/kg 

three times weekly 

Martin 

DF, et al 42 n=160 Oral valganciclovir 

900mg BID for 

3 weeks, followed by 

900mg QD for 1 week 

versus IV ganciclovir 

5mg/kg BID for 


5mg/kg QD for 

1 week 

Winston 

DJ, et al 43 n=64 Sequential IV and oral 

ganciclovir (6mg/kg 

IV QD for 2 weeks, 

followed by 1000mg 

every 8 hours oral 

ganciclovir) versus 

prolonged IV 

ganciclovir (6mg/kg 

QD for 2 weeks, 

followed by 6mg/kg 

QD 5 days per week) 

Jabs DA 44 n=61 Ganciclovir 

ophthalmic implant 

plus oral ganciclovir 

1000mg TID versus 

IV cidofovir 5mg/kg 

weekly for 2 doses, 


every other week 

In comparing valganciclovir and oral ganciclovir for the prophylaxis of CMV in solid 

organ transplant patients who were CMV-seronegative but receiving organs from 

CMV-seropositive donors: 

• At 6 months, CMV disease had developed in 12.1% and 15.2% of valganciclovir 

and ganciclovir patients, respectively. 

• At 12 months, CMV disease had developed in 17.2% and 18.4% of 

valganciclovir and ganciclovir patients, respectively. Additionally, the incidence 

of investigator-treated CMV disease events was comparable between treatment 

groups. 

• Oral valganciclovir was as effective and well-tolerated as oral ganciclovir for 

CMV prevention in high-risk solid organ transplant patients. 

In comparing oral ganciclovir to IV ganciclovir in patients at risk for CMV disease 

following allogenic BMT: 

• CMV-seropositive patients or patients receiving bone marrow from 

CMV-seropositive donors were randomized to IV ganciclovir (n=27) or oral 

ganciclovir (n=31) from engraftment to day 84. 

• Renal dysfunction, transfusion requirements, and significant nausea and 

vomiting were similar between treatment groups. 

• There were no documented cases of CMV disease in either treatment group 

during the study. 

• Oral ganciclovir was determined to be an effective, well-tolerated alternative to 

IV ganciclovir for prophylaxis of CMV disease. 

In comparing oral valganciclovir (n=80) to IV ganciclovir (n=80) for induction 

therapy for newly diagnosed CMV retinitis in patients with AIDS: 

• Progression of CMV was observed in 10% of patients receiving IV ganciclovir 

and 9.9% of patients receiving oral valganciclovir. 

• 77% of patients receiving IV ganciclovir and 71.9% receiving oral valganciclovir 

had a satisfactory response to induction therapy. 

• Median time to progression of retinitis was 125 days for IV ganciclovir and 

160 days for oral valganciclovir. 

• Adverse events were similar between treatment groups. 

• Oral valganciclovir was as effective as IV ganciclovir for induction treatment 

and long-term management of CMV retinitis in patients with AIDS. 

In comparing sequential IV and oral ganciclovir (n=32) to prolonged IV ganciclovir 

(n=32) for the prevention of CMV disease in CMV-seronegative liver transplant 

recipients with CMV-positive donors: 

• CMV disease occurred in 9.3% of patients receiving oral ganciclovir and 12.5% 

receiving IV ganciclovir within the first year after transplantation (P>0.2). 

• There were no deaths from CMV in either study group. 

• Both oral and IV ganciclovir were generally well-tolerated. 

• Results indicated that oral ganciclovir is as effective as IV ganciclovir for 

maintenance therapy after induction with IV ganciclovir. 

In comparing the ganciclovir ophthalmic implant plus oral ganciclovir to intravenous 

cidofovir for the treatment of cytomegalovirus retinitis in patients with AIDS: 

• Mortality was similar between treatment groups: 0.41 per person-year in 

ganciclovir patients and 0.49 per person-year in cidofovir patients (P=0.59). 

• Ocular outcomes (e.g., retinitis progression, loss of visual acuity) were similar 

between treatment groups. 

• Vitreous hemorrhage was more common in ganciclovir-treated patients (0.13 per 

person-year) than in cidofovir-treated patients (no cases) (P=0.14). 

• Uveitis was more common in the cidofovir group (0.35 per person-year) 

compared to the ganciclovir group (0.09 per person-year) (P=0.066). 

• Nephrotoxicity (serum creatinine greater than 1.6mg/dL) occurred at a rate of 

0.18 per person-year in the ganciclovir group and 0.48 per person-year in the 

cidofovir group (P=0.10). 

• Although the sample size for this study was small, the results suggest that the 

use of a ganciclovir implant plus oral ganciclovir and the use of intravenous 

245

Lalezari 

JP, et al. 45 n=48 Cidofovir 5mg/kg 

once weekly for 


once every other week 

Lalezari 

JP, et al 46 n=150 Cidofovir 5mg/kg 



5mg/kg or 3mg/kg 

once every other week 

Ocular 

Complicat 

ions of 

AIDS 

Research 

Group 47 n=64 Cidofovir 5mg/kg 



3mg/kg once every 

2 weeks versus 

cidofovir 5mg/kg once 

weekly for 2 weeks, 


once weekly every 

2 weeks versus 

deferral of therapy 

until progression of 

retinitis 

cidofovir are similar for controlling CMV retinitis but have different adverse 

event profiles. 

In comparing immediate (n=25) with deferred (n=23) cidofovir treatment in patients 

with AIDS and previously untreated CMV retinitis: 

• Median time to progression of CMV retinitis in the deferred group was 22 days 

compared to 120 days in the immediate treatment group (P

Perillo R, 

et al 50 n=5 Adefovir 5-30mg QD In 5 patients with chronic HBV who developed resistance to lamivudine after 9-19 

months of therapy: 

• 4 of the patients included developed resistance after liver transplantation and 1 

patient had stable cirrhosis. 

• 2-4 log 10 reductions in serum HBV DNA levels were observed in 4 patients after 

receiving adefovir therapy. The fifth patient became negative for serum HBV 

DNA after retransplantation in conjunction with hepatitis B immunoglobulin. 

• Serum alanine transaminase levels occurred in 4 patients. 

• The authors concluded that adefovir can be effective in treating 

lamivudine-resistant mutants of HBV. 

Schiff ER, 

et al 51 n=324 Adefovir 10mg QD In evaluating the effects of adefovir in pre- and post-liver transplant patients with 

recurrent chronic HBV and evidence of lamivudine-resistance: 

• 81% of pre-transplant patients and 34% of post-transplant patients who received 

48 weeks of treatment achieved undetectable serum HBV DNA levels. 

• Serum alanine aminotransferase, albumin, bilirubin, and prothrombin time 

normalized in 76%, 81% 50%, and 83% of pre-transplant patients and 49%, 

76%, 75%, and 20% of post-transplant patients, respectively. 

• Genotype revealed that 98% of 122 HBV baseline samples were lamivudine 

resistant. 

• No adefovir resistance mutations were identified after 48 weeks. 

• Adverse events in patients receiving adefovir were generally mild to moderate in 

severity. 

Benini F, 

et al 52 n=43 Ribavirin 1000mg or 

1200mg QD plus 

interferon-alfa 2b 

In evaluating the combination of ribavirin and interferon alfa-2b for the treatment of 

chronic HCV infection in patients experiencing relapses or non-responders to prior 

high-dose interferon: 

3MU 3 times per • Normalization of serum alanine aminotransferase levels and undetectable HCV 

week for 24 or 48 RNA were seen in 58.1% and 30.2% of patients, respectively. 

weeks • No significant difference in response was identified for previous non-responders 

of interferon therapy versus patients with relapses. 

• At the end of followup, 3 (7%) patients had a sustained response (2 interferon 

non-responders, 1 relapser). 

Brau N, et 

al 53 n=107 Interferon alfa-2b 

3MU 3 times per 

week with placebo for 

In evaluating the combination of ribavirin and interferon alfa-2b (n=53) versus 

interferon alfa-2b with placebo for 16 weeks followed by ribavirin 800 mg QD (n=54) 

for the treatment of chronic HCV infection in patients coinfected with HIV: 

16 weeks, followed by • Sustained viral response rate (ie, undetectable HCV RNA at 24 weeks 

ribavirin 800mg QD posttherapy) was comparable between groups: immediated ribavirin 11.3%, 

versus interferon delayed ribavirin 5.6% (P=0.32). 

alfa-2b (same dose) • At week 12, CD4 cell count increased in the immediate-ribavirin group (+4.1%, 

plus ribavirin 800mg P

Perillo R, 

et al 55 n=412 Interferon alfa-2b 

(3MU 3 times weekly) 

plus ribavirin 

1000-1200 mg QD 

versus peginterferon 

monotherapy (180mcg 

once weekly) 

Manns 

MP, et 

al 56 n=1530 Interferon alfa-2b 

(3 MU 3 times 

weekly) plus ribavirin 

1000-1200 mg QD 


alfa-2b (1.5mcg/kg 

each week) plus 

ribavirin 800 mg QD 


alfa-2b (1.5mcg/kg 

each week for 

4 weeks, then 

0.5mcg/kg each week) 

plus ribavirin 

1000-1200 mg QD for 

48 weeks 

McHutchi n=912 Interferon alfa-2b 

et al 57 interferon alfa-2b 

nson JG, 

(standard dose) versus 

(standard dose) plus 

ribavirin 

1000-1200 mg QD for 

24 or 48 weeks 

In evaluating the impact of peginterferon monotherapy versus combined interferon 

alfa-2b/ribavirin therapy on quality of life, work productivity, and medical resource 

utilization: 

• Patients receiving peginterferon monotherapy reported less impairment with 

respect to all measures of work functioning and productivity compared to 

patients receiving interferon alfa-2b/ribavirin. 

• The authors concluded that patients receiving peginterferon had improved work 

productivity, less activity impairment, better adherence, and decreased need for 

prescription drugs to treat adverse events. 

In assessing peginterferon alfa-2b with ribavirin versus interferon alfa-2b plus 

ribavirin for the treatment of chronic HCV: 

• Sustained virologic response was significantly higher in the higher-dose 

peginterferon group (54%) than the lower-dose peginterferon group (47%) or 

interferon group (47%). 

• In patients with genotype 1 HCV, sustained virologic response was 42%, 34%, 

and 33%, in the high-dose peginterferon, low-dose peginterferon, and interferon 

groups, respectively. 

• The rate of sustained virologic response for patients with genotypes 2 or 3 was 

about 80% for all treatment groups. 

• The authors concluded that peginterferon 1.5mcg/kg per week with ribavirin was 

the most effective therapy. 

In assessing the efficacy and safety of interferon alfa-2b monotherapy compared to a 

combination of interferon alfa-2b plus ribavirin for the initial therapy of patients with 

chronic HCV infection: 

• Sustained virologic response was higher in patients on combination therapy at 

both 24 and 48 weeks versus patients on interferon monotherapy. 

• In patients with genotype 1 HCV, the best response was observed in patients 

receiving combination interferon/ribavirin therapy. 

• Histologic improvement was also more common in patients on combination 

therapy versus monotherapy. 

• Drug dosages had to be reduced more frequently in the combination group and 

more treatment discontinuations occurred in these patients. 

• The authors concluded that combination therapy with interferon and ribavirin 

was more effective than treatment with interferon alone. 

Table 11. Additional Outcomes Evidence for Aerosolized Ribavirin in the Treatment of Respiratory Syncytial Virus 

Study Sample 

Size 

Treatment/ 

Duration 

Results 

Guergueri n=41 Ribavirin 6g/300mL 

al 58 

an AM, et 

versus placebo 

Rodriguez n=42 Aerosolized ribavirin 

WJ, et al 59 versus placebo 

In assessing the effect of aerosolized ribavirin on previously healthy infants requiring 

mechanical ventilation for respiratory distress secondary to RSV: 

• There were no significant differences between ribavirin and placebo with respect to 

ventilation, length of oxygen therapy, length of stay in intensive care, and total 

duration of hospital stay. 

• Both ribavirin and normal saline placebo were well-tolerated and no deaths 

occurred during the study. 

• Ribavirin was not effective in producing significant clinical outcomes in patients 

with RSV. 

In a prospective follow-up study of children who were previously healthy, were 

premature, or who had chronic pulmonary disease: 

• More reactive airway disease, wheezing, and pneumonia was observed in the 

placebo group (n=12) than the ribavirin group (n=23): mean score 22.3 and 15.8, 

respectively (P=0.07). For all years of the study the mean score was 22 for the 

placebo group (n=11) and 16 for the ribavirin group (n=22) (P=0.10). 

• Seven out of 13 ribavirin patients had normal or mild pulmonary function test 

results versus zero of 6 placebo patients (P=0.04). 

• Weighted severity scores suggested a long-term beneficial effect of ribavirin; 

248

Jefferson 

LS, et al 60 n=13 Ribavirin 6g/300mL 

over 18 hr/day versus 

ribavirin 6g/100mL 

over 2 hr divided TID 

Edell D, n=45 Ribavirin 6g/100mL 

et al 61 over 2 hr divided TID 

versus conservative 

treatment 

Moler n=223 Ribavirin versus no 

al 62 

FW, et 

therapy 

Long CE, n=54 Ribavirin versus 

et al 63 placebo 

however, the authors stated that larger numbers should be evaluated. 

In a study to evaluate the effect of ribavirin on respiratory system mechanics in pediatric 

patients with suspected RSV requiring mechanical ventilation: 

• Authors concluded that aerosolized ribavirin in infants and young children does not 

worsen respiratory system mechanics. 

In assessing the effect of aerosolized ribavirin compared to conservative treatment for 

previously healthy infants with severe RSV: 

• Conservative treatment included oxygen, IV fluids, albuterol nebulizers, IV 

corticosteroids, and oral ranitidine. 

• During a prospective 1-year follow-up period, the ribavirin group had significantly 

fewer episodes and reduced severity of reactive airway disease compared to the 

group receiving conservative therapy. 

• The ribavirin group also had significantly fewer hospitalizations related to 

respiratory illness compared to conservative therapy (25 versus 90 days per 

100 patients per year, respectively). 

• The authors concluded that early ribavirin therapy for RSV reduced the incidence 

and severity of reactive airway disease and decreased hospitalizations related to 

respiratory illness. 

In assessing the effect of aerosolized ribavirin compared to no therapy in previously 

healthy infants with RSV-associated respiratory failure on mechanical ventilation: 

• Prospective cohort study. 

• Use of ribavirin (n=91) was associated with prolonged duration of mechanical 

ventilation (P

IX. 

Conclusions 

The efficacy of acyclovir, famciclovir, and valacyclovir against HSV and VZV infections were 

similar based on several comparative studies. The CDC guidelines suggest all three antiherpetic 

virus agents can be used for the treatment and suppression of genital herpes. The difference in 

these three agents is the dosing schedule, with newer agents offering more convenient dosing. 

Selection of one agent for the preferred drug list should provide sufficient coverage for patients 

with HSV or VZV infections. Acyclovir is the only agent with an available generic product and 

the only agent recommended by the AAP for treatment of chickenpox in patients at risk for more 

severe disease. Treatment with these agents would be considered applicable to general use in the 

population. 

The efficacy of oral ganciclovir, intravenous ganciclovir, and oral valganciclovir for the treatment 

of CMV retinitis were similar based on several comparative studies. However, oral ganciclovir is 

indicated only for maintenance therapy of CMV retinitis in patients with stable retinitis following 

appropriate induction therapy with intravenous ganciclovir. Ganciclovir capsules are the only 

generic formulation available. Cidofovir is also an effective treatment option for CMV retinitis; 

however, comparative data for cidofovir versus ganciclovir or valganciclovir are lacking. 

Nephrotoxicity, which may be irreversible, is the major adverse event limiting duration of 

cidofovir treatment in a significant number of patients. Because there are only a limited number 

of medications available for the treatment of CMV retinitis, cidofovir represents a useful 

alternative in patients who do not respond to ganciclovir or valganciclovir therapy. The treatments 

for CMV retinitis do not represent therapeutic agents applicable to general use of the population. 

Oral ribavirin is recommended in combination with peginterferon for the treatment of chronic 

HCV infection by the American Association for the Study of Liver Diseases. Rebetol ® is 

available in two formulations (capsules and oral solution) and is indicated in combination with 

either interferon alfa-2b or peginterferon alfa-2b. Copegus ® is available as a tablet and is only 

indicated in combination with peginterferon alfa-2a. Treatment of HCV is not applicable to 

general use of the population. Use of ribavirin also is dependent on the brand of interferon used as 

combination products are available. 

Adefovir, lamivudine, and interferon-alfa are all recommended as options for first-line therapy of 

chronic HBV infection. 5,6 Adefovir is also recommended for use in patients that have 

demonstrated lamivudine resistance. Lamivudine and interferon have been evaluated in other 

reviews; therefore, comparative safety and efficacy data have not been extensively covered in this 

document. However, due to the relatively few options for therapy of chronic HBV and the utility 

of adefovir in the face of lamivudine-resistance, adefovir represents a valuable therapeutic option. 

Use of these agents for HBV is not applicable to use in the general population. 

Although aerosolized ribavirin demonstrates good in vitro activity against RSV, clinical efficacy 

data have been conflicting. Due to the lack of definitive efficacy, and potential toxicities of this 

medication, ribavirin is not generally used for the treatment of RSV, and would not be considered 

general use within the population. 

Within this class, the antiherpetic agents are important for general use in the population. All brand 

antiherpetic agents in this class are comparable to each other and to the generics and OTC 

products in the class and offer no significant clinical advantage over other alternatives in general 

use. Additionally, the treatments for CMV, HCV, HBV, and RSV are not within the scope of 

general use in the population, and should be available for their indicated special 

needs/circumstances via medical justification through the prior authorization process. 


No brand antiviral nucleoside/ nucleotide is recommended for preferred status. 

250

References 

1. Corey LC. Herpes Simplex Virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and 

Practice of Infectious Diseases. 5 th ed. Philadelphia, Pa: Churchill Livingstone; 2000:1564-1575. 

2. Knodel LC. Sexually Transmitted Disease. In: Dipiro JT, Talbert RL, Yee GC, 

Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 5 th ed. 

New York, NY: McGraw-Hill; 2002:1997-2016. 

3. Whitley RJ. Varicella-Zoster Virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and 

Practice of Infectious Diseases. 5 th ed. Philadelphia, Pa: Churchill Livingstone; 2000:1580-1585. 

4. Crumpacker CS. Cytomegalovirus. In: Mandell GL, Bennett JE, Dolin R, eds. 

Principles and Practice of Infectious Diseases. 5 th ed. Philadelphia, Pa: Churchill Livingstone; 

2000:1586-1596. 

5. Lok ASF, McMahon BJ. American Association for the Study of Liver Diseases 

(AASLD) Practice Guidelines for Chronic Hepatitis B. December, 2003. Available at: 

www.aasld.org. Accessed September 20, 2004. 

6. Lok ASF, McMahon BJ. American Association for the Study of Liver Diseases 

(AASLD) practice guideline for chronic hepatitis B: update of recommendations. Hepatology. 

2004;1-5. Available at: www.aasld.org. Accessed September 20, 2004. 

7. Strader DB, Wright T, Thomas DL, Seeff LB. American Association for the Study of Liver 

Diseases (AASLD) practice guideline for diagnosis, management, and treatment of hepatitis C. 

Hepatology. 2004;1147-1171. Available at www.aasld.org. Accessed September 20, 2004. 

8. National Institutes of Health. Consensus Development Conference Statement on the Management 

of Hepatitis C: 2002. National Institutes of Health. Available at: http://consensus.nih.gov. 


9. Polak MJ. Respiratory syncytial virus (RSV): overview, treatment, and prevention strategies. 

NBIN. 2004;14(1):15-23. 

10. National Center for HIV, STD, and TB Prevention, Division of Sexually Transmitted Diseases. 

Sexually Transmitted Treatment Guidelines 2002. Centers for Disease Control and Prevention 

(CDC). Available at www.cdc.gov/mmwr. Accessed September 20, 2004. 

11. American Academy of Pediatrics (AAP). In: Pickering LK, ed. 2003 Red Book: Report of the 

Committee on Infectious Diseases. 26 th ed. Elk Grove Village, Ill: American Academy of 

Pediatrics;2003:672-686. 

12. Gnann JW Jr, Whitley RJ. Herpes zoster [clinical practice]. N Engl J Med. 2002;347(5):340-346. 

13. Zovirax [package inserts]. Research Triangle Park, NC: GlaxoSmithKline; 2003. 

14. Valtrex [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2003. 

15. Famvir [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2002. 

16. US Public Health Service and the Infectious Disease Society of America. Guidelines for 

Preventing Opportunistic Infections Among HIV Infected Persons 2002. Centers for Disease 

Control and Infection. Available at: www.cdc.gov/mmwr. Accessed September 20, 2004. 

17. Cytovene-IV, Cytovene [package insert]. Nutley, NJ: Roche Laboratories Inc; 2000. 

18. Vistide [package insert]. Foster City, Calif: Gilead Sciences, Inc.; 2000. 

19. Centers for Disease Control and Prevention, Infectious Disease Society of America, and the 

American Society of Blood and Marrow Transplantation. Guidelines for Preventing Opportunistic 

Infections Among Hematopoietic Stem Cell Transplant Recipients 2000. Available at: 

www.cdc.gov/mmwr. Accessed September 20, 2004. 

20. Valcyte [package insert]. Nutley, NJ: Roche Laboratories Inc; 2003. 

21. American Academy of Pediatrics (AAP). In: Pickering LK, ed. 2003 Red Book: Report of the 

Committee on Infectious Diseases. 26 th ed. Elk Grove Village, Ill: American Academy of 

Pediatrics;2003:523-528. 

22. Drug Facts and Comparisons. Facts and Comparisons. St. Louis, Mo; 2004. 

23. American Hospital Formulary Service, AHFS Drug Information. American Society of Health- 

System Pharmacists. Bethesda, Md; 2004. 

24. Copegus [package insert]. Nutley, NJ: Roche Laboratories Inc; 2004. 

25. Rebetol [package insert]. Kenilworth, NJ: Schering Corporation; 2003. 

26. Virazole [package insert]. Costa Mesa, Calif: Valeant Pharmaceuticals International; 2004. 

27. Hepsera [package insert]. Foster City, Calif: Gilead Sciences, Inc.; 2004. 

251

28. Hansten PD, Horn JR, ed. Drug Interactions: Analysis and Management. Facts and Comparisons 

Publishing Group. St. Louis, Mo; 2004. 

29. Shafran SD, Tyring SK, Ashton R, et al. Once, twice, or three times daily famciclovir compared 

with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, 

multicenter, double-blind clinical trial. J Clin Virol. 2004;29:248-253. 

30. Warkentin DI, Epstein JB, Campbell LM, et al. Valacyclovir versus acyclovir for HSV 

prophylaxis in neutropenic patients. Ann Pharmacother. 2002;36:1525-1531. 

31. Shen MC, Lin HH, Lee SSJ, Chen YS, Chiang PC, Liu YC. Double-blind, randomized, acyclovircontrolled, 

parallel-group trial comparing the safety and efficacy of famciclovir and acyclovir in 

patients with uncomplicated herpes zoster. J Microbiol Immunol Infect. 2004;37(2):1684-1182. 

32. Lin WR, Lin HH, Lee SSJ, et al. Comparative study of the efficacy and safety of valaciclovir 

versus acyclovir in the treatment of herpes zoster. J Microbiol Immunol Infect. 2001;34(2):138- 

142. 

33. Tyring S, Belanger R, Bezwoda W, Ljungman P, Boon R, Saltzman RL. A randomized, 

double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes 

zoster in immunocompromised patients. Cancer Invest. 2001;19(1):13-22. 

34. Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs. aciclovir in immunocompetent 

patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind trial. 

Br J Dermatol. 2001;144(4):818-824. 

35. Romanowski B, Aoki FY, Martel AY, Lavender EA, Parsons JE, Saltzman RL. Efficacy and 

safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected 

individuals. AIDS. 2000;14(9):1211-1217. 

36. Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled 

comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital 

herpes infections. Arch Dermatol. 1998;134(2):185-191. 

37. Fife KH, Barbarash RA, Rudolph T, et al. Valaciclovir versus acyclovir in the treatment of 

first-episode genital herpes infection: results of an international, multicenter, double-blind, 

randomized clinical trial. Sex Transm Dis. 1997;24(8):481-486. 

38. Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus aciclovir in patient initiated 

treatment of recurrent genital herpes: a randomized, double-blind clinical trial. Genitourin Med. 

1997;73(2):110-116. 

39. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral therapy for herpes 

zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in 

immunocompetent patients 50 years and older. Arch Fam Med. 2000;9(9):863-869. 

40. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valgancilovir vs. oral ganciclovir for 

prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 

2004;4(4):611-620. 

41. Szer J, Durrant S, Schwarer AP, et al. Oral versus intravenous ganciclovir for the prophylaxis of 

cytomegalovirus disease after allogenic bone marrow transplantation. Intern Med J. 

2004;34(3):98-101. 

42. Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction 

therapy for cytomegalovirus retinitis. N Engl J Med. 2002;346(15):1119-1126. 

43. Winston DJ, Busuttil RW. Randomized controlled trial of sequential intravenous and oral 

ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of 

cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with 

cytomegalovirus-seropositive donors. Transplant. 2004;77(2):305-308. 

44. Jabs DA. The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the 

treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: the 

ganciclovir cidofovir cytomegalovirus retinitis trial. Am J Ophthalmol. 2001;131(4):457-467. 

45. Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for peripheral 

cytomegalovirus retinitis in patients with AIDS: a randomized, controlled trial. Ann Intern Med. 

1997;126(4):257-263. 

46. Lalezari JP, Holland GN, Kramer F, et al. Randomized, controlled study of the safety and efficacy 

of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with 

AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17(4):339-344. 

47. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical 

Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the 

252

HPMPC peripheral cytomegalovirus retinitis trial: a randomized, controlled trial. Ann Intern Med. 

1997;126(4):264-274. 

48. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e 

antigen-positive chronic hepatitis B. New Engl J Med. 2003;348(9):808-816. 

49. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of 

hepatitis B e antigen-negative chronic hepatitis B. New Engl J Med. 2003;348(9):800-807. 

50. Perrillo R, Schiff E, Yoshida E, et al. Adefovir dipivoxil for the treatment of lamivudine-resistant 

hepatitis B mutants. Hepatology. 2000;32(1):129-134. 

51. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant 

hepatits B in pre- and post-liver transplantation patients. Hepatology. 2003;38(6):1419-1427. 

52. Benini F, Distefano L, Baisini O, Pigozzi MG, Lanzini A. Efficacy and tolerability of combination 

therapy with interferon-alfa plus ribavirin in patients with chronic hepatitis c virus infection: a 

single-center study in relapsers and nonresponders to previous treatment with high-dose 

interferon-alfa monotherapy. Curr Ther Res. 2003;64(3):140-150. 

53. Brau N, Rodriguez TM, Prokupek D, et al. Treatment of chronic hepatitis c in HIV/HCVcoinfection 

with interferon (alpha)-2b + full-course vs. 16-week delayed ribavirin. Hepatology. 

2004;39(4):989-998. 

54. Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with 

interferon alfa-2b plus ribavirin for treatment of HIV/HCV coinfected patients. AIDS. 

2004;18(13):27-36. 

55. Perrillo R, Rothstein KD, Rubin R, et al. Comparison of quality of life, work productivity and 

medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b 

plus ribavirin as initial treatment in patients with chronic hepatitis C. J Viral Hep. 2004;11:157- 

165. 

56. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared 

with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized 

trial. Lancet. 2002;358(9286):958-965. 

57. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with 

ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. New 

Engl J Med. 1998;339(21):1485-1492. 

58. Guerguerian AM, Gauthier M, Lebel MH, Farrell CA, Lacroix J. Ribavirin in ventilated 

respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 1999;160:829-834. 

59. Rodriguez WJ, Arrobio J, Fink R, Kim HW, Milburn C. Prospective follow-up and pulmonary 

functions form a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial 

virus bronchiolitis. Ribavirin Study Group. Arch Pediatr Adolesc Med. 1999;153(5):469-474. 

60. Jefferson LS, Coss BJA, Englund JA, Walding D, Stein F. Respiratory system mechanics in 

patients receiving aerosolized ribavirin during mechanical ventilation for suspected respiratory 

syncytial viral infection. Pediatr Pulmonol. 1999;28(2):117-124. 

61. Edell D, Khoshoo V, Ross G, Salter K. Early ribavirin treatment of bronchiolitis: effect on longterm 

respiratory morbidity. Chest. 2002;122(3):935-939. 

62. Moler FW, Steinhart CM, Ohmit SE, Stidham GL. Effectiveness of ribavirin in otherwise well 

infants with respiratory syncytial virus-associated respiratory failure. J Pediatr. 1996;128(3):422- 

428. 

63. Long CE, Voter KZ, Barker WH, Hall CB. Long term follow-up of children hospitalized with 

respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or 

placebo. Pediatr Infect Dis J. 1997;16(11):1023-1028. 

64. Grant DM, Mauskopf JA, Bell L, et al. Comparison of valacyclovir and acyclovir for the 

treatment of herpes zoster in immunocompetent patients over 50 years of age: a cost consequence 

model. Pharmacotherapy 1997 Mar-Apr;17(2):333-41. 

65. Huse DM, Schainbaum D, Kirsch, et al. Economic evaluation of famciclovir in reducing the 

duration of postherptic neuralgia. Am J Health Syst Pharm 1997 May 15;54(10):1180-4. 

253

I. Overview 



Pharmacotherapy Review of Misc. Antivirals-Foscarnet 

AHFS 081892 


Foscarnet sodium (“foscarnet”), an intravenous antiviral agent, is an organic analog of inorganic 

pyrophosphate, and is structurally unrelated to other antiviral agents. Although foscarnet was first 

synthesized in the 1920s, almost 60 years later it was found to inhibit influenza virus RNA 

polymerase. This led to investigation of foscarnet for potential activity against herpes simplex 

virus types 1 and 2 and against cytomegalovirus. 

Foscarnet was approved by the FDA in September 1991 and is currently indicated for the 

treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency 

syndrome (AIDS). Safety and efficacy of foscarnet sodium have not been established for 

treatment of other CMV infections (e.g., pneumonitis, gastroenteritis), congenital or neonatal 

CMV disease, or non-immunocompromised individuals. Foscarnet sodium is also indicated for 

the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in 

immunocompromised patients. Safety and efficacy of foscarnet sodium have not been established 

for treatment of other HSV infections (e.g., retinitis, encephalitis), congenital or neonatal HSV 

disease, or HSV in non-immunocompromised individuals. 

Foscarnet is also being investigated for treatment of cytomegalovirus disease, herpes simplex, and 

varicella-zoster infection in HIV-infected patients. Unlike ganciclovir, foscarnet is not associated 

with major myelosuppressive toxicity and does not require phosphorylation before it becomes 

activated. 1,2 

This review encompasses all dosage forms and strengths. Table 1 lists the drug included in this 

review. 

Table 1. Misc. Antivirals in this Review 


Foscarnet* Injectable 24mg/ml Foscavir 

*No Generic Available. 

II. 


Cytomegalovirus Retinitis 

Ocular complications of acquired immunodeficiency syndrome (AIDS) are common. In HIVinfected 

patients 10-20% can expect to lose their sight in one or both eyes due to CMV retinitis. 

Foscarnet sodium is used for the treatment of CMV retinitis in patients with AIDS. The World 

Health Organization (WHO) guidelines recommend ganciclovir as the drug of choice and 

foscarnet as the next line agent for treatment and maintenance therapy of CMV retinitis. Foscarnet 

can induce stabilization or improvement of ocular manifestations, but the drug is only suppressive 

against the virus. The retinitis will recur and/or progress following discontinuation of therapy and 

may progress even in continued therapy in patients with AIDS unless improvement in 

immunocompetence is achieved. Combination therapy with foscarnet sodium and ganciclovir is 

1, 2, 3 

indicated for patients who have relapsed after monotherapy with either drug. 

254

Prevention of Recurrence of Cytomegalovirus Disease 

Suppressive or maintenance therapy (secondary prophylaxis) is recommended for HIV-infected 

patients. The Prevention of Opportunistic Infections Working Group of the U.S. Public Health 

Service and the Infectious Disease Society of America (USPHS/IDSA) in adults and adolescents 

recommends IV ganciclovir or IV foscarnet as drugs of choice. The USPHS/IDSA recommends 

that secondary prophylaxis should be restarted in adults or adolescents if the CD4+T cell count 

decreases to less than 100-150/mm 3 . 

Mucocutaneous Herpes Simplex Virus Infections 

Foscarnet is used in the management of acyclovir-resistant mucocutaneous herpes simplex virus 

(HSV-1 and HSV-2) infections in immunocompromised patients. Foscarnet is used in the 

management of severe HSV infections in HIV patients when the HSV is known or suspected of 

being caused by acyclovir-resistant strains of the virus. Since acyclovir-resistant HSV are 

resistant to valacyclovir and most are also resistant to famciclovir, the US Center for Disease 

Control and Prevention (CDC) recommends foscarnet until clinical resolution is attained. 

Varicella-Zoster Infections 

Although Foscarnet use in Varicella-Zoster infections is a non-FDA-approved indication, 

foscarnet has been used in the management of acyclovir-resistant Varicella-Zoster infections in 

1, 2, 4 

patients with AIDS. 

III. 

Indications of Misc. Antivirals-Foscarnet 

Foscarnet sodium has three FDA-approved indications: CMV retinitis in patients with AIDS, 

combination therapy with ganciclovir for patients who have relapsed after monotherapy with 

either drug, and HSV infections. Although non-FDA approved indications, foscarnet has been 

used for colitis, CMV prophylaxis, esophagitis, gastroenteritis, herpes zoster, and varicella-zoster 

virus. 

Table 2. FDA-Approved Indications 4, 5 

Drug 

Approved Indications 

Foscarnet 1. CMV Retinitis 

2. Relapsed CMV Retinitis 

3. Mucocutaneous Acyclovir-Resistant HSV Infections 

IV. 

Pharmacokinetic Parameters of the Misc. Antivirals-Foscarnet 

Due to foscarnet’s poor oral bioavailability, the drug is administered by intravenous infusion. 

Foscarnet accumulates in bone and is distributed into cartilage. The foscarnet terminal half-life is 

determined by urinary excretion, was 87.5+ 41.8 hours, possibly because of release of foscarnet 

from bone. Uptake of foscarnet into the bone matrix is likely due to its structural similarity to 

phosphate. Penetration into the cerebrospinal fluid has also been observed at concentrations that 

are 10% to 50% of plasma levels. CSF penetration is increased with meningeal inflammation. It 

is unknown whether the agent crosses the placenta or is distributed into breast milk. Foscarnet is 

not metabolized in the liver. Foscarnet exhibits triphasic kinetics. In patients with normal renal 

function, the distribution and elimination half-lives are 0.4-1.4 and 3.3-6.8 hours, respectively. 

The plasma half-life can be prolonged to up to eight hours in patients with creatinine clearances of 

44-90ml/min (see Dosage). The terminal half-life is estimated at 18-88 hours. Between 79-92% 

of a dose is eliminated unchanged in the urine through glomerular filtration and tubular secretion. 

Tubular reabsorption can occur. 1, 5 

255

Foscarnet 

Foscarnet selectively 

inhibits the viralspecific 

DNA 

polymerases and 

reverse transcriptases at 

the pyrophosphatebinding 

site. This 

occurs through 

prevention of 

pyrophosphate cleavage 

from deoxynucleoside 

triphosphate and 

elongation of the viral 

DNA chain. Foscarnet 

also inhibits HIV 

reverse transcriptase 

and hepatitis B DNA 

polymerase. 

12-22% 14-17% Biotransformation 

does not occur 

Active 

Metabolit 

es 

N o 

Elimination 

urinary 

excretion 

< 28% 

unchanged 

drug 

Table 3. Pharmacokinetic Parameters of the Misc. Antivirals-Foscarnet 1, 2 

Drug Mechanism of Action Bioavailability 

Protein 

Binding 

Metabolism 

Half- 

Life 

3 

hours 

V. Drug Interactions with the Misc. Antivirals-Foscarnet 

Table 4 lists the most documented (Level 1 and 4) drug-drug interactions for foscarnet. One level 

1 interaction is documented with foscarnet. 

Table 4. Drug Interactions of the Misc. Antivirals-Foscarnet 6 


Foscarnet 

Level 1 

delayed, major, suspected 

Foscarnet and cyclosporin The risk of renal failure may be increased due to possible additive 

or synergistic nephrotoxicity. 

Level 4 

moderate, possible 

Foscarnet and quinolones The risk of seizure may be increased due to t he possible 

additive or synergistic epileptogenic activity. 

Additional less severe drug-drug interactions have been documented with foscarnet and include 

the following drugs 1, 6 : 

• Nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, IV pentamidine) - Because of 

foscarnet’s tendency to cause renal impairment, avoid the use of foscarnet in combination 

with potentially nephrotoxic drugs, unless the potential benefits outweigh the risks to the 

patient. 

• Pentamidine IV - Penicillins (Level 4) - Concomitant treatment with foscarnet and IV 

pentamidine may have caused hypocalcemia, hypomagnesemia, and nephrotoxicity. 

Toxicity associated with concomitant use of aerosolized pentamidine has not been 

reported. 

• Zidovudine – Concurrent use of foscarnet and zidovudine may be associated with a 

potentiation of anemia. 

256

1, 4, 5 

VI. Adverse Drug Events of the Misc. Antivirals-Foscarnet 

Foscarnet use is associated with a black box warning with the following important prescribing 

information. 

1, 4, 5 

Black Box Warning 

Renal Impairment is the major toxicity of foscarnet. Continual assessment of a patient’s risk, 

frequent monitoring of serum creatinine with dose adjustment for changes in renal function and 

adequate hydration with administration are imperative (see administration and dosage). 

Seizures, related to alternations in plasma minerals and electrolytes, have been associated with 

foscarnet treatment. Therefore, patients must be carefully monitored for such changes and their 

potential sequelae. Mineral and electrolyte supplementation may be required. 

Foscarnet is indicated for the use only in immunocompromised patients with CMV retinitis and 

mucocutaneous acyclovir-resistant HSV infections (see indications). 

Note 

Due to the complex nature of the disease for which foscarnet is intended, differentiating between 

drug-induced adverse reactions from manifestations of the underlying disease process, is difficult. 

GU 

Renal function alterations, including increased serum creatinine, and abnormal renal function (see 

Warnings) occur in > 5% of patients. Patients differ in degree of foscarnet-induced renal 

dysfunction (i.e., change from baseline creatinine clearance). Patients with pre-existing renal 

disease should be closely monitored for renal toxicity. Following specific dosage guidelines for 

renal impairment is imperative (see Dosage). Baseline renal impairment has been associated with 

seizures occurring during treatment with foscarnet. Toxic nephropathy and uremia are rare (

other than electrolyte imbalance that have precipitated seizures in patients receiving foscarnet 

include a low baseline absolute neutrophil count and baseline renal impairment. 

Respiratory 

Respiratory complications, such as cough and dyspnea, have been experienced by at least 5% of 

patients receiving foscarnet. More serious but less frequently reported effects include pneumonia, 

pulmonary infiltration, pneumothorax, and hemoptysis (1-5%). Pulmonary hemorrhage is rare 

(

1, 2, 4 

VII. Dosing and Administration of the Misc. Antivirals-Foscarnet 

Table 6. Dosing and Administration for Foscarnet 


Foscarnet 

Sodium 

Foscarnet 

solution for 

injection 

24mg/ml 

Caution: 

Do not administer by rapid or bolus IV injection. Toxicity may be increased as a result of 

excessive plasma levels. Take care to avoid unintentional overdose; carefully control the 

rate of infusion by using an infusion pump. In spite of the use of an infusion pump, 

overdoses have occurred. 

Hydration: 

Hydration may reduce the risk of nephrotoxicity. It is recommended that 750 to 1000ml of 

normal saline or 5% dextrose solution should be given prior to the first infusion of foscarnet 

to establish diuresis. With subsequent infusions, 750 to 1000ml of hydration fluid should be 

given with 90 to 120mg/kg of foscarnet and 500ml with 40 to 60mg/kg of foscarnet. 

Hydration fluid may need to be decreased if clinically warranted. After the first dose, the 

hydration fluid should be administered concurrently with each infusion of foscarnet. 

Administration: 

Administer by controlled IV infusion, either by using a central venous line or a peripheral 

vein. The standard 24mg/ml solution may be used without dilution when using a central 

venous catheter for infusion. When a peripheral vein catheter is used, dilute the 24mg/ml 

solution to 12mg/ml with 5% dextrose in water or with a normal saline solution prior to 

administration to avoid local irritation of peripheral veins. Because the dose is calculated on 

the basis of body weight, it may be desirable to remove and discard any unneeded quantity 

from the bottle before starting with the infusion to avoid overdosage. 

Induction treatment: 

CMV retinitis: 

The recommended initial dose for patients with normal renal function is either 90mg/kg (1.5- 

to 2-hour infusion) every 12 hours or 60mg/kg over a minimum of one hour every eight 

hours for 2 to 3 weeks depending on clinical response. 

HSV infections: 

The recommended initial dose for acyclovir-resistant HSV patients with normal renal 

function is 40mg/kg (minimum 1 hour infusion) either every 8 or 12 hours for 2 to 3 weeks 

or until healed. 

An infusion pump must be used to control the rate of infusion. Adequate hydration is 

recommended to establish diuresis, both prior to and during treatment to minimize renal 

toxicity, provided there are no clinical contraindications. 

Maintenance treatment: 

90 to 120mg/kg/day (individualized for renal function) given as an IV infusion over two 

hours. Because the superiority of the 120mg/kg/day has not been established in controlled 

trials and given the likely relationship of higher plasma foscarnet levels to toxicity, it is 

recommended that most patients be started on maintenance treatment with a dose of 

90mg/kg/day. Escalation to 120mg/kg/day may be considered should early reinduction be 

required because of retinitis progression. Some patients who show excellent tolerance to 

foscarnet may benefit from initiation of maintenance treatment at 120mg/kg/day earlier in 

their treatment. An infusion pump must be used to control the rate of infusion with all doses. 

Again, hydration to establish diuresis both prior to and during treatment is recommended to 

minimize renal toxicity. 

Patients who experience progression of retinitis while receiving maintenance therapy may be 

retreated with the induction and maintenance regimens given above. 

259


1, 4, 5 

Table 7a. Special Dosing Considerations for the Misc. Antivirals-Foscarnet 

Drug Renal Dosing Pediatric Use Pregnancy 

Category 

Foscarnet 


Use with caution in patients with 

abnormal renal function because reduced 

plasma clearance of foscarnet will result 

in elevated plasma levels. In addition, 

foscarnet has the potential to further 

impair renal function. Safety and efficacy 

data for patients with baseline serum 

creatinine levels> 2.8mg/dL or measured 

24-hour creatinine clearances < 50ml/min 

are limited. Carefully monitor renal 

function at baseline and during induction 

and maintenance therapy with appropriate 

dose adjustments. If CCl falls below the 

limits of the dosing nomograms 

(0.4ml/min/kg) during therapy, 

discontinue foscarnet and monitor the 

patient daily until resolution of renal 

impairment is ensured. 

The safety and 

effectiveness in 

pediatric 

patients has not 

been 

established. 

C 

Can Drug Be 

Crushed/Stability 

At a concentration of 

12mg/ml in normal 

saline solution, 

foscarnet is stable for 

30days a 5 o C 

Dose adjustment: 

Individualize foscarnet dosing according 

to the patient's renal function status. 

Refer to table 7b for recommended doses 

and adjust the dose as indicated. 

1, 4, 5 

Table 7b. Foscarnet Renal Impairment Dosing-Induction 

Foscarnet Dosing Guide Based on CCl for Induction 

HSV: Equivalent to 

CMV: Equivalent to 

CCl 

(ml/min/kg) 

40mg/kg q 12 

hr 

40mg/kg q 8 

hr 

60mg/kg q 8 

hr 

90mg/kg q 12 

hr 

> 1.4 40 q 12 hr 40 q 8 hr 60 q 8 hr 90 q 12 hr 

> 1 to 1.4 30 q 12 hr 30 q 8 hr 45 q 8 hr 70 q 12 hr 

> 0.8 to 1 20 q 12 hr 35 q 12 hr 50 q 12 hr 50 q 12 hr 

> 0.6 to 0.8 35 q 24 hr 25 q 12 hr 40 q 12 hr 80 q 24 hr 



< 0.4 Not 

Not 

Not 

Not 

recommended recommended recommended recommended 

260

Table 7c. Foscarnet Renal Impairment Dosing-Maintenance 

Foscarnet Dosing Guide Based on Ccr for 

Maintenance 

CMV: Equivalent to 

90mg/kg/day 120mg/kg/day 

CCl 

(ml/min/kg) 

> 1.4 90 q 24 hr 120 q 24 hr 

> 1 to 1.4 70 q 24 hr 90 q 24 hr 

> 0.8 to 1 50 q 24 hr 65 q 24 hr 

> 0.6 to 0.8 80 q 48 hr 105 q 48 hr 

> 0.5 to 0.6 60 q 48 hr 80 q 48 hr 

> 0.4 to 0.5 50 q 48 hr 65 q 48 hr 

< 0.4 Not 

Not 

recommended recommended 

VIII. 

Comparative Effectiveness of the Misc. Antivirals-Foscarnet 

Table 8 describes clinical studies that have recently looked at the efficacy and place-in-therapy of 

foscarnet. 

Table 8. Additional Outcomes Evidence for Foscarnet 


Duration 

A randomized, 


comparing 

ganciclovir to 

ganciclovir plus 

foscarnet ( each 

at half dose) for 

preemptive 

therapy of 

cytomegalovirus 

infection in 

transplant 

recipients. 7 n=48 Full-dose ganciclovir 

(5mg/kg IV twice daily) 

versus half-dose 

ganciclovir(5mg/kg IV 

once daily) and halfdose 

foscarnet(90mg/kg 

IV once daily/ 

14 days 

261 

Results 

The goal of this randomized controlled trail was to determine the effectiveness 

and safety of full-dose ganciclovir (5mg/kg IV twice daily) versus half-dose 

ganciclovir (5mg/kg IV once daily) and half-dose foscarnet (90mg/kg IV once 

daily): 

• In the ganciclovir arm, 17 of the 24 patients reached the endpoint of being 

CMV negative by PCR within 14 days of therapy. 

• The half-dose ganciclovir and half-dose foscarnet arm, 12 of the 24 patients 

reached the endpoint of being CMV negative by PCR within 14 days of 

therapy. 

• Toxicity was greater in the combination therapy arm. 

• Summary: The study did not support the synergistic effect of ganciclovir 

plus foscarnet in vivo. 

n=48 Foscarnet versus 

Treatment of 

In examining the clinical effectiveness of the two different antivirals for 

randomized 

• Further evidence of CMV disease was seen in 35% of patients during 

comparison. 8 followup; time to progression was not significantly different between 

AIDS-associated 


ganciclovir infection with CMV, in terms visual analog score of symptoms, endoscopic 

appearances, histologic inflammation, and number of CMV inclusions: 


• In each treatment group, 73% has good clinical response. 

infection with 

foscarnet and 

ganciclovir: a 

• Foscarnet treated group showed 83% response and Ganciclovir treated 

group showed 85% response by endoscopy; Inclusion bodies disappeared 

from follow-up biopsies in 73% of these. 

recipients. 

• Summary: Both ganciclovir and foscarnet are effective first line agents for 

gastrointestinal CMV infection. Maintenance therapy does not prevent 

progression of disease. 

Combination n=279 Three therapeutic In examining the mortality, retinitis progression, visual acuity, visual fields, and

foscarnet and 

ganciclovir 

therapy vs 

monotherapy for 

the treatment of 

relapsed 


retinitis in 

patients with 

AIDS. The 


Retreatment 

Trial. The Studies 

of Ocular 

complication of 

AIDS Research 

Group in 

Collaboration 

with the AIDS 

Clinical Trials 

Group. 9 

regimens: 

* foscarnet group: 

induction with foscarnet 

at 90mg/kg IV q 12 hr 

for 2 weeks, followed 

by a maintenance dose 

of 120mg/kg per day 

* ganciclovir group: 

induction with 

ganciclovir at 5mg/kg 

IV q 12 hr for two 

weeks followed by 

maintenance at 

10mg/kg per day 

* continuation of 

previous maintenance 

therapy plus induction 

with the other drug 

(ganciclovir or 

foscarnet) for two 

weeks followed by 

maintenance therapy 

with both drugs 

(ganciclovir 5mg/kg per 

day and foscarnet at 

90mg/kg per day. 

morbidity: 

• The mortality rate was similar among the three groups: foscarnet group 8.4 

months, ganciclovir group 9.0 months, and combination therapy group 8.6 

months (P=.89). 

• Retinitis progression (determined by the Fundus Photograph Reading 

Center revealed that the combination therapy was the most effective 

regimen for controlling the retinitis. The median time to regression: 

foscarnet group 1.3 months, ganciclovir group 2.0 months, and combination 

therapy group 4.3 months (P=.001). 

• No difference was seen on the visual acuity outcomes. 

• The rates of visual field loss were: foscarnet group 28 degrees per month, 

ganciclovir group 18 degrees per month, and combination therapy group 16 

degrees per month (P=.009). 

• Rates of increased retinal area involved by CMV were as follows: foscarnet 

group 2.47% per month, ganciclovir group 1.4% per month, and 

combination therapy group 1.19% per month (P=.009). 

• Side effects were similar, but the combination group had the greatest 

negative impact of treatment on the quality of life measure. 

• Summary: For patients with AIDS and CMV retinitis whose retinitis has 

relapsed and can tolerate both drugs, combination therapy appears to be the 

most effective therapy to control CMV retinitis. 

Foscarnet vs 

ganciclovir for 


(CMV) 

antigenemia after 

allogenic 

hemopoietic stem 

cell 


(HSCT): a 

randomized 

study 10 n=39 15 days The goal of this trial was designed to compare foscarnet with ganciclovir as preemptive 

therapy for CMV infection in patients undergoing hemopoitic stem cell 

transplantation. Patients were randomized to receive foscarnet 90mg/kg q 12h vs 

ganciclovir 5mg/kg q12h for 15 days at the time of development of CMV Agemia. 

The study was designed to determine outcome of CMVAg-emia, 

progression to CMV disease and side effects of treatment. Increments of serum 

creatinine in the foscarnet group and cytopenia in the ganciclovir group were 

controlled by reducing the administered dose. 

• Clearance of CMVAg-emia was faster in the foscarnet group. 

• Failures of treatment occurred in 3/20 patients in foscarnet group vs 8/19 

patients in ganciclovir group. 

• Summary: Foscarnet and ganciclovir are effective for pre-emptive therapy 

of CMVAg-emia. Side effects can be managed with appropriate dose 

reduction. 

Foscarnet 

n=26 - Mucocutaneous herpes simplex virus in 26 patients was studied after patients 

mucocutaneous 

• Cessation of viral shedding was noted in all of the 11 patients that were 

herpes simplex 

recultured. 

virus infection in 

• The 14 patients that received vidarabine for acyclovir resistant HSV before 

26 AIDS patients: 

the foscarnet therapy did not see their HSV resolve. 

preliminary data 11 

treatment of 

received foscarnet. 

acyclovirresistant 

• Clinical response was noted in 81% of patients 

• Complete reepithelialization of HSV lesions occurred in 73% of 

patients. 

In vitro 


study of herpes 

simplex virus 

acyclovir and 

foscarnet. Are 

routine 


studies 

necessary 12 n=68 - Objective of study was to determine the prevalence of resistance of herpes 

simplex virus to acyclovir and foscarnet. 

• An in vitro susceptibility study of HSV strains isolated from HIV –infected 

and non-HIV infected patients was conducted by means of qualitative 

screening. 

• Results included investigating 84 HSV strains, 49 HIV-infected patients 

and 19 control patients. No strains in the control group were resistant to 

acyclovir. In HIV-infected patients one acyclovir resistant strain was 

to 

detected and one moderately resistant to acyclovir strain was detected. The 

moderately resistant strain had good response to acyclovir treatment. No 

resistance to foscarnet was detected. 

• Summary: Percentages to HSV strains resistant to acyclovir is low and 

resistance to foscarnet was not detected. Study suggests that routine in-vitro 

susceptibility testing of antiviral drugs used against HSV does not seem to 

262

e necessary. 


Dose Simplification: Since foscarnet is only available in a single formulation, there isn’t another 

agent or dosage formulation for which it can be compared to for dose simplification. Therefore, 

dose simplification does not apply to this particular class. 

Stable Therapy: Limited clinical data is available regarding changing from one antiviral agent 

for CMV to another agent, and the impact on the outcome of the disease. One study by Flores- 

Aguilar M et al. looked at the treatment of clinically resistant CMV retinitis. 13 In a study group of 

100 patients, 11 developed clinically resistant retinitis, despite at least eight weeks of induction 

doses of either foscarnet or ganciclovir. Therapeutic interventions for resistant infections included 

continuing high dose of the same antiviral drug, changing to an alternative antiviral agent, or 

combining antiviral therapy with foscarnet and ganciclovir. The use of combination therapy with 

foscarnet and ganciclovir was effective in halting progession of retinitis in three (75%) of four 

patients receiving combination therapy. 

Impact on Physician Visits: Not applicable. 

IX. 

Conclusions 

Use of foscarnet should be reserved for approved infections or infections resistant to other 

therapies. Use is likely limited to hospitalized patients, where intravenous therapy can be given 

and monitored appropriately. Because of the black box warning associated with foscarnet use, and 

the fact that the drug has limited indications, use of foscarnet is not applicable to the general 

population. Foscarnet should be available for such special needs/circumstances that require 

medical justification through the prior authorization program. 



use. 


No brand of foscarnet is recommended for preferred status. 

263

References 

1. Clinical Pharmacology, 2004. Available on-line at: www.cp.gsm.com. Accessed September 

2004. 



3. World Health Organization. WHO essential Medicines Library. WHO practical guidelines. 2 nd 

edition. Available at: www.who.int/emc. Accessed September 20, 2004. 

4. Astra-Zeneca. Foscavir package insert 



7. Mattes FM, Hainworth EG, Geretti AM, et al. A randomized, controlled trail comparing 

ganciclovir to ganciclovir plus foscarnet (each at half dose) for preemptive therapy of 

cytomegalovirus infection in transplant recipients. J Infect Dis. 2004 Apr;189(8): 1355-61. 

8. Chelsa and Westminister Hospital. Treatment of AIDS-associated gastrointestinal 

cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison. J Infect Dis. 

1995 Sept;172(3):622-8. 

9. No authors listed. Combination foscarnet and ganciclovir therapy vs monotherapy for the 

treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus 

Retreatment Trial. The Studies of Ocular complication of AIDS Research Group in Collaboration 

with the AIDS Clinical Trials Group. Arch ophthalmol. 1996 Jan;114(1):23-33. 

10. Moretti S, Zikos P, Van Lint MT et al. Foscarnet vs ganciclovir for Cytomegalovirus (CMV) 

antigenemia after allogenic hemopoietic stem cell transplantation (HSCT): a randomized study. 

Bone Marrow Transplant. 1998 Jul;22(2):175-80. 

11. Safrin S, Assaykeen T, Follansbee S, et al. Foscarnet treatment of acyclovir-resistant 

mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. J Infect Dis. 

1990 Jun;161(6):1078-84. 

12. Losada I, Canizares A, Hellin T, et al. In vitro susceptibility study of herpes simplex virus to 

acyclovir and foscarnet. Are routine susceptibility studies necessary. Enferm Infecc Microbiol 

Clin.2002 Jan;20(1): 25-7. 

13. Flores-Aguilar M, Kuppermann BD, Quiceno JI, et al. Pathophysiology and treatment of 

clinically resistant cytomegalovirus retinitis. Ophthalmology 1993 Jul;100(7):1022-31. 

264



Pharmacotherapy Review of the Amebicides 

AHFS 083004 


I. Overview 

Amebiasis is a parasitic infection caused by the protozoon Entamoeba histolytica (E. histolytica). 

In the United States and other developed countries, infection occurs primarily in immigrants from 

underdeveloped regions and travelers returning from underdeveloped regions. Institutionalized 

individuals (particularly the mentally retarded), homosexual males, and immunosuppressed 

individuals are also at high risk for infection. 1 Other Entamoeba strains that are morphologically 

identical to E. histolytica, but are nonpathogenic are Entamoeba dispar, Entamoeba coli, and 

Entamoeba hartmanni. 

Globally, amebiasis affects approximately 50 million people annually, with the highest prevalence 

being in the Indian subcontinent, southern and western Africa, the Far East, South America, and 

Central America. Globally, amebiasis causes nearly 100,000 deaths annually and is the third 

leading parasitic cause of death. 2 In the United States, prevalence of Entamoeba infection is 

approximately 4%, although only 10% of persons who are infected have symptomatic disease. 

Asymptomatic cyst carriers can be treated with the same drug regimen as those who have 

symptomatic intestinal amebiasis. 

The life cycle of E. histolytica involves two forms - cysts and trophozoites. Outside of the human 

body, E. histolytica can only survive in cyst form, and is therefore the form in which the organism 

is transmitted through contaminated feces, water, or food. Once inside the small intestine, the 

trophozoite is released from the cyst and becomes the motile (pseudopod) form. It may then 

invade the mucosal cells of the colon and produce ulcerative lesions and in rare cases, invade sites 

outside of the colon. However, only 10% of infected persons present with symptoms. In 90% of 

cases, the trophozoite will re-encyst due to unfavorable conditions in the colon and the infection 

will become asymptomatic. Re-encysted trophozoites may either stay in the bowel, or be released 

in the stool, where they can be transmitted to other humans. 

E. histolytica infections can remain inside the intestine or they can spread to include abscesses of 

the perineum, genitalia, pericardium, peritoneum, liver, lungs, and the brain in rare cases. Clinical 

manifestations of intestinal infection range from vague complaints of abdominal discomfort and 

malaise to severe abdominal cramps, flatulence, and bloody diarrhea with mucus. 1 Fever occurs 

only in 10-30% of patients. Additional, but uncommon manifestations of amebic colitis include 

fulminant colitis, ameboma, rectal fistulas, or vaginal fistulas. E. histolytica infections can spread 

to the liver via portal blood and cause liver abscess. Right upper quadrant pain, hepatomegaly, 

and liver tenderness with referred pain to the right or left shoulder usually suggests amebic liver 

abscess. 1 Liver abscesses that are located in the right lobe can spread to the lungs and pleura. 1 

Amebic pericarditis and amebic peritonitis are associated with left liver lobe rupture. The onset of 

cerebral amebiasis is abrupt and usually leads to death within 12-72 hours. 

Diagnosis of amebiasis may include microscopy, stool culture, antigen detection, serology, and 

molecular probes. 2 Microscopy and stool culture remain the most common methods of diagnosis 

in endemic areas, however it may be difficult to make a specific diagnosis since E. histolytica 

cannot be distinguished from E. dispar. Serum antibody detection is most useful in distinguishing 

between E. histolytica and other organisms as well as diagnosing extraintestinal disease where 

organisms may not be present in stool samples and is most useful in non-endemic areas. 

Colonoscopy or sigmoidoscopy may be used to diagnose amebic colitis in order to observe amebic 

ulcers and allow for biopsy or aspiration. Imaging studies such as chest radiography, ultrasound, 

CT scans, or MRI are useful in diagnosing extraintestinal disease. Another challenge of 

diagnosing amebiasis is to distinguish it from other gastrointestinal diseases, such as bacterial 

dysentery, inflammatory bowel disease, or ischemic colitis. 

265


review. 

Table 1. Amebicides in this Review 


Paromomycin Sulfate Oral Capsule *Humatin 

**Iodoquinol Oral Tablet, Powder Yodoxin, Diquinol 

Tinidazole Oral Tablet Tindamax 1 


**At this time, there are no active iodoquinol products in the Alabama Medicaid drug file database. 

1 Tindamax (tinidazole), a new drug, was approved in the summer of 2004. Per Alabama Medicaid P & T policy, tinidazole 

is eligible for review after it has been commercially available for at least 6 months. Tinidazole will be reviewed at a future 

time. 

II. 


Paromomycin is indicated for the treatment of acute and chronic intestinal amebiasis and is also 

indicated as adjunctive therapy in the management of hepatic coma. 4 Paromomycin has a 

spectrum of activity is similar to that of neomycin, but the drug is considered a luminal or contact 

amebicide. Paromomycin is not absorbed into systemic circulation, so its use is limited only to 

infection within the intestine (luminal infection). In the case of extraintestinal infection, a course 

of paromomycin will follow a course of another anti-infective agent, such as metronidazole. 

Iodoquinol is indicated for the treatment of intestinal amebiasis. Like paromomycin, iodoquinol is 

not absorbed into systemic circulation, so its use is limited only to infection within the intestine 

(luminal infection). In the case of extraintestinal infection, a course of iodoquinol will follow a 

course of another anti-infective agent, such as metronidazole. The exact mechanism of action of 

iodoquinol is unknown, but the drug is active against both the trophozoite and cyst forms of E. 

histolytica. 4 

The Centers for Disease Control and Prevention have instituted recommendations for preventing 

opportunistic infections among immunosuppressed patients such as those infected with human 

immunodeficiency virus (HIV) and hematopoietic stem cell transplant recipients (HSCT). 

Specifically, the 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in 

persons infected with HIV recommend that patients avoid sexual practices that might result in oral 

exposure to feces to reduce the risk for intestinal infections. 6 In addition, patients should take 

precautions when traveling to reduce the risk of food-borne and waterborne infections. 

Recommendations of the CDC concerning HSCT recipients are very specific in regards to travel 

safety, food safety practices, and safe sexual practices in the prevention of all types of 

opportunistic infections. 

Another luminal agent, diloxanide furoate, is frequently mentioned in the literature available on 

the treatment of amebiasis, but is not readily available in the United States, and is therefore not 

mentioned in this review. 

No additional guidelines were found on the use of amebicides. 

266

III. 

Comparative Indications of the Amebicide Antibiotics 

Table 2 lists indications for the two drugs in the amebicide class. Paromomycin has two FDA-approved indications: acute and chronic amebiasis and as 

adjunctive therapy in the treatment of hepatic coma. Iodoquinol has one FDA-approved use for the treatment of acute and chronic intestinal amebiasis. 

Table 2. Indications for the Amebicides 4, 8 

Drug Entamoeba histolytica Dientamoeba fragilis 

Diphyllobothrium latum 

Taenia saginata 

Taenia solium 

Dipylidium caninum 

Hymenolepis nana 

Paromomycin 

Iodoquinol 

✔ 

Acute and chronic 

intestinal amebiasis. Not 

effective alone for the 

treatment of extraintestinal 

amebiasis (i.e. liver 

abscess), where it must be 

combined with an 

absorbable anti-infective 

such as metronidazole. 

✔ 

Acute and chronic 

intestinal amebiasis. Not 

effective alone for the 

treatment of extraintestinal 

amebiasis (i.e. liver 

abscess), where it must be 

combined with an 

absorbable anti-infective 

such as metronidazole. 

✔ * 

Unlabeled use as an 

alternative agent in the 

treatment of certain 

tapeworm infections. 

Giardia lamblia 

✔ * * 



treatment of giardiasis. 

L. donovani 

L. braziliensis 

✔ * * * 



treatment of visceral 

and cutaneous 

leishmaniasis. 

Cryptosporidium muris 

✔ * * * * 



treatment of 

cryptosporidiosis in 

immunocompromised 

patients. 

Hepatic coma 

- - - - - 

✔ 

Indicated as 

adjunctive 

therapy in 

hepatic coma. 

* 

Uncontrolled trials suggest that paromomycin may be effective in the treatment of tapeworm infestations. 5 

** 

Paromomycin can be considered an alternative treatment of giardiasis, particularly in pregnant patients. 5 

*** 

There is evidence that paromomycin may be effective in the treatment of certain forms of leishmaniasis. 5 

**** 

There are favorable but inconsistent reports that paromomycin is useful in the treatment of cryptosporidiosis. 5

IV. 


Table 4 lists the pharmacokinetic parameters and mechanisms of action of the amebicide 

antibiotics. 

Table 3. Pharmacokinetic Parameters of the Amebicide Agents 4, 8 


Binding 

Paromomycin 

Iodoquinol 

An amebicidal and 

antibacterial aminoglycoside. 

Antibacterial activity closely 

parallels neomycin. 

Aminoglycosides acts by 

irreversibly binding to the 30S 

subunit of bacterial ribosomes, 

blocking the recognition step 

in protein synthesis and 

causing misreading of the 

genetic code. The ribosomes 

separate from messenger 

RNA, which causes death of 

the cell. 

Amebicidal against 

trophozoite and cyst forms of 

E. histolytica. Exact 

mechanism of action is 

unknown. 

Poorly absorbed. 

Almost 100% of the 

drug is excreted in 

the stool. 


(~8%). Eliminated in 

the stool. Less than 

10% recovered in the 

urine mostly as 

glucuronides. 


Metabolites 

Elimination 

- - - Biliary;

VI. 

Adverse Drug Events of the Amebicidal Agents 

The most common adverse reactions to paromomycin are nausea, abdominal cramps, and diarrhea 

at does greater than 3gm daily. 4 Inadvertent absorption through ulcerative bowel lesions may 

result in eighth cranial nerve damage (ototoxicity) and renal damage. 4 Prolonged or repeated use 

of paromomycin may result in bacterial or fungal overgrowth leading to secondary infections. 4 

Paromomycin is contraindicated in patients with a history of previous sensitivity reactions and in 

patients with intestinal obstruction. 8 

The most common adverse reactions to iodoquinol include skin eruptions, urticaria, pruritus, 

nausea, vomiting, abdominal cramps, diarrhea, and pruritus ani. 4 Fever, chills, headache, vertigo, 

and thyroid enlargement have also been reported. 4 Prolonged high dosage therapy has been 

associated with optic neuritis, optic atrophy, and peripheral neuropathy and is therefore why the 

drug is not indicated for the treatment of chronic diarrhea. 4 Iodoquinol is contraindicated in 

patients with previous history of sensitivity to iodine and 8-hydroxyquinolines (i.e. iodoquinol, 

iodochlorhydroxyquin) and in patients with hepatic damage. 10 

Specific percentages of adverse events were not available for the amebicidal agents. 

4, 5, 10 

Table 5. Common Adverse Events Reported for the Amebicidal Agents 

Adverse Event Paromomycin Iodoquinol 


Malaise 


Edema 

Hypotension 

Hypertension 




Diarrhea 

Pruritis ani 



Chills 

Fever 

Headache 

Optic neuritis 

Optic atrophy 

Peripheral neuropathy 

Ototoxicity 

- - 

- - 

b 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

- 


Skin eruptions 

Pruritus 

Urticaria 

- 

- 

- 

b 

b 

b 

Renal 

- - 

Renal damage 

Other 

Thyroid enlargement - b 


269

VII. 

Dosing and Administration for the Amebicidal Agents 

Table 6. Dosing for the Amebicidal Agents 4, 5 


Paromomycin 

Sulfate 

250mg oral capsule Intestinal Amebiasis (symptomatic luminal infection or asymptomatic cystcarriers) 

Adults and children: 25 to 35mg/kg/day in 3 divided doses with meals for 5 to 

10 days. 

Hepatic coma 

Adults: 4gm daily in divided doses administered at regular intervals for 5 to 6 

days. 

Iodoquinol 

210mg oral tablet, 

650mg oral tablet 

Other Notes 

• Since paromomycin is not well absorbed, patients with extraintestinal 

amebiasis should be treated with another anti-infective first (such as 

metronidazole) to eradicate extraintestinal infection, followed by a 

course of paromomycin to eradicate luminal infection. 

• Asymptomatic cyst carriers can be treated like patients with 

symptomatic infection to eradicate cysts which could eventually be 

passed on and infect others. Patients infected with non-pathologic 

strains of Entamoeba, such as E. dispar, do not need to be treated. 

• Unlabeled uses: Dientamoeba fragilis (25 to 30 mg/kg/day in 3 doses 

for 7 days). Diphyllobothrium latum, Taenia saginata, Taenia solium, 

and Dipylidium caninum (adults: 1gm every 15 minutes for 4 doses; 

pediatric: 11mg/kg every 15 minutes for 4 doses). Hymenolepis nana 

(45mg/kg/day for 5 to 7 days). 

Intestinal Amebiasis (symptomatic luminal infection or asymptomatic cystcarriers) 

Adults: 650mg 3 times daily after meals for 20 days. 

Children: 40mg/kg daily (maximum 650mg per dose) in 3 divided doses for 20 

days. Do not exceed 1.95gm in 24 hours for 20 days. 

Other Notes 

• Since iodoquinol is not well absorbed, patients with extraintestinal 

amebiasis should be treated with another anti-infective first (such as 

metronidazole) to eradicate extraintestinal infection, followed by a 

course of iodoquinol to eradicate luminal infection 

• Asymptomatic cyst carriers can be treated like patients with 

symptomatic infection to eradicate cysts which could eventually be 

passed on and infect others. Patients infected with non-pathologic 

strains of Entamoeba, such as E. dispar, do not need to be treated. 

270


5, 16 

Table 7. Special Dosing Considerations for the Amebicidal Agents 

Drug Renal Hepatic Pediatric Use 

Paromomycin 

Sulfate 

Dosing 

Dosing 

No No Same dosing schedule as 

adults. 

Iodoquinol No No Although dosing in children is 

well established, children may 

be more susceptible to the side 

effects of optic atrophy, optic 

neuritis, and peripheral 

neuropathy, especially with 

prolonged high-dose therapy. 

Pregnancy 

Category 

C - Limited 

information is 

available, but the 

drug is not well 

absorbed, therefore 

teratogenic effect is 

minimized. 

C - Safety for use 

in pregnancy has 

not been 

established. 

Can Drug Be Crushed 

Information regarding the 

opening of paromomycin sulfate 

capsules is not available, per the 

manufacturer. 

Tablets may be crushed and 

mixed with food such as 

applesauce or chocolate syrup if 

unable to swallow. 

271

VIII. 

Comparative Effectiveness of the Amebicidal Agents 

In a search of Medline and Ovid, no recent studies were found comparing the efficacy of 

paromomycin versus iodoquinol. Both agents are accepted as the standard treatment of luminal 

amebic infections. Most recent studies evaluate the effectiveness of paromomycin in treating 

conditions other than intestinal amebiasis, such as leishmaniasis, giardiasis, trichomoniasis, 

tapeworm infestation, and cryptosporidiosis in HIV-positive patients, which are currently 

unlabeled uses for paromomycin. A few of the larger studies are described in Table 8. Very small 

studies and case reports are not listed. In addition, a few microbiological studies were found 

suggesting the possibility of E. histolytica resistance to current treatment regimens. A summary of 

the most pertinent one can be found in Table 8. 

Sullam, N=114 7 day treatment with 

al. 12 intestinal amebiasis 

PM, et 

paromomycin for 

White 

AC, et 

al. 13 n=10 Paromomycin 25- 


placebo for 14 days 

for cryptosporidiosis 

Hewitt 

RG, et 

al. 14 n=35 Paromomycin 500mg 

4 times daily for 42 

days vs. placebo for 

21 days followed by 

paromomycin 500mg 

4 times daily for 21 

days for 

cryptosporidiosis 

El-on J, et 

al. 15 n=39 Ointment containing 

15% paromomycin 

and 12% or 5% 

methylbenzothonium 

chloride 

Table 8. Additional Outcomes Evidence for the Amebicides 


Results 

Duration 

Samuelso 

n, et al. 11 - - Three sets of experiments were performed to better characterize the multi-drug 

resistant phenotype of the emetine-resistant amebae. Emetine is the oldest drug used 

to treat amebic infection. Mutant amoebae were cross-resistant to certain drugs used 

to treat luminal amebiasis (iodoquinol), but not those used to treat systemic infection. 

This, combined with isolated reports of failed treatment courses, suggest that drugresistant 

amebae may develop over time, which warrants further investigation. 

114 homosexual men were evaluated who had mild-to-moderate intestinal amebiasis. 

All patients received 25-35 mg/kg daily in three divided doses for 7 days. The results: 

• Of the 80 patients with gastrointestinal complaints at the onset of therapy, 

55 (80%) of 69 were asymptomatic within 4 to 6 weeks after completion of 

treatment and 11 were lost to follow-up. 

• Paromomycin produced long-term eradication of intestinal E. histolytica 

infection in 92% of all men evaluated. The rate of microbiologic cure 

among patients with symptoms at onset of therapy was comparable to that 

of asymptomatic individuals. 

• Paromomycin was well tolerated, with mild diarrhea during therapy the 

only frequent adverse effect (67%). 

In a double-blind trial, 10 patients with AIDS and cryptosporidiosis were placed on 

either paromomycin 25-30mg/kg/day for 14 days and then switched to placebo, or 

vice versa: 

• During the paromomycin treatment phase, oocyst excretion and stool 

frequency both decreased more in the treatment phase than in the placebo 

phase (P


Dose Simplification: In most cases, the amebicidal agents in this class are given for a brief 

duration (acute use). Long-term high dose therapy is not recommended for either of the two drugs 

in this class. Therefore, research into dose simplification within this class is not applicable. 

Stable Therapy: Limited clinical data is available on resistance to the amebicidal medications in 

humans. Most of the articles available were from a microbiological standpoint suggesting that 

resistance is a potential problem that warrants closer examination. Although the clinical evidence 

does not suggest problems with resistance patterns in the U.S, resistance to the amebicidal drugs 

should be considered in patients who have previously been treated for amebic infections and in 

those with apparent treatment failure. 

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal clinical 

literature relevant to use of the amebicides and their impact on physician visits. 

IX. 

Conclusions 

Parasitic infections caused by the organism E. histolytica present in three ways: asymptomatic 

intestinal infection, symptomatic intestinal infection, and extraintestinal infection. Asymptomatic 

intestinal infection and mild symptomatic intestinal infection are both treated with a course of a 

luminal amebicide (paramomycin or iodoquinol). At this time, iodoquinol is not available in the 

Alabama Medicaid drug file. Extraintestinal infection (outside of the intestinal lumen) and severe 

intestinal infection (amebic dysentery) must be treated with a tissue agent. 2 Metronidazole is the 

drug of choice, followed by a course of one of the luminal agents to eradicate organisms still 

remaining in the intestine. 

No studies were found that compared the efficacy of paromomycin and iodoquinol directly in the 

treatment of intestinal amebiasis. Both are accepted as standard, equally efficacious treatment in 

patients with asymptomatic intestinal infection and mild symptomatic intestinal infection. There 

is more information available about the safety of paromomycin in the use of pregnant women, 

although both drugs belong to pregnancy category C. 2, 5 



use. 


No brand amebicide is recommended for preferred status. 

273

References 

1. Anandan JV. Parasitic Diseases. In: Pharmacotherapy. A Pathophysiologic Approach. Dipiro 

JT, Talbert RL, Hayes, PE, et al. Eds. Elsevier Science Publishing. New York. 1989. Pg. 1194- 

1195. 

2. Ayeh-Kumi, PF, Petri, WA, et al. Diagnosis and Management of Amebiasis. Infect Med 2002 

Oct:19(8):375-382. 

3. World Health Organization (WHO) Infectious Diseases. www.who.int accessed September 2004. 


5. Micromedex, Healthcare Series;DrugDex Drug Evaluations 2004. 

6. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected 

with human immunodeficiency virus. Rockville (MD): U.S. Department of Health and Human 

Services, Public Health Service;2001 Nov 28. 

7. Centers for Disease Control and Prevention (CDC). Guidelines for preventing opportunistic 

infections among hematopoietic stem cell transplant recipients. MMWR Oct 20 2000;49;RR-10. 

8. Humatin package insert; Monarch Pharmaceuticals Rev. June 2001 


10. Yodoxin package insert; Glenwood, LLC Rev. January 2003 

11. Samuelson, JC, Burke, A, Courval, JM. Susceptibility of an Emetine-Resistant Mutant of 

Entamoeba histolytica to Multiple Drugs and to Channel Blockers. Antimicrobial Agents and 

Chemotherapy Nov, 1992; 36(11):2392-2397. 

12. Sullam PM, Slutkin G, Gottlieb AB, et al. Paromomycin therapy of endemic amebiasis in 

homosexual men. Sex Transm Dis. 1986 Jul-Sept;13(3):151-155. 

13. White AC, Jr, Chappell, CL, Hayat CS, et al. Paromomycin for cryptosporidiosis in AIDS: a 

prospective, double-blind trial. J Infec Dis 1994 Aug;170(2):419-424. 

14. Hewitt RG, Yiannoutsos CT, Higgs, ES, et al. Paromomycin: no more effective than placebo for 

treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. 

Clin Infec Dis.2000 Oct;31(4):1084-1092. 

15. El-on J, Halevy S, Grunwald MH, et al. Topical treatment of Old World cutaneous leishmaniasis 

caused by leishmania major: a double-blind control study. J Am Acad Dermatol 1992 Aug;27(2 pt 

1):227-231. 

16. Horga MA. EMedicine – Amebiasis. Updated July 1, 2004. Accessed at 

www.emedicine.com/ped/topic80.htm September 2004. 

274



Pharmacotherapy Review of the Antimalarial Agents 

AHFS 083008 


I. Overview 

Globally, malaria continues to be one of the most important and devastating infectious diseases in 

developing regions of the world. More than 40% of the world’s population lives in areas where 

malaria transmission occurs, resulting in an estimated 300-500 million cases of malaria each year 

attributing to 750,000-2 million deaths. 1 

While the transmission of malaria was eradicated in the United States in the 1950s, the threat of 

malaria is still a concern due to the number of U.S. travelers who visit areas where malaria is 

present. Travelers returning from malaria-endemic countries of the world are the vast majority of 

diagnosed cases of malaria in the U.S. Still, congenital infections, infections acquired through 

exposure to infected blood or blood products, and infections acquired through local mosquitoborne 

transmission do occur. 2 In 2002, 1,337 cases of malaria, including eight deaths, were 

reported in the U.S. Other facts pertaining to malaria in the U.S. include: 3 

• Between 1957 and 2003, in the U.S., 63 outbreaks of locally transmitted mosquito-borne 

malaria have occurred. In such outbreaks, local mosquitoes become infected by biting 

persons carrying malaria parasites (acquired in endemic areas) and then transmit malaria 

to local residents. 

• Of the ten species of Anopheles mosquitoes found in the U.S., the two species that were 

responsible for malaria transmission prior to eradication (Anopheles quadrimaculatus in 

the east and Anopheles freeborni in the west) are still widely prevalent; thus there is a 

constant risk that malaria could be reintroduced in the U.S. 

• Malaria in humans is caused by one of four protozoan species of the genus Plasmodium: 

P. falciparum, P. vivax, P. ovale, or P. malariae. All are transmitted by the bite of an 

infected female Anopheles mosquito. 4 

• Of the 1,337 malaria cases reported for 2002 in the U.S., all but five were imported. 

Plasmodium falciparum, the most severe and life-threatening form of the disease, was 

identified in over 50% of the 1,337 cases in 2002. 

• During 1963-1999, 93 cases of transfusion-transmitted malaria were reported in the U.S.; 

approximately two thirds of these cases could have been prevented if the implicated 

donors had been deferred according to established guidelines. 

Antimalarial drugs are prescribed to treat infections from one of the four the Plasmodium species 

or to provide prophylactic protection to individuals who are visiting malaria-endemic countries 

from being infected. This review encompasses all dosage forms and strengths. Table 1 lists the 

single entity antimalarial drugs included in this review. 

Table 1. Single Entity Antimalarial Products in this Review 


Chloroquine Phosphate Oral Tablet* / Injection Aralen Phosphate 

Chloroquine HCl Injection Aralen HCL 

Halofantrine HCl Not Available in US Halfan 

Hydroxychloroquine Sulfate Oral Tablet* Plaquenil 

Mefloquine HCl Oral Tablet* Lariam 

Primaquine Phosphate Oral Tablet* / Powder* Primaquine 

Pyrimethamine Oral Tablet Daraprim 

Quinine Sulfate Oral Capsule* /Oral Tablet* Quinine 


275

II. 


Guidelines for the treatment and prevention of malaria have been established by the Centers for 

Disease Control and Prevention. The CDC guidelines provide clinicians clinical criteria to 

consider for appropriate selection of prophylactic therapy or treatment in malaria infected patients. 

Prophylaxis: 5 

Antimalarial agents prescribed for prophylactic purposes incorporate several strategies to prevent 

malarial infections. Primary prophylaxis is a strategy that uses antimalarial medications prior to, 

during, and after the exposure period to prevent the initial infection. The duration of therapy after 

the travel period is dependent on the antimalarial agent prescribed; four weeks after travel with 

chloroquine or mefloquine, seven days after travel with Atovaquone/proguanil. Drugs with longer 

half-lives, which are taken weekly, offer the advantage of a wider margin of error if the traveler is 

late with a dose than drugs with short half-lives, which are taken daily. Terminal prophylaxis is a 

strategy that uses an antimalarial drug towards the end of the exposure period, or immediately 

thereafter, to prevent relapses or delayed-onset clinical presentations of malaria caused by P. vivax 

or P. ovale. Primaquine is used in this purpose for terminal prophylaxis to decrease the risk of 

relapses by acting against the liver stages of the two plasmodium species. Primaquine is usually 

administered for 14 days after the traveler has left a malaria-endemic area. Terminal prophylaxis 

with primaquine for prevention of relapses is generally indicated for persons who have had 

prolonged exposure in malaria-endemic areas. 

In selecting an appropriate chemoprophylactic regimen before travel, the traveler and the healthcare 

provider should consider several factors. The travel itinerary should be reviewed and 

compared with the information on areas of risk in a given country to determine whether the 

traveler will actually be at risk for acquiring malaria. Whether the traveler will be at risk for 

acquiring drug-resistant P. falciparum malaria should also be determined. 

Resistance to antimalarial drugs has developed in many regions of the world. Chloroquineresistant 

P. falciparum has been confirmed in all areas with P. falciparum malaria except the 

Dominican Republic, Haiti, Central America west of the former Panama Canal Zone, Egypt, and 

some countries in the Middle East. In addition, resistance to sulfadoxine-pyrimethamine is 

widespread in the Amazon River Basin are of South America, much of Southeast Asia, other parts 

of Asia, and, increasingly, in large parts of Africa. Mefloquine resistance has been confirmed on 

the borders of Thailand with Burma and Cambodia, in the western provinces of Cambodia, and in 

the eastern states of Burma. Health-care providers are advised to consult with the latest 

information on resistance patterns before prescribing prophylaxis for their patients. 

Treatment: 6 

Treatment of malaria infections should not be initiated without confirmed laboratory diagnosis and 

should be initiated immediately thereafter. Three main factors should dictate the course of 

treatment in patients diagnosed with malaria: 

• The infecting Plasmodium species. P. falciparum infections can cause rapidly 

progressive, severe illness or death while the non-falciparum (P. vivax, P. ovale, or P. 

malariae) species rarely cause severe manifestations; P. vivax and P. ovale infections 

require treatment for the hypnozoite forms that remain dormant in the liver and can cause 

a relapsing infection; and P. falciparum and P. vivax species have different drug 

resistance patterns in differing geographic regions. For P. falciparum infections, the 

urgent initiation of appropriate therapy is especially critical. 

• The clinical status of the patient. Patients diagnosed with malaria are categorized as 

having either uncomplicated or severe malaria. Uncomplicated malaria can be effectively 

treated with oral antimalarial drugs. However, patients with one or more of the following 

symptoms are considered to have manifestations of more severe disease and should be 

treated aggressively with parenteral antimalarial therapy: 

276

• Impaired consciousness/coma 

• Severe normocytic anemia 

• Renal failure 

• Pulmonary edema 

• Acuter respiratory distress syndrome 

• Circulatory shock 

• Disseminated intravascular coagulation 

• Spontaneous bleeding 

• Acidosis 

• Hemoglobinuria 

• Jaundice 

• Repeated generalized convulsions 

• Parasitemia of > 5% 

• The drug susceptibility of the infecting parasites as determined by the geographic areas 

where the infection was acquired. Knowledge of the geographic area where the infection 

was acquired provides information on the likelihood of drug resistance of the infecting 

parasite and enables appropriate drug product, or drug combination selection and 

treatment course. 

All cases of malarial infections should be reported to state health departments which forward the 

information on to the CDC. Drug product selection and dosing in the treatment of malarial 

infections will be addressed further in this review. It is important to continue monitoring the 

patient’s clinical and parasitologic status after initiation of antimalarial therapy. Blood smears 

should be conducted to confirm adequate parasitologic response to treatment. In infections with P. 

falciparum or suspected chloroquine-resistant P. vivax, blood smears should show evidence of 

parasite density decreases, followed by clearance. 

277

Antimalarial Agents – Single Entity Products 

III. 

Comparative Indications for Single Entity Antimalarial Agents 

Table 2 lists the FDA-approved indications for single entity antimalarial agents. 

Table 2. FDA-Approved Indications for the Single-Entity Antimalarial Agents 7 

Prophylaxis 

Treatment 

Generic Drug Name P. vivax P. malariae P. ovale P. falciparum P. vivax P. malariae P. ovale P. falciparum 

Chloroquine Phosphate 

✔ ✔ ✔ ✔* ✔ ✔ ✔ ✔* 

Chloroquine HCl 

Hydroxychloroquine Sulfate 

Mefloquine HCl 

Primaquine Phosphate 

Pyrimethamine 

Quinine Sulfate 

✔ ✔ ✔ ✔* 

✔ ✔ ✔ ✔* ✔ ✔ ✔ ✔* 

✔ ✔** ✔ ✔** 

✔ *** ✔ *** ✔ *** ✔ *** 

✔ 

✔ ✔ ✔ ✔** 

* Susceptible strains. 

**For susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains). 

***For chemoprophylaxis of susceptible strains of plasmodia only. Pyrimethamine is not suitable as a prophylactic agent for travelers to 

most areas because of prevalent resistance worldwide. 

Table 3. Malaria Prophylaxis and Treatment Therapy Choices 

Clinical Diagnosis or Plasmodium 

species 

Prophylaxis 8 

Treatment 9 

Areas where P. falciparum is sensitive to 

Chloroquine 

Areas where P. falciparum is resistant to 

Chloroquine 


Chloroquine and Mefloquine 

Uncomplicated malaria / P. falciparum or 

species not identified. 

Drug(s) of Choice 

Chloroquine phosphate 

Alternative: Hydroxychloroquine sulfate. 

(Travelers unable to take Chloroquine or Hydroxychloroquine should take 

Mefloquine, Doxycycline, or Atovaquone/Proguanil) 

Mefloquine 

Atovaquone/Proguanil 

Doxycycline 

(Primaquine may be used in rare instances and after consultation with malaria 

experts and only in travelers unable to take Mefloquine, Atovaquone/Proguanil, 

or Doxycycline. Because Primaquine can cause fatal hemolysis in G6PDdeficient 

persons, laboratory testing is required to rule out G6PD deficiency.) 


Doxycycline 

Chloroquine-sensitive: 

Adult: Chloroquine phosphate 

Pediatric: Chloroquine phosphate 

Chloroquine-resistant or unknown resistance: 

Adult: (one of the following) 

1. Quinine sulfate plus one of the following: 

a. Doxycycline 

b. Tetracycline 

c. Clindamycin 

2. Mefloquine 

Pediatric: (one of the following) 





2. Atovaquone/Proguanil 

278

Uncomplicated malaria / P. malariae 

Uncomplicated malaria / P. vivax or P. 

ovale 

Uncomplicated malaria / P. vivax in 

areas of Chloroquine resistance 

Uncomplicated malaria: alternatives for 

pregnant women 

Severe malaria / P. falciparum 



Adult: Chloroquine phosphate + Primaquine phosphate 

Pediatric: Chloroquine phosphate+ Primaquine phosphate 


1. Quinine sulfate + Primaquine phosphate + Doxycycline or 

Tetracycline 

2. Mefloquine plus Primaquine phosphate 


1. Quinine sulfate + Primaquine phosphate + Doxycycline or 

Tetracycline 

2. Mefloquine plus Primaquine phosphate 



Chloroquine-resistant P. falciparum: 

Quinine sulfate + Clindamycin 

Chloroquine-resistant P. vivax: 

Quinine sulfate 

Adult: Quinidine gluconate IV, plus one of the following: 

1. Doxycycline IV 

2. Tetracycline oral 

3. Clindamycin IV 

Pediatric: Quinidine gluconate IV, plus one of the following: 

1. Doxycycline IV 

2. Tetracycline oral 

3. Clindamycin IV 

279

IV. 


Table 4 lists the pharmacokinetic parameters and mechanisms of action of the Single-Entity 

Antimalarial products. 

10, 11, 12, 13, 14 

Table 4. Pharmacokinetic Parameters of the Single-Entity Antimalarial Agents 

Drug Mechanism of Bioavailability Protein Metabolism Active 

Chloroquine 

Phosphate 


Hydroxychloroquine 

Sulfate 

Mefloquine HCl 

Action 

Acts primarily 

as a blood 

schizonticide. 

The drug’s 

Antimalarial 

action is unclear 


as a blood 


The drug’s 

Antimalarial 



as a blood 


The drug’s 

Antimalarial 



as a blood 


The drug’s 

Antimalarial 


Readily 

absorbed 

Readily 

absorbed 

Readily 

absorbed 

Absolute oral 

absorption has 

not been 

determined 

since an IV 

formulation is 

not available. 

The 


of the tablet 

formulation 

compared with 

an oral solution 

was over 85%. 

Food 

significantly 

enhances the 

rate and extent 

of absorption 

by 40%. 

Binding 

55% Undergoes 

appreciable 

degradation in the 

tissues it is 

deposited. Up to 

70% of drug is 

excreted 

unchanged. 

55% Undergoes 

appreciable 


tissues it is 



excreted 

unchanged. 

55% Undergoes 

appreciable 


tissues it is 



excreted 

unchanged. 

Metabolites 

Yes 

Desethylchoroquine 

accounts for 

20% of urinary 

excretion 

Yes 


accounts for 


excretion 

Yes 


accounts for 


excretion 

Elimination 

Renal; 

Urinary 

excretion is 

enhanced by 

urinary 

acidification. 

Renal; 

Urinary 

excretion is 

enhanced by 

urinary 


Renal; 

Urinary 

excretion is 

enhanced by 

urinary 


98% Liver No Bile and 

Feces; 9% is 

excreted 

unchanged in 

urine 

Half- 

Life 

30-60 

days- 

30-60 

days 

30-60 

days 

2-4 

weeks

Primaquine 

Phosphate 

Pyrimethamine 

Quinine Sulfate 

Acts as a blood 

and tissue 

schizonticide 

that disrupts the 

parasite’s 

mitochondria 

and bind to 

native DNA. 

This activity 

disrupts the 

metabolic 

process and 

inhibits the 

gametocyte and 

exoerythhrocyte 

forms. 

A folic acid 

antagonist that 

possesses blood 

and some tissue 

schizonticidal 

activity. 


as a blood 


The drug’s 

Antimalarial 

action is unclear. 

Readily 

absorbed 

Readily 

absorbed 

Readily 

absorbed, 

mainly from 

the upper small 

intestine. 

98% Liver Yes 

Carboxyprimaquine 

with less 

antimalarial 

activity than 

parent drug. 

87% Liver Insufficient 

Data 

Feces; < 1% 

excreted 

unchanged in 

the urine. 

Renal. 

70-85% Liver No Renal; 

excretion is 

more rapid in 

acidic urine 

3-7 

hours 

4 days 

4-5 

hours 


There are several drug interactions associated with Antimalarial agents that are addressed in Table 

5. Severity level 1 interactions were reported with quinine and mefloquine. 

Table 5. Drug Interactions of the Single-Entity Antimalarial Agents 15 


Quinine Level 1 (delayed, major, 

suspected) 

Quinine and nonsedating 

antihistamines 

Quinine may inhibit the hepatic metabolism of 

Astemizole, increasing Astemizole concentrations 

Quinine 

Mefloquine 

Mefloquine 

Quinine 


suspected) 

Level 1 (rapid, major, 

suspected) 


suspected) 



Quinine and warfarin 

Halofantrine and Mefloquine 

Ziprasidone and Mefloquine 

Quinine and nondepolarizing muscle 

relaxants 

and possible cardiotoxicity. 

Quinine may inhibit the hepatically 

synthesized clotting factors and potentiate 

anticoagulation. 

Administration of halofantrine simultaneously or 

subsequent to Mefloquine can increase risk of lifethreatening 

arrhythmias through additive 

prolongation of the QT interval. 

Ziprasidone when administered in patients on 

Mefloquine can increase risk of life-threatening 

cardiac arrhythmias, including torsades de pointes 

through synergistic or additive prolongation of QT 

interval. 

The pharmacologic effects of nondepolarizing 

muscle relaxants may be enhanced by Quinine, 

requiring close monitoring of neuromuscular 

function. 

Quinine Level 2 (delayed, 


Quinine and Digoxin 

Quinine appears to decrease the biliary clearance of 

Digoxin leading to a probable increase in serum 

Digoxin levels with possible toxicity. 

Quinine Level 2 (delayed, Ketoconazole and Quinine Ketoconazole inhibits Quinine metabolism 

281

Quinine 

Quinine 

Chloroquine 

Chloroquine 

Hydroxychloro 

quine 

Hydroxychloro 

quine 

Hydroxychloro 

quine 

Quinine 

Quinine 

Quinine 

Mefloquine 

Chloroquine 

Chloroquine 

Chloroquine 

Chloroquine 

Quinine 



Moderate, probable) 




suspected) 


suspected) 






possible) 














possible) 


possible) 


possible) 

Rifamycins and Quinine 

Quinine and Succinylcholine 

Cimetidine and Chloroquine 

Oral Magnesium Salts and 

Chloroquine 

Hydroxychloroquine and Betablockers 

Hydroxychloroquine and Betablockers 

Hydroxychloroquine and Digoxin 

Quinine and Amantadine 

Quinine and Carbamazepine 

Quinine and Phenobarbital 

Metoclopramide and Mefloquine 

Chloroquine and Cyclosporine 

Chloroquine and Penicillamine 

Chloroquine and Methotrexate 

Aluminum salts and Chloroquine 

Cimetidine and Quinine 

(CYP3A4). Quinine serum levels may be elevated, 

increasing therapeutic and toxic effects. 

Rifamycins increase the hepatic clearance of 

Quinine resulting in a reduction in Quinine’s 

therapeutic effects. 

Quinine may slow the metabolic rate for 

succinylcholine, thereby prolonging neuromuscular 

blockade produced by succinylcholine. 

The pharmacologic effects of chloroquine may be 

increased as a result of decreased Chloroquine 

metabolism caused by Cimetidine’s inhibition of 

hepatic mixed function oxidases. 

Oral Magnesium salts administered with 

Chloroquine may adsorb Chloroquine, decreasing 

Chloroquine’s therapeutic effect. The antacid 

activity of Magnesium salts may also be reduced. 

Plasma concentrations and cardiovascular effects of 

certain Beta-blockers may be increased due to 

Hydroxychloroquine’s inhibition of CYP2D6- 

mediated Beta-blocker metabolism. 

Hydroxychloroquine inhibits CYP2D6-mediated 

Beta-blocker metabolism, increasing plasma 

concentrations and CV effects of certain Betablockers. 

Mechanism unknown. Serum levels of Digoxin 

may increase, enhancing Digoxin action or toxicity. 

Quinine may inhibit renal clearance of Amantadine 

in men, causing elevations in serum Amantadine 

concentrations and increasing risk of toxicity. 

Quinine may inhibit Carbamazepine metabolism 

(CYP3A4), elevating Carbamazepine 

concentrations and increasing the pharmacologic 

and adverse effects. 

Quinine increases Phenobarbital serum 

concentrations, increasing the pharmacologic and 

adverse effects due to inhibition of Phenobarbital 

metabolism. 

Mefloquine’s serum concentrations may be elevated 

with possible increases in toxicity (GI, CNS, CV) 

due to metoclopramide’s effect in increasing gastric 

emptying time and increasing the rate of 

Mefloquine absorption in the small intestine. 

Chloroquine decreases Cyclosporin metabolism, 

elevating serum concentrations and increasing 

toxicity risks. 

Mechanism unknown. The pharmacologic and toxic 

effects of Penicillamine may be increased. 

Mechanism unknown. Chloroquine may reduce the 

bioavailability of Methotrexate, decreasing its 

antirheumatic effect. 

Oral Aluminum salts may adsorb Chloroquine, 

decreasing Chloroquine’s absorption and 

therapeutic effect. 

Cimetidine may reduce Quinine metabolism by 

inhibiting the hepatic microsomal mixed-function 

oxidase enzyme system, reducing Quinine clearance 

and increasing elimination half-life. 

282


• Quinine and Aluminum containing antacids: Aluminum-containing antacids may delay or 

decrease absorption of concurrent quinine. 

• Quinine and Mefloquine: Do not use concurrently. ECG abnormalities or cardiac arrest 

may occur as well as the risk of convulsions. 

• Quinine and Urinary alkalinizers: Urinary alkalinizers administered concurrently with 

quinine may increase quinine levels with potential toxicity. 

• Mefloquine and Beta-blockers: There is one reports of cardiopulmonary arrest with full 

recovery in a patient taking propranolol and mefloquine. 

• Mefloquine and Chloroquine: Concomitant use of mefloquine with chloroquine increases 

the risk of convulsion. 

• Mefloquine and Live attenuated bacterial vaccines: Vaccinations with attenuated live 

bacteria should be completed at least three days before the first dose of mefloquine. 

• Mefloquine and Anticonvulsants: Coadministration may reduce seizure control by 

lowering the plasma levels of the anticonvulsants. 

• Primaquine and Quinacrine: Do not administer Primaquine to patients who have recently 

received quinacrine due to the potential toxicity that may arise from antimalarial 

compounds which are structurally related to Primaquine. 

• Pyrimethamine and Antifolate drugs or agents associated with myelosuppression (e.g. 

Proguanil, zidovudine, methotrexate, sulfonamides, TMP-SMX): Concurrent use of 

antifolic acids and pyrimethamine may increase the risk of bone marrow suppression. 

• Pyrimethamine and Lorazepam: Mild hepatotoxicity has been reported when lorazepam 

and pyrimethamine were coadministered. 

VI. 

Adverse Drug Events of the Single-Entity Antimalarial Agents 

The majority of adverse drug reactions associated with the single-entity Antimalarial products tend 

to involve gastrointestinal disturbances or CNS effects. When used to treat for acute malaria, 

many symptoms possibly attributable to the drugs could not be distinguished from symptoms 

usually attributable to the disease itself. 

The 4-Aminoquinolone products (eg. Chloroquine, Hydroxychloroquine, Primaquine) should be 

used in extreme caution in patients with glucose-6-phosphate dehydrogenase deficiency. 

Table 6 lists the most common adverse events reported for these single-entity agents: 

17, 18, 19, 20, 21 

Table 6. Common Adverse Events (%) Reported for the Single-Entity Antimalarial Agents 

Adverse Event 


Malaise 

Myalgia 


Anginal Symptoms 

Edema 

Hypotension 

Hypertension 

Vasculitis 

Bardycardia 

Tachycardia 

Extrasystoles 

Palpitations 

Chest Pain 

ECG Changes 




Diarrhea 

Hepatitis 


Chloroquine 

Phosphate 

Chloroquine 

HCL 


Sulfate 

Mefloquine Primaquine Pyrimethamine Quinine 

- - - - 

- - 

b 

b 

- 

- - 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 



Fatigue 

Fever 

Headache 

Syncope 

Restlessness 

Tinnitus 

Confusion 

Drowsiness 

Convulsions 

Emotional Disturbances 

Hepatic 


Hepatitis 

Jaundice 



Alopecia 

Rash 

Pruritus 

Urticaria 

Edema 

Pigment changes 

Hematologic 

Neutropenia 




Hypothrombinemia 


Leukopenia 

Blood dyscrasias 

Megaloblastic anemia 

Pancytopenia 

Hematuria 

Renal 



Ophthalmic 

Visual disturbances 

Photophobia 

Diplopia 

Mydriasis 

Optic atrophy 

Night blindness 

Retinal damage 

Other 

Cinchonism 

Hypoglycemia 

Psychotic/Paranoid Rx 

Cardiomyopathy 

Atrophic glossitis 

Rhythm disorders 

Pulmonary eosinophilia 

Hypersenstivity Rxn 

Hyperphenylalaninemia 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

- 

b 

b 

b 

b 

b 

VII. 

Dosing and Administration for the Single-Entity Antimalarial Agents 

22, 23, 24, 25, 26, 27 

Table 7. Dosing for the Single-Entity Antimalarial Agents 


Chloroquine 

Phosphate 

250mg tablet 

(Equiv to 150mg base) 

500mg tablet 


5mg injection 


Dosage of Chloroquine phosphate is often expressed in terms of equivalent chloroquine 

base. 

Malaria Suppression 

Adults – 300mg (base) weekly, on the same day each week. Begin 1-2 weeks prior to 

exposure; continue for 8 weeks after leaving endemic area 

If suppressive therapy is not begun prior to exposure, double the initial loading dose 

and give in two divided doses, 6 hours apart (adults – 600mg base; children – 10mg 

base/kg). 

Children – Administer 5mg base/kg weekly up to a maximum adult dose of 300mg 

base. 

Treatment of Acute Malaria 

Adult – An initial dose of 1gm (=600mg base) followed by an additional 500mg 

(=300mg base) after 6-8 hours and a single dose of 500mg (=300mg base) on each of 

two consecutive days. This represents a total dose of 2.5gm Chloroquine phosphate or 

1.5gm base in three days. 



Sulfate 

50mg/ml injection 

(Equiv to 40mg/ml base) 

200mg tablet 


Adults of low body weight/infants/children – An initial dose of 10mg base per kg (but 

not exceeding a single dose of 600mg base). The second dose is administered 6 hours 

after the first dose and is 5mg base per kg (but should not exceed a single dose of 

300mg base). The third dose is administered 24 hours after the first dose and is 5mg 

base per kg. The fourth dose is administered 36 hours after the first dose and is 5mg 

base per kg. 


Adult – 160 to 200mg base (4-5ml) IM initially; repeat in 6 hours if necessary. Do not 

exceed 800mg (base) total dose in the first 24 hours. Begin oral dosage as soon as 

possible and continue for 3 days until approximately 1.5gm base has been 

administered. 

Other suggested dosages include 2.5mg base/kg every 4 hours or 3.5mg/kg every 6 

hours; repeat if necessary, maximum 25mg/kg/day. 

Children – Infants and children are extremely susceptible to overdosage. Severe 

reactions and deaths have occurred. The recommended single dose if 5mg base/kg; 

repeat in 6 hours. Do not exceed 10mg/kg/24 hours. 


Adults – 310mg (base) weekly, in the same day each week. Begin 1-2 weeks prior to 

exposure; continue for 8 weeks after leaving endemic area 

If suppressive therapy is not begun prior to exposure, double the initial loading dose 

and give in two divided doses, 6 hours apart (adults – 620mg base; children – 10mg 

base/kg). 

Children – Administer 5mg base/kg weekly up to a maximum adult dose. 


Adult – An initial dose of 620mg base followed by a second dose of 310mg base after 

6 hours and single doses of 310mg base on each of two consecutive days. This 

represents a total dose of 1.55gm base in three days. An alternative method employing 

a single dose of 620mg base, has also proved effective. 

Adults of low body weight/infants/children – An initial dose of 10mg base per kg (but 

not exceeding a single dose of 620mg base). The second dose is administered 6 hours 

285

after the first dose and is 5mg base per kg (but should not exceed a single dose of 

310mg base). The third dose is administered 18 hours after the second dose and is 5mg 

base per kg. The fourth dose is administered 24 hours after the third dose and is 5mg 

base per kg. This represents a total administered dose of 25mg base per kg of body 

weight over a three day period. 

Mefloquine 250mg tablet Malaria Suppression 

Adults – 250mg weekly, in the same day each week. Begin 1 week prior to exposure; 

continue for 4 weeks after leaving endemic area. Tablets should not be taken on an 

empty stomach and should be administered with at least 8oz of water. 

In certain cases (eg, when a traveler is taking other medication), it may be desirable to 

start prophylaxis 2-3 weeks prior to exposure, in order to ensure that the combination 

of drugs is well tolerated. 

Children – The recommended prophylactic dose of Mefloquine is approximately 

5mg/kg body weight once weekly. One 250mg Mefloquine tablet should taken once 

weekly in pediatric patients weighing over 45kg (100lbs). In pediatric patients 

weighing less than 45kg, the weekly dose decreases in proportion to body weight: 

30 to 45kg: ¾ tablet 

20 to 30kg ½ tablet 

10 to 20kg ¼ tablet 

5 to 10kg 1/8 tablet 

Experience with Mefloquine in infants less than 3 months old or weighing less than 

5kg is limited. 

Treatment of Mild to Moderate Malaria 

Adults caused by P. vivax or Mefloquine-susceptible strains of P. Falciparum – Five 

tablets (1,250mg) Mefloquine to be given as a single oral dose. The drug should not be 

taken on an empty stomach and should be administered with at least 8oz of water. 

Children caused by Mefloquine-susceptible strains of P. Falciparum – 20 to 25mg/kg 

body weight. Splitting the total therapeutic dose into 2 doses taken 6-8 hours apart may 

reduce the occurrence or severity of adverse effects. Experience with Mefloquine in 

infants less than 3 months old or weighing less than 5kg is limited. The drug should 

not be taken on an empty stomach and should be administered with ample water. The 

tablets may be crushed and suspended in a small amount of water, milk or other 

beverage for administration to small children and other persons unable to swallow them 

whole. 

In pediatric patients, the administration of Mefloquine for the treatment of malaria has 

been associated with early vomiting. In some cases, early vomiting has been cited as a 

possible cause of treatment failure. If a significant loss of drug product is observed or 

suspected because of vomiting, a second full dose should be administered to patients 

who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30-60 

minutes after a dose, an additional half-dose should be given. If vomiting occurs, the 

patient should be monitored closely and alternative malaria treatment considered if 

improvement is not observed within a reasonable period of time. 

The safety and effectiveness of Mefloquine to treat malaria in children below the age of 

6 months have not been established. 

Primaquine 

26.3mg tablet 


In both adults and children, if a full-treatment course with Mefloquine does not lead to 

improvement within 48 to 72 hours, Mefloquine should not be used for retreatment. 

An alternative therapy should be used. Similarly, if previous prophylaxis with 

Mefloquine has failed, Mefloquine should not be used for curative treatment. 

Treatment of P. vivax Malaria 

Patients suffering from an attack of P. vivax malaria or having parasitized red blood 

cells should receive a course of Chloroquine. 

Adult – 30mg (base) taken orally daily for 14 days. 

Children – 0.6mg base/kg taken orally, daily for 14 days. 

286

Pyrimethamine 25mg tablet Malaria Suppression 

Pyrimethamine is rapidly absorbed and therefore prophylactic cover can be expected 

shortly after the first dose. Prophylaxis should commence before arrival in an endemic 

area and be continued for four weeks after returning to a non-malarious area. 

Adults and children >10 years of age – 25mg orally every week. 

Children (4-10 years of age) – 12.5mg orally every week. 

Infants and children 10 years of age – 50mg orally daily for 2 days. 

Children (4-10 years of age) – 25mg orally daily for 2 days. 

Infants and children


Sulfate 

No No No special dosing consideration NR Crushing tablets and putting each dose in 

capsules; contents of capsules may be 

mixed with jam, jelly, or jello. 

Mefloquine No No WHO recommends mefloquine 

for all children and infants 3 

months or older, or 5 kilograms 

or more in areas where 

chloroquine resistance is 

prevalent 

C 

Crushing tablet and suspending in water, 

milk, or other beverage if patient is 

unable to swallow it whole. 

Primaquine No No No special dosing consideration NR No data is available on crushing of tablet. 

Pyrimethamine No No No special dosing consideration C Tablets may be split. The manufacturer 

reports no data is available on the 

bioequivalency of crushing the tablets for 

use in suspensions, nor is data available 

on use of the suspension when given per 

tube. 

Quinine No Special 

caution in 

the use of 

Quinine in 

patients with 

concurrent 

liver 

disease. 

No special dosing consideration X No data is available on crushing of tablet 

or emptying contents of capsule. 

288

VIII. Comparative Effectiveness of the Single-Entity Antimalarial Agents 

Not all of the agents in this class can be used for the same malarial infections. 

Table 9. Additional Outcomes Evidence for the Single-Entity Antimalarial Agents 


Results 

Duration 

Ibrahim 

MH, et 

al 31 n=98 Quinine PO/IV In comparing 3 quinine treatment regimens against P. Falciparum malaria that had 

failed to respond to chloroquine treatment, the 93 patients were randomly allocated to 

1 of 3 regimens for seven days of therapy: 

• PO/IV quinine at doses 10mg/kg TID (32 patients) 

• PO/IV quinine at doses 10mg/kg BID (31 patients) 

• PO/IV quinine at doses 15mg/kg QD 

There was no significant difference in the parasite-clearance times observed in the 

three groups. In the treatment of chloroquine-resistant P. falciparum malaria in 

Sudan, once-daily treatment with quinine, in a relatively low daily dose, appears as 

effective as the TID treatment often recommended. 

White NJ, 

et al 32 n=50 Chloroquine IM 

3.5mg (base)/kg q6h 

An open paired randomized comparison of chloroquine IM and quinine IM was 

conducted in 50 Gambian children with severe falciparum malaria: 

Quinine IM 20mg 

(salt)/kg, followed by 

• 8 children died, 6 from the quinine-treated, and 2 from the chloroquinetreated. 

10mg/kg q12h. • Chloroquine reduced parasitaemia significantly more rapidly than did 

quinine, but other measures of the therapeutic response were similar in the 

two groups. 

• The findings did not support the proposition that quinine is intrinsically 

superior to chloroquine in the treatment of severe drug-sensitive falciparum 

Baird JK, 

et al 33 n=99 Primaquine 0.5mg 

base/kg QOD 

Chloroquine 5mg 

base/kg Qwk 

Mengesha Metaanalysis 

T, et al 34 

Chloroquine 

Amodiaquine 

Mefloquine 

Sulfadoxine- 

Pyrimethamine 

Halofantrine 

malaria. 

A controlled clinical trial comparing primaquine versus chloroquine for prophylaxis 

among non-immune transmigrants for Java and Bali in the region of Irian Jay, 

Indonesia. 45 subjects received 0.5mg of primaquine base/kg QOD, and 54 people in 

the same village received weekly 5mg of chloroquine base/kg for 16-19 weeks. 

The subjects taking chloroquine were 5 times more likely to suffer an episode of 

malaria than those taking primaquine. The minimum protective efficacy of 

primaquine was 74% for P. falciparum and 90% for P vivax infections. 

A meta-analysis study evaluated the efficacy and safety of chloroquine and alternative 

Antimalarial drugs used in six African countries including Ethiopia, Kenya, Uganda, 

Cote D’Ivoire, Gambia and Nigeria. Findings from the 6 countries showed a higher 

efficacy of amodiaquine and quinine >90%) in malaria treatment compared to 

chloroquine (>70%). 

Pharmacokinetic profile demonstrates that all these drugs have similar therapeutic 

effects, but differ in their adverse reactions, contraindications, and half-life. 

Randriana 

rivelojosia 

M, et al 35 - - Plasmodium falciparum isolates in patients with uncomplicated malaria attack were 

used in 293 in-vitro tests conducted with at least one Antimalarial agent. The purpose 

of the in-vitro testing was to determine the sensitivity of Plasmodium falciparum to 

the major Antimalarial drugs in Madagascar: 

• All of the successfully tested isolates were sensitive to halofantrine (n=56). 

• All of the successfully tested isolates were sensitive to quinine (n=199). 

• 94.2% of the successfully tested isolates were sensitive to chloroquine 

(n=205). 

• 98% of the successfully tested isolates were sensitive to mefloquine 

(n=199) 

The in-vitro sensitivity of P. falciparum to quinine, mefloquine and halofantrine 

encourages the use of these drugs as alternative in case of chloroquine treatment 

failures.

Schwartz 

E, et al 36 n=106 Prophylactic 

Therapies involving: 

Primaquine 

Doxycycline 

Mefloquine 

Kofoed K, 

et al 37 n=320 Prophylactic 

Therapies involving: 

Chloroquine/proguanil 

Mefloquine 

Atovaquone/proguanil 

A retrospective analysis of travelers who joined rafting trips in an area in Ethiopia 

where both P. vivax and P. falciparum are hyperendemic: 

• Of the 106 travelers who received primaquine, 5.7% developed malaria. 

• Of the 19 doxycycline recipients, 53% developed malaria. 

• Of the 25 mefloquine recipients, 52% developed P. vivax malaria (> 3 

months after return from the area). 

Primaquine was shown to be a safe and effective prophylactic drug against both P. 

falciparum and P. vivax malaria in travelers. 

An open case-control study was initiated to study 320 permanent residents in 

Denmark who were returning from abroad with malaria. This group was compared 

with a group of 600 travelers who were not infected with malaria and matched by age, 

sex, and destination. Information on the use of chemoprophylaxis and the length of 

stay in malarious areas were obtained by questionnaire. 

200 cases of P falciparum malaria were identified of which 103 had used 

chloroquine/proguanil, 16 used mefloquine, and 3 used atovaquone/proguanil as 

prophylaxis; the others had taken other drugs or nor prophylaxis: 

• The risk of malaria increased with increasing exposure. 

• Compliance to prophylactic treatment was lower, especially for mefloquine 

users in malaria cases compared to controls. 

• The estimated efficacy of chloroquine/proguanil, mefloquine, and 

atovaquone/proguanil in fully compliant users was 1:599, 1:2,232 and 

1:1,943, respectively, P. falciparum cases per prescription. 

• Chloroquine/proguanil was less efficient compared with mefloquine. 

Warhurst 

DC,et al 38 - - An analysis conducted to determine whether patients treated for autoimmune disease 

with hydroxychloroquine could achieve effective prophylaxis on 

hydroxychloroquine/proguanil against chloroquine-resistant P. falciparum, in place of 

the traditional prophylactic regimen of adding chloroquine/proguanil and the likely 

toxicity that would arise when Chloroquine is administered in persons being treated 

with hydroxychloroquine. 

Weiss 

WR, et 

al 39 - Prophylactic regimens 

of: 

1. Daily Primaquine 

2. Daily Doxycycline 

3. Weekly Chloroquine 

with proguanil 

4. Weekly mefloquine 

with vitamin 

5. Daily vitamin 

The in-vitro test results confirmed that hydroxychloroquine/proguanil prophylaxis 

was 8.8 times less active in a chloroquine-resistant P. falciparum than 

chloroquine/proguanil treatment. Hydroxychloroquine is therefore contraindicated in 

prophylaxis of treatment of chloroquine-resistant falciparum malaria. 

Primaquine was tested as a prophylactic drug against P. falciparum in a region in 

western Kenya in which malaria his holoendemic. Children 9-14 years old were 

randomized to receive regimens of daily primaquine, daily doxycycline, daily 

proguanil plus weekly chloroquine, daily vitamin plus weekly mefloquine, or daily 

vitamin alone. Primaquine, doxycycline, and mefloquine were equally effective in 

preventing both symptomatic and asymptomatic malarial infections. Chloroquine 

plus proguanil was the least effective regimen. There was not toxicity from daily 

primaquine during the 11 weeks of the study. Findings show that primaquine can be 

successfully used as a causal prophylactic regimen against falciparum malaria in 

western Kenya; chloroquine plus proguanil was not as efficacious as the three other 

preventive regimens. 


Dose Simplification: In most cases, the antimalarial agents in this class are given as a single dose 

or for a brief duration (acute use), depending on the malarial plasmodium being treated. When 

given for longer durations, most doses are prescribed once weekly, given on the same day of the 

week. Malaria treatment often requires initial dosing, followed by a second dose in the same day, 

and then subsequent daily dosing for 2-3 days. Mefloquine offers a single oral treatment dose, 

while quinine is dosed three times daily for up to 12 days. No data was found in a literature search 

looking at the dosing frequency patterns of the antimalarial drugs and any benefit of single oral 

treatment doses on the outcome of disease. 

290

Stable Therapy: Significant clinical data is available on resistance to the Antimalarial agents in 

humans. Guidelines established by the CDC consider resistance prevalence in relation to the 

endemic malarial regions and origins of infection. Chloroquine-resistant P. falciparum has been 

confirmed in all areas with P. falciparum malaria except the Dominican Republic, Haiti, Central 

America west of the former Panama Canal Zone, Egypt, and some countries in the Middle East. 

In addition, resistance to sulfadoxine/pyrimethamine is widespread in the Amazon River Basin 

area of South America, much of Southeast Asia, other parts of Asia, and increasingly in large parts 

of Africa. Resistance to Mefloquine has been confirmed on the borders of Thailand with Burma 

and Cambodia, in the western provinces of Cambodia, and in the eastern states of Burma 

Because of prevalent resistant plasmodium strains, and varying side effects among the antimalarial 

agents, health care providers need to closely monitor patient response to therapy regimens and 

modify, if necessary to ensure successful suppression or treatment. 

Impact on Physician Visits: A literature search did not reveal clinical literature relevant to use of 

the antimalarials and their impact on physician visits. 

IX. 

Conclusions 

Antimalarial agents recommended in the suppression and treatment of malaria by the CDC include 

chloroquine products, hydroxychloroquine, mefloquine, primaquine, quinine, and the combination 

agent, atovaquone-proguanil. All single-entity antimalarial products listed in the CDC guideline 

have generic equivalent products on the market. 

All brand products within the single-entity antimalarial agents are comparable to the generics in 

this class and offer no significant clinical advantage over other alternatives in general use. 


No brand single entity antimalarial product is recommended for preferred status. 

291

Antimalarial Agents – Combination products 


review. 

Table 1. Combination Antimalarial Products in the Review 


Atovaquone and Proguanil HCl Oral Tablet Malarone 

Malarone Pediatric 

Pyrimethamine and Sulfadoxine Oral Tablet Fansidar 

I. Comparative Indications for Combination Antimalarial Agents 

Table 2 lists the FDA-approved indications for combination antimalarial agents. 

Table 2. FDA-Approved Indications for the Combination Antimalarial Agents 40 

Prophylaxis 

Treatment 

Generic Drug Name P. vivax P. malariae P. ovale P. falciparum P. vivax P. malariae P. ovale P. falciparum 

Sulfadoxine/Pyrimethamine 

✔** ✔* 

Atovaquone/Proguanil HCl 

* Susceptible strains. 

** Malaria prophylaxis with Sulfadoxine/Pyrimethamine is not routinely recommended and should only be considered to travelers to areas 

where chloroquine-resistant P. falciparum malaria is endemic and sensitive to Sulfadoxine/Pyrimethamine, and when alternative drugs are 

not available or are contraindicated. However, strains of P. falciparum may be encountered which have developed resistance to 

Sulfadoxine/Pyrimethamine. 

✔ 

✔ 

Table 3. Malaria Prophylaxis and Treatment Therapy Choices 

Clinical Diagnosis or Plasmodium 

species 

Prophylaxis 41 

Areas where P. falciparum is sensitive to 

Chloroquine 


Chloroquine 


Chloroquine and Mefloquine 

Drug(s) of Choice 


Alternative: Hydroxychloroquine sulfate. 

(Travelers unable to take Chloroquine or Hydroxychloroquine should take 

Mefloquine, Doxycycline, or Atovaquone/Proguanil) 

Mefloquine 


Doxycycline 

(Primaquine may be used in rare instances and after consultation with malaria 

experts and only in travelers unable to take Mefloquine, Atovaquone/Proguanil, 

or Doxycycline. Because Primaquine can cause fatal hemolysis in G6PDdeficient 

persons, laboratory testing is required to rule out G6PD deficiency.) 


Doxycycline 

292

Treatment 42 

Uncomplicated malaria / P. falciparum or 

species not identified. 




Chloroquine-resistant or unknown resistance: 






4. Mefloquine 






4. Atovaquone/Proguanil 

293

II. 


Table 4 lists the pharmacokinetic parameters and mechanisms of action of the combination 

antimalarial products. 

43, 44, 45, 46 

Table 4. Pharmacokinetic Parameters of the Combination Antimalarial Agents 

Drug Mechanism of Action Bioavailability Protein Metabolism Active 

Sulfadoxine / 

Pyrimethamine 

Sulfadoxine – 

synergistically acts at the 

state immediately 

preceding that of 

pyrimethamine. 

Pyrimethamine – 

interferes with the 

synthesis of folinic acid 

within the parasite 

inhibiting the conversion 

of dihydrofolate to 

tetrahydrofolate. 

Both 

compounds are 

readily absorbed 

Binding 

Sulf = 

90-95% 

Pyrim = 

87% 

Both 

compounds 

are 

metabolized 

in the liver 

Elimination Half- 

Metabolites 

Life 

No Renal Sulf = 

200hrs 

Pyri = 

100hrs 

Atovaquone / 

Proguanil HCl 

Together, the combination 

achieves a sequential 

blockade of 2 enzymes 

involved in the 

biosynthesis of folinic 

acid within the parasite. 

Atovaquone – action has 

not been fully elucidated. 

It is thought that 

Atovaquone inhibits 

mitochondrial electron 

transport of P. falciparum 

and thus pyrimidine 

synthesis. 

Proguanil HCl – requires 

metabolism to cycloguanil 

for Antimalarial activity; 

cycloguanil is a potent 

inhibitor of plasmodial 

dihydrofolate Reductase, 

resulting in inhibition of 

nucleic acid synthesis 

Atovaquone is 

highly lipophilic 

with low 

aqueous 

solubility. 


of Atovaquone 

(23%) shows 

considerable 

variability from 

patient to 

patient. 

Proguanil is 

readily absorbed 

Atov = 

>99% 

Prog = 

75% 

Atovaquone 

is not 

metabolized 

Proguanil is 

extensively 

metabolized 

in the liver to 

the active 

metabolite. 

Yes 

Proguanil is a 

prodrug that is 

metabolized to 

the active 

metabolite, 

cycloguanil via 

hepatic 

cytochrome 

P450 

isoenzyme 

CYP2C19. 

Atovaquone 

is excreted 

in the feces 

unchanged. 

Proguanil is 

excreted 

renally as 

the active 

metabolite. 

Atov 

= 2-3 

days 

Prog = 

12- 

21hrs 

Together, the synergistic 

activity of the two agents 

in falciparum malaria is 

unclear; an enhanced 

effect of cycloguanil, 

facilitated by the 

Atovaquone mediated 

reduction in pyrimidine 

nucleotide pools has been 

speculated. 

294

III. 

Drug Interactions 

There are several drug interactions associated with Combination Antimalarial agents that are 

addressed in Table 5. 

Table 5. Drug Interactions of the Combination Antimalarial Agents 47 


Atovaquone Level 2 (delayed, 


Atovaquone and Zidovudine 

Atovaquone appears to elevate serum Zidovudine 

concentrations by inhibiting the glucuronidation of 

Zidovudine, increasing the risk of Zidovudine 

Atovaquone 

Atovaquone 


moderate, Possible) 


moderate, unlikely) 

Atovaquone and Etoposide 

Atovaquone and Azithromycin 

toxicity. 

Mechanism unknown. Etoposide plasma 

concentration may be elevated, increasing risk 

of toxicity. 

Mechanism unknown. Azithromycin serum 

concentrations may be reduced, decreasing the 

pharmacologic effect. 


• Sulfadoxine/Pyrimethamine and Chloroquine: There have been reports that may indicate 

an increase in incidence and severity of adverse reactions when chloroquine is used with 

Sulfadoxine/Pyrimethamine tablets as compared with the use of 

Sulfadoxine/Pyrimethamine tablets alone. 

• Sulfadoxine/Pyrimethamine and Antifolic drugs: Do not use antifolic drugs (eg, 

sulfonamides or TMP-SMX combinations) while the patient is receiving 

Sulfadoxine/Pyrimethamine tablets for Antimalarial prophylaxis. 

• Sulfadoxine/Pyrimethamine and Goitrogens, diuretics, hypoglycemic agents: The 

sulfonamides bear certain chemical similarities to some goitrogens, diuretics 

(acetazolamide and the thiazides), and oral hypoglycemic agents. Diuresis and 

hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity 

may exist with these agents. 

• Atovaquone/Proguanil and Tetracycline: Concomitant treatment with tetracyclines has 

been associated with approximately 40% reduction in plasma concentrations of 

Atovaquone. 

• Atovaquone/Proguanil and Metoclopramide: Concomitant treatment with 

metoclopramide has been associated with decreased bioavailability of Atovaquone. 

• Atovaquone/Proguanil and Rifampin: Concomitant administration of rifampin is known 

to reduce Atovaquone levels by approximately 50%. The concomitant administration of 

these agents is not recommended. The mechanism of this interaction is unknown. 

IV. 

Adverse Drug Events of the Combination Antimalarial Agents 

The majority of adverse drug reactions associated with the single-entity Antimalarial products tend 

to involve gastrointestinal disturbances or CNS effects. When used to treat for acute malaria, 

many symptoms possibly attributable to the drugs, could not be distinguished from symptoms 

usually attributable to the disease itself. 

The manufacturer of Sulfadoxine/Pyrimethamine has issued a warning of the fatalities that have 

occurred with their product due to severe reactions, including Stevens-Johnson syndrome and 

toxic epidermal necrolysis. Discontinuation of therapy is advised at the first appearance of skin 

rash, if a significant reduction in the count of any formed blood element is noted, or upon the 

occurrence of active bacterial or fungal infections. In addition, fatalities associated with the 

administration of sulfonamides have occurred due to severe reactions, including fulminant hepatic 

necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. While severe, these 

reactions are rare. 

295

Table 6. Common Adverse Events (%) Reported for the Combination Antimalarial 

49, 50, 51, 52 

Agents 

Adverse Event Sulfadoxine/Pyrimethamine Atovaquone/Proguanil HCl 


Malaise 

Myalgia 

Chills 

- 

b 

b 

b 

- 




Diarrhea 


Glossitis 

Stomatitis 



Fatigue 

Fever 

Headache 

Syncope 

Restlessness/Insomnia 

Tinnitus 

Convulsions 

Mental Depression 

Hepatic 


Hepatitis 

Hepatic Necrosis 

Hepatic Granulomas 


Dermatitis 

Rash 

Pruritus 

Urticaria 

Phototoxicity 

Pigment changes 

Toxic Epidermal Necrolysis 

Erythema Nodosum 

Hematologic 

Neutropenia 




Hypothrombinemia 


Leukopenia 

Megaloblastic anemia 

Pancytopenia 

Thombocytopenia Purpura 

General Anemia 

Renal 

Crystalluria 


Ophthalmic 

Iritis 

Amblyopia 

Other 

Periarteritis Nodosa 

Apathy 

Bronchospasms 

Pulmonary Eosinophilia 


Spontaneous Abortion 

Hypoalbuminemia 

Pulmonary infiltrates 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

- 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 

b 


17% 

12% 

8% 

5% 

b 

b 

b 

b 

b 

b 

b 

- 

b 

296

V. Dosing and Administration for the Combination Antimalarial Agents 

53, 54 

Table 7. Dosing for the Combination Antimalarial Agents 


Sulfadoxine 

/Pyrimethamine 

500mg Sulfadoxine / 

25mg Pyrimethamine 

Tablets 


The first dose of Sulfadoxine 500mg/Pyrimethamine 25mg is taken 1 or 2 days before 

departure to an endemic area; continue administration during the stay and for 4-6 weeks 

after return. 

Age Once Weekly Once Every 2 Weeks 

Adults 

Pediatric (>2mo to 18yrs) 

>45 kg 

31-45kg 

21-30kg 

11-20kg 

5-10kg 

1 Tablet 

1½ Tablet 

1 Tablet 

¾ Tablet 

½ Tablet 

¼ Tablet 

2 Tablets 

NA 

NA 

NA 

NA 

NA 


A single dose of the following number of Sulfadoxine 500mg/Pyrimethamine 25mg 

tablets is used in sequence with Quinine or alone: 

Atovaquone 

/Proguanil HCl 

250mg Atovaquone / 

100mg Proguanil HCl 

Tablet 

62.5mg Atovaquone / 

25mg Proguanil HCl 

Pediatric Tablet 

Age 

Single Dose 

Adults 

2-3 Tablets 

Pediatric (>2mo to 18yrs) 

>45 kg 

3 Tablets 

31-45kg 

2 Tablets 

21-30kg 

1½ Tablets 

11-20kg 

1 Tablet 

5-10kg 

½ Tablet 


Start prophylactic treatment with Atovaquone/Proguanil 1 or 2 days before entering a 

malaria-endemic area and continue daily during the stay and for 7 days after return. 

Adults – Take 250mg Atovaquone/100mg Proguanil HCl (1 tablet) orally per day. 

Children – The dosage for prevention of malaria in pediatric patients is based upon body 

weight: 

Weight 

(kg) 


Total Daily Dose 

Dosage Regimen 

11-20 62.5mg/25mg 1 pediatric tablet daily 

21-30 125mg/50mg 2 pediatric tablets as a single daily dose 

31-40 187.5mg/75mg 3 pediatric tablets as a single daily dose 

> 40 250mg/100mg 1 adult strength tablet as a single daily dose 


Adults – Take 1000mg Atovaquone/400mg Proguanil HCl (4 tablets) orally as a single 

daily dose for 3 consecutive days. 

Children – The dosage for treatment of malaria in pediatric patients is based upon body 

weight: 

Weight 

(kg) 


Total Daily Dose 

Dosage Regimen 

5-8 125mg/50mg 2 pediatric tablets daily for 3 consecutive days 

9-10 187.5mg/75mg 3 pediatric tablets daily for 3 consecutive days 

11-20 250mg/100mg 1 adult strength tablet daily for 3 consecutive 

days 


days 


days 

> 40 1000mg/400mg 4 adult strength tablet daily for 3 consecutive 

days 

297


55, 56, 57 

Table 8. Special Dosing Considerations for the Combination Antimalarial Agents 

Drug Renal Dosing Hepatic Pediatric Use Pregnancy 

Sulfadoxine 

/Pyrimethamine 

Atovaquone 

/Proguanil HCl 

Dosing 

No No Sulfadoxine/Pyrimethamine 

should not be given to infants 

less than 2 months of age 

because of inadequate 

development of the glucuronideforming 

enzyme system. 

Yes 

Should not be 

used in patients 

with severe renal 

impairment 

(CrCl

Bustos DG, et 

al 60 n=110 Malaria treatment regimens 

of: 

1. Atovaquone/prog 

uanil 

2. Chloroquine 

3. Chloroquine, 

sulfadoxine, 

pyrimethamine 

Results: 

• Cure rates did not differ significantly between patients treated with 

atovaquone/proguanil (100%) and those treated with 

pyrimethamine/sulfadoxine (98.8%). 

• Patients treated with atovaquone/proguanil had a significantly shorter 

fever clearance time than patients treated with 

pyrimethamine/sulfadoxine (mean, 30.4 vs 44.9hrs; P

VII. 

Conclusions 

Antimalarial agents recommended in the suppression and treatment of malaria by the CDC include 

chloroquine products, hydroxychloroquine, mefloquine, primaquine, quinine, and the combination 

agent atovaquone-proguanil. Clinical comparative and efficacy studies show both combination 

agents are highly effective, while there are no significant differences between the agents in terms 

of fever and parasite clearance time, and cure rates. 


generics in the class and offer no significant advantage over other alternatives in general use. 

VIII. Recommendations 

No brand combination antimalarial agent is recommended for preferred status. 

300

References 

1 Centers for Disease Control and Prevention, Treatment Guidelines: Treatment of Malaria 

(Guidelines for Clinicians). Available at http://www.cdc.gov/malaria/pdf/treatmenttable.pdf. 

Accessed September 2004. 

2 Shah, S., et al., Malaria Surveillance—United States, 2002. MMWR Surveill Summ, 2004. 53(1) 

p. 21-34. 

3 Centers for Disease Control and Prevention, Malaria Facts. Available at 

http://www.cdc.gov/malaria/facts.htm. Accessed September 2004. 




5 Centers for Disease Control and Prevention, Health Information for International Travel, 2003- 

2004. Available at http://www.cdc.gov/travel/diseases/malaria/index.htm. Accessed September 

2004. 




7 Kastrup EK, ed. Drug Facts and Comparisons. Facts and Comparisons. St. Louis. 2004. 



2004. 





11 Gruber J. Hydroxychloroquine-Chloroquine; Pharmacokinetic Data. Available at 

http://www.lymenet.de/literatur/hydroxychloroquine.htm. Version: July 23, 2004. Accessed 

September 2004. 

12 Lariam ® [Medication Guide]. Nutley, NJ: F. Hoffmann-La Roche LTD; May 2004. 

13 The South African Medicines Formulary: Antiprotozoals, Part 2: Antimalarials. Available at 

http://web.uct.ac.za/depts/mmi/jmoodie/p01part2.html. Accessed September 2004. 

14 Daraprim® Tablet; Pharmacokinetic properties. Available at 

http://emc.medicines.or.uk/emc/assets/c/html/displaydoc.aspdocumentid=729. Accessed 


15 Tatro, ed. Drug Interaction Facts. Facts and Comparisons. St. Louis. 2004. 




19 Aralen ® [Prescribing Information]. New York, NY: Sanofi-Synthelabo; June 2003. 

20 Plaquenil ® [Prescribing Information]. New York, NY: Sanofi-Synthelabo; April 2002. 

21 Daraprim ® [Prescribing Information]. Research Triangle Park, NC: GlaxoSmithKline; March 

2003. 


23 Aralen ® [Prescribing Information]. New York, NY: Sanofi-Synthelabo; June 2003. 

24 Plaquenil ® [Prescribing Information]. New York, NY: Sanofi-Synthelabo; April 2002. 


26 Daraprim® Tablet; Posology and Method of Administration. Available at 

http://emc.medicines.or.uk/emc/assets/c/html/displaydoc.aspdocumentid=729. Accessed 





28 MICROMEDEX ® Healthcare Series, Thomson MICROMEDIX, Greenwood Village, Colorado; 

Edition Expires 12-2004. 


301

30 Klasco, RK ed. USP DI ® Drug Information for the Health Care Professional. Thomson 

MICROMEDIX, Greenwood Village, Colorado; 2004. 

31 Ibrahim MH, Elbashir MI, Naser A, Aelbasit IA, Kheir NM, Adam I. Low-dose Quinine is 

effective in the treatment of Chloroquine-resistant Plasmodium falciparum malaria in Easter 

Sudan. Ann Trop Med Parasitol. 2004 Jul; 98(5): 441-5. 

32 White NJ, Krishna S, Waller D, Craddock C, Kwiatkowski D, Brewster D. Open comparison of 

intramuscular chloroquine and quinine in children with sever chloroquine-sensitive falciparum 

malaria. Lancet. 1989 Dec 2;2(8675): 1313-6. 

33 Baird JK, Fryauff DJ, Basri H, Bangs MJ, Subianto B, Wiady I, Purnomo, Leksana B, Masbar 

S, Richie TL, et al. Primaquine for prophylaxis against malaria among non-immune transmigrants 

in Irian Jaya, Indonesia. Am J trop Med Hyg, 1995 Jun; 52(6): 479-84. 

34 Mengesha T, Makonnen E. Comparative efficacy and safety of chloroquine and alternative 

Antimalarial drugs: a meta-analysis from six African countries. East Afr Med J. 1999 Jun: 76(6): 

314-9. 

35 Randrianarivelojosia M, Ratsimbasoa A, Randrianasolol L, Randrianarijaona A, Jambou R. Invitro 

sensitivity of Plasmodium falciparum in chloroquine, halofantrine, mefloquine and quinine in 

Madagascar. East Afr Me J. 2002 May; 79(5): 237-41. 

36 Schwartz E, Regev-Yochay G. Primaquine as prophylaxis for malaria for non-immune travelers: 

A comparison with mefloquine and doxycycline. Clin Infect Dis. 1999 Dec; 29(6): 1502-6. 

37 Kofoed K, Petersen E. The efficacy of chemoprophylaxis against malaria with chloroquine plus 

proguanil, mefloquine, and atovaquone plus proguanil in travelers from Denmark. J Travel Med. 

2003 May-Jun; 10(3): 150-4. 

38 Warhurst DC, Steele JC, Adagu IS, Craig JC, Cullander C. Hydroxychloroquine is much less 

active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with it 

physicochemical properties. J Antimicrob Chemother. 2003 Aug; 52(2): 188-93. 

39 Weiss WR, Oloo AJ, Johnson A, Koech D, Hoffman SL. Daily primaquine is effective for 

prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and 

chloroquine plus proguanil. J Infect Dis. 1995 Jun; 171(6): 1569-75. 

40 Fansidar ® [Product Information]. Nutley, NJ: F. Hoffmann-La Roche LTD; August 2004 



2004. 







45 Malarone ® [Prescribing Information]. Research Triangle Park, NC: GlaxoSmithKline; 

September 2004 


47 Tatro, ed. Drug Interaction Facts. Facts and Comparisons. St. Louis. 2004. 














302

57 Klasco, RK ed. USP DI ® Drug Information for the Health Care Professional. Thomson 

MICROMEDIX, Greenwood Village, Colorado; 2004. 

58 Llanos-Cuentas A, Campos P, Clendenes M, Canfield CJ, Hutchinson DB. Atovaquone and 

proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment 

of acuter Plasmodium falciparum malaria in Peru. Braz J Infect Dis. 2001 Apr; 5(2): 67-72. 

59 Mulenga M, Sukwa TY, Canfield CJ, Hutchinson DB. Atovaquone and proguanil versus 

pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia. Clin Ther. 

1999 May; 21(5): 841-52. 

60 Bustos DG, Canfield CJ, Canete-Miguel E, Hutchinson DB. Atovaquone-proguanil compared 

with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium 

falciparum malaria in the Philippines. J Infect Dis. 1999 Jun; 179(6): 1587-90. 

303

I. Overview 



Pharmacotherapy Review of the Misc. Antiprotozoals 

AHFS 083092 


Protozoal infections of the gastrointestinal tract occur worldwide and cause significant morbidity 

and mortality. Prevalence is higher in developing countries and areas unable to afford proper 

sanitation. In the United States, protozoal and other parasitic infections are most common in 

immigrants and recent travelers, institutional settings, daycare centers, pregnant women, and in 

immunocompromised patients. The drugs to be reviewed in this class are indicated for various 

parasitic and protozoal infections. Two of the drugs to be reviewed are also used to treat 

infections caused by anaerobic, gram negative, and gram positive bacteria. Pertinent parasites and 

protozoa will be discussed. 

Cryptosporidiosis 

Cryptosporidiosis is caused by the coccidian parasite Cryptosporidium parvum. The parasite is 

transmitted by ingestion of oocysts excreted in the feces of infected humans or animals. 1 

Transmission generally occurs through person-to-person contact, ingestion of contaminated 

drinking or recreational water, ingestion of contaminated food, from animal to person, or by direct 

contact with contaminated feces or environmental surfaces. 1 Cryptosporidium oocysts are highly 

resistant to chemical disinfectants used to treat drinking water and small numbers are even able to 

escape filtration. 1 Highest rates of occurrence are in persons aged 1-5 years and in patients with 

AIDS. 2 

In immunocompetent patients, Cryptosporidiosis is manifested as acute, self-limiting diarrhea 

lasting 7 to 14 days and may be accompanied by nausea, abdominal cramping, and low-grade 

fever. In the United States, approximately 2.5% of non-immunocompromised patients have 

oocyts of C. parvum and approximately 30% of non-immunocompromised patients are seropositive 

for C. parvum. Cryptosporidiosis was rarely reported until the beginning of the AIDS 

epidemic. In patients with AIDS, the infection is usually chronic and more severe. In the past, 

10-15% of patients with AIDS developed cryptosporidiosis. 2 However, with the introduction of 

highly active anti-retroviral therapy, the incidence has dropped. 

Giardiasis 

Giardiasis is caused by the protozoa Giardia lamblia (also known as Giardia intestinalis) and is 

the most common intestinal parasite in the United States. 3 Prevalence in the United States is as 

high as 3-13% and carrier rates are as high as 30-60% 5 Giardiasis is not associated with 

significant mortality except in children and pregnant women who can become extremely 

dehydrated. Person-to-person transmission of the cyst form of the protozoa is the most common 

means of infection. However, because it can survive in cyst form outside of the human body, 

Giardia can be found in soil, food, recreational water, or contaminated feces. The trophozoite 

form of the protozoa causes intestinal symptoms including diarrhea, flatulence, greasy stools, 

stomach cramps, and nausea. Symptoms usually occur 1 to 2 weeks after infection. 4 Anorexia, 

malaise, and weight loss are also common. Chronic infection can lead to nutritional deficiencies 

due to malabsorption. 

Amebiasis 

Amebiasis is caused by the protozoa Entamoeba histolytica. Entamoeba is transmitted in cyst 

form through contaminated water, food, or feces. The trophozoite form of the protozoa is 

responsible for symptomatic infection. E. histolytica infections can remain inside the intestine or 

they can spread to include abscesses of the perineum, genitalia, pericardium, peritoneum, liver, 

lungs, and the brain in rare cases. Clinical manifestations of intestinal infection range from vague 

304

complaints of abdominal discomfort and malaise to severe abdominal cramps, flatulence, and 

bloody diarrhea with mucus. 3 Fever occurs only in 10-30% of patients. In the United States, 

prevalence of Entamoeba infection is approximately 4%, although only 10% of persons who are 

infected have symptomatic disease. Institutionalized individuals (particularly the mentally 

retarded), homosexual males, immunosuppressed patients, and recent travelers are at highest risk 

for infection. 

Balantidiasis 

Balantidiasis is caused by the protozoa Balantidium coli. Balantidiasis is not very common in the 

United States, with an estimated prevalence of 1%. 6 Sporadic infections have been reported in 

institutionalized settings. Internationally, balantidiasis is associated with those who frequently 

come in contact with swine and generally demonstrates mortality only in patients who are 

malnourished or immunocompromised. Balantidiasis is transferred from person-to-person or 

animal to person in the cyst form and can exist outside of the human body in contaminated water 

or feces. Most infections are asymptomatic, but acute illness can present as diarrhea, mucus and 

blood in the stools, nausea, and intestinal colic. 

Trichomoniasis 

Trichomoniasis is a sexually transmitted protozoal infection caused by Trichomonas vaginalis. In 

the United States, trichomoniasis affects 2 to 3 million women annually. 7 Prevalence in men 

ranges from 8-31%. 7 The organism can survive for short period of time on moist surfaces, such as 

bathing or toilet articles. Symptoms in women range from none in asymptomatic carriers to 

severe pelvic inflammatory disease. Common symptoms include yellow to grayish vaginal 

discharge, vaginal odor, vaginal itching, and dysuria. 3 Infected pregnant women are 30% more 

likely than uninfected women to have a low birth weight infant. 7 Symptoms in men range from 

none in asymptomatic carriers to urethral discharge, pruritus, dysuria, urethritis, and prostatitis. 3 

Pneumocystis Carinii Pneumonia 

Pneumocystis carinii (also known as Pneumocystis jiroveci) is a unicellular eukaryote that is 

sometimes regarded as a protozoan because of its susceptibility to anti-protozoal drugs. 

Pneumocystis carinii pneumonia (PCP) is a major source of morbidity and mortality in 

immunocompromised patients. 8 It is the most common opportunistic respiratory infection in HIV 

patients and is also a pathogen in patients with a history of malignancy, autoimmune diseases, and 

organ transplant. 8 PCP is transmitted through inhalation of air-borne cysts that infect the 

respiratory tract. Most people in the United States show seroconversion by age 3, but only 

immunocompromised patients develop clinical disease. 8 Early in the HIV epidemic, 75% of HIV 

patients developed PCP at some point. With the addition of prophylactic therapy, the range is now 

10-20% with a mortality rate of 10-20% . 8 Since the additional of prophylactic therapy, incidence 

of PCP in other immunocompromised patients has dropped to 0-10% with a mortality rate of 

40%. 8 Classic symptoms of PCP include non-productive cough, fever, dyspnea, chest pain, 

sputum production, and tachypnea. 

305


review. 

Table 1. Misc. Antiprotozoals in this Review 


Nitazoxanide Powder for Oral Suspension, Oral Tablet Alinia 

Metronidazole Oral Tablet, Oral Extended Release Tablet, Oral 

Capsule, Lyophilized Powder for Injection, 

Injection 

*Flagyl 

*Flagyl ER 

Flagyl IV, Metro IV, Flagyl IV RTU 

Protostat (D/c’d) 

Atovaquone Oral Suspension Mepron 

Trimetrexate 

Lyophilized Powder for Injection 

Neutrexin 

glucuronate 

Pentamidine 

Isethionate 

Solution for Inhalation, Injection 

NebuPent 

*Pentam 300 

Furazolidone Oral Tablets, Oral Liquid **Furoxone 


** Per manufacturer, Furoxone has been unavailable for 2 years with no release date. 

II. 



The current drug of choice for cryptosporidiosis in non-HIV infected patients is nitazoxanide. 9 

However, nitazoxanide has not been shown to be superior to placebo in HIV-infected patients. 9 

Nitazoxanide is the first drug to be approved for the treatment of cryptosporidiosis and the first to 

become available as a liquid for the treatment of giardiasis. 10 Nitazoxanide is approved for the 

treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia in pediatric patients 

aged 1 through 11 years. 11 Nitazoxanide’s exact mechanism of action us unknown, but it is 

believed to interfere with anaerobic energy metabolism. Nitazoxanide inhibits the growth of 

Cryptosporidium oocysts and Giardia trophozoites. Nitazoxanide is also active against Isospora 

belli, Entamoeba histolytica, as well as various helminths. 10 

Prior to the introduction of nitazoxanide, paromomycin and azithromycin were used in the 

treatment of cryptosporidiosis, but without clearly demonstrated effectiveness. 10 In the treatment 

of giardiasis, metronidazole was the treatment of choice prior to the introduction of nitazoxanide. 

However, nitazoxanide has the advantage of being a liquid formulation, better tolerated, and has a 

shorter duration of treatment. 10 

In the guidelines for the diagnosis and management of foodborne illnesses, the CDC has 

recommendations for the diagnosis and treatment of illness caused by contaminated food sources. 

Specifically, paromomycin and nitazoxanide are recommended in severe illness of children aged 

1-11 years. 11 The CDC has also posted guidelines for the prevention of transmission through 

water and food sources, person-to-person transmission, animal-to-person transmission, and 

prevention of exposure in HIV infected persons. 1 

Giardiasis 

The drugs of choice for the treatment of giardiasis are currently metronidazole and nitazoxanide, 

with tinidazole and paromomycin as alternatives. 9 In the treatment of giardiasis, metronidazole 

was the treatment of choice prior to the introduction of nitazoxanide. However, nitazoxanide has 

the advantage of being a liquid formulation, better tolerated, and has a shorter duration of 

treatment. 10 In the guidelines for the diagnosis and management of foodborne illnesses, the CDC 

has recommendations for the diagnosis and treatment of illness caused by contaminated food 

sources. Metronidazole is listed as the treatment of choice for giardiasis. 12 

306

Amebiasis 

The drugs of choice for the treatment of amebiasis caused by Entamoeba histolytica vary 

depending on severity of disease. The recommended treatment for asymptomatic to mild intestinal 

disease is iodoquinol or paromomycin. 9 The drugs of choice for moderate to severe intestinal 

disease or for extraintestinal disease are metronidazole or tinidazole. 9 In the guidelines for the 

diagnosis and management of foodborne illnesses, the CDC has recommendations for the 

diagnosis and treatment of illness caused by contaminated food sources. Metronidazole and a 

luminal agent (iodoquinol or paromomycin) are listed as the treatments of choice for giardiasis. 12 

Balantidiasis 

The drug of choice for the treatment of balantidiasis is tetracycline with metronidazole and 

iodoquinol as alternatives. 9 Because tetracycline is not recommended in pregnant women or 

children due to potential discoloration of permanent teeth, metronidazole would be a useful 

alternative. 


The drugs of choice for the treatment of trichomoniasis are metronidazole or tinidazole. 9 Brigham 

and Woman’s Hospital has published guidelines for the diagnosis and treatment of common 

gynecological problems. Recommended treatment for the treatment of trichomoniasis is oral 

metronidazole. 13 During pregnancy, common practice is to consider deferring treatment until after 

the first trimester, although the CDC recommends pregnant women can be treated even in the first 

trimester to prevent adverse fetal outcome. 13 

Pneumocystis Carinii (Jiroveci) Pneumonia 

The drug of choice for the treatment of Pneumocystis carinii pneumonia (PCP) is 

trimethoprim/sulfamethoxazole (SMZ/TMP) with alternatives being primaquine plus clindamycin, 

trimethoprim plus dapsone, pentamidine, trimetrexate glucuronate, or atovaquone. The drug of 

choice for the primary and secondary prophylaxis of PCP is trimethoprim/sulfamethoxazole with 

alternatives being dapsone, dapsone plus pyrimethamine, pentamidine aerosol, or atovaquone. 9 

Guidelines exist for the prevention and treatment of PCP in persons infected with HIV, and in 

patients who have recently received solid organ, blood, or bone marrow transplants. 

The 2001 USPHS/DSA guidelines for the prevention of opportunistic infections in person infected 

with HIV, as well as additional sources, recommend PCP prophylaxis regimens in patients with 

one or more prior episodes of PCP, a CD4+ count of less than 200 cells/mm 3 , thrush associated 

14, 15 

with HIV, or unexplained fevers greater than 100 degrees F for more than two weeks. Of the 

drugs in this review, aerosolized pentamidine and atovaquone are alternative choices to the 

recommended regimen of SMZ/TMP. Primary prophylaxis can be discontinued in patients 

responding to highly active anti-retroviral therapies (HAART) who have had an increase in CD4+ 

T-cell counts of greater than 200 cells/mm 3 for at least three months. 14 Of the drugs in this review, 

intravenous pentamidine, atovaquone, and trimetrexate glucuronate are alternative choices to the 

recommended regimen of SMZ/TMP. 

In the case of solid organ, blood, or bone marrow transplant recipients, the CDC recommends 

prophylaxis for PCP from the time of transplant to a minimum of six months for all patients, and 

greater than six months for those receiving immunosuppressive therapy or those with graft-versus 

host disease. 16,17 Of the drugs in this review, inhaled pentamidine is the best alternative to the 

preferred drug SMZ/TMP. 16 

307

III. 

Comparative Indications of the Misc. Anti-Protozoals 

Table 2 lists the FDA-approved indications for the miscellaneous anti-protozoal agents. Table 3 

further describes the major protozoal organisms and the treatments of choice. 

Table 2. FDA-Approved Indications for the Misc. Anti-Protozoals 11 

Drug Cryptosporidium 

parvum 

Giardia 

lamblia 

Entamoeba 

histolytica 

Trichomonas 

vaginalis 

Balantidium 

coli 

Nitazoxanide 

Metronidazole 

Atovaquone 

✔ 

✔ 

Misc. organisms (i.e. 

Bacteroides sp., 

Fusobacterium sp., 

Clostridium sp., 


Peptococcus sp., 

Peptostreptococcus sp.) 

✔ ✔ ✔ ✔ ✔ 

Pneumocystis 

carinii 

✔ 

Vibrio 

cholerae 

Trimetrexate 

glucuronate 

✔ 

Pentamidine 

Isethionate 

✔ 

Furazolidone * ✔ ✔ 

* Furazolidone is also active against various intestinal bacterial that cause diarrhea such as E. coli, Campylobacter, Enterobacter, Proteus, 

Salmonella, Shigella, and staphylococci. 

9, 11 

Table 3. Major Protozoal Infections, Causative Organisms, and Treatments of Choice 

Infection Organism Drug(s) of Choice (+ alternatives) 


Cryptosporidium 

parvum 

Nitazoxanide 1 

Giardiasis Giardia lamblia Metronidazole, Nitazoxanide (Tinidazole, Paromomycin, 

Furazolidone) 

Amebiasis 

Entamoeba 

histolytica 

Intestinal infection: Paromomycin, Iodoquinol 

Severe intestinal or extraintestinal infection: 

Metronidazole or Tinidazole followed by Paromomycin or 

iodoquinol) 

Balantidiasis Balantidium coli Tetracycline (Metronidazole, Iodoquinol) 


Pneumocystis carinii pneumonia 

(PCP) 

Trichomonas 

vaginalis 

Pneumocystis carinii 

Metronidazole, Tinidazole 

Treatment: SMZ/TMP (Primaquine plus Clindamycin, 

Trimethoprim plus Dapsone, intravenous Pentamidine, 

Atovaquone) 

Prophylaxis: SMZ/TMP (Dapsone, Dapsone plus 

Pyrimethamine, inhaled Pentamidine, Atovaquone) 

1 

Ntazoxanide is only indicated in infections in children age 1 through 11 years. Effectiveness in HIV-infected patients has not 

been consistently proven. 

308

IV. 

Pharmacokinetic Parameters of the Misc. Anti-Protozoals 

Nitazoxanide 

Metronidazole 

Atovaquone 

of Action 

Believed to be 

due to 

interference 

with the 

pyruvate: 

ferredoxin 

oxidoreductase 

enzymedependent 

electron 

transfer 

reaction, 

which is 

essential to 

anaerobic 

energy 

metabolism. 

Undergoes 

intracellular 

chemical 

reduction via 

mechanisms 

unique to 

anaerobic 

metabolism. 

Reduced 

metronidazole 

is cytotoxic 

and interacts 

with DNA to 

cause a loss of 

helical 

structure, 

strand 

breakage, and 

therefore 

inhibition of 

nucleic acid 

synthesis and 

cell death. 

Not fully 

known. 

Possibly cidal 

by inhibiting 

mitochondrial 

electrontransport 

chain 

at site of 

cytochrome 

bc1 complex, 

ultimately 

inhibiting the 

synthesis of 

nucleic acid 

and ATP. 

Well absorbed 

orally 

(at least 80%). 

Oral peak 

serum in 1 to 

2 hours. 

Plasma 


are 

proportional to 

dose. 

Oral 

suspension has 

two-fold 


over oral 

tablets. 


of each 

increases twofold 

when 

given with 

meals (47% 

suspension 

and 23% 

tablet). 

Binding 

>99% Tizoxanide – 

eliminated in 

urine, bile 

and feces 

309 

Tizoxanide 

glucuronide 

– eliminated 

in urine and 

bile 

94% fecal. 

Active 

Metabolites 

Yes – 

tizoxanide 

and 

tizoxanide 

glucuronide 

Yes – 2- 

hydroymethyl 

Elimination 

Biliary; 

Trimetrexate 

glucuronate 

Pentamidine 

Isethionate 

(Intravenous) 

Pentamidine 

Isethionate 

(Inhaled) 

Furazolidone 

A folate 

antagonist that 

inhibits the 

enzyme 

dihydrofolate 

reductase, 

therefore 

disrupting 

DNA, RNA, 

and protein 

synthesis 

resulting in 

cell death. 

Not fully 

understood. 

May interfere 

with nuclear 

metabolism 

and inhibit the 

synthesis of 

DNA, RNA, 

proteins and 

phospholipids. 

Not fully 

understood. 

May interfere 

with nuclear 

metabolism 

and inhibit the 

synthesis of 

DNA, RNA, 

proteins and 

phospholipids 

Microbicidal. 

Minimizes 

development 

of resistant 

organisms by 

interfering 

with several 

bacterial 

enzyme 

systems. Also 

acts as an 

MAOI. 

Very 

lipophilic. 

Injectable. 10- 

30% excreted 

unchanged in 

urine, 50% 

excreted in 

feces as 

unchanged 

drug;

V. Drug Interactions of the Misc. Anti-Protozoals 

Administering atovaquone with food can increase its absorption two-fold. 

Metronidazole may interfere with chemical analyses for AST, ALT, LDH, triglycerides, and 

hexokinase glucose. Table 5 illustrates drug interactions with the agaents in this class. 

Table 5. Drug Interactions of the Misc. Anti-Protozoals 19 


Nitazoxanide - Nitazoxanide and highly protein 

bound drugs 

Nitazoxanide is highly protein bound, 

therefore use with caution when administering 

with other highly protein-bound drugs due to 

Metronidazole 


major, established) 

Metronidazole and warfarin 

Metronidazole Level 2 (rapid, 

moderate, 

suspected) 

Metronidazole and ethanol 

Metronidazole Level 4 (delayed, Metronidazole and lithium 


Metronidazole Level 4 (delayed, Metronidazole and hydantoins 


Metronidazole Level 2 (delayed, Metronidazole and barbiturates 

moderate, 

suspected) 

Metronidazole Level 2 (delayed, Metronidazole and disulfiram 

moderate, 

suspected) 

Metronidazole Level 5 (delayed, Metronidazole and cimetidine 

minor, possible) 

Atovaquone - Atovaquone and highly protein 

bound drugs 

Atovaquone 


moderate, 

suspected) 

Atovaquone and zidovudine 

311 

competition for binding sites. 

Liver metabolism of warfarin may be 

decrease, therefore increasing the 

anticoagulant effect of warfarin. 

Disulfiram-like reaction due to accumulation 

of acetaldehyde by interference with the 

oxidation of alcohol. 

May cause serum lithium levels to increase. 

Phenytoin levels may increase due to 

decreased clearance. 

Metronidazole’s elimination can be 

accelerated, resulting in decreased plasma 

levels. 

May result in acute psychosis or confused 

state. 

Metronidazole serum levels may increase due 

to decreased clearance. 

Atovaquone is highly protein bound, 

therefore use with caution when 

administering with other highly proteinbound 

drugs due to competition for 

binding sites. Phenytoin has not been 

affected. 

Atovaquone can inhibit the glucuronidation of 

zidovudine, therefore elevating serum 

zidovudine concentrations. 

Atovaquone - Atovaquone and rifamycins Decrease in plasma concentrations of 

atovaquone and increase in plasma 

concentrations of rifampin. 

Atovaquone 

Trimetrexate 

glucuronate 

Trimetrexate 

glucuronate 

Pentamidine 

Isethionate 

(injectable) 

Furazolidone 



Atovaquone and etoposide 

- Trimetrexate and drugs that 

inhibit cytochrome P450 (i.e. 

erythromycin, fluconazole, 

rifampin, rifabutin) 

- Trimetrexate imidazole drugs 

(clotrimazole, ketoconazole, 

miconazole) 


major, suspected) 



Pentamidine and ziprasidone 

Furazolidone and Ethanol 

Mechanism unknown. Atovaquone may 

elevate etoposide concentrations. 

Could result in trimetrexate toxicity, due to 

decreased metabolism. 

Could result in inhibited trimetrexate 

metabolism, resulting in toxicity. 

Prolongation of QT interval could result in 

cardiac arrythmias. 

Inhibition of enzymes responsible for 

conversion of acetaldehyde to acetate could

Furazolidone 

Furazolidone 

Furazolidone 

Furazolidone 

Furazolidone 


major, suspected) 


moderate, 

suspected) 


major, possible) 


major, possible) 



Furazolidone and 

Sympathomimetics 

Furazolidone and Anorexiants 

Furazolidone and Levodopa 

Furazolidone and Meperidine 

Furazolidone and Tricyclic 

antidepressants 

cause a disulfiram-like reaction. 

Furazolidone may increase the pressor 

sensitivity to mixed and indirect-acting 

sympathomimetics possibly resulting in 

hypertension. Direct-acting sympathomimetics 

(eg, dobutamine [eg, Dobutrex]) are not 

affected. 

Increased sensitivity to pressor response of 

anorexiants due to MAO inhibition. 

Efficacy and adverse effects of levodopa could 

be increased due to inhibition of MAO. 

Unknown. Could include agitation, seizures, 

diaphoresis, fever, coma. 

Possible augmentation or release of amines in 

the CNS could cause variable effects including 

psychosis. 

VI. 

Adverse Drug Events of the Misc. Anti-Protozoal Agents 

Table 6. Common Adverse Events (%) Reported for the Misc. Anti-Protozoal Agents 11 

Adverse Event Nitazoxanide Metronidazole Atovaquone * Trimetrexate 

glucuronate ** 


Malaise 

Infection 

Influenza symptoms 

Moniliasis 

Myalgia 


Edema 

Hypotension 

Hypertension 

Chest pain 




Diarrhea 



Appetite increase 

Flatulence 

Metallic taste 

Dry mouth 



Fatigue 

Fever 

Headache 



Pressure 

Collapse 

Confusion 

Drowsiness 

Hepatic 


Hepatitis 

Jaundice 



Alopecia 

Rash 

Sweat 

- 

b 

b 

- 

- 

- 

- 

- 

- 

- 

7.8 

1.1 

2.1 

- 

- 

b 

b 

- 

- 

b 

- 

b 

1.1 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

7 

6 

3 

- 

- 

- 

- 

- 

4 

10 

4 

- 

- 

- 

- 

9 

2 

4 

- 

- 

18 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

- 

- 

- 

- 

- 

b 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

312 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

- 

- 

- 

- 

- 

b 

- 

b 

- 

- 

- 

- 

b 

- 

Pentamidine 

isethionate 

(injectable) 

- 

b 

- 

- 

- 

- 

- 

0.9 

- 

- 

- 

5.9 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

1.7 

- 

8.7 

- 

- 

- 

- 

3.3 

- 

Pentamidine 

isethionate 

(inhaled) 

- 

- 

- 

- 

- 

b 

- 

- 

- 

- 

b 

- 

b 

b 

b 

- 

b 

- 

- 

- 

b 

- 

b 

- 

- 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

Furazolidone 

- 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

-

Pruritus b - - - - - - 

Hematologic 

Neutropenia 


Anemia 


Leukopenia 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

b 

- 

b 

b 

- 

- 

- 

1.2 

1.7 

2.8 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

Renal 



- 

- 

- 

- 

- 

- 

- 

- 

- 

0.5 

- 

- 

- 

- 

- 

- 

Metabolic 

Increased creatinine 

Electrolyte imbalance 

Hypoglycemia 

Hypocalcemia 

GU 

Vaginitis 

Genital pruritus 

Abnormal urine 

Dysmenorrhea 

UTI 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

15 

5 

3 

3 

2 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

23 

- 

2.4 

0.2 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

- 

- 

Respiratory 

Rhinitis 

URTI 

Sinusitis 

Pharyngitis 

Cough 

Other 

Angioedema 

Convulsions 

4 

4 

3 

3 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 


• Percentages varied for atovaquone and trimetrexate adverse effects based upon each study and each drug being compared against. It is 

difficult to distinguish adverse events from underlying effects of HIV. 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

b 

b 

b 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

- 

VII. 

Dosing and Administration for the Misc. Anti-Protozoals 

Agents9, 11 

Table 7. Dosing for the Anti-Protozoal 


Nitazoxanide 100mg/5ml powder Children 12 to 47 months: 5ml every 12 hours for 3 days 

for oral suspension, 

500mg tablet Children 4 to 11 years: 10ml every 12 hours for 3 days 

Metronidazole 



750mg extended 

release tablet 

375mg capsules 

500mg powder for 

injection 

5mg/ml injection 

Other Notes 

• Take with food. 

• Safety and efficacy has not been established for infants less than 1 year 

of age. 

Intestinal Amebiasis: 

750mg three times daily for 5 to 10 days 

Amebic liver abscess: 

500 or 750mg three times daily for 5 to 10 days 

Children: 35 to 50 mg/kg/24 hours (max 750mg/dose) in 3 divided doses for 

10 days 

Giardiasis: 

250mg three times daily for 5 days 

Children: 15mg/kg/day in three doses for 5 days 

Trichomoniasis: 

1 day treatment: 2gm either as single dose or in two divided doses in one day. 

7 day treatment: Adults: 250mg three times daily for 7 days 

313

Atovaquone 

Trimetrexate 

glucuronate 

Pentamidine 

Isethionate 

(Intravenous) 

Pentamidine 

Isethionate 

750mg/5ml 

suspension 

25mg powder for 

injection 

300mg injection 

300mg aerosol 

314 

Children: 5mg/kg/dose three times daily for 7 days 

Balantidiasis: 

As alternative to tetracycline: 750mg three times daily for 5 days 

Children: 35-50mg/kg/day in three doses for 5 days. 

Other Notes 

• Take with meals for snack to lessen GI irritation. 

• ER tablets should be taken on an empty stomach. 

• When used to treat trichomoniasis, treat sexual partner as well, even if 

asymptomatic. 

Avoid alcohol during treatment and for 4 days after. 

PCP prophylaxis: 

Age 13 to adult: 1500mg once daily with a meal. 

PCP treatment: 

Age 13 to adult: 750mg twice daily with food for 21 days 

Failing to take doses with food can result in a two-fold decrease in 

absorption. 

Trimetrexate must be given with concurrent leucovorin to avoid potentially 

serious or life-threatening toxicities. Leucovorin must be given daily during 

trimetrexate therapy and for 72 hours past the last dose. 

Moderate to severe PCP in adults >18 years old: 

45mg/m 2 once daily IV over 60 to 90 minutes. Leucovorin may be administered 

IV at a dose of 20mg/m 2 over 5 to 10 minutes every 6 hours for a total daily dose 

of 80mg/m 2 or orally as 4 doses of 20mg/m 2 spaced equally throughout the day. 

Round up dose to next 25mg increment. Length of therapy is 21 days of 

trimetrexate and 24 days of leucovorin. 

Toxicity grades 1 through four are listed below in ascending order: 

Neutrophils /mm 3 Platelets/mm 3 Trimetrexate Leucovorin 

>1,000 >75,000 45mg/m 2 once daily 20mg/m 2 q 6 h 

750-1000 50,000-75,000 45mg/m 2 once daily 40mg/m 2 q 6 h 

500-749 25,000-49,999 22mg/m 2 once daily 40mg/m 2 q 6 h 

(Inhaled) 

Furazolidone 

100mg tablets 

50mg/15ml liquid 

(Both unavailable 

with no release date) 

5-7 L/min. 

Average of 5mg/kg/day given in four divided doses. Do not exceed 8.8 

mg/kg/day due to nausea. 

Adults: 100mg four times daily 

Children: (5 years or older) 25 to 50 mg four times daily 

(1 to 4 years) 17 to 25 mg four times daily 

(1 month to 1 year) 8 to 17 mg four times daily. 

Avoid alcohol during treatment and for up to 4 days after. 

Avoid foods containing tyramine. 

Avoid OTC and prescription sympathomimetics. 


11, 18 

Table 8. Special Dosing Considerations for the Misc. Anti-Protozoal Agents 

Drug Renal Hepatic Pediatric Use Pregnancy 

Dosing Dosing 

Nitazoxanide No No Only indication is for children 

aged 1 through 11 years. 

Safety and effectiveness has 

not been established in 

patients < 1 year old. 

Metronidazole 

Reduce to 

50% of 

normal 

dose for 

GFR < 

10ml/min 

Yes – 

monitor 

for 

toxicity 

Atovaquone No Yes – 

use with 

caution 

Trimetrexate 

glucuronate 

Pentamidine 

Isethionate 

(Intravenous) 

Interrupt 

tx if 

serum 

creatinine 

>2.5mg/dl 

Interrupt 

tx if 

LFT’s < 

5 times 

upper 

limit of 

normal 

range. 


children has not been 

established except in 

treatment of amebiasis. 

Newborns show a diminished 

capacity to eliminate. 

No information is available of 

the efficacy in pediatric 

patients. Clinical experience 

is limited to data in 

immunocompromised patients 

aged 1 month to 13 years. 

Safety and efficacy has not 

been established for patient < 

18 years of age. Data 

indicated two children treated 

successfully without adverse 

event. 

No No Data is limited, however 

dosing is the same as adults. 

Category 

B 

B 

C 

D 

C 

Can Drug Be Crushed/Stability 

Available in liquid. No data available 

on administration per tube. 

Tablets may be crushed and 

suspended in cherry syrup. Stable for 

30 days at ambient room temperature 

or refrigerated. 

IV form must be diluted or 

neutralized unless in RTU form. 

Reconstituted IV form is stable for 96 

hours when stored

than 1 month old due to 

possibility of hemolytic 

anemia. 

formulations. 

VIII. Comparative Effectiveness of the Misc. Anti-Protozoals 

Table 9. Additional Outcomes Evidence for the Misc. Anti-Protozoals 


Duration 

Ortiz JJ, 

et al. 20 n=110 Nitazoxanide for 3 

days vs. 

metronidazole for 5 

days for giardiasis 

Amadi B n=100 Nitazoxanide for 

et al. 21 cryptosporidiosis 

Colby C, 

et al. 22 n=39 Atovaquone vs. 

SMZ/TMP following 

autologous stem cell 


(ASCT) 

Dohn M, n=109 Atovaquone vs. IV 

et al. 23 pentamidine in the 

treatment of PCP 

El-Sadr , n=1057 Dapsone vs. 

et al. 24 atovaquone for PCP 

prophylaxis 

Results 

100 children with giardiasis were randomized to either a 3-day course of nitazoxanide 

or a 5-day course of metronidazole: 

• Diarrhea had resolved in 85 % of the nitazoxanide group vs. 80% for 

metronidazole. 

• Only mild, transient adverse events were reported. 

• Results: a 3-day course of nitazoxanide is as efficacious as a 5-day course of 

metronidazole in the treatment of giardiasis in children. 

50 HIV positive children and 50 HIV-negative children with C. parvum were 

randomly assigned to either nitazoxanide or placebo: 

• In HIV-negative children, diarrhea resolved in 56% of drug group vs. 23% of 

placebo. 

• In HIV-negative children, C. Parvum was eradicated form stool in 52% of drug 

group vs. 14% placebo. 

• HIV positive patients did not benefit from nitazoxanide. 

39 post-ASCT patients were studied. 16 patients received atovaquone and 19 patients 

received SMZ/TMP for the prevention of PCP: 

• None of the patients treated with atovaquone were removed from the study due 

to treatment associated adverse events. 40% of the patients randomized to 

SMZ/TMP dropped out of the study due to drug intolerance. 

• None of the patients treated developed PCP. 

• Atovaquone is better tolerated than SMZ/TMP in the prophylaxis of PCP after 

ASCT. 

109 patients with HIV and mild to moderate PCP received either atovaquone (n=56) 

or IV pentamidine (n=53) for 21 days: 

• More patients were successfully treated with atovaquone (57%) than with IV 

pentamidine (40%), but more patients failed to respond to atovaquone (29%) 

than pentamidine(17%). 

• Discontinuation of treatment due to adverse events was more common with 

pentamidine (36%) than with atovaquone (4%). 

• Atovaquone and IV pentamidine have similar efficacy in the treatment of PCP, 

but atovaquone may have fewer adverse events. 

1057 HIV-positive patients (298 had a history of PCP) were randomized to receive 

either daily atovaquone (536) or daily dapsone (521): 

• 122 of 536 atovaquone patients developed PCP vs. 135 of 521 dapsone patients. 

• Among the 546 patients who were receiving dapsone at base line, the relative 

risk of discontinuation because of adverse events was 3.78 for atovaquone as 

compared with dapsone, among those not receiving dapsone at base line, it was 

0.42. 

• Among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone 

and dapsone are similarly effective for the prevention of P. carinii pneumonia. 

Results support the continuation of dapsone prophylaxis among patients who are 

already receiving it. However, among those not receiving dapsone, atovaquone 

is better tolerated and may be the preferred choice for prophylaxis against P. 

carinii pneumonia. 

316

Chan C, et 

al. 25 n=549 Atovaquone 

suspension vs. 

pentamidine aerosol 

for PCP prophylaxis 

549 HIV-positive patients who were intolerant to SMZ and/or TMP were randomized 

to receive either atovaquone suspension or aerosolized pentamidine: 

• The incidence of treatment-limiting adverse events was significantly higher with 

atovaquone than with pentamidine. 

• There was no significant difference in the time using therapy. 

• Incidences of PCP and death were higher in patients receiving 750mg 

atovaquone than 1500mg atovaquone. 

• Atovaquone 1500mg daily had similar efficacy to that of aerosolized 

pentamidine. 


Dose Simplification: In most cases, the antiprotozoal agents in this class are given as a single 

dose or for a brief duration (acute use), depending on the infection being treated. When given for 

longer durations, such as PCP prophylaxis, dosing is once daily. 

Stable Therapy: There is little evidence of resistance to antiprotozoal therapy in the literature. 

The majority of time that standard therapy was discontinued for a particular indication, the cause 

is intolerability to the drug of choice. There are many reports in the literature of resistance to 

anti-protozoal drugs, particularly in the treatment of trichomoniasis and giardiasis. Resistance 

against metronidazole is frequently reported, and there is cross-resistance within the family of 5- 

nitroimidazole drugs. There is also evidence that resistance to the drugs used to treat PCP is also 

developing, including SMZ/TMP, atovaquone and pentamidine. 

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal clinical 

literature relevant to use of the antiprotozoals and their impact on physician visits. 

IX. 

Conclusions 

Nitazoxanide is the first drug to be approved for Cryptosporidiosis. Although it does not seem to 

be anymore efficacious than metronidazole in the treatment of giardiasis, it does have the 

advantage of being a liquid formulation. Therefore, nitazoxanide’s primary use is in the treatment 

of Cryptosporidiosis. Treatment of this infectious disease is not applicable to the general 

population. 

In the treatment of giardiasis, metronidazole in the drug of choice, therefore furazolidone does not 

offer any advantage over metronidazole due to its current unavailability, brand name status, and 

drug interaction profile. 

In the treatment of Pneumocystis carinii pneumonia, SMZ/TMP is the drug of choice. However, 

due to intolerability, injectable pentamidine, atovaquone and trimetrexate are alternatives to 

standard therapy. Injectable pentamidine is available generically. Atovaquone and trimetrexate 

are not available generically. Injectable pentamidine and atovaquone show similar efficacy in the 

treatment of PCP, although atovaquone may be better tolerated. Trimetrexate has a disadvantage 

compared to atovaquone due to the need to administer with leucovorin and its inability to be used 

in pregnancy or in children and would be considered a third-line agent. 

In the prophylaxis of Pneumocystis carinii pneumonia, SMZ/TMP is the drug of choice. However, 

due to intolerability, aerosolized pentamidine or atovaquone are alternatives to standard therapy. 

Neither drug is available generically. Aerosolized pentamidine and atovaquone show similar 

efficacy to each other. Aerosolized pentamidine has the advantage of being better tolerated, but 

unlike systemic agents, offers no protection against other types of infections. 15 Treatment and 

prophylaxis therapies for Pneumocystis carinii pneumonia are not applicable to the general 

population. 

The primary role of the drugs in this class, as pertinent to general use in the population, is for the 

treatment of giardiasis, amebiasis, balantidiasis, and trichomoniasis. The drug in this class 

indicated for these infectious diseases is metronidazole. Metronidazole is available as a generic 

317

formulation. Therefore, all brand anti-protozoal agents in this class are comparable to each other 

and to the generics and OTC products in the class and offer no significant clinical advantage over 

other alternatives in general use. Additionally, the therapies for Cryptosporidiosis and 

Pneumocystis carinii pneumonia are not within the scope of general use in the population, and 

should be available for their indicated special needs/circumstances via medical justification 

through the prior authorization process. 


No brand antiprotozoal agent is recommended for preferred status. 

318

References 

1. Juranek DD. Centers for Disease Control and Prevention (CDC). Cryptosporidiosis: Sources of 

Infection and Guidelines for Prevention. Accessed at www.cdc.gov September 2004. 

2. Eisen, D. Cryptosporidiosis. Accessed at www.emedicine.com. Topic #484. Last updated 

March 2004. 

3. Anandan JV. Parasitic Diseases. In: Pharmacotherapy. A Pathophysiologic Approach. 

Dipiro JT, Talbert RL, Yee GC, et al. Eds. Elsevier Science. New York. 1989. Pg. 1197-1198. 

4. Centers for Disease Control and Prevention (CDC). Giardia Infection: Fact Sheet for the 

General Public. Accessed at www.cdc.gov September 2004. 

5. Pennardt, A. Giardiasis. Accessed at www.emedicine.com. Topic #215. Last updated June 

2004. 

6. Chijide, VM. Balantidiasis. Accessed at www.emedicine.com Topic # 203. Last updated March 

2002. 

7. Perkins AM. Trichomoniasis. Accessed at www.emedicine.com Topic # 2308. Last updated 

August 2004. 

8. Schreibman TS. Pneumocystis Carinii Pneumonia. Accessed at www.emedicine.com Topic # 

1850. Last updated August 2004. 

9. Abramowicz, M, Editor. The Medical Letter on Drugs and Therapeutics, Drugs for Parasitic 

Infections. The Medical Letter, Inc. New York August 2004. 

10. Abramowicz, M, Editor. The Medical Letter on Drugs and Therapeutics, Nitazoxanide (Alinia) 

– A New Anti-protozoal Agent. The Medical Letter, Inc. New York April 2003. 


12. Centers for Disease Control and Prevention (CDC). Guidelines for the Diagnosis and 

Management of Foodborne illnesses. MMWR Apr 16 2004;53;RR-4. 

13. Lifford, K, et al. Brigham and Women’s Hospital: Common gynecological problems: a guide to 

diagnosis and treatment. Boston (MA) Brigham and Woman’s Hospital; 2002. 


infections in HIV infected persons. MMWR Jun 2002 14;51 (RR8)1-52. 

15. Chaisson RE,Bishai W. The Management of Pneumocystis carinii, Toxoplasmosis, and HSV 

infections in patients with HIV disease. Last updated July 1999. Accessed at www.medscape 

.com September 2004. 


infections among hematopoietic stem cell transplant recipients. MMWR Oct 20 2000;49;RR- 

10. 

17. Cincinnati Children’s Hospital Medical Center. Evidence based clinical practice guidelines for 

pneumocystis carinii pneumonia prophylaxis following solid organ or blood and marrow 

transplants. Cincinnati, OH. 2001 Jan 12. 

18. Micromedex, Healthcare Series;DrugDex Drug Evaluations 2004. 


20. Ortiz JJ, Ayoub A, Gargala G, et al. Randomized clinical study of nitazoxanide compared to 

metronidazole in treatment of symptomatic giardiasis in children from northern Peru. Aliment 

Pharmacol Ther Sept 2001;15(9):1409-1415. 

21. Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in 

Zambian children with cryptosporidiosis. Lancet Nov 2, 2002;360(9343):1375-1380. 

22. Colby C, McAfee S, Sackstein R, et al. A prospective randomized trial comparing toxicity and 

safety of atovaquone with SMZ/TMP as PCP prophylaxis following ASCT. Bone Marrow 

Transplant Oct 1999;24(8):897-902. 

23. Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous 

pentamidine for PCP pneumonia in patients with AIDS. Ann Intern Med 1994 Aug;121(3):174- 

180. 

24. El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the 

prevention of PCP in patients with HIV who cannot tolerate sulfonamides or trimethoprim. N 

Eng J Med Dec 1998;339(26):1889-95. 

25. Chan C, Montaner J, Lefebvre E, et al. Atovaquone suspension compared with aerosolized 

pentamidine for prevention of PCP in HIV-infected subjects intolerant of SMZ and/or TMP. J 

of Infec Dis 1999;180:369-376. 

319



New Drug Pharmacotherapy Review 

Climara Pro (Estradiol/Levonorgestrel Transdermal System) 

Estrogen Replacement Products, Combination Agents, AHFS 681604 


I. Overview 

Multiple hormone replacement treatments are available for women, including combination agents for 

use in women with a uterus, to avoid risk of endometrial cancer. Progestins are combined with 

estrogens for three reasons: 1) to decrease the risk of estrogen-induced irregular bleeding, endometrial 

hyperplasia and carcinoma; 2) to protect against breast cancer; and 3) to enhance estrogen prophylaxis 

of osteoporosis. 1 

The estradiol / levonorgestrel (Climara Pro) transdermal system is the second approved and available 

combination estrogen/progestin transdermal system. The new transdermal system is available as 

0.045mg/day estradiol and 0.015mg/day of levonorgestrel. This review encompasses all dosage forms 

and strengths of the new drug. 

The estradiol / norethindrone acetate (Combipatch) system was included in the original estrogen 

combination agent class review in March 2004. The original review of the estrogen replacement 

products, combination agents, is available in full for reference in Appendix 1. Other oral 

estrogen combination agents are available with estradiol, conjugated estrogen, and esterified 

estrogens. There are generic alternatives on the market for one oral estrogen combination 

product (Estratest / H.S.); however, no generic alternatives are available for the transdermal 

estrogen replacement combination products. This review encompasses all dosage forms and 

strengths. 

II. 


The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 fold greater 

than in non-users, and appears dependent on duration of treatment and on estrogen dose. In 

addition, the greatest risk is associated with prolonged use, with increased risks of 15 to 24 fold 

for five to ten years or more. 2 

Information from the Women’s Health Initiative (WHI) trial about estrogens and progestins 

continues to have significant public health implications for postmenopausal women. The 

combined estrogen/progestin arm of the WHI study was stopped early because the increased risk 

of breast cancer and cardiovascular events exceeded the specified benefits. Additional results 

from the study are presented in Table 1. Many women’s health organizations now suggest that 

ERT / HRT be used only for management of vasomotor symptoms, using the lowest dose for the 

shortest duration. Topical vaginal products should especially be considered when ERT / HRT is 

only being considered for the treatment of vaginal atrophy. In addition, labeling for some oral 

combination estrogens has been updated to reflect the following changes: 2 

♦ 

Estrogens and progestins should not be used for the prevention of cardiovascular 

disease. 

Since the March P&T meeting, results of the estrogen-alone arm of the Women’s Health Initiative 

(WHI) have suggested similar results as found earlier with the combination estrogen agents; 

estrogen-alone hormone therapy had no effect on coronary heart disease risk but increased the risk 

of stroke in postmenopausal women. The WHI also found that estrogen-alone therapy 

significantly increased the risk of deep vein thrombosis, had no significant effect on the risk of 

breast or colorectal cancer, and reduced the risk of hip and other fractures. 3 

320

As a result of requests for information on the approved labeling for hormone replacement 

products, and information from the WHI studies, the Food and Drug Administration (FDA) has 

established a website on estrogen and progestin therapies for postmenopausal women. 4 The 

website at www.fda.gov contains information for patients and healthcare professionals including 

product labeling, FDA Talk Papers, treatment guidelines, and additional resources for relating 

women’s health information. 

Table 1. Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI A 5, 6 

Event 

Relative Risk CE/MPA vs. 

Placebo at 5.2 Years (95% 

Placebo 

n=8,102 

CE/MPA 

n=8,506 

CI*) 

Absolute Risk per 10,000 Person-Years 

CHD Events 

Non-fatal MI 

CHD death 

1.29 (1.02-1.63) 

1.32 (1.02-1.72) 

1.18 (0.70-1.97) 

30 

23 

6 

37 

30 

7 

Invasive Breast Cancer B 1.26 (1.00-1.59) 30 38 

Stroke 1.41 (1.07-1.85) 21 29 

Pulmonary Embolism 2.13 (1.39-3.25) 8 16 

Colorectal Cancer 0.63 (0.43-0.92) 16 10 

Endometrial Cancer 0.83 (0.47-1.47) 6 5 

Hip Fracture 0.66 (0.45-0.98) 15 10 

Death Due to Other Cause 0.92 (0.74-1.14) 40 37 

Global Index C 1.15 (1.03-1.28) 151 170 

Deep Vein Thrombosis D 2.07 (1.49-2.87) 13 26 

Vertebral Fractures D 0.66 (0.44-0.98) 15 9 

Other Osteoporotic Fractures D 0.77 (0.69-0.86) 170 131 

CE 0.625mg Conjugated Estrogens 

MPA 2.5mg Medroxyprogesterone 

A Adapted from JAMA 2002;288:321-333. 

B Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer. 

C A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, 

stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. 

D Not included in the Global index. 

* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. 

III. 

Indications 

The estradiol / levonorgestrel (Climara Pro) transdermal system is indicated in women with an 

intact uterus, for the treatment of moderate to severe symptoms associated with menopause. 6 

In comparison, estradiol / norethindrone (Combipatch) has indications for the treatment of 

vasomotor symptoms, atrophic vaginitis, hypogonadism, primary ovarian failure, and castration. 

Most of the oral estrogen combination agents are indicated for the treatment of vasomotor 

symptoms, atrophic vaginitis, and osteoporosis prevention. 

321

IV. 

Pharmacokinetics 

5, 6, 8 

Table 2. Pharmacokinetic Parameters of Select Combination Estrogen Agents 

Drug 

Time to Reach Peak Protein Metabolism Elimination Half-Life (T 1/2 ) 

Estradiol / 

norethindrone 

(Activella) 

Estradiol / 

levonorgestrel 

(Climara Pro) 

Estradiol / 

norethindrone 

(Combipatch ) 

Esterified 

estrogens / 

methyltestosterone 

(Estratest) 

Ethinyl estradiol / 

norethindrone 

(FemHRT) 

Concentration (T max ) 

Estradiol- 5-8 hours 

Norethindrone- 0.5- 

1.5 hours 

Estradiol-36 hours 

Levonorgestrel-48 

hours 

Estradiol- 12-24 

hours 

Norethindrone- 24 

hours 

Esterified estrogens- 

NA 

Methyltestosterone- 

NA 


Binding 

98% First-pass in 

the liver 

Primarily 

urine 

Estradiol- 12-14 hours 

Norethindrone- 8-11 hours 

- Liver Urine Estradiol- 3 ± 0.67 hours 

Levonorgestrel- 28 ± 6.4 

hours 

- Skin, Liver Urine Estradiol- 2-3 hours 

Norethindrone- 6-8 hours 

98% First-pass in 

the liver 

1-2 hours >95% First-pass in 

the liver 

Primarily 

urine 

Primarily 

Urine 

Esterified estrogens-NA 

Testosterone-10- 

100minutes 

Ethinyl Estradiol- 23.9 

hours 

Norethindrone- 13.3 hours 

In-vivo and in-vitro studies have shown that estrogens are metabolized partially by cytochrome 

P450 3A4. 6, 7 This includes the Climara Pro transdermal system. Therefore, inducers or inhibitors 

of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort, 

phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, 

possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding 

profile. CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, 

ritonavir, and grapefruit juice may increase plasma concentrations of estrogens and may result in 

side effects. Additionally, levonorgestrel is metabolized through hydroxylation by the following 

cytochrome P450 enzymes: 3A, 2E, and 2C. Inducers or inhibitors of these enzymes may either, 

respectively, decrease the therapeutic effects or result in side effects. Dosage adjustments 

(increased or decreased) may be necessary to manage the induction or inhibition of estrogens 

when given in combination with interacting drugs. 

As all estrogens are metabolized similarly, drug interactions are common with these agents as a 

class. Most importantly, there are no major severity (level 1) drug interactions that have been 

documented with estrogens. 

VI. 


As a result of the WHI results and current treatment guidelines, women should be treated with the 

lowest estrogen dose possible, to minimize risk of adverse events. Table 3 lists the reported 

adverse events in >3% of patients. 

Additionally, the irritation potential of the estradiol / levonorgestrel transdermal system was 

assessed in a 3-week irritation study. 6 Visual assessments of irritation were made on day 7 of each 

wear period, and were compared for a Climara Pro placebo patch and a Climara placebo patch. 

Mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Climara Pro 

placebo and 0.20 (week 1), 0.26 (week 2), and 0.12 (week 3) for the Climara placebo. No 

irritation scores were greater than 2 at time in any subject during the study. In controlled trials, 

withdrawals due to application site reactions occurred in 2.1% of patients in the symptom study 

and in 8.5% of patients in the 1-year endometrial protection study. In comparison, use of 

322

Combipatch in studies did not result in any discontinuations due to application site reactions, of 

which occurred only in 4% of patients. 8 

Table 3. Clinical Adverse Events with Estradiol / Levonorgestrel Transdermal 6 

Adverse Event 

Climara Pro 

n=212 

Estradiol (E 2) 

n=204 



Accidental Injury 

Back Pain 

Flu Syndrome 

Infection 

Pain 

9 (4.2) 

7 (3.3) 

13 (6.1) 

10 (4.7) 

7 (3.3) 

11 (5.2) 

11 (5.4) 

6 (2.9) 

12 (5.9) 

13 (6.4) 

10 (4.9) 

13 (6.4) 


Hypertension 7 (3.3) 9 (4.4) 

Digestive 

Flatulence 8 (3.8) 5 (2.5) 

Metabolic and Nutritional 

Edema 

Weight Gain 

8 (3.8) 

6 (2.8) 

5 (2.5) 

10 (4.9) 


Arthralgia 9 (4.2) 10 (4.9) 

Nervous System 

Depression 

Headache 

Respiratory 

Bronchitis 

Sinusitis 

Upper Respiratory Infection 


Application Site Reaction 

Breast Pain 

Rash 

Urogenital 

Urinary Tract infection 

Vaginal Bleeding 

Vaginitis 

12 (5.7) 

11 (5.2) 

9 (4.2) 

8 (3.8) 

28 (13.2) 

86 (40.6) 

40 (18.9) 

5 (2.4) 

7 (3.3) 

78 (36.8) 

4 (1.9) 

7 (3.4) 

14 (6.9) 

7 (3.4) 

12 (5.9) 

26 (12.7) 

69 (33.8) 

20 (9.8) 

10 (4.9) 

8 (3.9) 

44 (21.6) 

6 (2.9) 

VII. 


Use of estrogen alone or in combination with a progestin should be limited to the lowest effective 

dose available and for the shortest duration consistent with treatment goals and risks for the 

individual woman. All patients should be reevaluated on a 3-6 month basis to determine if 

treatment is still necessary. Table 4 compares the dosing regimens for both available estrogen 

combination transdermal systems. 

Table 4. Dosing for the Transdermal Estrogen Combination Systems 6, 8 

Drug Dose/Frequency/Duration Available strengths 

Estradiol/Levonorgestrel 1 patch once weekly for 0.045mg estradiol /0.015mg 

(Climara Pro) 

Estradiol/Norethindrone 

(Combipatch) 

28 days 

1 patch twice a week for 

28 days 

levonorgestrel per day patch 

0.05mg estradiol/ 0.14mg 

norethindrone per day patch 

0.05mg 

estradiol/0.25mg 

norethindrone per day patch 

323

VIII. Effectiveness 

Multiple studies have evaluated the efficacy of transdermal estrogen combination systems. These 

studies are presented in Table 6. Additionally, the incidence of endometrial hyperplasia during 

continuous combined treatment with the estradiol / levonorgestrel (Climara Pro) transdermal 

system was evaluated in a study of 412 postmenopausal women. Results are illustrated in Table 5. 

Table 5. Incidence of Endometrial Hyperplasia During Continuous Combined Treatment 

with the Estradiol / Levonorgestrel Transdermal System 6 

0.045mg Estradiol / 

0.015mg Levonorgestrel 

(Climara Pro) 

n=210 

Estradiol (E 2 ) 0.045mg 

n=202 

# of patients with biopsies at ≥ 

124 139 

6 months 1 

# of patients with biopsies at 1 

102 110 

year 2 

# (%) of patients with 

0 (0%) 19 (17.3%) 

hyperplasia 3 

95% Confidence interval 0-3.55% 9.75-24.79% 

n=number of intent-to-treat subjects. 

1 

Defined as at least 180 days of treatment. 

2 

Defined as at least 323 days of treatment. 

3 

Includes hyperplasia occurring at any time after initiation of treatment as a proportion of patients with biopsies at 1 

year. 

Table 6. Efficacy of the Transdermal Estrogen Combination Systems 

Study Sample Duration Results 

Estradiol / levonorgestrel 

transdermal patch vs. placebo for 

vasomotor symptoms 6 n=183 12 week 

randomized, 

placebo 

In evaluating the efficacy of the 0.045mg estradiol / 0.030mg 

levonorgestrel transdermal system when administered once 

weekly for moderate to severe vasomotor symptoms: 

controlled 

trial 

• The estradiol / levonorgestrel transdermal system 

was shown to be statistically better than placebo at 

weeks 4 and 12 for relief of both the number and 

Oral conjugated estrogen plus 

medroxyprogesterone vs. 

transdermal estradiol plus oral 

medroxyprogesterone on 

hypertriglyceridemia 9 n=61 3month, 

randomized 

trial 

Transdermal estradiol / 

levonorgestrel on bleeding pattern 

in postmenopausal women 10 n=468 4 week, 

randomized, 

multicenter 

study 

severity of moderate to severe hot flashes. 

Women participants included those who had received oral 

conjugated estrogen (0.625mg) plus 2.5mg 

medroxyprogesterone daily for 12 months, and developed 

triglyceride concentrations exceeding 150mg/dl. Patients 

were then randomly assigned to continue their current 

regimen or change to transdermal estradiol plus the same dose 

of medroxyprogesterone. Results indicated: 

• Serum concentrations of triglyceride and very-lowdensity 

lipoprotein triglyceride decreased 

significantly after changing to transdermal estradiol 

(triglyceride, from 226.0 +/- 43.9 to 110.5 +/- 44.1 

mg/dL, P < 0.01). 

• No changes were seen in concentrations of lowdensity 

lipoprotein cholesterol or high-density 

lipoprotein cholesterol. 

In evaluating the bleeding pattern and acceptability with use 

of transdermal estradiol alone for 2 weeks, followed by 

transdermal estradiol / levonorgestrel for 2 weeks: 

• The occurrence of cyclic bleeds was dose-dependent, 

with an increase at higher dosages; the frequency of 

a cyclic bleed per treatment cycle was 40% in the 

50/10 micrograms/24 h patch, 62% in the 75/15 

324

Transdermal estradiol / 

n=293 

levonorgestrel in 3 strengths (E 2 

0.045mg/day with 0.015, 0.030, 

or 0.040mg/day) 11 

Two 

prospective 

multicenter, 

double-blind, 

randomized, 

controlled 

trials 

micrograms/24 h patch and 76% in the 100/20 

micrograms/24 h patch. 

• The incidence of intermittent bleeding also increased 

with higher doses, from 22% in the 50/10 group to 

35% in the 100/20 group; 20% of women in the 

50/10 group did not bleed at all; the corresponding 

figures for the 75/15 and 100/20 groups were 7% 

and 0%, respectively. 

• Time of onset of cyclic bleeding was constant in all 

groups. The mean duration of cyclic bleeding was 

constant within each group, but increased from 4.4 

days in the 50/10 to 6.3 days in the 100/20 group. 

• The regularity and predictability of cyclic bleeding 

were high in all groups. Recurrence of cyclic bleeds 

was acceptable for most women (90%). 

Study 1: Patients received transdermal estradiol 0.045mg/day 

with 0.030 or 0.040mg/day levonorgestrel, or placebo for 3 

28-day cycles. 

Results: 

• Transdermal estradiol 0.045mg/day with 0.030 and 

0.040mg/day of levonorgestrel significantly 

decreased the number and severity of hot flushes 

when compared with placebo. 

• Symptom relief was seen as early as 2 weeks post 

treatment. 

n=845 

Efficacy and tolerability of 

transdermal estradiol / 

levonorgestrel as HRT in 

postmenopausal women 12 - 12 week 

double-blind, 

placebo 

controlled 

treatment 

phase, 

followed by a 

12 week 

open, follow- 

Study 2: Patients received transdermal estradiol 

0.045mgmg/day with 0.015, 0.030, or 0.040mg/day 

levonorgestrel, or transdermal estradiol 0.045mg/day as 

monotherapy for thirteen 28-day treatment cycles. 

Results: 

• No women receiving transdermal estradiol / 

levonorgestrel developed endometrial hyperplasia 

compared with 19 (12.8%) who received 

transdermal estradiol 0.045 mg/day alone (p < 

0.001 for each dose). 

• Significant improvements from baseline in scores 

on the Women's Health Questionnaire for 

vasomotor symptoms, sleep problems, sexual 

function, cognitive difficulties, and total score were 

noted at all or most time points with both 

transdermal estradiol / levonorgestrel and with 

estradiol alone. 

• Application-site reactions, vaginal hemorrhage, 

and breast pain were the most common adverse 

events reported with transdermal E2/LNG. The 

proportion of women with amenorrhea increased 

over time in all treatment groups in study 2. 

In evaluating the efficacy and tolerability of a 7-day 

transdermal sequential estradiol / levonorgestrel patch (2 

weeks of estradiol monotherapy patch followed by 2 weeks of 

the combination patch) with that of placebo in women aged 

40-65 with an intact uterus: 

• The sequential use of a 7-day estradiol patch and a 7- 

day estradiol / levonorgestrel patch was superior to 

placebo in reducing menopausal symptoms, and was 

well tolerated. 

325

up phase • At the end of the treatment phase, there was a 

statistically significant reduction in the Kupperman 

Index score (a measure of menopause symptoms) 

versus placebo (P

References 

1. Mullins PM, Pugh MC, Moore AO. Hormone Replacement Therapy. In: Pharmacotherapy. A 

Pathophysiologic Approach. Dipiro JT, Talbert RL, Yee GC, et al. Eds. Appleton & Lange. 

Connecticut. 1997. Pg. 1635-46. 

2. Prempro and Premphase ® [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003. 

3. P&T Community. WHI study finds no heart disease benefit, increased stroke risk with estrogen 

alone. Available at: www.ptcommunity.com. Accessed June 2, 2004. 

4. Estrogen and estrogen with progestin therapies for postmenopausal women. U.S. Food and Drug 

Administration. Available at: www.fda.gov/cder/drug/infopage/estrogens_progestins. Accessed 

June 2, 2004. 

5. Kastrup EK, Ed. Drug Facts and Comparisons. Facts & Comparisons. St. Louis. 2004. 

6. Climara Pro [package insert]. Montville, NJ: Berlex;2003. 

7. Tatro DS, Ed. Drug Interaction Facts. Facts & Comparisons. St. Louis. 2004. 

8. Murray L, Senior Editor. Package Insert for Combipatch. In: Physicians’ Desk Reference, PDR 

Edition 58, 2004. Thomson PDR. Montvale, NJ. 2004. 

9. Sanada M, Tsuda M, Kodama I, et al. Substitution of transdermal estradiol during oral estrogenprogestin 

therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause 

2004;11(3):331-336. 

10. Van de Weijer PH, Sturdee DW, von Holst T. Estradiol and levonorgestrel: effects on bleeding 

pattern when administered in a sequential combined regimen with a new transdermal patch. 

Climacteric 2002 Mar;5(1):36-44. 

11. Shulman LP, Yankov V, Uhl K. Safety and efficacy of a continuous once-a week 17beta-estradiol 

/ levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety 

in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled 

trials. Menopause 2002 May-Jun;9(3):195-207. 

12. von Holst T, Salbach B. Efficacy of a new 7-day transdermal sequential estradiol / levonorgestrel 

patch in women. Maturitas 2002 Mar 25;41(3):231-42. 

13. Siseles NO, Benencia H, Mesch V, et al. Once and twice a week transdermal estradiol delivery 

systems: clinical efficacy and plasma estrogen levels. Climacteric 1998 Sep;1(3):196-201. 

327



New Drug Pharmacotherapy Review- 

Symbyax (Olanzapine and Fluoxetine capsules) 

AHFS Class 281604 


I. Overview 

The depressive phase of bipolar disorder is associated with substantial morbidity, functional 

impairment, suicide, and other causes of excess mortality. 1 Patients with bipolar disorder 

experience depressive symptoms more than three times longer than they experience manic 

symptoms. 2 Treatment options for bipolar depression remain somewhat limited. Lithium or 

lamotrigine are currently considered first-line pharmacologic options for bipolar depression, based 

on the 2002 American Psychiatric Association (APA) treatment guidelines. (See “Evidence Based 

Medicine and Current Treatment Guidelines” below.) These agents are effective, but are not 

always associated with complete response, and in some cases are associated with treatmentlimiting 

side effects. 2 Overall, the treatment of bipolar depression is understudied, both in absolute 

terms and in comparison with the treatment of acute bipolar mania. 1 Since publication of the 2002 

APA guidelines, several new clinical studies regarding the acute treatment and prevention of 

bipolar depression have been published that may impact future treatment recommendations. 1 

Symbyax ® is a combination of two psychotropic agents, olanzapine and fluoxetine, indicated for 

the treatment of depressive episodes associated with bipolar disorder. Fluoxetine is a selective 

serotonin reuptake inhibitor (SSRI), while olanzapine has high affinity binding to serotonin, 

dopamine, muscarinic, histamine, and alpha 1 -adrenergic receptors. Although the exact mechanism 

of this combination product is unknown, it is proposed that the activation of three monoaminergic 

neural systems (serotonin, norepinephrine, and dopamine) is responsible for its enhanced 

antidepressant effect. 3 

Efficacy of the combination of olanzapine and fluoxetine in the treatment of bipolar I depression 

has been demonstrated in two clinical trials of identical study design (data were pooled and 

published in one article). 2 In these studies, olanzapine monotherapy significantly improved 

symptoms of bipolar depression, and the olanzapine/fluoxetine combination had an even stronger 

antidepressant effect without a greater risk of switch into mania. 

Olanzapine/fluoxetine combination is currently available as the brand product Symbyax ® and is 

available as 6mg/25mg, 6mg/50mg, 12mg/25mg, and 12mg/50mg capsules (mg olanzapine/mg 

fluoxetine). AHFS class 281604 was originally reviewed in July 2003, and this review has been 

included in the Appendix for reference. This review encompasses all dosage forms and strengths 

of the new drug. 

II. 


According to the APA 2002 treatment guidelines, the first-line pharmacological treatment for 

bipolar depression is the initiation of either lithium or lamotragine. 4 As an alternative, especially 

for more severely ill patients, some clinicians will initiate simultaneous treatment with lithium and 

an antidepressant. When an acute depressive episode does not respond to initial treatment at 

optimal doses, next steps include adding lamotrigine (if not used initially), bupropion, or 

paroxetine. Alternative next steps include adding a different SSRI, venlafaxine, or a monoamine 

oxidase inhibitor (MAOI). Antidepressant monotherapy is not recommended. 

The use of antidepressants in bipolar disorder is controversial. The APA guidelines recommend a 

cautious and limited, rather than routine, use of antidepressants in combination with mood 

stabilizers due to a risk of switching into mania and long-term worsening of bipolar illness. 5 On 

328

the other hand, the results of recent studies lend insight into both the degree to which mood 

stabilizers reduce the risk of switching associated with antidepressant treatment, and the 

magnitude of risk of depressive relapse after antidepressant discontinuation. 1 

III. 

Indications 

Olanzapine/fluoxetine combination is indicated for the treatment of depressive episodes associated 

with bipolar disorder. Its effectiveness for maintaining antidepressant response in this patient 

population beyond 8 weeks has not been established in controlled clinical studies. 

IV. 


Concomitant administration of fluoxetine and olanzapine has resulted in small increases in the 

mean maximum concentration of olanzapine (≈16%), increases in the mean area under the curve 

(≈17%), and a small decrease in mean apparent clearance of olanzapine (≈16%). 3 The terminal 

half-life is not affected, so the time to reach steady state should not be altered. The overall steadystate 

plasma concentrations of olanzapine and fluoxetine when given as the combination in 

therapeutic dose ranges were comparable with those typically attained with each of the 

monotherapies. The observed small change in olanzapine clearance likely reflects the inhibition of 

a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, 

and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual 

components is expected to reasonably characterize the overall pharmacokinetics of the 

combination. 3 

Table 1. Pharmacokinetic Parameters of Olanzapine/Fluoxetine 3 

Olanzapine 

Fluoxetine 

Tmax 4 hr 6 hr 

Food Effect 

Does not affect rate or extent of • Delays absorption by 1-2 hrs 

absorption 

• No affect on systemic bioavailability 

Protein Binding 93% 94.5% 

Metabolism 

Highly metabolized by: 

Extensive, via CYP2D6, to norfluoxetine 

• Direct glucuronidation 

(active) and other metabolites 

• Cytochrome P450 1A2 and 2D6 

(minor), and flavin-containing 

monooxygenase system 

Elimination • Elimination half-life ≈ 21 to 54 

hrs 

• Metabolites excreted in urine 

(57%) and feces (30%) 

Elimination half-life 

• Parent drug: 1 to 3 days (acute) and 4 to 6 

days (chronic) 

• Active metabolite: 4 to 16 days 

Metabolites excreted in urine (57%) and feces 

(30%) 

329


Because the metabolism of fluoxetine involves the CYP2D6 system, concomitant therapy with 

drugs also metabolized by this enzyme system may lead to drug interactions. 

Table 2. Clinically Significant Drug Interactions 3,6 

Drug Interaction Management 

Alprazolam 

Fluoxetine inhibits alprazolam 

metabolism 

Monitor for signs of alprazolam 

intoxication. Reduce alprazolam dose; 

switch to a different benzodiazepine 

with less interaction potential (e.g., 

Antihypertensive agents 

Carbamazepine 

Clozapine 

Diazepam 

ECT 

Ethanol 

Haloperidol 

Levodopa, dopamine 

agonists 

Lithium 

MAOI 

NSAID/aspirin 

Phenytoin 

Olanzapine may induce 

hypotension, thereby enhancing the 

effects of antihypertensive agents 

Carbamazepine significantly 

increases olanzapine clearance and 

may reduce efficacy. 

Fluoxetine decreases 

carbamazepine metabolism, thus 

increasing carbamazepine levels. 

Fluoxetine decreases clozapine 

metabolism, thus increasing 

clozapine levels. 

Co-administration with olanzapine 

may potentiate olanzapine-induced 

orthostatic hypotension; Fluoxetine 

may prolong diazepam half-life 

Rare reports of prolonged seizures 

in patients on fluoxetine receiving 

ECT 

Co-administration may potentiate 

sedation and orthostatic 

hypotension. 

Elevated haloperidol blood levels 

with fluoxetine 

Olanzapine may antagonize the 

effects of these agents 

Both increased and decreased 

lithium levels have been observed 

with concomitant fluoxetine 

therapy. Lithium toxicity and 

serotonergic effects have been 

reported. 

Serious, sometimes fatal, reactions 

have been reported in patients 

receiving combination therapy and 

in patients receiving an MAOI 

after recently discontinuing 

fluoxetine. 

Increased risk of bleeding during 

concurrent use with SSRIs 

Elevated plasma levels of 

phenytoin with clinical toxicity due 

to inhibition of phenytoin 

metabolism by fluoxetine 

330 

lorazepam) 

Consider lower initial doses. 

Advise patients of risk, especially during 

initial dose titration 

Monitor for olanzapine efficacy and 

adjust dose as needed. Monitor 

carbamazepine levels and for signs of 

carbamazepine toxicity. Adjust 

carbamazepine doses accordingly. 

Monitor for signs of clozapine toxicity. 

Reduce clozapine dose if indicated 

Consider lower initial doses. 

Advise patients of risk, especially during 

initial dose titration 

Use cautiously in patients with history 

of seizures or with conditions that 

potentially lower seizure threshold. 

Avoid combination if at all possible. 

Due to risk of haloperidol toxicity and 

QT interval prolongation, concurrent 

administration is not recommended. 

Monitor patients for efficacy of antiparkinsonim 

agents. 

Monitor lithium levels. 

Use is contraindicated with, and for 5 

weeks after discontinuation of 

fluoxetine. 

Monitor for signs of bleeding. 

Monitor phenytoin levels with initiation 

of fluoxetine and periodically to assure 

stability. Also monitor levels for several 

weeks after discontinuation of

Drug Interaction Management 

fluoxetine. Adjust phenytoin dose 

accordingly. 

Pimozide 

Possible additive effects with Avoid concurrent use. 

fluoxetine on the QT interval 

leading to bradycardia 

Sumatriptan 

Rare postmarketing reports of 

weakness, hyperreflexia, and 

incoordination with fluoxetine 

Closely monitor patient for adverse 

effects. 

Thioridazine 

Tricyclic 

antidepressants (TCA) 

Tryptophan 

Warfarin 

Narrow therapeutic 

index drugs 

metabolized by 

CYP2D6 (e.g., 

flecainide, vinblastine) 

Omeprazole, rifampin, 

other CYP1A2 or 

glucoronyl transferase 

inducers 

Digitoxin, other drugs 

tightly bound to plasma 

proteins 

Elevated plasma levels of 

thioridazine with resultant increase 

in potential of dose-related QT c 

interval prolongation, which is 

associated with serious ventricular 

arrhythmias and sudden death 

Increased TCA plasma levels >2- 

to 10-fold due to inhibition of 


Adverse reactions including 

agitation, restlessness, and 

gastrointestinal distress, possibly 

due to additive effects with 

fluoxetine 

Altered anticoagulant effects 

including increased bleeding due to 

inhibition of warfarin metabolism 

by fluoxetine 

Increased plasma concentration of 

object drug due to inhibition of 


Increased olanzapine clearance 

resulting in decreased plasma 

levels 

Shift in plasma concentrations of 

object drug potentially resulting in 

an adverse effect 

Use is contraindicated with, and for 5 

weeks after discontinuation of 

fluoxetine. 

Monitor TCA plasma level and reduce 

dose if indicated. 

Monitor patients for signs of serotonin 

syndrome. 

Closely monitor INR and patient for 

signs of increased anticoagulation. 

Consider dose reduction of the object 

drug, or initiate at low end of dose range 

if patient already receiving fluoxetine, or 

has received in the previous 5 weeks. 

Monitor for olanzapine efficacy and 

adjust dose as needed. 

Monitor for increased digoxin levels and 

for signs and symptoms of toxicity. 

CYP = cytochrome P450; ECT = electroconvulsive therapy; MAOI = monoamine oxidase inhibitor; NSAID = non-steroidal antiinflammatory 

drug; TCA = tricyclic antidepressant 

IV. 


In short-term, controlled premarketing studies, 10% of patients receiving olanzapine/fluoxetine 

discontinued treatment due to adverse events compared with 4.6% for placebo. The most 

commonly observed adverse events associated with olanzapine/fluoxetine (≥5% and at least twice 

that for placebo) were: asthenia, edema, increased appetite, peripheral edema, pharyngitis, 

somnolence, thinking abnormal, tremor, and weight gain. 3 Table 3 lists adverse events reported in 

≥2% of patients receiving olanzapine/fluoxetine in controlled trials (with an incidence of twice or 

more that for placebo). 

331

Table 3. Treatment-Emergent Adverse Events: Incidence in Controlled Clinical Trials 3 

Adverse Event (%) Symbyax ® 

Bipolar Depression 

(n = 86) 

Symbyax ® 

Controlled 

(n = 571) 

Placebo 

(n = 477) 


Asthenia 13 15 3 

Accidental injury 5 3 2 

Fever 4 3 1 

Cardiovascular System 

Hypertension 2 2 1 

Tachycardia 2 2 0 


Diarrhea 19 8 7 

Dry mouth 16 11 6 

Increased appetite 13 16 4 

Tooth disorder 1 2 1 

Metabolic and Nutritional Disorders 

Weight gain 17 21 3 

Peripheral edema 4 8 1 

Edema 0 5 0 

Musculoskeletal System 

Joint disorder 1 2 1 

Twitching 6 2 1 

Arthralgia 5 3 1 

Nervous System 

Somnolence 21 22 11 

Tremor 9 8 3 

Thinking abnormal 6 6 3 

Lidibo decreased 4 2 1 

Hyperkinesia 2 1 1 

Personality disorder 2 1 1 

Sleep disorder 2 1 1 

Amnesia 1 3 0 

Respiratory System 

Pharyngitis 4 6 3 

Dyspnea 1 2 1 


Ambylopia 5 4 2 

Ear pain 2 1 1 

Otitis media 2 0 0 

Speech disorder 0 2 0 

Urogenital System 

Abnormal ejaculation 7 2 1 

Impotence 4 2 1 

Anorgasmia 3 1 0 

The “Bipolar Depression” column shows the incidence of adverse events with Symbyax ® in the bipolar depression studies. The 

“Symbyax ® -Controlled” column shows the incidence in the controlled Symbyax ® studies. The placebo column shows the incidence in 

the pooled controlled studies that included a placebo arm. 

332

Selected Warnings and Precautions 3 

• Clinical worsening and suicide risk: Patients treated with antidepressants should be observed 

closely for clinical worsening and suicidality, especially at the beginning of therapy or at the 

time of dose changes. (See “FDA Public Health Advisory March 22, 2004” below) 

• Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated 

with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with 

atypical antipsychotics, including olanzapine, either alone or concomitantly with fluoxetine. 

(See “Consensus Statement on Antipsychotic Drugs and Obesity and Diabetes”) 

• Orthostatic Hypotension: Orthostatic systolic blood pressure decrease of ≥30 mm Hg occurred 

in 7.3%, 1.4%, and 1.4% of the olanzapine/fluoxetine, olanzapine, and placebo groups, 

respectively in bipolar depression studies. Use with caution in patients with known 

cardiovascular disease, cerebrovascular disease, or conditions that predispose patients to 

hypotension. 

• Mania/Hypomania: There was no statistically significant difference in the incidence of manic 

events between olanzapine/fluoxetine- and placebo-treated patients. However, the limited 

controlled trial experience of olanzapine/fluoxetine in bipolar depression and the cyclical 

nature of bipolar disorder warrant close monitoring for the development of symptoms of 

mania/hypomania during treatment with olanzapine/fluoxetine. 

• Weight gain: The mean weight increase for olanzapine/fluoxetine-treated patients was 

statistically significantly greater than placebo-treated (3.6 kg vs. –0.3 kg) and fluoxetinetreated 

(3.6 kg vs. –0.7 kg) patients, but not significantly different from olanzapine-treated 

patients (3.6 kg vs. 3.0 kg). Fourteen percent of olanzapine/fluoxetine-treated patients met the 

criterion for having gained >10% of their baseline weight, compared with

Table 4. Monitoring protocol for patients on atypical antipsychotics 9 * 

Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 

years 

Personal/family history X X 

Weight (BMI) X X X X X 

Waist circumference X X 

Blood pressure X X X 

Fasting plasma glucose X X X 

Fasting lipid profile X X X 

*More frequent assessments may be warranted based on clinical status 

Subsequent to the publication of the consensus statement, the Food and Drug Administration 

(FDA) asked all manufacturers of atypical antipsychotic medications to add a warning statement 

to their product labeling describing the increased risk of hyperglycemia and diabetes in patients 

taking these medications. 10 

VII. 


Olanzapine/fluoxetine should be administered once daily in the evening, generally beginning with 

the 6mg/25mg capsule. Dosage adjustments, if indicated, can be made according to efficacy and 

tolerability. Antidepressant efficacy was demonstrated in a dose range of olanzapine 6 to 12mg 

and fluoxetine 25 to 50mg. The safety of doses above 18mg/75mg has not been evaluated in 

clinical trials. 3 

Special Dosing Considerations: 3 

• The starting dose of olanzapine/fluoxetine 6mg/25mg should be used for patients with a 

predisposition to hypotensive reactions, patients with hepatic impairment, or patients who 

exhibit a combination of factors that may slow the metabolism of the drug (female gender, 

geriatric age, nonsmoking status). Dose escalation, when indicated, should be performed with 

caution in these patient populations. 

• Neonates exposed to fluoxetine or other SSRIs late in the third trimester have developed 

complications requiring prolonged hospitalization, respiratory support, and tube feeding. The 

physician may consider tapering fluoxetine in the third trimester. 

• Symptoms associated with discontinuation of fluoxetine and other SSRIs have been reported 

(dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, 

headache, lethargy, emotional lability, insomnia, and hypomania). Patients should be 

monitored for these symptoms. A gradual reduction in the dose rather than abrupt cessation is 

recommended whenever possible. 

• The long elimination half-lives of fluoxetine and norfluoxetine assure that active drug will 

persist in the body for weeks, even when dosing is stopped. This is of potential consequence 

when drug discontinuation is required or when drugs are prescribed that might interact with 

fluoxetine and norfluoxetine following the discontinuation of fluoxetine. 


The efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I 

depression was evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled 

study. 2 A total of 833 patients were assigned to receive placebo (n=377), olanzapine (n=370) or 

olanzapine-fluoxetine combination (n=86; 6/25, 6/50, or 12/50mg/d administered as separate 

capsules taken together once daily in the evening). Eligible subjects were adults (age ≥18 years) 

who met DSM-IV criteria for bipolar I disorder, were depressed, had a Montgomery-Ashberg 

Depression Rating Scale (MADRS) total score of at least 20, and a history of at least one previous 

manic or mixed episode of sufficient severity to require treatment with a mood stabilizer or an 

antipsychotic agent. The primary measure of efficacy was the change in MADRS total score from 

baseline to week 8. Secondary efficacy measures included the Clinical Global Impressions 

Bipolar Version-Severity of Depression scale (CGI-BP-S), the Young Mania Rating Scale 

(YMRS), and the Hamilton Anxiety Rating scale (HAM-A) scores. Rates of and times to response 

334

(≥50% improvement in MADRS total score from baseline to an end point and completion of at 

least 4 weeks of study) and remission (MADRS score of 12 or less at an endpoint and completion 

of at least 4 weeks of study) were also assessed. 

Patients taking olanzapine-fluoxetine had the highest rate of completion (64.0%) compared with 

olanzapine (48.4%) or placebo (38.5%). From week 1 to the end of the study, the olanzapine and 

combination groups demonstrated significantly greater improvements in MADRS total scores than 

those receiving placebo (p

IX. 

Conclusions 

The combination of olanzapine and fluoxetine has demonstrated efficacy in the treatment of 

bipolar I depression in two clinical trials of identical study design (data were pooled and published 

in one article). 2 In these studies, olanzapine therapy significantly improved symptoms of bipolar 

depression, and the olanzapine/fluoxetine combination had an even stronger antidepressant effect 

(but not statistically significant) without a greater risk of switch into mania. 

The response rates achieved with the olanzapine/fluoxetine combination in these clinical trials 

appear similar to those achieved with lamotrigine, and possibly superior to those achieved with 

divalproex sodium in respective, placebo-controlled trials of those agents. 2,13,14 Such comparisons 

are limited, however, by methodological and sample differences between trials. 

The adverse event profile for the olanzapine/fluoxetine combination in clinical trials was similar to 

that of olanzapine monotherapy but also included higher rates of nausea and diarrhea. In addition, 

both active treatment groups were associated with significant weight gain, potentially clinically 

significant orthostatic hypotension, and elevations in nonfasting blood glucose and cholesterol 

levels. 

Use of the olanzapine/fluoxetine combination beyond 8 weeks has not been studied, nor has any 

advantage of the combination product over co-administration of the two ingredients separately (as 

in the clinical trials) been demonstrated. Furthermore, the question remains as to whether similar 

results could be achieved using other atypical antipsychotic agents in combination with a selective 

serotonin reuptake inhibitor or other antidepressants. 

Therefore, olanzapine/fluoxetine combination (Symbyax®) is comparable to the other brands in 

this class and to the generics and OTC products in this class and offers no significant advantage 

over other alternatives in general use. 


No brand of olanzapine/fluoxetine is recommended for preferred status. 

336

References 

1. Keck PE, Nelson EB, McElroy SL. Advances in the pharmacologic treatment of bipolar 

depression. Biol Psychiatry. 2003;53:671-679. 

2. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine 

combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60(11):1079- 

88. 

3. Eli Lilly and Company. Symbyax (olanzapine and fluoxetine HCl) prescribing 

information. Indianapolis (IN): March 2004. 

4. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar 

disorder (revision). http://www.psych.org/psych_pract/treatg/pg/bipolar_revisebook_1.cfm#a 

(Accessed September 20, 2004). 

5. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case 

for caution. Bipolar Disord. 2003;5:421-33. 

6. Thomson MICROMEDEX. Drug-Reax® Interactive Drug Interactions. MICROMEDEX® 

Healthcare Series Vol. 121 expires 9/2004. Accessed September 23, 2004. 

7. FDA Public Health Advisory: Worsening depression and suicidality in patients being treated 

with antidepressant medications. March 22, 2004. 

http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm (Accessed 

September 23, 2004). 

8. FDA Talk Paper. FDA Issues Public Health Advisory on Cautions for Use of Antidepressants 

in Adults and Children. March 22, 2004. 

http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01283.html (Accessed September 23, 

2004). 

9. American Diabetes Association, American Psychiatric Association, American Association of 

Clinical Endocrinologists, and the North American Association for the Study of Obesity. 

Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes 

Care. 2004;27:596-601. 

10. MedWatch 2004 Safety Alert: Zyprexa (olanzapine) 

http://www.fda.gov/medwatch/SAFETY/2004/zyprexa.htm (Accessed September 23, 2004). 

11. Shi L, Namjoshi MA, Swindle R, et al. Effects of olanzapine alone and olanzapine/fluoxetine 

combination on health-related quality of life in patients with bipolar depression: Secondary 

analyses of a double-blind, placebo-controlled, randomized clinical trial. Clin Ther. 

2004;26:125-134. 

12. Olanzapine/fluoxetine (Symbyax) for bipolar depression. The Medical Letter. 2004;46:23-24. 

13. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind, placebo-controlled study of 

lamotrigine monotherapy in outpatients with bipolar I depression: Lamictal 602 Study Group. 

J Clin Psychiatry. 1999;60:79-88. 

14. Sachs G, Altshuler LL, Ketter TA, et al. Divalproex versus placebo for the treatment of 

bipolar depression. Paper presented at: 2001 Annual Meeting of the American College of 

Neuropsychopharmacology; December 10,k 2001;Waikoloa, HI. 

337



New Drug Pharmacotherapy Review-Pexeva 

AHFS 281604 


I. Overview 

Pexeva is a new salt formulation of the selective serotonin reuptake inhibitor, paroxetine. 

Previously, all brand and generic formulations of paroxetine have been in the hydrochloride salt 

form (e.g., Paxil®, Paxil CR, generics). Pexeva contains the same active moiety, paroxetine, 

but in the mesylate salt form. Although paroxetine mesylate is considered to be bioequivalent to 

paroxetine hydrochloride, it is not AB rated to paroxetine hydrochloride due to the difference in 

salt form and therefore is considered a pharmaceutical alternative to, but not pharmaceutically 

equivalent to paroxetine hydrochloride. According to the manufacturer, the FDA did not require 

clinical trials for the approval of paroxetine mesylate due to the bridging toxicology and 

pharmacokinetic studies conducted by Synthon Pharmaceuticals, combined with existing data and 

published literature regarding the safety and efficacy of paroxetine hydrochloride. 1,2 As a 

selective serotonin reuptake inhibitor (SSRI), paroxetine is effective in the treatment of a variety 

of psychiatric disorders. The SSRI drug class has emerged as the drug class of choice over many 

other psychopharmacological treatments due to an improved safety and tolerability profile as 

compared to other classes (e.g., tricyclic antidepressants, monoamine oxidase inhibitors, etc.). 

AHFS class 281604 was originally reviewed in July 2003, and this review has been included in the 

Appendix for reference. This review encompasses all dosage forms and strengths of paroxetine 

mesylate. 

II. 


Depression 3-6 

Psychotherapy and antidepressant medications are effective in the treatment of depression. More 

than 50% of people with major depression experience marked improvement or complete remission 

of symptoms when antidepressant therapy is initiated. 3 Initial antidepressant choices used in the 

treatment of depression include SSRIs, venlafaxine, mirtazapine, and bupropion. Additional 

agents that have shown efficacy include tricyclic antidepressants and monoamine oxidase 

inhibitors (usually reserved for non-responders to other therapies). Selective serotonin reuptake 

inhibitors are generally considered first-line therapy for the pharmacologic therapy of depression 

due to their safety and tolerability as compared to many other antidepressants. 

The treatment of clinical depression includes three phases: an acute phase, a continuation phase, 

and a maintenance phase. Treatment during the acute phase may last anywhere from 4 to 12 

weeks, with a recommended minimum of 6 to 8 weeks. Drug therapy during this phase attempts to 

achieve remission or a return to the patient’s baseline level of symptoms and functioning. After 

achieving remission, the patient enters the continuation phase of treatment, where the patient is 

kept symptom free for the duration of the current episode. Recommended duration of therapy 

ranges from 6-12 months. The goal during the maintenance phase is to protect susceptible patients 

against new or future major depressive episodes. The treatment length required for maintenance 

therapy has not yet been fully determined, and will vary depending on the frequency and severity 

of prior major depressive episodes. A maintenance period of 2 to 3 years is appropriate for some 

patients with a recurrence, while life-long maintenance therapy may be most appropriate for 

patients with recurrent episodes of depression. 

338

Panic Disorder 7-9 

Panic disorder is estimated to have a lifetime prevalence of 2-4%. It is often accompanied by 

comorbid depression. According to practice guidelines developed by the American Psychiatric 

Association in 1998, treatment of panic disorder involves psychotherapy and pharmacological 

treatment, or a combination of both. Neither psychotherapy nor drug therapy has been proven to 

be superior to the other, but the combination of treatment modalities may be more efficacious than 

either alone. Recommended pharmacologic therapy involves an antidepressant (preferably an 

SSRI) with benzodiazepines utilized for initial rapid control of symptoms when needed. 

Antidepressant therapy may take anywhere from 4-12 weeks for full effect of therapy. Initial 

dosing of SSRIs is half that of doses used to treat depression, with subsequent dose titration. 

Benzodiazepines are used for early symptom control in combination with other pharmacologic 

and/or psychotherapeutic modalities. The guidelines recommend continuation of treatment with 

antidepressants for 12-18 months before drug discontinuation is attempted. Some patients may 

require chronic therapy for control of symptoms. Despite these guidelines recommending 

antidepressant therapy as first line therapy for panic disorder, a recent study of anxiety disorders 

found that the increase in SSRI use among these patients has been very modest, with 

benzodiazepines being the most common class of drugs used to treat this disorder. 7 

Obsessive-Compulsive Disorder (OCD) 10-12 

OCD affects about 2-3% of the U.S. population. Practice guidelines for OCD were last published 

in 1997. Updated practice guidelines for the treatment and management of OCD are expected in 

2006 by the American Psychiatric Association. The most effective treatments for OCD include 

cognitive-behavioral therapy and drug therapy with SSRIs. Full benefit of treatment may not be 

seen for 10-12 weeks, and doses of SSRIs needed may be higher than those typically used for 

depression. There is a high rate of relapse after SSRI therapy is discontinued, but this risk may be 

decreased with ongoing cognitive-behavioral therapy. Aside from SSRIs, clomipramine and 

venlafaxine are alternative agents for the treatment of OCD. 

III. Comparative Indications 13-15 

Paroxetine mesylate has three FDA-approved indications: Depression, obsessive-compulsive 

disorder (OCD), and panic disorder. 

Table 1. Indications for Paroxetine Mesylate 

Indication 

Generalized anxiety disorder (GAD) 

Major depressive disorder 

Obsessive compulsive disorder (OCD) 

Panic disorder 

Post-traumatic stress disorder (PTSD) 

Premenstrual dysphoric disorder (PMDD) 

Social anxiety disorder 

Paroxetine mesylate 

 

 

 

IV. Pharmacokinetic Parameters 13,16 

The efficacy of paroxetine in depression, obsessive-compulsive disorder (OCD), and panic 

disorder is thought to be related to the inhibition of serotonin reuptake in the central nervous 

system, thereby enhancing serotonergic activity. Paroxetine mesylate is completely absorbed into 

the bloodstream after oral administration and is extensively metabolized via oxidation, 

methylation, and conjugation. The metabolites have shown no more than 1/50 of the potency of 

the parent compound on inhibiting serotonin reuptake and are not considered significant 

contributors to drug activity. Paroxetine exhibits nonlinear kinetics with increasing dose and 

duration of use due to saturation of one of the metabolizing enzymes, CYP 450 2D 6 . Paroxetine 

distributes throughout the body and is excreted primarily as metabolites in the urine (64%) and 

feces (36%). Increased plasma concentrations have been observed in elderly patients, and patients 

with renal or hepatic impairment may experience two- to four-fold increases in plasma 

339

concentrations. Initial dosing needs to be reduced and length of dose titration interval should be 

lengthened in these populations. Paroxetine is roughly 95% protein bound with an elimination 

half-life of about 15-20 hours, reaching steady-state concentrations in roughly 10-14 days. 

V. Drug Interactions 13,16,17 

Paroxetine therapy is contraindicated in conjunction with monoamine oxidase inhibitors (MAOIs) 

due to the increased risk of serotonin syndrome or neuroleptic malignant syndrome. For patients 

switching therapy between these drugs (paroxetine or an MAOI), at least two weeks should elapse 

before the other agent is started. The concomitant use of paroxetine and thioridazine is also 

contraindicated due to the increased risk of serious cardiac arrhythmias with combined use. There 

are numerous additional potential interactions between paroxetine and other drugs listed in the 

table below. 

Table 2. Drug-Drug Interactions with Paroxetine 17 

Interacting Drugs Significance* Mechanism 

Sympathomimetics 

Amphetamine 

Benzphetamine 

Dextroamphetamine 

Diethylpropion 

Methamphetamine 

Phendimetrazine 

Phenmetrazine 

Phentermine 

Level 1 

(major / 

suspected) 

Unknown; increased risk of serotonin 

syndrome 

Selective 5-HT1 receptor 

antagonists (“triptans”) 

MAO Inhibitors 

**CONTRAINDICATED** 

Level 1 

(major / 

suspected) 

Level 1 

(major / 

probable) 

Sibutramine Level 1 

(major / 

suspected) 

Risperidone Level 1 

(major / 

suspected) 

NSAIDs Level 2 

(moderate / 

suspected) 

Tricyclic antidepressants 

Amitriptyline 

Desipramine 

Imipramine 

Nortriptyline 

Level 2 

(moderate / 

suspected) 

Possibly rapid accumulation of serotonin in the 

CNS; increased risk of serotonin syndrome 

Possibly rapid accumulation of serotonin in the 

CNS; increased risk of serotonin syndrome 

Additive serotonergic effects; increased risk of 

serotonin syndrome 

• Possibly rapid accumulation of serotonin 

in the CNS; increased risk of serotonin 

syndrome 

• Inhibition of risperidone metabolism 

leading to elevated risperidone plasma 

concentrations and risk for adverse events 

Unknown; the risk for adverse GI events may 

be increased 

Paroxetine may inhibit the metabolism of these 

TCAs leading to increased risk for TCA 

toxicity 

340

Table 2 (cont) 


Phenothiazines 

**THIORIDAZINE 

CONTRAINDICATED** 

Level 2 

(moderate / 

probable) 

Cyclosporine Level 2 

(moderate / 

suspected) 

Cyproheptadine Level 2 

(moderate / 

probable) 

Propafenone Level 2 

(moderate / 

suspected) 

St. John’s Wort Level 2 

(moderate / 

suspected) 

Zolpidem Level 3 

(minor / 

suspected) 

L-Tryptophan Level 4 

(moderate / 

possible) 

Oxycodone Level 4 

(moderate / 

possible) 

Beta-Blockers 

Carvedilol 

Metoprolol 

Propranolol 

Macrolide antibiotics 

Clarithromycin 

Erythromycin 

Troleandomycin 

Heparins 

Dalteparin 

Enoxaparin 

Heparin 

Tinzaparin 

Level 4 

(moderate / 

possible) 

Level 4 

(major / 

possible) 

Level 4 

(moderate / 

possible) 

Cimetidine Level 4 

(moderate / 

possible) 

Metoclopramide Level 4 

(major / 

possible) 

Wafarin Level 4 

(moderate / 

possible) 

Trazodone Level 4 

(major / 

possible) 

Phenytoin Level 4 

(moderate / 

possible) 

Paroxetine may cause decreased phenothiazine 

metabolism leading to increased toxicity 

including cardiac arrhythmias with thioridazine 

SSRIs may inhibit CYP3A4 metabolism 

leading to cyclosporine toxicity 

Cyproheptadine, a serotonin antagonist, may 

lead to decreased antidepressant efficacy of 

SSRIs 

Paroxetine may inhibit the metabolism of 

propafenone leading to increased toxicity 

Possible additive serotonin reuptake inhibition 

leading to increased sedative-hypnotic effects 

Possible inhibition of zolpidem metabolism 

leading to increased zolpidem effects 

Combination of inhibition of serotonin 

reuptake and increased substrate availability 

from tryptophan supplementation leading to 

toxicity 

Unknown; increased risk of serotonin 

syndrome 

Inhibition of CYP2D6 metabolism of betablockers 

leading to increased beta-blocker 

effect (bradycardia) 

Potential inhibition of SSRI metabolism 

leading to increased risk of serotonin syndrome 

SSRI-induced impairment of platelet function 

leading to increased risk of bleeding with 

heparin 

Cimetidine may inhibit first pass metabolism 

of SSRIs leading to increased SSRI plasma 

levels and potential for toxicity 

Unknown; potential increased risk, for 


Unknown; the anticoagulant effect of warfarin 

may be increased (potentially increased 

bleeding with unaltered PT) 

Inhibition of trazodone metabolism leading to 

increased serotonin levels and the risk for 


Unknown; serum levels of paroxetine and 

phenytoin have been reported, leading to 

reduced efficacy 

341



Linezolid Level 4 

(major / 

possible) 

Nefazodone Level 4 

(major / 

possible) 

Tramadol Level 4 

(major / 

possible) 

*Efacts classification (Severity / Documentation) 

Possible excessive accumulation of serotonin 

leading to serotonin syndrome 

Additive or synergistic effects on serotonin; 

increased risk of serotonin syndrome 

Additive serotonin effects; increased risk of 


Additional drug-drug interactions included in the package labeling include phenobarbital 

(potentially reduced plasma levels of paroxetine leading to decreased efficacy), 

flecainide/encainide (similar to propafenone above), quinidine (inhibition of CYP2D6 enzyme), 

procyclidine (increased levels of procyclidine leading to anticholinergic side effects), and 

theophylline (increased toxicity). 

VI. Adverse Drug Events 13,16 

Adverse events seen most commonly with paroxetine use involve the gastrointestinal system, 

CNS, sexual dysfunction, sweating, and asthenia. Dose comparison studies in major depressive 

disorder have shown an increased incidence of some adverse events with increasing dose, but this 

dose dependency was not seen in trials in OCD or panic disorder. Patients may adapt to some 

adverse events over a 4-6 week time period (e.g., nausea and dizziness), but other adverse effects 

may remain (e.g., asthenia, dry mouth and somnolence). 

Paroxetine is not approved for use in patients

Table 3. Most Common Reasons for Paroxetine Discontinuation in Clinical Trials 

Major Depressive 

Disorder 

OCD 

Panic Disorder 

Adverse Event Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo 

CNS 

Somnolence 2.3% 0.7% -- 1.9% 0.3% 

Insomnia -- -- 1.7% 0% 1.3% 0.3% 

Agitation 1.1% 0.5% -- 

Tremor 1.1% 0.3% -- 

Dizziness -- -- 1.5% 0% 


Constipation -- -- 1.1% 0% 

Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 

Diarrhea 1.0% 0.3% -- 

Dry mouth 1.0% 0.3% -- 

Vomiting 1.0% 0.3% -- 

Other 

Asthenia 1.6% 0.4% 1.9% 0.4% 

Abnormal 

1.6% 0% 2.1% 0% 

ejaculation 

Sweating 1.0% 0.3% -- 

Impotence -- 1.5% 0% 

Adapted from “Adverse Reactions: Associated with Discontinuation of Treatment” table, package labeling. 13 

The following table lists the most commonly observed adverse events associated with paroxetine 

use in clinical trials, where the incidence was >5% and at least twice as common as placebo. 

Table 4. Most Commonly Observed Adverse Events in Paroxetine Clinical Trials 

Adverse Event Paroxetine Placebo 

Major Depressive Disorder 1 (n=421) (n=421) 

Nausea 26% 9% 

Somnolence 23% 9% 

Asthenia 15% 6% 

Dizziness 13% 6% 

Insomnia 13% 6% 

Ejaculatory disturbance 13% 0% 

Sweating 11% 2% 

Other male genital disorders 10% 0% 

Tremor 8% 2% 

Decreased appetite 6% 2% 

Nervousness 5% 3% 

OCD 2 (n=542) (n=265) 

Somnolence 24% 7% 

Nausea 23% 10% 

Abnormal ejaculation 23% 1% 

Dry mouth 18% 9% 

Constipation 16% 6% 

Dizziness 12% 6% 

Tremor 11% 1% 



Impotence 8% 1% 

343


Adverse Event Paroxetine Placebo 

Panic Disorder 3 (n=469) (n=324) 

Abnormal ejaculation 21% 1% 

Asthenia 14% 5% 


Libido decreased 9% 1% 

Tremor 9% 1% 

Female genital disorders 9% 1% 


Impotence 5% 0% 

1 Duration of trials = 6 weeks; paroxetine dose range = 20-50mg/day 

2 Duration of trials = 12 weeks; paroxetine dose range = 20-60mg/day 

3 Duration of trials = 10-12 weeks; paroxetine dose range = 10-60mg/day 

VII. Dosing and Administration 13,16 

Paroxetine mesylate should be administered as a single daily dose with or without food. It is 

formulated in 10mg, 20mg, 30mg, and 40mg tablets. The 20mg tablet is scored. If dose increases 

are desired, the dose should be increased by 10mg per day at intervals of at least one week. 

Table 5. Dosing and Indication for Paroxetine Mesylate 

Indication Initial Dose Maximum Dose 

Depression 20mg once daily 50mg daily 

OCD 20mg once daily 60mg daily 

Panic disorder 10mg once daily 60mg daily 


For elderly or debilitated patients, or those with severe renal or hepatic impairment, paroxetine 

mesylate should be initiated at a dose of 10mg once daily and should not exceed 40mg daily. 

Adverse effects such as dizziness, sensory disturbances, agitation, anxiety, nausea, and sweating 

may be experienced if paroxetine is discontinued too abruptly. When discontinuing treatment 

with paroxetine, gradual reduction in dose is recommended to avoid withdrawal-like symptoms. 

Recommendations for dose tapering include 10mg/day dose reduction at weekly intervals. When 

the patient has received 20mg/day for 1 week, the drug may be stopped. 

VIII. Comparative Effectiveness 

Efficacy data in the package labeling for paroxetine mesylate is the same as that found in the 

package labeling for paroxetine hydrochloride due to the FDA approval process described in the 

Overview. According to package labeling, efficacy data for paroxetine was contributed from six 

placebo-controlled trials for major depressive disorder, two studies for OCD, and three studies for 

panic disorder. Details for these studies are not included in the package labeling. Additional 

clinical trials are summarized in the table below. 

344

Table 6. Clinical Trials of Paroxetine in Major Depressive Disorder, OCD & Panic Disorder 

StudyDesign/ Treatment Endpoints Results 

Sample/Duration 

Baldwin DS, et.al. 20 Paroxetine 20- 

40mg/day 

Double blind Nefazodone 200- 

600mg/day 

N=108 

4 months 

(Depression) 

• HAM-D 

• HAM-A 

• CGI 

• Montgomery- 

Ashberg Depression 

Rating Scale 

• Patient Global 

Assessment Scale 

• No significant 

differences between 

treatment regimens in 

treatment efficacy or 

adverse events 

• Both therapies were 

efficacious in maintaining 

remission during the 

continuation phase 

Ballenger JC, et.al. 21 

Double blind 

N=278 

10 weeks 

(Panic disorder) 

Bandelow B, et.al. 22 

Double blind 

N=225 

12 weeks 

(Panic disorder) 

Paroxetine 10mg, 

20mg or 40mg/day 

• Sertraline 

50-150mg/day 

• Paroxetine 

40-60mg/day 

• Percent of 

patients free from 

panic attacks 

• Change from 

baseline in number of 

full panic attacks 

• Percentage 

of patients with 50% 

reduction in full panic 

attacks 

• CGI score 

• Panic and 

Agoraphobia Scale 

(PAS) 

• CGI 

Significant differences for 

40mg dose only compared 

to placebo in 3 endpoints: 

% patients free from panic 

attacks, number of full 

panic attacks, and CGI 

score (p35% decrease in Y-BOCS 

score) 

• No difference between 

groups in anxiety scale 

• Significantly better 

improvement in depression 

scale at end of study with 

paroxetine (p=0.042) 

• Both treatments 

equally efficacious; similar 

rates of adverse events 

345


StudyDesign/ 


Fava M, et.al. 24 

Double blind 

N=284 

10-16 weeks 

(Depression) 

Kroenke K, et.al. 25 

Open label 

N=537 

9 months 

(Depression) 

Montgomery S. 26 

Meta-analysis 

N=1924 (P) 

N=141 (C 

N=1693 (T) 

39 studies 

(Depression) 

Mundo E, et.al. 27 

Single blind 

N=30 adults 

10 weeks 

(OCD) 

Treatment Endpoints Results 

Fluoxetine 20- 

60mg/day 

Sertraline 50- 

200mg/day 

Paroxetine 20- 

60mg/day 

Fluoxetine 23.4mg 

mean dose/day 

Sertraline 72.8mg 

mean dose/day 

Paroxetine 23.5mg 

mean dose/day 

Paroxetine 

Clomipramine 

TCAs 


60mg/day 

Fluvoxamine 200- 

300mg/day 

Citalopram 40- 

60mg/day 

• >50% decrease 

or total score 50% decrease or 

total score 50% reduction 

in HAM-D; 39-48% of 

patients met criteria of total 

HAM-D score 0.05) 

• Paroxetine had 

significantly lower 

incidence of adverse events 

compared to clomipramine 

(p=0.02) and other TCAs 

(p


StudyDesign/ 


Wade A, et.al. 28 

Double blind 

N=197 

6 months 

(Depression) 

Treatment Endpoints Results 


30mg/day 

Mirtazapine 30- 

45mg/day 

• >50% decrease 

or total score


No brand of paroxetine mesylate (Pexeva) is recommended for preferred status. 

348

References 

1. Synthon Pharmaceuticals, LTD. Pexeva: frequently asked questions. Accessed via 

internet at www.pexeva.com/healthcare/faq.htm on 9/18/2004. 

2. FDA Center for Drug Evaluation and Research: Electronic Orange Book: Approved 

Drug Products with Therapeutic Equivalence Evaluations. Accessed via internet at 

www.fda.gov/cder/orange/default.htm on 9/20/2004. 

3. Practice guideline for the treatment of patients with major depressive disorder (revision). 

American Psychiatric Association. Am J Psychiatry. 2000 Apr. 157(suppl 4):1-45. 

4. Paykel ES. Continuation and maintenance therapy in depression. British Medical 

Bulletin. 2001;57:145-159. 

5. VHA/DOD clinical practice guideline for the management of major depressive disorder 

in adults. Washington (DC): Department of Veterans Affairs (U.S.); 2000. 

6. Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental 

health care. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2004 

May. 

7. Bruce SE, Vasile RG, Goisman RM, et.al. Are benzodiazepines still the medication of 

choice for patients with panic disorder with or without agoraphobia Am J Psychiatry 

2003;160:1432-1438. 

8. American Psychiatric Association. Practice guideline for the treatment of patients with 

panic disorder. Am J Psychiatry 1998;155(May supplement). 

9. Doyle AD, Pollack MH. Long-term management of panic disorder. J Clin Psychiatry 

2004;65(suppl 5):24-28. 

10. March JS, Frances A, Kahn DA, Carpenter D, eds. The expert consensus guideline series: 

treatment of obsessive-compulsive disorder. J Clin Psychiatry 1997;58 (suppl 4). 

Accessed via internet at www.psychguides.com/ocgl.html on 9/22/2004. 

11. Jenike MA. Obsessive-compulsive disorder. N Engl J Med 2004;350:259-265. 

12. Kaplan A, Hollander E. A review of pharmacologic treatments for obsessive-compulsive 

disorder. Psychiatric Services 2003;54:1111-1118. 

13. Synthon Pharmaceuticals, LTD. Pexeva package labeling. Chapel Hill, NC. Accessed 

9/18/2004 via internet at www.pexeva.com. 

14. GlaxoSmithKline. Paxil package labeling, Research Triangle Park, NC. Accessed 

9/18/2004 via internet at www.paxil.com. 

15. GlaxoSmithKline. Paxil CR package labeling. Research Triangle Park, NC. Accessed 

9/18/2004 via internet at www.paxilcr.com. 

16. Paroxetine monograph. Clinical Pharmacology, 2004. Accessed September 15, 2004 via 

internet at: www.cp.gsm.com. 

Wolters Kluwer Health, Inc. EFacts: Drug Interaction Facts. Accessed September 18. 

2004 via internet at: www.factsandcomparisons.com. 

17. FDA. FDA statement on recommendations of the psychopharmacologic drugs and 

pediatric advisory committees 9/16/2004. Accessed September 21, 2004 via internet at 

www.fda.gov/bbs/topics/news/2004/NEW01116.html. 

18. APA. APA statement on the FDA’s hearing on antidepressant use in pediatric patients 

9/16/2004. Accessed 9/21/2004 via internet at www.psych.org. 

19. Baldwin DS, Hawley CJ, Mellor’s K. A randomized, double-blind, controlled 

comparison of nefazodone and paroxetine in the treatment of depression: safety, 

tolerability, and efficacy in the continuation phase treatment. J Psychopharmacol 

2001;15(3):161-165. 

20. Ballenger JC, Wheadon DE, Steiner M, et.al. Double-blind, fixed-dose, placebocontrolled 

study of paroxetine in the treatment of panic disorder. Am J Psychiatry 

1998;155:36-42. 

21. Bandelow B, Behnke K, Loenoir S, et.al. Sertraline versus paroxetine in the 

treatment of panic disorder: an acute, double-blind noninferiority comparison. J Clin 

Psychiatry 2004;65(3):405-13. 

22. Denys D, van der Wee N, van Megen H, Westenberg H. A double blind comparison 

of venlafaxine and paroxetine in obsessive-compulsive disorder. J Clin 

Psychopharmacol 2003;23(6):568-575. 

349

23. Fava M, Hoog SL, Judge RA, et.al. Acute efficacy of fluoxetine versus sertraline and 

paroxetine in major depressive disorder including effects of baseline insomnia. J Clin 

Psychopharmacol 2002;22:137-147. 

24. Kroenke K, West SL, Swindle R, et.al. Similar effectiveness of paroxetine, 

fluoxetine, and sertraline in primary care. JAMA 2001;286:2947-2955. 

25. Montgomery SA. A meta-analysis of the efficacy and tolerability of paroxetine 

versus tricyclic antidepressants in the treatment of major depression. Int Clin 

Pyschopharmacol 2001;16:169-178. 

26. Mundo E, Bianchi L, Bellodi L. Efficacy of fluvoxamine, paroxetine, and citalopram 

in the treatment of obsessive-compulsive disorder: a single-blind study. J Clin 

Psychopharmacol. 1997;17(4):267-71. 

27. Wade A, Crawford, GM, Angus M, et.al. A randomized, double-blind, 24 week 

study comparing the efficacy and tolerability of mirtazapine and paroxetine in 

depressed patients in primary care. Int Clin Psychopharm 2003;18:133-141. 

28. Åberg-Wistedt A, Ågren H, Ekselius L, et.al. Sertraline versus paroxetine in major 

depression: Clinical outcome after six months of continuous therapy. J Clin 

Psychopharmacol 2000;20(6):645-652. 

29. Hollander E, Allan A, Steiner M, et.al. Acute and long-term treatment and 

prevention of relapse of obsessive-compulsive disorder with paroxetine. J Clin 

Psychiatry 2003;64:1113-1121. 

30. Doyle A, Pollack MH. Long-term management of panic disorder. J Clin Psychiatry 2004; 

65[suppl 5]:24-28. 

350



New Drug Pharmacotherapy Review- 

Spiriva (Tiotropium) 



I. Overview 

Tiotropium is a long acting, quaternary ammonium derived from ipratropium. Both agents are 

nonselective muscarinic antagonists of M1, M2, and M3 receptors. Although compared to 

ipratropium, tiotropium has a 6 to 20 fold greater affinity for these receptors. 1 Additionally, the 

muscarinic receptor-drug complex half-lives differ between the two anticholinergics; for 

tiotropium the muscarinic receptor-drug complex half lives average 14.6 hours, 3.6 hours, and 

34.7 hours for the M1, M2, and M3 receptors, respectively. For ipratropium, the muscarinic 

receptor-drug complex half lives average 0.11 hours, 0.035 hours, and 0.26 hours for the M1, M2, 

and M3 receptors, respectively. 2 

Both agents are bronchodilators used for patients with chronic obstructive pulmonary disease 

(COPD), with tiotropium used as once daily therapy compared to the four times daily use of 

ipratropium. At the end of one year of treatment, tiotropium improved FEV 1 trough over baseline 

by 120 ml while ipratropium had a negative effect on FEV 1 trough , with a decline of 30 ml from 

baseline(p

acetylcholine at muscarinic receptors while β 2 -agonists like albuterol and salmeterol stimulate β 2 

receptors. The nonbronchodilator effects of these drug classes differ as well. For example, 

muscarinic receptors play a role in mucus secretion, while long-acting β 2 -agonists have effects on 

mucociliary transport and neutrophils. The potential benefit of combining these two types of 

bronchodilators for those with COPD makes sense, but no clinical data are available to fully 

support this idea. 5 Of note, while a methylxanthine like theophylline is also considered a weak 

bronchodilator, reviewers no longer recommend theophylline as initial therapy. 5,8 

Tashkin and Cooper have developed an algorithm that specifically suggests combining tiotropium 

with salmeterol or formoterol for those with Stage III or Stage IV COPD; these reviewers are 

confident that data demonstrating additive effects of ipratropium and either salmeterol or 

formoterol can be extrapolated to combining tiotropium with the latter two agents. 5 In the same 

issue of Chest, however, the editorial addressing the Tashkin and Cooper piece does not support 

combination long-acting bronchodilator therapy. Although the rationale is compelling given their 

complementary mechanisms of bronchodilation, the authors believe it is premature to support 

long-acting bronchodilator therapy combination. 7 

Table 1. Classification of Chronic Obstructive Pulmonary Disease 4 

Stage 

Characteristics 

0: At Risk 

• Normal spirometry 

• Chronic symptoms (cough, sputum production) 

I: Mild COPD 

II: Moderate COPD 

III: Severe COPD 

IV: Very Severe COPD 

• FEV 1 /FVC < 70% 

• FEV 1 > 80% predicted 

• With or without chronic symptoms (cough, 

sputum production) 

• FEV 1 /FVC < 70% 

• < 50% < FEV 1 < 80% predicted 



• FEV 1 /FVC < 70% 

• < 30% < FEV 1 < 50% predicted 



• FEV 1 /FVC < 70% 

• FEV 1

Table 2. Chronic Obstructive Pulmonary Disease Therapy by Stage 4 

0: At I:Mild II:Moderate III:Severe IV: Very Severe 

Risk 

Avoidance of Risk Factors, influenza vaccine 

Add short-acting bronchodilator when needed 

Add regular treatment with one or more long-acting 

bronchodilators; Add rehabilitation 

Add inhaled corticosteroids if repeated 

exacerbations 

Add long-term 

oxygen if chronic 

respiratory failure. 

Consider surgical 

treatments 

Table 3. Use of Bronchodilators in Stable COPD 4 

• Bronchodilator medications are central to symptom management in COPD 

• Inhaled therapy is preferred. 

• The choice between β 2 -agonist, anticholinergic, theophylline, or combination therapy 

depends on availability and individual response in terms of symptom relief and side effects. 

• Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce 

symptoms. 

• Long-acting inhaled bronchodilators are more effective and convenient, but more expensive. 

• Combining bronchodilators may improve efficacy and decrease the risk of side effects 

compared to increasing the dose of a single bronchodilator. 

III. 

Indications 

Ipratropium is indicated for the long-term once daily, maintenance treatment of bronchospasm 

associated with COPD, including chronic bronchitis and emphysema. 9 

IV. 


Table 4 summarizes the pharmacokinetics of tiotropium. Tiotropium, administered via dry powder 

inhalation, is primarily delivered to the GI tract; the rest goes to the lung. 9 

Table 4. Pharmacokinetic Parameters of Tiotropium 9 

Tmax (minutes) • 5 

Absolute Bioavailability • 19.5% 

Protein Binding • 72% 

Metabolism • Nonenzymatically cleaved to the alcohol N- 

methylscopine and dithieneglycolic acid, both 

inactive 

Elimination • Urinary excretion 14% 

• 86% goes through the GI tract and is eliminated 

via feces 


None known. 

353

VI. 


The adverse events reported with tiotropium, ipratropium, and placebos are summarized in Table 

5. 

Table 5. Adverse Events with Tiotropium 9 

Placebo-controlled trials 

Adverse Tiotropium Placebo 

Reaction (n=550) 

(n=371) 

Gastrointest 

inal 

Ipratropium-controlled trials 

Tiotropium Ipratropium 

(n=356) 

(n=179) 

Abdominal 

pain 

Constipation 

Dry mouth 

Dyspepsia 

Vomiting 

5 

4 

16 

6 

4 

3 

2 

3 

5 

2 

6 

1 

12 

1 

1 

6 

1 

6 

1 

2 

Respiratory 

Epistaxis 

Pharyngitis 

Rhinitis 

Sinusitis 

Upper 

respiratory 

tract 

infection 

4 

9 

6 

11 

41 

2 

7 

5 

9 

37 

1 

7 

3 

3 

43 

1 

3 

2 

2 

35 

Miscellaneous 

Accidents 

Chest pain 

(nonspecific) 

Edema, 

dependent 

Infection 

Moniliasis 

Myalgia 

Rash 

Urinary tract 

infection 

13 

7 

5 

4 

4 

4 

4 

7 

11 

5 

4 

3 

2 

3 

2 

5 

5 

3 

3 

1 

3 

4 

2 

4 

8 

2 

5 

3 

2 

3 

2 

2 

VII. 


Tiotropium is administered as a single daily 18 µg (one capsule) dose via a HandiHaler ® dry 

powder inhaler. It may be administered in the morning, midday, or evening with similar effects. 9 

354


Tiotropium is one of the few drugs that have come to market in the United States with strong 

clinical data available in published form. Table 6 summarizes the results of two placebocontrolled 

studies, two comparative studies with ipratropium, and one comparative study vs. 

salmeterol. 

Two placebo-controlled studies with tiotropium demonstrated that the active treatment was more 

effective than placebo in improving lung function and decreasing the amount of rescue medication 

in the first study of 13 weeks 10 and more effective than placebo in improving lung function, 

decreasing the amount of rescue medication, decreasing the number of exacerbations, decreasing 

the number of hospitalizations, and improving quality of life measures (via the St George’s 

Respiratory Questionnaire) in a 1 year follow-on study. 11 In both the placebo-controlled studies, 

tiotropium had an increased incidence of drug mouth, p

Table 6. Clinical Efficacy Studies for Tiotropium 

Treatment (n) 

[duration] {Ref} 

Tiotropium qd 

vs. placebo qd 

via dry powder 

inhaler (470) [13 

wks]{10} 

Tiotropium qd 

vs. placebo qd 

via dry powder 

inhaler (921) [12 

mo]{11} 

Tiotropium qd 

vs. ipratropium 

qid via metered 

dose inhaler 

(288) [13 

wks]{12} 

Tiotropium qd 

vs. ipratropium 

qid via metered 

dose inhaler 

(535) [12 

mo]{13} 

Tiotropium qd 

vs. salmeterol 

bid and placebo 

bid, both by 

metered dose 

inhaler (623) [6 

mo]{15} 

Change in Trough 

FEV 1 at End of 

Study (Liters) 

T +0.11, P – 0.04 

(p

Stable Therapy: Patients who’s COPD is controlled on ipratropium should not be switched to 

tiotropium. As discussed in recent reviews, neither the GOLD guidelines nor clinical data strongly 

support a specific drug, combinations of drugs, or the order in which the drugs should be 

employed. Therefore, if a patient is well managed on a ‘cocktail’ of ipratropium and other agents 

(i.e., β 2 -agonists and/or corticosteroids) there is no clinical reason to change this regimen. 4-6,8 

Impact on Physician Visits: Most of the clinical data published to date has included evaluation 

of health resources, as measured by fewer hospital visits. Information on potential impact on 

physician visits with tiotropium is available from two studies. In the long term comparative study 

of tiotropium and ipratropium, the difference between tiotropium and ipratropium for unscheduled 

visits was statistically significant, p=0.04. 14 In the comparative study of tiotropium and 

salmeterol, unscheduled physician visits were fewer in the tiotropium group compared to the 

salmeterol group, but this difference was not statistically significant. 16 

IX. 

Conclusions 

Although tiotropium is chemical derivative of ipratropium, it differs markedly from the current 

COPD standard anticholinergic agent. Tiotropium has a 6 to 20 fold greater affinity than 

ipratropium for target muscarinic receptors. Where ipratropium must be administered four times 

daily, tiotropium is considered a long-acting, once-daily anticholinergic because of the 

dramatically different, prolonged muscarinic receptor-drug complex half lives. 1,2 

In addition to these chemical and pharmacodynamic differences, the clinical data for tiotropium 

demonstrate differences from ipratropium as well. Particularly in the one year comparative study, 

the differences between the agents can be seen. Tiotropium improved FEV 1 trough over baseline 

by 120 ml while ipratropium had a negative effect on FEV 1 trough, with a decline of 30 ml from 

baseline(p

References 

1. Haddad EB, Mak JCW, Barnes PJ. Characteristics of [ 3 H]Ba 679 BR, a slowly dissociating 

muscarinic antagonist, in human lung: radioligand binding and autoradiographic mapping. Mol 

Pharmacol 1994; 45:899-907. 

2. Disse B, Speck GA, Rominger KL. Witek TJ, Hammer R. Tiotropium: mechanistical 

considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64:457-464. 

3. Vincken W, van Noord JA, Greefhorst APM, et al. Improved health outcomes in patients with 

COPD during 1 year’s treatment with tiotropium. Eur Resp J 2002;19:209- 216. 

4. Global Initiative for Chronic Obstructive Lung Disease, World Health Organization, National 

Heart, Lung and Blood Institute. Global strategy for the diagnosis, management, and prevention 

of chronic obstructive pulmonary disease. Bethesda (MD): Global Initiative for Chronic 

Obstructive Lung Disease, World Health Organization, National Heart, Lung and Blood Institute; 

2001. Executive Summary.Updated 2004. url:// www.goldcopd.com Accessed: September 15, 

2004 

5. Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stabel 

COPD. Chest 2004; 125:249-259 

6. Sin DD, McAlister FA, Man SFP, Anthonisen NR. Contemporary management of chronic 

obstructive pulmonary disease: Scientific review. JAMA 2003; 290:2301-2312. 

7. Cazzola M, Matera MG. Long-acting bronchodilators are the first choice option for the treatment 

of stable COPD. Chest 2004; 125:9-11. 

8. Faulkner MA, Hilleman DE. Pharmacologic treatment of chronic obstructive pulmonary disease: 

past, present, and future. Pharmacotherapy 2003; 23:1300-1315. 

9. Product information for Spiriva HandiHaler ® . Boehringer Ingelheim Pharmaceuticals Inc. 

Ridgefield, CT. January 2004. 

10. Casaburi R, Briggs DD, Donohue JF, et al. The spirometric efficacy of once-daily dosing with 

tiotropium in stable COPD. Chest 2000 118:1294-1302. 

11. Casaburi R, Mahler DA, Jones A, et al. A long-term evaluation of once-daily tiotropium in 

chronic obstructive pulmonary disease. Eur Resp J 2002;19:217-224. 

12. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ.A randomised controlled 

comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary 

disease. The Dutch Tiotropium Study Group. Thorax. 2000; 55:289-294. 

13. Vincken W, van Noord JA, Greefhorst APM, et al. Improved health outcomes in patients with 

COPD during 1 year’s treatment with tiotropium. Eur Resp J 2002;19:209- 216. 

14. Oosterbrink JB, Rutten-van Molen MPMH, Van Noord JA, Vinken W. One year costeffectiveness 

of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. Eur 

Respir J. 2004; 23:241-249. 

15. Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing 

lung function and health status changes in COPD patients treated with Tiotropium or salmeterol. 

Chest. 2002; 122:47-55.\ 

16. Brusaasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes 

following treatment for six month with once daily tiotropium compared with twice daily 

salmeterol in patients with COPD. Thorax 2003; 58:399-404. 

358



New Drug Pharmacotherapy Review - Caduet 



I. Overview 

Caduet ® is a combination of two drugs: atorvastatin, a selective, competitive inhibitor of HMG- 

CoA reductase (statin, cholesterol-lowering agent); and amlodipine, a long-acting dihydropyridine 

calcium antagonist (calcium channel blocker, antihypertensive/antianginal agent). 1 

Atorvastatin, which is also available as the brand product Lipitor ® , inhibits HMG-CoA reductase, 

the rate limiting enzyme that converts 3-hydroxy-3-methylglutary-coenzyme A to mevalonate, a 

precursor of sterols (including cholesterol). 

Amlodipine is also available as the brand product Norvasc ® . Amlodipine inhibits the 

transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, which the 

contractile processes are dependent upon. 

Both hyperlipidemia and hypertension are risk factors for the development of coronary heart 

disease (CHD). 2,3 Therefore, appropriate cholesterol and blood pressure control is essential to 

reduce the risk of morbidity and mortality associated with CHD. Atorvastatin/amlodipine 

(Caduet ® ) is the first combination product combining both a cholesterol-lowering agent and an 

antihypertensive/antianginal agent. Neither atorvastatin nor amlodipine are available generically. 4 

There are various combination strengths available for atorvastatin/amlodipine. 1 This review 

encompasses all atorvastatin/amlodipine dosage forms and strengths. The HMG-CoA Reductase 

Inhibitor (AHFS 240608) pharmacotherapy review in full is available for reference in Appendix 

1. 

II. 


Hyperlipidemia 2,3 

The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) has issued 

recommendations for cholesterol management. According to the ATP III guidelines, therapy with 

lipid-altering agents is one of several components of multiple-risk-factor intervention in 

individuals at increased risk for CHD due to hypercholesterolemia. Therapeutic lifestyle changes 

(TLC) and drug therapy are the two major treatment modalities. The TLC Diet stresses reductions 

in saturated fat and cholesterol intake. The following table defines LDL-C goals and cutpoints for 

initiation of TLC and for drug consideration based on the updated ATP III guidelines, 3 issued July 

13, 2004. These updates advise physicians to consider new, more intensive treatment options for 

people at high and moderately high risk for a heat attack. The new guidelines are endorsed by the 

National Heart, Lung, and Blood Institute (NHLBI), the American College of Cardiology, and the 

American Heart Association. 

359

Table 1. LDL-C Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug 

Therapy in Different Risk Categories Based on Updated ATP III Guidelines 3 

LDL Level at 

LDL Goal Which to Initiate LDL Level at Which to Consider 

Risk Category 

High-Risk: CHD or CHD Risk 

Equivalents* 

(10-year risk >20%) 

Moderately-High Risk: 2+ 

Risk Factors† 

(10-year risk 10-20%) 

Moderate-Risk: 2+ Risk 

Factors† 

(10-year risk

NEW GOALS: 

• For high-risk patients, the update lowers the threshold for drug therapy to an LDL-C of 

100mg/dL or higher and recommends drug therapy for those high-risk patients whose LDL-C 

is 100 to 129mg/dL. Previously this threshold for drug therapy was an LDL-C of 130mg/dL, 

and made drug treatment optional for LDL-C of 100 to 129mg/dL. 

• For moderately high-risk patients, the goal remains an LDL-C

Angina 7 

The American College of Cardiology/American Heart Association Task Force for the 

Management of Patients with Chronic Stable Angina has issued treatment guidelines. 

Recommendations to prevent Myocardial Infarction and Death and to Reduce Angina Symptoms 

include the following pharmacologic therapy: 

• Aspirin in the absence of contraindication. Evidence also suggests low-intensity 

anticoagulation with warfarin in addition to aspirin. 

—If aspirin is absolutely contraindicated, clopidogrel. 

• Beta-blockers as initial therapy in the absence of contraindications in patients with or without 

prior MI. Evidence also suggests long-acting nondihydropyridine calcium antagonists instead 

of beta-blockers as initial therapy: 

—If beta-blockers are contraindicated or initial beta-blocker therapy is not effective, calcium 

antagonists (short-acting, dihydropyridines should be avoided) should then be 

administered. 

—If beta-blockers are unacceptable due to side effects, calcium channel-antagonists 

(short-acting, dihydropyridines should be avoided) or long-acting nitrates may be a 

substitute. No conclusive evidence exists to indicate that either long-acting nitrates or 

calcium antagonists are superior for long-term treatment for symptomatic relief of angina, 

however, the guidelines say that long-acting calcium antagonists are often preferable to 

long-acting nitrates for maintenance therapy because of their sustained 24-hour effects. 

• Angiotensin converting enzyme inhibitor (ACEI) in all patients with coronary artery disease 

who also have diabetes and/or left ventricular systolic dysfunction. Evidence also suggests 

use in CAD or other vascular disease. 

• LDL-C lowering therapy in subjects with documented or suspected CAD and LDL-C 

>130mg/dL, with a target

—There is a positive family history of premature cardiovascular disease, or 

—Two or more other CVD risk factors are present. 

Amlodipine 

14. Hypertension: Amlodipine is indicated for the treatment of hypertension. It may be used 

alone or in combination with other antihypertensive agents; 

15. Chronic Stable Angina: Amlodipine is indicated for the treatment of chronic stable angina, 

for the treatment of confirmed or suspected vasospastic angina and for the treatment of 

hypertension. Amlodipine may be used alone or in combination with other antianginal or 

antihypertensive agents; 

16. Vasospastic Angina (Prinzmetal's or Variant Angina): Amlodipine is indicated for the 

treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as 

monotherapy or in combination with other antianginal drugs. 

*Note the indications for atorvastatin/amlodipine are exactly the same as for its individual components, atorvastatin and 

amlodipine (Lipitor ® and Norvasc ® , respectively). 8,9 

IV. Pharmacokinetic Parameters 1 

Peak concentrations for amlodipine and atorvastatin are achieved at 6 to 12 hours and 1 to 2 hours 

post-dosing, respectively. The rate and extent (bioavailability) of atorvastatin and amlodipine 

from atorvastatin/amlodipine are not significantly different from the bioavailability of each 

medication administered separately. As noted with atorvastatin administration separately, 

administration of atorvastatin/amlodipine with food reduces the rate and extent of absorption of 

atorvastatin by approximately 32% and 11%, respectively. However, LDL-C reduction is similar 

whether atorvastatin is given with or without food. Pharmacokinetic parameters for atorvastatin 

and amlodipine following separate administration are provided in the following table. 

Table 3. Pharmacokinetic Parameters of Atorvastatin and Amlodipine Following Lipitor ® and 

Norvasc ® Administration Separately 1 

Parameter Atorvastatin Amlodipine 

Absolute Bioavailability 14% 64-90% 

T max 1-2 hours 6-12 hours 

Steady State Levels 

achieved by Day 

7-8 

Plasma Protein Binding ≥98% 93% 

Food Effect on 

None 


Metabolism 

Excretion 

T 1/2 

Although rate of absorption is 

decreased by 25% and extent of 

absorption is decreased by 9%, LDL- 

C reduction is similar if given with or 

without food. 

Extensively metabolized to orthoand 

parahydroxylated derivatives and 

various beta-oxidation products 

which in vitro contribute to 70% of 

circulating HMG-CoA inhibitory 

activity. In vitro suggests metabolism 

via CYP 3A4. 

Parent compound and metabolites 

primarily excreted in bile, but no 

enterohepatic recirculation and

Special Pharmacokinetic Considerations: 

Elderly patients: Amlodipine clearance is reduced (AUC increased 40-60%). Thus, a lower initial 

amlodipine dose may be required. Although, atorvastatin concentrations are higher in elderly 

(40% for C max and 30% for AUC), clinical data suggests a greater degree of LDL-lowering at any 

dose in this population compared to younger subjects. 

Renal Impairment: No effect on either atorvastatin or amlodipine concentrations. Thus, dose 

adjustment is not necessary. Hemodialysis is not expected to effect concentrations of either drug 

due to extensive binding to plasma proteins. 

Hepatic Impairment: Amlodipine concentrations are increased (AUC 40-60%). Thus, a lower 

initial dose may be required. Atorvastatin concentrations are markedly increased in chronic 

alcoholic liver disease and by at least 4-fold for both C max and AUC in Childs-Pugh A disease. 

C max and AUC are increased by 16- and 11-fold, respectively, in Childs-Pugh B disease. Due to 

these atorvastatin increases, atorvastatin/amlodipine is contraindicated in patients with active liver 

disease or unexplained persistent elevations in transaminases. 


No drug interaction studies have been conducted with the combination product 

atorvastatin/amlodipine; thus, the following information has been provided regarding drug 

interactions of atorvastatin and amlodipine administered separately. 1 

Due to the atorvastatin component, there is a warning when atorvastatin/amlodipine is used with 

certain medications. Since there is an increased risk for myopathy and rhabdomyolysis when 

coadministered with cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole 

antifungals, use cautiously. Dosage reduction of atorvastatin and monitoring for side effects is 

warranted to properly manage these interactions. Specific clinically significant (level 1 [major] 

and level 2 [moderate]) drug interactions with atorvastatin/amlodipine are listed in the table 

below. 10 

364

Table 4. Level 1 Drug Interactions with Atorvastatin/Amlodipine ®10 

Drug Significance Mechanism Management 

Macrolide 

Antibiotics 

(azithromycin, 

clarithromycin, 

erythromycin) 

Level 1 (Delayed, 

Major, Probable) 

Severe myopathy/rhabdomyolysis may occur due 

to suspected increased atorvastatin 

concentrations due CYP3A4 inhibition. A PK 

study determined that atorvastatin concentrations 

increased ~40% during coadministration with 

Suspend statin until antibiotic therapy complete 

or administer alternative statin therapy such as 

fluvastatin and pravastatin which are not 

metabolized by CYP3A4. 

Cyclosporine 

Gemfibrozil 

Nefazadone 

Protease 

Inhibitors 

(amprenavir, 

indinavir, 

lopinavir/ritonavir, 

nelfinavir, 

ritonavir, 

saquinavir) 

Bile Acid 

Sequestrants 

(cholestyramine, 

colestipol) 

Nondihydropyricine 

Calcium 

Channel 

Blockers 

(diltiazem, 

verapamil) 

Azole 

Antifungals 

(fluconazole, 

itraconazole, 

ketoconazole, 

voriconazole) 

Grapefruit Juice 

Rifamycins 

(rifampin, 

rifabutin) 


Major, Probable) 


Major, Suspected) 


Major, Suspected) 


Moderate, 

Suspected) 


Moderate, 

Suspected) 


Moderate, 

Probable) 

Level 2 (Rapid, 

Moderate, 

Probable) 

Level 2 (Moderate, 

Suspected) 


Moderate, 

Suspected) 

erythromycin. 

Myolysis and rhabdomyolysis may occur due to 

increased plasma levels and side effects of statins 

due to a suspected decrease in metabolism. 

Severe myopathy/rhadomyolysis may occur and 

the mechanism is unknown. 

The risk of statin-induced rhabdomyolysis and 

myositis may be increased with certain agents in 

this class due to possible nefazodone inhibition 

of metabolism by CYP3A4. 

Atorvastatin levels may be elevated, increasing 

the risk of side effects (eg, rhabdomyolysis) due 

to suspected inhibition of atorvastatin first-pass 

metabolism CYP3A4. 

Pharmacologic effects of atorvastatin may be 

reducted due to reduced GI absorption. Note 

clinical study found that although atorvastatin 

levels were reduced by ~25% during 

coadministration with colestipol, LDL-C 

reduction was greater when the agents were 

coadministered versus given alone. 

Plasma concentrations of certain statins may be 

elevated, increasing the risk of toxicity (eg, 

rhabdomyolysis, myositis) possibly due to 

inhibition of first-pass metabolism (CYP3A4). 

Note a PK study determined steady state digoxin 

concentrations were increased by ~20%. 

Increased plasma levels and side effects (eg, 

rhabdomyolysis) of statins may occur due to 

inhibition of first-pass hepatic metabolism of 

CYP3A4. 

Increased serum levels and side effects (eg, 

rhabdomyolysis) of certain statins due to 

inhibition of first-pass metabolism (CYP3A4) in 

the small intestine. 

Statin levels may be reduced, decreasing the 

pharmacologic effects due to induction of firstpass 

metabolism (CYP3A4) in the intestine and 

liver. 

If coadministration cannot be avoided, monitor 

patients more closely for side effects and 

consider reducing the dose of atorvastatin while 

carefully monitoring the response. 

Avoid statin therapy unless benefits outweigh 

the risks. 

If coadministration cannot be avoided, monitor 

patients more closely for side effects or avoid 

statin therapy unless benefits outweigh the risks 

Monitor patients more closely for side effects or 

avoid statin therapy unless benefits outweigh the 

risks. 

Separate administration times by as much as 

possible (at least 4 hr before the statin), 

preferably giving the bile acid sequestrant 

before meals. 

If coadministration of these agents cannot be 

avoided, monitor patients more closely for side 

effects and possibly reduce statin dose. Digoxin 

levels should be monitored during atorvastatin 

therapy and reductions in dosage may be 

needed. 

If coadministration cannot be avoided, consider 

reducing the statin dose and carefully monitor 

the patient's response. 

Avoid coadministration with grapefruit 

products. 

Monitor the clinical response of the patient; if 

an interaction is suspected, it may be necessary 

to administer alternative therapy. Increase statin 

dose if needed. 

Most of the drug interactions listed above can be managed with appropriate dosing modifications 

and monitoring. Atorvastatin should not be used concomitantly with nefazodone and protease 

inhibitors unless the benefits of therapy outweigh the risks for potential side effects. However, 

nefazodone and protease inhibitors are used in specific patient populations and not the general 

population, for which we are evaluating the use of atorvastatin/amlodipine. When considering the 

general population, use of any statin would not be precluded due to potentially harmful drug 

interactions. 

365

VI. Adverse Drug Events 1 

Atorvastatin/amlodipine has been evaluated for safety in 1,092 patients in double-blind, placebo 

controlled trials in patients with co-morbid hypertension and dyslipidemia. 

Atorvastatin/amlodipine is generally well-tolerated, and most adverse events have been mild or 

moderate in severity with no peculiar events specific to the combination. Adverse events are 

similar in terms of nature, severity, and frequency to those reported with separate administration of 

atorvastatin and amlodipine. 

Atorvastatin 

Of 2,502 patients treated with atorvastatin during clinical trials, 3 times the upper limit of normal [ULN] occurring on two or more 

occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in 

clinical trials. The incidence of these abnormalities is dose dependent with 0.2%, 0.2%, 0.6%, and 

2.3% for 10, 20, 40, and 80mg tablets, respectively. These changes generally occurred within the 

first three months of treatment. Upon dose reduction, drug interruption, or discontinuation, 

transaminase levels return to or near pretreatment levels without sequelae. Due to this adverse 

event, liver function tests should be performed prior to and at 12 weeks following both initiation 

of therapy and any increase in dosage, and periodically (e.g., semiannually) thereafter. If 

increases in transaminases occur, patients should be monitored until the abnormalities resolve. If 

an increase in ALT or AST of >3 times ULN persists, a reduction in dose or discontinuation of 

atorvastatin/amlodipine is recommended. 

Skeletal Muscle Abnormalities 

Similar to other HMG-CoA reductase inhibitors, rare cases of rhabdomyolysis with acute renal 

failure secondary to myoglobinuria have been reported. In addition to rhabdomyolysis, myalgia 

has been reported. Myopathy, defined as muscle aches or muscle weakness in conjunction with 

increases in creatinine phosphokinase (CPK) values >10 times ULN, should be considered in any 

patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. 

Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, 

particularly if accompanied by malaise or fever. Atorvastatin/amlodipine should be discontinued 

if markedly elevated CPK levels occur, or if myopathy is diagnosed or suspected. This risk is 

increased during concomitant administration with cyclosporine, fibric acid derivatives, 

erythromycin, niacin, and azole antifungals. If coadministration benefits outweigh these risks, 

patients should be carefully monitored and periodic CPK determinations may be considered. 

Atorvastatin/amlodipine therapy should be temporarily withheld or discontinued in any patient 

with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to 

the development of renal failure secondary to rhabdomyolysis. 

Adverse events reported in ≥2% of subjects regardless of causality during atorvastatin clinical 

trials are listed in the following table. 

366

Table 5. Atorvastatin Adverse Events Reported in ≥2% of Subjects During Clinical Trials* 1 

Placebo 

n=270 

10mg 

n=863 

Atorvastatin Dosage 

20mg 40mg 

n=36 n=79 

80mg 

n=94 

Body System/Adverse Event 


Infection 

10.0 10.3 2.8 10.1 7.4 

Headache 

7.0 

5.4 16.7 2.5 6.4 

Accidental Injury 

3.7 

4.2 

0.0 

1.3 3.2 

Flu Syndrome 

1.9 

2.2 

0.0 

2.5 3.2 


0.7 

2.8 

0.0 

3.8 2.1 

Back Pain 

3.0 

2.8 

0.0 

3.8 1.1 

Allergic Reaction 

2.6 

0.9 

2.8 

1.3 0.0 

Asthenia 

1.9 

2.2 

0.0 

3.8 0.0 


Constipation 

1.8 

2.1 

0.0 

2.5 1.1 

Diarrhea 

1.5 

2.7 

0.0 

3.8 5.3 

Dyspepsia 

4.1 

2.3 

2.8 

1.3 2.1 

Flatulence 

3.3 

2.1 

2.8 

1.3 1.1 

Respiratory System 

Sinusitis 

2.6 

2.8 

0.0 

2.5 6.4 

Pharyngitis 

1.5 

2.5 

0.0 

1.3 2.1 


Rash 0.7 3.9 2.8 3.8 1.1 

Musculoskeletal System 

Arthralgia 

Myalgia 

1.5 

1.1 

*Includes adverse events regardless of causality. 

2.0 

3.2 

Amlodipine 

Of over 11,000 patients treated with amlodipine during clinical trials, discontinuation due to 

adverse events was required in ~1.5% of patients, which was not significantly different than 

placebo (~1%). Most adverse events were of mild or moderate severity, with headache and edema 

being the most common (edema is dose dependent as described in following table). 

0.0 

5.6 

5.1 

1.3 

0.0 

0.0 

367

Table 6. Amlodipine Adverse Events During Clinical Trials 1 

Dose-Related Amlodpine Adverse Events 

Amlodipine 

2.5mg 

5mg 

10mg 

Placebo 

n=520 

Adverse Event n=275 n=296 

n=268 

Edema 1.8 3.0 10.8 0.6 

Dizziness 1.1 3.4 3.4 1.5 

Flushing 0.7 1.4 2.6 0.0 

Palpitation 0.7 1.4 4.5 0.6 

Other Amlodipine Adverse Events in >1.0% Subjects in Placebo-Controlled Trials 

Amlodipine (%) 

Adverse Event 

n=1,730 

Headache 7.3 7.8 

Fatigue 4.5 2.8 

Nausea 2.9 1.9 

Abdominal Pain 1.6 0.3 

Somnolence 1.4 0.6 

Gender-Related Differences in Dose-Related Adverse Events 

Placebo (%) 

n=1,250 

Amlodpine 

Placebo 

Adverse Event 

Male % 

n=1,218 

Female % 

N=512 

Male % 

n=914 

Edema 5.6 14.6 1.4 5.1 

Flushing 1.5 4.5 0.3 0.9 

Palpitations 1.4 3.3 0.9 0.9 

Somnolence 1.3 1.6 0.8 0.3 

VII. Dosing and Administration 1 

Female % 

n=336 

General Dosing Considerations 

Atorvastatin/amlodipine can be used in several different situations: 

1. Substitution for atorvastatin and amlodipine following appropriate dose titration of the 

medications separately with the equivalent atorvastatin/amlodipine tablet. 

2. Substitution with increased amounts of atorvastatin, amlodipine, or both for additional lipid 

lowering, antianginal, or blood pressure lowering effects. 

3. As initial therapy for one indication and continuation of treatment of the other. The 

recommended starting dose should be selected based on the continuation of the component 

being used and the recommended starting dose for the added new therapy. 

4. As initial treatment for hyperlipidemia and either hypertension or angina. The recommended 

starting dose should be based on the appropriate combination of recommendations for the 

initial components. 

The maximum dose of atorvastatin/amlodipine is 10mg for the amlodipine component and 80mg 

for the atorvastatin component, administered once daily. A standard cholesterol-lowering diet 

should be initiated before starting atorvastatin therapy, and the patient should continue on this diet 

during atorvastatin/amlodipine therapy. Atorvastatin/amlodipine can be administered as a single 

dose at any time of day, with or without food. 

368

Available Dosage Strengths: 

• Amlodipine/atorvastatin 5/10mg 








Note: An atorvastatin/amlodipine formulation containing amlodpine 2.5mg is not available, 

and this amlodipine dose is recommended in specific situations as described below. 

Atorvastatin Dosing 

Adults: 

The recommended starting dose for Hypercholesterolemia (Heterozygous Familial and 

Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) is 10 or 20mg once 

daily. 

• Initiation with a higher dose (e.g., 40mg) may be considered for patients requiring large 

LDL-C reductions (e.g., >45%). 

• Lipid levels should be evaluated within 2 to 4 weeks after initiation and/or upon titration, 

and dose adjusted accordingly. 

• LDL-C levels should be used to initiate and evaluate response. 

Dosage in Homozygous Familial Hypercholesterolemia is 10 to 80mg daily and should be 

used in adjunct to other lipid-lowering therapy (e.g., LDL apheresis). 

Pediatrics (10-17 years): 

The recommended starting dose is 10mg daily with a maximum of 20mg daily. Doses >20mg 

have not been evaluated in this population. 

• Dosage adjustments may be made at intervals of 4 weeks or more. 

Amlodipine Dosing 

Adults: 

Initial antihypertensive dose is 5mg once daily with a maximum dose of 10mg once daily. 

• Elderly and/or small, fragile individuals should be started on 2.5mg once daily. This 

dose may also be used when adding amlodipine to other antihypertensive therapy. 

• Dose adjustment should proceed over 7 to 14 days; however, titration may occur more 

rapidly if clinically warranted and the patient is assessed frequently. 

Initial recommended dose for chronic stable or vasospastic angina is 5-10mg once daily. 

• The lower dosage of 5mg is suggested in the elderly and in patients with hepatic 

insufficiency. 

• Most patients require 10mg for clinical effect. 

Pediatrics (6-17 years): 

Recommended dose is 2.5 to 5mg once daily. Doses >5mg have not been studied. 

Special Considerations for Use 

• Contraindicated in patients with active liver disease or unexplained elevations of serum 

transaminases. 

• Contraindicated in patients with a known hypersensitivity to any component of the 

medication. 

• Pregnancy Category X. Contraindicated in Pregnancy and Lactation. 

• Dose adjustment not needed in renal impairment. Hemodialysis not expected to 

significantly enhance clearance of either component. 

• Atorvastatin/amlodipine formulation containing 2.5mg of amlodipine is unavailable. 

369


RESPOND Study 1 

A double-blind, placebo controlled study evaluated the safety and efficacy of 

atorvastatin/amlodipine (Caduet ® ) in 1,660 patients with co-morbid hypertension and 

dyslipidemia. Patients were treated with various fixed doses of atorvastatin/amlodipine (e.g., 5/10, 

10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80), amlodipine alone (5 or 10mg), atorvastatin alone 

(10, 20, 40, or 80mg), or placebo. All medication was administered once daily. Additional risk 

factors in this population other than hypertension and dyslipidemia included diabetes mellitus 

(15%), smokers (22%), and a positive family history of cardiovascular disease (14%). Following 

eight weeks of therapy, all eight atorvastatin/amlodipine combination treatment groups 

demonstrated statistically significant dose-related reduction in systolic and diastolic blood 

pressure (SBP and DBP, respectively), and LDL-C compared to placebo. There was no overall 

modification on the effect of either component on SBP, DBP, and LDL-C. 

Table 7. Efficacy of Combined Treatments in Reducing Systolic Blood Pressure 1 

Parameter/Analysis 

AML 0mg Mean Change (mmHg) 

(Placebo) 

Difference versus 

Placebo (mmHg) 

AML 5mg Mean Change (mmHg) 

ATO 0mg 

(Placebo) 

-3.0 

- 

-12.8 

ATO 

10mg 

-4.5 

-1.5 

-13.7 

ATO 

20mg 

-6.2 

-3.2 

-15.3 

ATO 

40mg 

-6.2 

-3.2 

-12.7 

ATO 

80mg 

-6.4 

-3.4 

-12.2 

AML 10mg 



Mean Change (mmHg) 

-9.8 

-16.2 

-10.7 

-15.9 

-12.3 

-16.1 

-9.7 

-16.3 

-9.2 

-17.6 



-13.2 

-12.9 

-13.1 

-13.3 

-14.6 

Table 8. Efficacy of Combined Treatments in Reducing Diastolic Blood Pressure 1 


ATO 0 mg 

(Placebo) 

ATO 

10mg 

ATO 

20mg 

AML 0mg Mean Change (mmHg) -3.3 -4.1 -3.9 

(Placebo) 


- -0.8 -0.6 


AML 5mg Mean Change (mmHg) -7.6 -8.2 -9.4 

ATO 

40mg 

-5.1 

-1.8 

-7.3 

ATO 

80mg 

-4.1 

-0.8 

-8.4 

AML 10mg 



Mean Change (mmHg) 

-4.3 

-10.4 

-4.9 

-9.1 

-6.1 

-10.6 

-4.0 

-9.8 

-5.1 

-11.1 



-7.1 

-5.8 

-7.3 

-6.5 

-7.8 

Table 9. Efficacy of Combined Treatments in Reducing LDL-C (% Change from Baseline) 1 


ATO 0mg 

(Placebo) 

ATO 

10mg 

ATO 

20mg 

ATO 

40mg 

ATO 

80mg 

AML 0mg Mean % Change -1.1 -33.4 -39.5 -43.1 -47.2 

(Placebo) 



370

Based on these results, the efficacy in terms of SBP and DBP reduction with 

atorvastatin/amlodipine versus therapy with amlodpine monotherapy was similar. In addition, 

with respect to LDL-C reduction, the efficacy with atorvastatin/amlodipine was similar to the 

efficacy of atorvastatin monotherapy. 

GEMINI Study 11 

Preliminary data of a randomized, open-label, noncomparative study evaluated the efficacy and 

safety of atorvastatin/amlodipine (Caduet ® ) as initial or added-on (integrated) therapy in the 

treatment of concomitant hyptertension and dyslipidemia (n=1,220). Subjects underwent lifestyle 

modifications and received atorvastatin/amlodipine (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 

10/80) daily with dose titration to improve blood pressure and lipid control. The primary endpoint 

was the percentage of subjects achieving goal blood pressure and LDL-C levels as established by 

the JNC VI and NCEP ATP III guidelines, respectively. 

All subjects (n=1,220) received study drug and had a mean blood pressure of 146.6±11.0/ 

87.9±8.6mmHg and mean LDL-C level of 152.7±33.2mg/dL. At 14 weeks, 57.7% achieved both 

blood pressure and LDL-C goals. Therapy was well tolerated, with 4.8% discontinuing due to 

adverse events: 11.9% due to respiratory tract infections, 8.8% due to edema, 5.4% due to 

headache, and 4.3% due to myalgia. 

Additional Studies 

The AVALON study is a prospective, multi-center study which is evaluating the safety and 

efficacy of atorvastatin/amlodipine (Caduet ® ) versus placebo or either agent alone in the treatment 

of co-morbid hypertension and dyslipidemia (n=847). The only information available was 

presented at a Medical Conference. Data at eight weeks indicates significantly more subjects 

treated with atorvastatin/amlodipine attained goal LDL-C levels compared to subjects treated with 

amlodipine monotherapy (82.1% versus 12.4%), and significantly more subjects treated with 

atorvastatin/amlodipine attained goal BP compared to atorvastatin monotherapy (51.0% versus 

32.3%). In addition, significantly more patients treated with atorvastatin/amlodipine (45.6%) 

attained both goal LDL-C and BP, compared to those treated with amlodipine (8.3%) and 

atorvastatin (28.6%) monotherapies. This study did not compare atorvastatin/amlodipine 

(Caduet ® ) versus coadministration of amlodipine and atorvastatin monotherapies. (Note, written 

information provided by manufacturer based on Data on File). 


Dose Simplification: No clinical data is available for the combination of 

atorvastatin/amlodipine (Caduet ® ), comparing adherence rates in patients given the 

combination agent versus therapy with each separate agent. The AVALON study 

presented above showed clinical benefit of the combination agent when compared with 

either agent as monotherapy, but no studies have compared the combination 

atorvastatin/amlodipine agent with use of coadministration of atorvastatin and 

amlodipine. 

Stable Therapy: A literature search of Medline and Ovid did not reveal clinical data on 

changing from other therapies to atorvastatin/amlodipine. 

Impact on Physician Visits: A literature search of Medline and Ovid did not reveal 

clinical data pertinent to use of atorvastatin/amlodipine and impact on physician visits. 

371

IX. 

Conclusions 

Recommended doses of atorvastatin/amlodipine have demonstrated dose-dependent reductions in 

both LDL-C and blood pressure which are both significant risk factors for the development of 

CHD. Efficacy and safety of this combination is similar to the individual agents administered 

separately (e.g., LDL-C reduction is similar to atorvastatin monotherapy, and BP reduction is 

similar to amlodipine monotherapy). No studies have compared the efficacy of 

atorvastatin/amlodipine to amlodipine and atorvastatin monotherapies administered 

concomitantly. Atorvastatin/amlodipine reduced LDL-C levels from ~33% to ~49% with the 

greatest reduction seen with the 80mg atorvastastin formulation. Systolic and diastolic BP were 

reduced by 12.2-17.6mmHg and 7.3-11.1mmHg. Preliminary data indicates, approximately 58% 

of subjects with co-morbid hyperlipidemia and hypertension achieved both BP and LDL-C goals 

based on current practice guidelines. Data regarding the efficacy of atorvastatin/amlodipine in the 

treatment of angina is not available in the Published Medical Literature. However, based on the 

similarity in pharmacokinetics of atorvastatin and amlodipine following atorvastatin/amlodipine 

(Caduet ® ) administration compared to atorvastatin and amlodipine pharmacokinetics when 

administered separately, theoretically, efficacy should be similar. 

One concern is with the available atorvastatin/amlodipine dosage forms. A formulation containing 

2.5mg of amlodipine is not available. This is the recommended starting dose for amlodipine in 

elderly and/or small, fragile individuals. This dose may also be used when adding amlodipine to 

other antihypertensive therapy. The combination product has no clinical advantage over 

amlodipine (Norvasc ® ) and atorvastatin (Lipitor ® ) in respect to BP reduction achieved with 

amlodipine (Norvasc ® ) and LDL-C lowering achieved with atorvastatin (Lipitor ® ). 

Therefore, atorvastatin/amlodipine (Caduet ® ) is comparable to the drugs in this class and to the 

generics and OTC products and offers no significant clinical advantage over other alternatives in 

general use. 


No brand of the combination atorvastatin/amlodipine (Caduet ® ) is recommended for preferred 

status. 

372

References 

1. Caduet ® [package Insert]. NewYork, NY: Pfizer Labs. 2004. 

2. Grundy SM, Cleeman JI, Bairey Merz NC, et al for the Coordinating Committee of the 

National Cholesterol Education Program. NCEP report: implications of recent clinical 

trials for the National Cholesterol Education Program, Adult Treatment Panel III 

Guidelines. Circulation. 2004;110:227-239. 

3. Executive summary of the third report of the National Cholesterol Education Program 

(NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in 

adults (adult treatment panel III). JAMA. 2001;285(19):2486-2497. 

4. US Department of Health and Human Services Food and Drug Administration Center for 

Drug Evaluation and Research Office of Pharmaceutical Science and Generic Drugs. 

Electronic Orange Book: Approved Drug Products with Therapeutic Equivalence 

Evaluations. Current through July 2004. Available at: 

http://www.fda.gov/cder/ob/default.htm. Accessed September 23, 2004. 

5. Chobanian AV, Bakris GL, Black HR, et al and the National High Blood Pressure 

Education Program Coordinating Committee. JNC 7: seventh report of the Joint National 

Committee on prevention, detection, evaluation, and treatment of high blood pressure. 

Hypertension. 2003;42:1206-1252. 

6. US Department of Health and Human Services. Seventh Report of the Joint National 

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 

Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. Accessed 

September 23, 2004. 

7. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the 

management of patients with chronic stable angina: a report of the American College of 

Cardiology/American Heart Association Task Force on Practice Guidelines (Committee 

to Update the 1999 Guidelines for the Management of Patients with Chronic Stable 

Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/stable.pdf. 

8. Lipitor ® [package insert]. New York, NY: Pfizer Labs. July 2004. 

9. Norvasc ® [package insert]. New York, NY: Pfizer Labs. June 2003. 

10. Facts and Comparisons Online. 2004. Wolters Kluwer Health, Inc. Available at: 

http://www.efactsweb.com/index.asp. Accessed September 23, 2004. 

11. Blank R, LaSalle J, Reeves R, Piper BA, Sun F. Amlodipine/atorvastatin single pill dual 

therapy improves goal attainment in the treatment of concomitant hypertension and 

dyslipidemia: the GEMINI study [abstract]. J Am Coll Cardiol. 2004;43(suppl A):447A. 

373

Pharmacotherapy Review Packet

Create successful ePaper yourself

Delete template?

Save as template?