DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1430 elapse between courses. In such cases, leukocyte counts should be
carried out before, during, and after each course of treatment.
Treatment failures owing to the presence of metronidazoleresistant
strains of T. vaginalis are becoming increasingly common.
Most of these cases can be treated successfully by giving a second
2-g dose to both patient and sexual partner. In addition to oral therapy,
the use of a topical gel containing 0.75% metronidazole or a
500- to 1000-mg vaginal suppository will increase the local concentration
of drug and may be beneficial in refractory cases.
Metronidazole is an effective amebicide and is the agent of choice
for the treatment of all symptomatic forms of amebiasis, including
amebic colitis and amebic liver abscess. The recommended dose
is 500-750 mg metronidazole taken orally three times daily for
7-10 days, or for children, 35-50 mg/kg/day given in three divided
doses for 7-10 days.
Although standard recommendations are for 7-10 days’ duration
of therapy, amebic liver abscess has been treated successfully by
short courses (2.4 g daily as a single oral dose for 2 days) of metronidazole
or tinidazole (Stanley, 2003). E. histolytica persist in most
patients who recover from acute amebiasis after metronidazole therapy,
so it is recommended that all such individuals also be treated
with a luminal amebicide.
Although effective for the therapy of giardiasis, metronidazole
has yet to be approved for treatment of this infection in the U.S.
However, tinidazole is approved for the treatment of giardiasis as a
single 2-g dose and is appropriate first-line therapy. Metronidazole
is a relatively inexpensive, highly versatile drug with clinical efficacy
against a broad spectrum of anaerobic and microaerophilic bacteria.
It is used for the treatment of serious infections owing to
susceptible anaerobic bacteria, including Bacteroides, Clostridium,
Fusobacterium, Peptococcus, Peptostreptococcus, Eubacterium, and
Helicobacter. The drug is also given in combination with other
antimicrobial agents to treat polymicrobial infections with aerobic
and anaerobic bacteria. Metronidazole achieves clinically effective
levels in bones, joints, and the CNS. Metronidazole can be given
intravenously when oral administration is not possible. A loading
dose of 15 mg/kg is followed 6 hours later by a maintenance dose of
7.5 mg/kg every 6 hours, usually for 7-10 days. Metronidazole is
used as a component of prophylaxis for colorectal surgery and is
employed as a single agent to treat bacterial vaginosis. It is used in
combination with other antibiotics and a proton pump inhibitor in
regimens to treat infection with H. pylori (Chapter 45).
Metronidazole is used as primary therapy for Clostridium difficile
infection, the major cause of pseudomembranous colitis. Given
at doses of 250-500 mg orally three times daily for 7-14 days (or
even longer), metronidazole is an effective and cost-saving alternative
to oral vancomycin therapy. However, a reported increase in
treatment failures and higher rates of disease recurrence with
metronidazole (as compared to oral vancomycin) are raising questions
about the role of metronidazole as first-line therapy
(McFarland, 2008). Finally, metronidazole is also used in the treatment
of patients with Crohn’s disease who have perianal fistulas,
and it can help control colonic (but not small bowel) Crohn’s disease.
However, high doses (750 mg three times daily) for prolonged
periods may be necessary, and neurotoxicity may be limiting
(Podolsky, 2002). Metronidazole and other nitroimidazoles can sensitize
hypoxic tumor cells to the effects of ionizing radiation, but
these drugs are not used clinically for this purpose.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Toxicity, Contraindications, and Drug Interactions. The toxicity of
metronidazole has been reviewed (Raether and Hanel, 2003). Side
effects only rarely are severe enough to discontinue therapy. The
most common are headache, nausea, dry mouth, and a metallic taste.
Vomiting, diarrhea, and abdominal distress are experienced occasionally.
Furry tongue, glossitis, and stomatitis occurring during therapy
may be associated with an exacerbation of candidiasis.
Dizziness, vertigo, and very rarely, encephalopathy, convulsions,
incoordination, and ataxia are neurotoxic effects that warrant discontinuation
of metronidazole. The drug also should be withdrawn
if numbness or paresthesias of the extremities occur. Reversal of serious
sensory neuropathies may be slow or incomplete. Urticaria,
flushing, and pruritus are indicative of drug sensitivity that can
require withdrawal of metronidazole. Metronidazole is a rare cause
of Stevens-Johnson syndrome (toxic epidermal necrolysis); one
report described a high rate of this syndrome among individuals
receiving high doses of metronidazole and concurrent therapy with
the antihelminthic mebendazole (Chen et al., 2003).
Dysuria, cystitis, and a sense of pelvic pressure have been
reported. Metronidazole has a well-documented disulfiram-like
effect, and some patients experience abdominal distress, vomiting,
flushing, or headache if they drink alcoholic beverages during or
within 3 days of therapy with this drug. Patients should be cautioned
to avoid consuming alcohol during metronidazole treatment even
though the risk of a severe reaction is low. By the same token,
metronidazole and disulfiram or any disulfiram-like drug should not
be taken together because confusional and psychotic states may
occur. Although related chemicals have caused blood dyscrasias,
only a temporary neutropenia, reversible after discontinuation of
therapy, occurs with metronidazole.
Metronidazole should be used with caution in patients with
active disease of the CNS because of its potential neurotoxicity. The
drug also may precipitate CNS signs of lithium toxicity in patients
receiving high doses of lithium. Plasma levels of metronidazole can
be elevated by drugs such as cimetidine that inhibit hepatic microsomal
metabolism. Moreover, metronidazole can prolong the prothrombin
time of patients receiving therapy with coumadin
anticoagulants. The dosage of metronidazole should be reduced in
patients with severe hepatic disease.
Given in high doses for prolonged periods, metronidazole is
carcinogenic in rodents; it also is mutagenic in bacteria (Raether and
Hanel, 2003). Mutagenic activity is associated with metronidazole
and several of its metabolites found in the urine of patients treated
with therapeutic doses of the drug. However, there is no evidence
that therapeutic doses of metronidazole pose any significant
increased risk of cancer to human patients. There is conflicting evidence
about the teratogenicity of metronidazole in animals. Although
metronidazole has been taken during all stages of pregnancy with
no apparent adverse effects, its use during the first trimester generally
is not advised.
Miltefosine
Miltefosine (IMPAVIDO) is an alkylphosphocholine
(APC) analog that was developed originally as an anticancer
agent. Its antiprotozoal activity was discovered
in the 1980s during the time that it was being evaluated
for cancer chemotherapy. In 2002, it was