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LEARNING OBJECTIVES

Continuing Education Lesson

Upon successfully completing this lesson,

the pharmacist will be able to:

1. Recognize the mechanisms of antibiotic

resistance in respiratory tract bacterial

pathogens

2. Describe the epidemiology of resistance

in respiratory tract pathogens in the

Canadian setting

3. Describe the optimal use of antibiotics for

acute respiratory tract infection in adults

4. Describe the role of the community

pharmacist in recognizing, managing and

preventing antibiotic resistance

Instructions

1. After carefully reading this lesson, study

each question and select the one answer you

believe to be correct. Circle the appropriate

letter on the attached reply card or

answer online for immediate results at

www.canadianhealthcarenetwork.ca.

2. To pass this lesson, a grade of 70%

(14 out of 20) is required. If you pass,

your CEU(s) will be recorded with the

relevant provincial authority(ies).

(Note: some provinces require individual

pharmacists to notify them.)

answering options

A. Answer online for immediate results at

www.canadianhealthcarenetwork.ca

B. Mail or fax the printed answer card to

(416) 764-3937. Your reply card will be

marked and you will be advised of your

results within six to eight weeks in a

letter from Rogers Publishing.

NOTE: All faxed or mailed reply cards must

be submitted one month before lesson

expiry date.

This CE lesson is published by Rogers Publishing Limited

(Pharmacy Group), One Mount Pleasant Rd., Toronto, Ont.

M4Y 2Y5. Tel.: (416) 764-3916 Fax: (416) 764-3931. No part

of this CE lesson may be reproduced, in whole or in part,

without the written permission of the publisher. © 2010

Antibiotic Resistance

and the Optimal Use of

Antibiotics for Acute

Community-Acquired

Respiratory Tract

Infection in Adults

By Curtis Harder, BSc (Pharm), ACPR, PharmD

JUNE 2010

The author, expert reviewers and Rogers Publishing have each declared that there is no real or potential conflict of interest with

the sponsor of this CE lesson.

Introduction

Medicine was revolutionized in 1928 with

the discovery of penicillin, a treatment for

gram-positive bacterial infections that would

become the most widely used antibiotic to

date. 1,2 Prior to the 1930s, bacterial infection

was a common cause for hospitalization,

often resulting in death or disability. 3 However,

as with the rapid emergence of penicillin

resistance in Staphylococcus aureus, the problem

of resistance has quickly followed the

development and use of almost every other

antibiotic. 4 A pattern has become apparent

– with increasing use of any particular agent,

observation of resistance shortly follows. In

APPROVED FOR

1.25 CEUs

Approved for 1.25 CE units by the Canadian

Council on Continuing Education in Pharmacy.

CCCEP #1065-2010-062-I-P.

Not valid for CE credits after May 19, 2013.

a 1992 published article, this pattern, coupled

with the reduction in development of new

antibiotic agents, led ML Cohen to describe

the possibility of a “post-antibiotic era” in a

call for greater attention to the problem of

antibiotic resistance. 3 Subsequently, calls like

this have led to the concept of “antimicrobial

stewardship.” 5

Although antimicrobial stewardship interventions

to conserve antibiotics have largely

focused on hospitals, 6 many of the underlying

philosophies carry over to the community.

The community pharmacist has a key role

in ensuring the optimal use of antimicrobials.

Suboptimal and/or inappropriate use of anti-

SUPPORTED BY AN EDUCATIONAL GRANT FROM


iotics can be driven by the focus on the

individual patient, rather than the impact on

the environment or population. It can also

be driven by a belief that greater and longer

administration of treatment is better and/or

that all-encompassing antibiotic coverage is

necessary to account for potential resistance.

Other common factors responsible for suboptimal

and/or inappropriate use include

inadequate knowledge, fear of litigation,

patient pressure, product marketing and time

constraints forcing a prescriber to provide an

antibiotic prescription rather than an explanation

of why an antibiotic is unnecessary. 5

When community pharmacists appreciate

these factors, they can address inappropriate

use of antibiotics through education of both

patients and prescribers, and through direct

intervention when inappropriate antibiotic

use is recognized.

Emergence and Epidemiology of

Antibiotic-Resistant Organisms

Affecting the Respiratory Tract

Respiratory tract infection (RTI), including

acute bacterial rhinosinusitis (ABRS), acute

exacerbation of chronic bronchitis (AECB)

and community-acquired pneumonia

(CAP), is a common problem. Despite often

being viral in origin, RTI is a frequent cause

of patients seeking medical attention and

of antibiotic prescriptions. Streptococcus

pneumoniae, Haemophilus influenzae and

Moraxella catarrhalis are the three most

prevalent bacteria responsible for ABRS,

AECB and CAP. 7-10 With increasing use of

newer antibiotic agents for the treatment

of RTI, concerns have been growing

about antibiotic resistance, especially in

S. pneumoniae and H. influenzae. 11-13

Shortly after the discovery of penicillin,

resistance was observed in S. pneumoniae

but the clinical significance was not appreciated

until the 1970s, when strains that were

either intermediately sensitive or resistant

to penicillin (i.e., both considered penicillin

non-susceptible S. pneumoniae, or PNSP,

defined by the minimum inhibitory concentration,

or MIC, of penicillin) were first

detected in several distinct regions in

the world. 14,15 Subsequently, resistance of

S. pneumoniae to beta-lactams and other

antibiotic classes has become widespread. 15

However, data from the Canadian Respiratory

Organism Susceptibility Study

(CROSS) for 1998–2006 demonstrated that

the prevalence of PNSP was relatively stable

at 16–25% with small year-to-year variations

but no apparent increase overall. 16 The

clinical relevance of in vitro penicillin resistance

has been debated since treatment success

with penicillin, despite the presence of

PNSP, has been observed. 17 This discrepancy

may be a result of inappropriate definitions

of susceptibility: until 2007, the definitions

were based on those developed for meningitis

and were likely overly conservative. 18

The MIC breakpoints for penicillin susceptibility

in conditions other than meningitis

were recently increased. 18

Increases in resistance of S. pneumoniae

to macrolides have been observed more

recently, together with a steady rise in use

of azithromycin and clarithromycin.

Between 1995 and 2005, macrolide resistance

in Canada increased from 3.7% to

19.0% (p=0.003), disproportionately

coupled with an increase in macrolide prescriptions

from 106.7 prescriptions/1,000

persons to 123.2 prescriptions/1,000 persons

(p=0.003). 12 This phenomenon is not

completely understood but may relate to

total macrolide consumption increasing

beyond an arbitrary critical threshold

necessary to select for resistant strains. 12

Resistance continued to increase from

2003–2005, even though the number of

azithromycin and clarithromycin prescriptions

remained stable and erythromycin

prescriptions declined. 12 In 2006, the last

year for which there are data, macrolide

resistance stabilized at 18.7%. 16

These figures encompass both “low-level”

and “high-level” resistance that is mediated

by different mechanisms (see Mechanisms

of Resistance below). The clinical relevance

of low-level macrolide resistance, about 60%

of all macrolide resistance in Canada, 16 is not

clearly understood. 19 Resistance type may

vary depending on location, as demonstrated

by 2000/2001 data from Quebec showing

that 58% of macrolide-resistant S. pneumoniae

strains had high-level resistance. 20

Precisely because of resistance of S. pneumoniae

to other antibiotics, later-generation

fluoroquinolones (levofloxacin and moxifloxacin)

have become important tools for

treating RTI, but increasing resistance has

been observed with this antibiotic class.

Between 1997 and 2006, fluoroquinolone

prescriptions increased by 72%, driven in

part by a large increase in respiratory fluoroquinolone

prescriptions, which increased

by 416.2% between 1999 and 2006. 11

Although S. pneumoniae resistance to all

fluoroquinolones increased between 1998

and 2006, the most significant increase

was to ciprofloxacin, rising from 0.6%

to 7.3%. 11 Levofloxacin and moxifloxacin

resistance were at 2% and 1.5%, respectively,

in 2006. 11 Although ciprofloxacin is

not a recommended treatment for RTI, its

use for other indications has increased the

prevalence of S. pneumoniae with the first

of two mutational steps, conferring resistance

to ciprofloxacin but not to the thirdand

fourth-generation fluoroquinolones.

Since the introduction of the H. influenzae

serotype b (Hib) conjugate vaccine, most

disease caused by H. influenzae is now caused

by non-type b or non-typeable (NT) strains,

which are not covered by the vaccine. 13

Resistance of H. influenzae to ampicillin and

other antibiotics, mediated by beta-lactamase

production, has been documented. 21 However,

resistance to ampicillin in Canada has

decreased during the last two decades (21.1%

in 1990–1999 to 16.4% in 2000–2006). 13

The CROSS study data similarly demonstrate

a decrease in beta-lactamase-producing

H. influenzae (resistant to amoxicillin and

ampicillin) from 24% in 1998 to 19.8%

in 2005. 16 However, non-beta-lactamasemediated

resistance to ampicillin has been

noted. 13 There is little resistance to ceftriaxone,

ciprofloxacin or moxifloxacin. 13

In Canada, M. catarrhalis remains nearly

100% susceptible to amoxicillin/clavulanic

acid, clarithromycin and cefuroxime. 16

Mechanisms of Resistance

Microbes have provided us with many of

the useful antibiotics (e.g., beta-lactams) in

use today and many of the genetic determinants

for resistance have been present in bacteria

as natural defense mechanisms. Biochemical

means to control microbial

growth, expressed by microbes themselves,

as well as means to evade such control, predate

the “antibiotic era.” 22, 23 Antibiotic

resistance is seen when there is genetic mutation,

expression of a latent resistance gene

and/or acquisition of genes with resistance

determinants. The clinical, agricultural and/

or veterinary use of antibiotics has selectively

applied pressure to favour the overgrowth

of organisms with these genetic determinants

for resistance, which can emerge

2 | Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults Answer online at www.canadianhealthcarenetwork.ca | June 2010


through any or all of these mechanisms. 22

Bacteria can then manifest resistance to

antibiotics in three general ways: alterations

in antibiotic binding sites, production of

efflux proteins and production of antibioticdegrading

enzymes. 9

Mechanisms of resistance of the major

pathogens implicated in RTI are summarized

in Table 1. Resistance of S. pneumoniae

to antibiotics is mediated by alterations in

antibiotic binding sites and production of

antibiotic efflux pumps. Multiple alterations

of penicillin-binding proteins (PBPs),

enzymes responsible for the cross-linking of

peptidoglycan in the bacterial cell wall,

result in resistance to penicillin and other

beta-lactams. 9 This type of resistance can be

overcome with use of more potent betalactams

and higher doses to ensure adequate

concentrations (e.g., high-dose amoxicillin).

10,24 Alterations in the 23S rRNA of the

50S ribosomal subunit, usually encoded by

the erythromycin ribosome methylation

(erm) gene, are responsible for the reduced

affinity for macrolide antibiotics, restricting

their ability to decrease bacterial protein

synthesis. 9,25 This mechanism results in

high-level macrolide resistance, characterized

by MICs that are substantially greater

than susceptible organisms. Fluoroquinolone

resistance is seen with alterations in

genes encoding for their targets, DNA

gyrase and/or topoisomerase IV, enzymes

required for bacterial DNA replication (the

newer third- and fourth-generation fluoroquinolones

having affinity for both enzymes,

and ciprofloxacin and earlier generation

fluoroquinolones preferentially binding to

DNA gyrase). 9 Increased doses of macrolides

and fluoroquinolones are not an effective

strategy to overcome resistance.

Production of antibiotic efflux pumps by

S. pneumoniae confers resistance to the

macrolides and fluoroquinolones but not

the beta-lactams. Resistant S. pneumoniae

can produce active-transport pumps,

encoded by pneumococcal multidrug resistance

(pmr) and macrolide efflux (mef) genes

that remove macrolides and fluoroquinolones

from the intracellular to the extracellular

space before they can reach their

ribosomal target. 9 With macrolides, this

mechanism of resistance results in low-level

resistance, characterized by MICs that are

potentially attainable at the site of infection

(e.g., in the alveolar epithelial lining fluid)

Table 1 Key acute respiratory tract infection organisms and mechanisms

of resistance

Organism Mechanism of

resistance

S. pneumoniae Alteration in

antibiotic binding

site(s)

Production of antibiotic

efflux pumps

H. influenzae Production of

antibiotic-degrading

enzymes (e.g., betalactamases)

Alteration in antibiotic

binding site(s)

Production of antibiotic

efflux pumps

M. catarrhalis Production of

antibiotic-degrading

enzymes (e.g., betalactamases)

Antibiotics

affected

Beta-lactams

(e.g., amoxicillin)

Fluoroquinolones

Macrolides

Tetracyclines

Macrolides

Fluoroquinolones

Beta-lactams

Fluoroquinolones

Macrolides

Beta-lactams

Strategy to overcome

resistance

Increase dose of beta-lactam

(e.g., amoxicillin 1 g)

Use antibiotic from another class

Use antibiotic from another class

Use antibiotic from another class

Use antibiotic from another class

Use antibiotic from another class

Addition of a beta-lactamase

inhibitor; use of a beta-lactam

more stable against betalactamases

(cefuroxime, cefixime)

Use antibiotic from another class

This common intrinsic resistance

mechanism does not usually

confer in vitro resistance to

azithromycin and clarithromycin

Addition of a beta-lactamase

inhibitor; use of a beta-lactam

stable against beta-lactamases

(cefuroxime, cefixime)

but not in the blood. 19 This feature has led

some to question whether the macrolides

retain potential utility in the treatment of

uncomplicated (e.g., non-bacteremic) infections

where the organism is considered to

demonstrate low-level resistance by official

MIC breakpoints. 19

The major mechanism of antibiotic resistance

of H. influenzae and M. catarrhalis

involves the production of beta-lactamase,

an enzyme responsible for hydrolyzing the

beta-lactam ring of penicillins, most cephalosporins

and related antibiotics. Two strategies

are useful for overcoming this type of

resistance: the addition of a beta-lactamase

inhibitor (e.g., clavulanic acid added to

amoxicillin) to preserve the beta-lactam ring

of the antibiotic, and the use of beta-lactam

antibiotics that are more stable against the

actions of beta-lactamases (e.g., cefuroxime,

cefixime). 9 Increasing the dose of the betalactam

antibiotic is not effective against

beta-lactamase production because this

enzyme is recycled after each interaction

with a beta-lactam. 9 Resistance of H. influenzae

to fluoroquinolones can occur with

alterations in genes encoding for DNA

gyrase or topoiosomerase IV, a similar mechanism

to that of S. pneumoniae. 9 Although

most H. influenzae isolates demonstrate a

level of resistance to macrolides through an

intrinsic efflux mechanism, this organism

is still regarded as susceptible to clarithromycin

and azithromycin. 25

Relationship Between Antibiotic

Use and Resistance

Even though determinants of antibiotic

resistance predated the antibiotic era, the

increased prevalence of resistant organisms

is directly correlated with the selective pressure

applied by antibiotic use. Because

community-acquired RTI often results in

the prescription of antibiotics (regardless of

whether the infection is bacterial), and

because the problem of resistance in RTI

has evolved so quickly, there is much concern

about the appropriate use of these

agents. 9,14,25,26

Although there is a clear link between

antibiotic exposure and resistance, the

relationship is not straightforward. For

instance, it has been shown that previous

exposure to one antibiotic can predict resistance

of S. pneumoniae to antibiotics from

another class. 27,28 In one study, beta-lactam

June 2010 | Answer online at www.canadianhealthcarenetwork.ca Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults | 3


or macrolide use in the previous six months

was associated with penicillin resistance

in pneumococcal bacteremia. 28 Similarly,

pneumococcal penicillin resistance was associated

with the use of penicillin, trimethoprim/sulfamethoxazole

(TMP/SMX) or

azithromycin in the previous three months. 27

In the same study, TMP/SMX resistance was

associated with previous use of TMP/SMX,

penicillin and/or azithromycin. Clarithromycin

use was associated with erythromycin

resistance, while azithromycin use was associated

with penicillin, ceftriaxone, TMP/SMX

and erythromycin resistance. These relationships

emphasize the importance of considering

recent antibiotic therapy even for nonrelated

indications when selecting a current

regimen. With macrolide antibiotics in particular,

they suggest that use of longer-acting

agents (e.g., azithromycin) may be more

detrimental in terms of emerging resistance

as compared to shorter-acting agents (e.g.,

clarithromycin).

The relationship between antibiotic resistance

and clinical failure remains unclear. 15

Factors other than antibiotic susceptibility

are often implicated in clinical failures, clouding

the picture. For example, in a prospective

study of 844 hospitalized patients with S.

pneumoniae bacteremia, discordant therapy

(i.e., antibiotics for non-susceptible strains)

with penicillin and third-generation cephalosporins

was not associated with an

increased risk in mortality, although treatment

with cefuroxime was. 17 The patients in

this study represented those with more severe

disease in whom the impact of antibiotic

non-susceptibility might be of particular relevance

and yet this was not the case. Substantial

in vitro pneumococcal resistance to

macrolides exists, but the data on resultant

clinical failure are contradictory and/or

unclear. 19 This may reflect methodological

limitations of the studies or the pharmacokinetic

properties of macrolides that allow

them to achieve high concentrations in respiratory

tissues, thus overcoming potential

resistance (specifically low-level type, as previously

discussed). 19,26 Nonetheless, with a

significant prevalence of antibiotic resistance

to a variety of different agents, and an incomplete

understanding of the relationship to

clinical failure, it behooves us to be cautious

and judicious in our use of these agents. For

this reason, national, regional and local therapeutic

guidelines are regularly updated to

reflect changing rates in clinically significant

resistant bacteria. These guidelines aim to

optimize therapy for the individual and minimize

emerging resistance in the society by

selecting the most appropriate antibiotic

regimen.

Optimal Use of Antibiotics

for RTI: Acute Bacterial

Rhinosinusitis, Acute

Exacerbation of Chronic

Bronchitis and Community-

Acquired Pneumonia

When antibiotic treatment is indicated for

the management of RTI, the goals of therapy

should include resolution of initial signs and

symptoms, cure of infection, prevention of

complications from the infection and adverse

effects of antibiotic treatment, and overall

improvement in quality of life. General considerations

in establishing the best antibiotic

treatment for RTI should include evidence

of efficacy, spectrum of activity, the likely

pathogens involved, the likelihood of antibiotic

resistance, the drug safety profile and

patient preferences. The specific antibiotic

treatment for ABRS, AECB and CAP are

discussed below and a summary of treatment

recommendations is provided in Table 2.

Acute Bacterial Rhinosinusitis

Rhinosinusitis is a symptomatic inflammation

of the paranasal sinuses and nasal cavity,

typically caused by extension of an upper

respiratory tract infection (URTI). 7 Acute

rhinosinusitis (ARS), lasting less than four

weeks, is usually viral with only an estimated

0.5% to 2% of cases complicated by bacterial

infection. 29 Despite this, more than

20% of antibiotics prescribed to adults are

for sinusitis treatment. 2,30

Even when bacterial infection is implicated,

ARS is usually self-limited and often

will resolve without antibiotic treatment. For

example, a double-blind placebo-controlled

trial comparing amoxicillin with placebo

assessed resolution of symptoms within 14

days in patients with clinical signs and symptoms

of sinusitis lasting longer than seven

days, showed no difference in clinical

improvement as reported by the patients. 31

Of note, over half of the patients still had

symptoms at 14 days. 31 A recent meta-analysis

of 13 trials comparing oral antibiotic treatment

to placebo for uncomplicated ARS

found that clinical cure and clinical improvement

occurred in 45% and 73%, respectively,

by 14 to 15 days in patients who received the

placebo. 24 Based on an absolute improvement

in clinical cure by 15% at 7–12 days with

antibiotics, the number needed to treat

(NNT) is seven. 24 However, the corresponding

11% absolute increase in adverse events

yields a number needed to harm (NNH) of

nine, in relative balance with the NNT. 24

This meta-analysis, although comprehensive,

is limited by its broad inclusion criteria that

do not distinguish between viral and bacterial

illness. Although numerous trials have been

conducted to assess a variety of antibiotic

classes, including penicillins, macrolides,

fluoroquinolones, tetracyclines, cephalosporins

and folate inhibitors, a recent systematic

review failed to show any clinically meaningful

differences between any particular agent

or class in the treatment of ARS. 32

Patients with ARS experience purulent

nasal discharge, nasal congestion and/or facial

pain/pressure. Presenting features are not

reliable indicators of the etiology of the infection;

however, patients with systemic symptoms

(e.g., temperature >38.5, lethargy,

myalgia) and/or severe signs/symptoms (e.g.,

facial pain, headache, swelling, erythema)

should be referred to a physician, and the

risk of complications likely will warrant antibiotic

treatment. Bacterial rhinosinusitis

should be presumed when a patient has (a)

symptoms or signs of ARS lasting 10 days or

more beyond the onset of URTI symptoms

or (b) symptoms or signs of ARS that worsen

within 10 days after an initial improvement

(“double worsening”). 7

Antibiotic treatment should target S.

pneumoniae, H. influenzae and M. catarrhalis.

Amoxicillin is first-line treatment for

acute bacterial rhinosinusitis because of its

safety, efficacy, low cost, and narrow microbiologic

spectrum, and should typically be

given for 10 days. 7,33,34 For patients with a

true beta-lactam allergy, doxycyline or

TMP/SMX are reasonable alternatives. 33 An

increased dose of amoxicillin (i.e., to 1 g

PO TID-QID) can be used for treatment

failure and/or antibiotic use in the previous

three months, to overcome potential

S. pneumoniae resistance. This strategy is

also reasonable for patients living in a household

with a child in daycare. 7 Other options

to address potential resistance are provided

in Table 2 and should be based on safety,

convenience and cost.

4 | Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults Answer online at www.canadianhealthcarenetwork.ca | June 2010


Table 2 Treatment of acute bacterial rhinosinusitis, bronchitis and community-acquired pneumonia 7,8,10,33,34,37,45

Acute bacterial rhinosinusitis Bronchitis Community-acquired pneumonia

≥98% viral cause; antibiotics

NOT indicated

Consider bacterial cause and/or antibiotic

treatment in patients with the following

features:

• signs/symptoms for 10 days or more

• symptoms that worsen after an initial

improvement (double worsening)

• severe symptoms and/or significant

worsening

• immunocompromise

Usual etiology:

• Streptococcus pneumoniae 20-43%

• Haemophilus influenzae 22-35%

• Moraxella catarrhalis 2-10%

• Oropharyngeal anaerobes

Empiric antibiotic selection

First-line:

• amoxicillin x 10 days

Beta-lactam allergy:

• doxycycline x 10 days †

• TMP/SMX x 10 days

Treatment failure or antibiotics in last

three months:

• high-dose amoxicillin x 10 days

• amoxicillin/clavulanic acid x 10 days

• cefuroxime axetil x 10 days

• azithromycin x 3 days ‡

• clarithromycin OR clarithromycin XL

x 10 days ‡

• levofloxacin x 5-10 days

• moxifloxacin x 5-10 days

ACUTE BRONCHITIS

Viral cause in majority of cases;

antibiotics NOT indicated

Bordetella pertussis is rarely implicated

and is the sole indication for antibiotic

treatment of acute bronchitis; suspicion

and treatment should be limited to

patients with high probability of exposure

(e.g., outbreaks)

ACUTE EXACERBATION OF CHRONIC

BRONCHITIS

At least 50% of exacerbations are infectious

in nature.

Three cardinal signs/symptoms warranting

antibiotic treatment:

• increased dyspnea

• increased sputum volume

• increased sputum purulence

Increased sputum purulence plus only one

other sign/symptom warrants antibiotic

treatment

Usual etiology:

• respiratory viruses

• Haemophilus influenzae

• Streptococcus pneumoniae

• Moraxella catarrhalis

Empiric antibiotic selection

Simple exacerbation:

• amoxicillin x 7-10 days

• doxycycline x 7-10 days †

• TMP/SMX x 7-10 days

Complicated exacerbation (treatment failure,

four or more episodes/year or antibiotics in

last three months):

• amoxicillin/clavulanic acid x 7-10 days

• cefuroxime axetil x 7-10 days

• azithromycin x 3 days ‡

• clarithromycin OR clarithromycin XL

x 10 days ‡

• levofloxacin x 5 days

• moxifloxacin x 5 days

Bacterial cause in majority of cases;

antibiotic treatment typically indicated

Usual etiology in outpatients

(in descending order of frequency):

• Streptococcus pneumoniae

• Mycoplasma pneumoniae

• Haemophilus influenzae

• Chlamydophila pneumoniae

• respiratory viruses

Additional organisms to consider in

presence of comorbidity*:

• Staphylococcus aureus

• Moraxella catarrhalis

• Enterobacteriaceae

Empiric antibiotic selection

No antibiotics in last three months:

• azithromycin x 5 days

• clarithromycin OR clarithromycin XL

x 7-10 days

• doxycycline x 7-10 days

• erythromycin x 7-10 days

Antibiotics in last three months

and/or comorbid factors*:

• high-dose amoxicillin OR amoxicillin/

clavulanic acid OR cefuroxime axetil

x 7-10 days PLUS

- azithromycin x 5 days

- clarithromycin x 7-10 days

- clarithromycin XL x 7-10 days

• levofloxacin x 5 days

• moxifloxacin x 7-10 days

* Comorbid factors: chronic heart, lung,

liver or renal disease, diabetes, alcoholism,

immunosuppressing conditions or use of

immunosuppressing medications

TAKING ANTIBIOTICS IN THE LAST THREE MONTHS IS A RISK FACTOR FOR RESISTANT S. PNEUMONIAE. CARE SHOULD BE TAKEN TO AVOID USING AGENTS FROM THE SAME

CLASS OF ANTIBIOTICS IF POSSIBLE.

Use of a macrolide antibiotic is a reasonable option in settings where resistance to doxycycline is significant (>20%).

‡ A macrolide antibiotic may be inappropriate in settings where high-level resistance (erm-mediated) is the predominant form (e.g., province of Quebec).

Antibiotic doses: amoxicillin 500 mg PO TID; high-dose amoxicillin 1000 mg PO TID-QID; amoxicillin/clavulanic acid 500 mg PO TID or 875 mg PO BID; azithromycin 500 mg

PO daily (ABRS and AECB), 500 mg once then 250 mg daily (CAP); cefuroxime axetil 500 mg PO BID; clarithromycin 500 mg PO BID or XL 1000 mg PO daily; doxycycline 200 mg

once then 100 mg PO BID; levofloxacin 750 mg PO daily; moxifloxacin 400 mg PO daily; TMP/SMX DS 1 tablet PO BID

Acute Bronchitis

Acute bronchitis is a self-limited inflammatory

condition of the bronchi characterized

by a cough that persists for more than five

days but less than three weeks, and is usually

associated with sputum production that may

or may not be purulent. 35 It is almost always

caused by viruses, and numerous studies

have shown conclusively that routine

antibiotic treatment is unwarranted. 35,36

Treatment is mostly limited to supportive

measures. The presence of fever suggests a

different diagnosis, such as pneumonia or

influenza infection.

Acute Exacerbation of Chronic

Bronchitis

Chronic obstructive pulmonary disease

(COPD) is a respiratory disorder largely

caused by smoking, characterized by progressive,

partially reversible airway obstruction

and lung hyperinflation, systemic manifestations,

and increasing frequency and severity

of exacerbations. 8 An acute exacerbation of

chronic bronchitis (AECB) associated with

COPD occurs when there is a significant and

acute change in dyspnea, cough or sputum

production that may warrant a change in

medication requirements. 37 At least half of

these episodes are due to infection. 8,37

Antibiotics serve a role in the patient

managed in the community who demonstrates

three cardinal signs/symptoms:

June 2010 | Answer online at www.canadianhealthcarenetwork.ca Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults | 5


increased dyspnea, increased sputum volume

and increased sputum purulence. 37

Only two signs/symptoms are necessary if

one of these is increased sputum purulence.

37 Antibiotic treatment should target

H. influenzae, M. catarrhalis and S. pneumoniae,

although respiratory viruses can also

be implicated. 37 Amoxicillin, doxycycline or

TMP/SMX are all appropriate first-line

agents for uncomplicated AECB because of

their safety, efficacy and low cost. 33,34

Complicated AECB is characterized by

previous treatment failure, frequent episodes

of AECB (four or more per year) and/or

receipt of antibiotics in the previous three

months, each of these factors increasing the

risk of beta-lactam-resistance and involvement

of gram-negative species, including

Klebsiella and Pseudomonas species. 8 A number

of alternatives for complicated AECB

are provided in Table 2 but, because of

potentially limited activity of the macrolides

against H. influenzae, clarithromycin and

azithromycin should be reserved for patients

with true beta-lactam allergy. 33

Community-Acquired Pneumonia

Pneumonia is an infection of the lower respiratory

tract involving the lung parenchyma.

Together with influenza, it is the sixth leading

cause of death in the United States and causes

more death and disease than any other infection.

38,39 Although the etiology can be broad

and may include bacteria, fungi and viruses,

the organisms most frequently responsible

for infection in patients managed in the community

include S. pneumoniae, Mycoplasma

pneumoniae, H. influenzae, Chlamydophila

pneumoniae and respiratory viruses. 10 Because

bacterial involvement is most often the case,

antibiotics are the mainstay of therapy. 10

Patients with pneumonia usually present with

cough (>90%), dyspnea (66%), sputum production

(66%) and pleuritic chest pain

(50%), although nonrespiratory symptoms

can predominate. 40

Validated scoring tools can identify

patients who may be managed as outpatients.

41-43 The CURB-65 is a simple tool

comprised of five factors, each assigned one

point: confusion, blood urea nitrogen level

(BUN) >7 mmol/L, respiratory rate ≥30

breaths/minute, low blood pressure (systolic


e encouraged to return unused antibiotics

to their pharmacy for destruction, should

they not complete their treatment course,

to minimize ecological exposure and potential

contribution to bacterial resistance.

Summary

RTI is a common problem often treated

with antibiotics, even when a bacterial cause

is unlikely. When bacteria are implicated,

the three most common organisms, S. pneumoniae,

H. influenzae and M. catarrhalis,

have all demonstrated antibiotic resistance.

The community pharmacist serves a critical

role in ensuring appropriate use of antibiotics

by being aware of the relationship

between antibiotic use and resistance and

by using that knowledge to educate patients

and intervene when inappropriate use is

recognized. Judicious use of these precious

agents is necessary to preserve our current

armamentarium.

References available online at www.canadianhealthcarenetwork.ca

Go to Pharmacists, Education, Archives, More CCCEP-approved CE Lessons.

QUESTIONS — Answer online at www.canadianhealthcarenetwork.ca, CE section, Quick Search CCCEP #1065-2010-062-I-P

1. Name the three species most

commonly implicated as causes of

acute bacterial rhinosinusitis (ABRS),

acute exacerbation of chronic bronchitis

(AECB) and community-acquired

pneumonia (CAP).

a) Streptococcus pneumoniae, Staphylococcus

aureus, Escherichia coli

b) Staphylococcus aureus, Escherichia coli,

Klebsiella pneumoniae

c) Streptococcus pneumoniae, Haemophilus

influenzae, Moraxella catarrhalis

d) Haemophilus influenzae, Mycoplasma

pneumoniae, Legionella pneumophila

e) Streptococcus pneumoniae, Mycoplasma

pneumoniae, Legionella pneumophila

2. In Canada, what proportion of

S. pneumoniae isolates demonstrated

macrolide resistance in 2006?

a) 50%

c) 15–30%

9. Which antibiotic is considered first-line

treatment for ABRS?

a) azithromycin

b) amoxicillin

c) cefuroxime axetil

d) moxifloxacin

e) ciprofloxacin

10. Which of the following statements

about acute bronchitis is true?

a) Antibiotics have been shown by numerous

studies to improve acute bronchitis.

b) Most cases of acute bronchitis are caused

by bacteria.

c) Most cases of acute bronchitis are caused

by viruses.

d) Acute bronchitis is a condition that will

continue to worsen unless treated.

e) Most patients with acute bronchitis

should be treated for S. pneumoniae.

CB is a 65-year-old female with COPD who

tells you, the community pharmacist,

that she has had another “flare-up” of

her disease and she presents you with

a prescription for azithromycin. She is

frustrated as this is the sixth time in

the last year that she has had to go on

antibiotics. Upon reviewing her medication

profile, you notice that she has received two

prescriptions for azithromycin in the last

two months. When asked, CB mentions that

the previous treatments did not seem to

work very well.

11. What factors are present in CB that

make you worry about the involvement

of a resistant organism?

a) more than three exacerbations in the

last year

b) multiple courses of the same antibiotic

in the last three months

c) potential failure of recent azithromycin

treatment

d) evidence of an inadequate response to

previous treatments

e) all of the above

June 2010 | Answer online at www.canadianhealthcarenetwork.ca Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults | 7


QUESTIONS continued…

Answer online at www.canadianhealthcarenetwork.ca, CE section, Quick Search CCCEP #1065-2010-062-I-P

12. Which of the following would represent

three cardinal symptoms warranting

the use of antibiotics in CB?

a) fatigue, increased dyspnea, increased

sputum volume

b) hoarseness, increased dyspnea, increased

sputum volume

c) increased dyspnea, increased sputum

volume, increased sputum purulence

d) increased sputum purulence, fatigue,

headache

e) tachypnea, increased dyspnea, unproductive

cough

13. To ensure appropriate use of antibiotics,

what would you suggest to CB’s physician

as a reasonable alternative regimen?

a) clarithromycin 500 mg PO BID

b) amoxicillin 500 mg PO TID

c) doxycycline 100 mg PO BID

d) moxifloxacin 400 mg PO daily

e) TMP/SMX DS 1 tab PO BID

BR, a 35-year-old healthy male, visits your

pharmacy looking for a sinus medication

to treat the severe sinus pain that he has

been experiencing after “getting a cold”

two weeks ago. When you inquire, he tells

you that his sinus symptoms developed

one week ago and had seemed to improve

but then suddenly got worse. He says he

has felt feverish and achy and has been

taking ibuprofen and acetaminophen for

the pain without much relief. You think

he is suffering from ARS.

14. Why might you suggest BR visit

his physician or a walk-in clinic to be

assessed for antibiotic treatment?

a) Most cases of ARS are caused by bacteria

and require antibiotic treatment.

b) His “double worsening” is a sign that

this may be ABRS.

c) He has sinus pain requiring analgesics

and/or decongestants.

d) He has pain unrelieved by ibuprofen.

15. BR sees his physician who

subsequently phones in a prescription

for amoxicillin. While talking with her,

you note that BR has developed hives

when taking amoxicillin in the past.

What would be the most reasonable

alternative antibiotic regimen to

recommend?

a) doxycycline 200 mg PO once, then

100 mg PO BID x 10 days

b) levofloxacin 750 mg PO x 5 days

c) cefuroxime axetil 500 mg PO BID

x 10 days

d) clarithromycin 500 mg PO BID x 10 days

16. While filling BR’s prescription, you

note that he had a prescription filled two

months ago for ciprofloxacin. Without

any further information, which of the

following would be the most appropriate

antibiotic choice for BR?

a) clarithromycin or clarithromycin XL

b) levofloxacin

c) moxifloxacin

d) none of the above

e) all of the above

17. DE, a 70-year-old male patient

of yours, visits your pharmacy

complaining about a “bad cough”

and wonders if you have a cough

medicine that could help him.

He appears diaphoretic and, when

asked, he mentions feeling particularly

dizzy today. You have DE measure his

blood pressure. The result, repeated

twice, is 85/50 mm Hg. Based on

this information, what is DE’s

CRB-65 score?

a) 0 d) 3

b) 1 e) 4

c) 2

18. Which of the following antibiotics

is most appropriate for treating CAP

in a patient with no comorbidities

and no antibiotic use in the last

three months?

a) TMP/SMX d) ciprofloxacin

b) moxifloxacin e) cefuroxime axetil

c) clarithromycin

19. Which of the following conditions/

factors is not a concern with respect to

beta-lactam resistance of S. pneumoniae

when treating CAP?

a) smoking

b) exposure to a child who attends day care

c) chronic heart, lung, liver or renal disease

d) immunosuppression

e) alcoholism

20. Which of the following is/are (a)

common factor(s) responsible for the

inappropriate prescribing of antibiotics?

a) patient pressure

b) time constraints

c) fear of litigation

d) marketing of antibiotics

e) all of the above

Faculty: Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults

About the author

Dr. Curtis K Harder practices as a Clinical

Pharmacy Specialist in Adult Intensive Care with

the Vancouver Island Health Authority (VIHA) in

Victoria, B.C. He serves as a Clinical Instructor

for the Faculty of Pharmaceutical Sciences at

the University of British Columbia, and regularly

teaches and precepts pharmacy residents and

students. He maintains a special interest in the

area of infectious diseases, giving presentations

on related topics regularly, and is engaged in

infectious diseases-related research. He is also an

active member of the VIHA Antimicrobial Review

Committee and is a contributor to local infectious

diseases guidelines issued by this group.

Reviewers

All lessons are reviewed by pharmacists for

accuracy, currency and relevance to current

pharmacy practice.

This lesson is valid until May 19, 2013.

Information about antibiotic resistance and the

optimal use of antibiotics for acute communityacquired

respiratory tract infection in adults

may change over the course of this time.

Readers are responsible for determining the

most current aspects of this topic.

Continuing Education Project Manager

Sheila McGovern, Toronto, Ont.

CE Designer

Shawn Samson, TwoCreative.ca

For information about CE marking, please contact

Mayra Ramos at (416) 764-3879, fax (416) 764-

3937 or mayra.ramos@rci.rogers.com. No part

of this CE lesson may be reproduced, in whole

or in part, without the written permission of

the publisher. © 2010

8 | Antibiotic Resistance and the Optimal Use of Antibiotics for Acute Community-Acquired Respiratory Tract Infection in Adults Answer online at www.canadianhealthcarenetwork.ca | June 2010


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