ab for cap

8/12/2019 AB for CAP

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Antibiotics for community acquired pneumonia in adult

outpatients (Review)

Bjerre LM, Verheij TJM, Kochen MM

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library2004, Issue 2

http://www.thecochranelibrary.com

Antibiotics for community acquired pneumonia in adult outpatients (Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAntibiotics for community acquired pneumonia in adult outpatients (Review)



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[Intervention Review]

Antibiotics for community acquired pneumonia in adultoutpatients

Lise M Bjerre1, Theo JM Verheij2, Michael M Kochen1

1Department of General Practice/Family Medicine, University of Gttingen, Gttingen, Germany.2Julius Center for General Practiceand Patient-Oriented Research, University Medical Center Utrecht, Utrecht, Netherlands

Contact address: Lise M Bjerre, Department of General Practice/Family Medicine, University of Gttingen, Humboldtallee 38,Gttingen, D-37073 , [email protected]@gwdg.de.

Editorial group:Cochrane Acute Respiratory Infections Group.Publication status and date:Unchanged, published in Issue 3, 2009.Review content assessed as up-to-date: 24 February 2004.

Citation: Bjerre LM, Verheij TJM, Kochen MM. Antibiotics for community acquired pneumonia in adult outpatients.CochraneDatabase of Systematic Reviews2004, Issue 2. Art. No.: CD002109. DOI: 10.1002/14651858.CD002109.pub2.


A B S T R A C T

Background

Community-acquired pneumonia (CAP) is a common condition representing a significant disease burden for the community, par-ticularly for the elderly. Because antibiotics are helpful in treating CAP, they are the standard treatment and CAP thus contributessignificantly to antibiotic use, which is associated with the development of bacterial resistance and side-effects. Although several studieshave been published concerning CAP and its treatment, the available data arises mainly from studies conducted in hospitalized patientsand outpatients. There is no concise summary of the available evidence that can help clinicians in choosing the most appropriateantibiotic.

Objectives

To summarize the evidence currently available from randomized controlled trials (RCTs) concerning the efficacy of alternative antibiotictreatments for CAP in ambulatory patients above 12 years of age.

Search strategy

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library,2003, issue 2) which containsthe Cochrane Acute Respiratory Infections Groups Specialized Register; MEDLINE (January 1966 to September week 3, 2003), andEMBASE (January 1974 to March 2003).

Selection criteria

We included all randomized controlled trials (RCTs) in which one or more antibiotics were tested for the treatment of CAP inambulatory adolescent or adult patients. Studies testing one or more antibiotic and reporting the diagnostic criteria used in selectingpatients as well as the clinical outcomes achieved were included. No language restrictions were applied.

Data collection and analysis

Data were extracted and study reports assessed by two independent reviewers (LMB and TJMV). Authors of studies were contactedas needed to resolve any ambiguities in the study reports. The data were analyzed using the Cochrane Collaborations RevMan 4.2.2Software. Differences between reviewers were resolved by discussion and consensus.

1Antibiotics for community acquired pneumonia in adult outpatients (Review)

mailto:[email protected]:[email protected]:[email protected]:[email protected]


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Main results

Three randomized controlled trials involving a total of 622 patients aged 12 years and older diagnosed with community acquired pneu-monia were included. The quality of the studies and of the reporting was variable. A variety of clinical, radiological and bacteriologicaldiagnostic criteria and outcomes were reported. Overall there was no significant difference in the efficacy of the various antibioticsunder study.

Authors conclusions

Currently available evidence from RCTs is insufficient to make evidence-based recommendations for the choice of antibiotic to beused for the treatment of community acquired pneumonia in ambulatory patients. Pooling of study data was limited by the very lownumber of studies. Individual study results do not reveal significant differences in efficacy between various antibiotics and antibioticgroups. Multi-drug comparisons using similar administration schedules are needed to provide the evidence necessary for practicerecommendations.

P L A I N L A N G U A G E S U M M A R Y

Not enough evidence from trials on the comparative effects of different antibiotics for community-acquired pneumonia

Pneumonia, or infection involving the lungs, is responsible for a significant number of deaths worldwide. Pneumonia is especially l ife-threatening in older people and people with other illnesses that may affect the immune system (such as diabetes). Antibiotics are themost commonly used treatment for pneumonia, and these can vary in their effectiveness and adverse effects. The review studied theeffects of antibiotics for patients with pneumonia acquired and treated in the community (as opposed to people acquiring pneumoniawhile in hospital, and/or being treated for pneumonia in hospital). There were not enough trials to compare the effects of differentantibiotics for pneumonia acquired and treated in the community.

B A C K G R O U N D

Description of the condition

Community acquired pneumonia (CAP) is a common conditionthat carries a high burden of mortality and morbidity, particularlyin elderly populations. Prospective studies carried out in the UK,Finland and the USA have estimated the annual incidence of CAPin community-dwellingadults at 5 to 11 cases per1000 adult pop-ulation; the incidence is known to vary markedly with age, beinghigher in the very young and the elderly (Foy 1979;Woodhead

1987;Jokinen 1993).It is the most important cause of death from infectious causes inthe industrialized world and the sixth most important cause ofdeath overall (IDSA 2000). CAP can be caused by a broad rangeof pathogens including bacteria, atypical agents and viruses (IDSA2000). In fact, more than 100 different microorganisms have beenassociated with CAP (Loeb 2002). Furthermore, a patient withCAP can be befallen by more than one microbe, as in the case of abacterial superinfection of an underlying influenza infection. The

mostcommon pathogensinclude, dependingon the patient popu-lation tested, Streptococcus pneumoniae (S. pneumoniae) (usually byfar the most common), Chlamydia pneumoniae (C. pneumoniae),Haemophilus influenzae (H. influenzae), Mycoplasma pneumoniae

(M. pneumoniae) and influenza viruses (IDSA 2000;Loeb 2002).

Description of the intervention

Antibiotics are the mainstay in the treatment of CAP, since thecausative organisms usually respond to this them. Consequently,CAP contributes significantly to antibiotic use, which is associated

with the development of bacterial resistance. In treating patientswith CAP, the choice of antibiotic is a difficult one. Factors tobe considered are the possible etiologic pathogen, the efficacy ofthe substance, potential side-effects, the treatment schedule andits effect on adherence to treatment, the particular regional resis-tance profile of the causative organism, and co-morbidities thatmight influence the range of potential pathogens (such as in cysticfibrosis) or the dosage (as in the case of renal insufficiency).Significant costsare associatedwith the diagnosisand management




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of CAP. In the UK, 22% to 42% of adults with CAP are admittedto hospital (Woodhead 1987;Guest 1997), and of those, 5% to10% need to be admitted to an intensive care unit (Torres 1991;BTS 1992).

How the intervention might work

Many clinical trials have been performed to evaluate and com-pare the efficacy of antibiotics for CAP, however the vast majorityof them were conducted in hospitalized patients. These patientsusually suffer from more severe manifestations of the disease andoften have other co-morbid conditions that affect their response totreatment and their time to recovery. Consequently, it is unclear towhat extent results comparing the efficacy of different antibioticsin hospitalized patients can be extrapolated to outpatients.

Why it is important to do this reviewNumerous guidelines exist to aid clinicians with the treatmentof CAP: in recent years, guidelines have been published, amongothers, by the American Thoracic Society (ATS 2001), the Infec-tious DiseasesSociety of America (IDSA 2000, updated December2003:IDSA 2003), the British Thoracic Society (BTS 2001), andthe Canadian Community-Acquired Pneumonia Working Group(CCAPWG 2000). All these guidelines include recommendationfor the choice of antibiotic treatment for CAP in ambulatory pa-tients, however the evidence on which these recommendations arebased stems from studies carried out almost exclusively in hospi-talized patients. Thus, although many studies have been publishedconcerning CAP and its treatment, there is no concise summary

of the available evidence concerning its treatment in ambulatoryoutpatients.This review addresses the comparative efficacy of antibiotic treat-ments for community acquired pneumonia (CAP) in outpatientsabove 12 years of age.

O B J E C T I V E S

The objectives of this review are:

1. To assess and compare the efficacy of individualantimicrobial therapies with respect to clinical, radiological andbacteriological outcomes in adult outpatients with CAP;

2. To assess and compare the efficacy of antibiotic drugs acrossdrug groups.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised trials of antibiotics in adolescent and adult out-patients with CAP reporting on clinical parameters, cure rates ormortality were included.

Types of participants

Outpatients of either gender over 12 years of age with:1. Symptoms and signs consistent with an acute lower

respiratory tract infection associated with new radiographicshadowing for which there is no other explanation (e.g. notpulmonary oedema or infarction)

2. The illness is the primary clinical problem and is managedas pneumonia

(modified from the criteria for CAP as defined by the British Tho-racic Society )

Types of interventions

All double-blind randomized controlled comparisons of one an-tibiotic and a placebo or at least two antibiotics used to treat com-munity acquired pneumonia were included. Trials comparing twodoses or two different application formsof the same drug were notincluded.Most of the available studies compare the effects of two antibi-otics. Comparisons involving intravenous drugsare usually carried

out in a hospital setting. However, as this might occasionally beperformed in an ambulatory setting, we did not a priori excludestudies dealing with intravenous drug applications.Trials allowingconcurrent useof othermedications suchas antitus-sives, antipyretics, bronchodilators, or mucolytics were included ifthey allowed equal access to such medications for patients in botharms of the trial.

Types of outcome measures

1. Clinical response: improvement of signs and symptoms.Where possible, duration of clinical signs and symptoms wereused as outcome measures. We used a clinical definition of cure

as the primary outcome since radiographic resolution lags behindclinical improvement (Macfarlane 1984).

2. Radiologic response: resolution or improvement of a newfinding on chest x-ray after antibiotic therapy

3. Bacteriologic response: negative sputum culture in patientspreviously found to have had pathogens in their sputum.

4. Hospitalization.5. Mortality.




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Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials(CENTRAL) (The Cochrane Library, 2003, issue 2, 2003) whichcontains the Cochrane Acute Respiratory Infections Group Spe-cialized Register; MEDLINE (January 1966 to week 3, September2003), and EMBASE (January 1974 to March 2003).MEDLINE (SilverPlatter)#1 explode Antibiotics- / all subheadings in MIME,MJME#2 antibiotic*#3 #1 or #2#4 explode Community-Acquired-Infections / all subheadings inMIME,MJME#5 explode Pneumonia- / all subheadings in MIME,MJME#6 #4 and #5#7 community acquired pneumonia#8 #6 or #7#9 #3 and #8#10 Randomized-Controlled-Trial in pt#11 controlled-clinical-trial in pt#12 explode Randomized-Controlled-Trials / all subheadings inMIME,MJME#13 explode Random-Allocation / all subheadings inMIME,MJME#14 explode Single-Blind-Method / all subheadings inMIME,MJME#15 explode Double-Blind-Method / all subheadings inMIME,MJME

#16 #10 or #11 or #12 or #13 or #14 or #15#17 (TG=animal) not ((TG=animal) and (TG=human))#18 #16 not #17#19 clinical-trial in pt#20 explode Clinical-Trials / all subheadings in MIME,MJME#21 (clin* near trial*) in ti#22 (clin* near trial*) in ab#23 explode Placebos- / all subheadings in MIME,MJME#24 placebo* in ti#25 placebo* in ab#26 random* in ti#27 random* in ab#28 (singl* or doubl* or tripl* or trebl*) near (blind* or mask*)

#29 #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28#30 #29 not #17#31 #18 or #30#32 #9 and #31

Searching other resources

Studies were also identified by checking the bibliographies ofstudies and review articles retrieved, and if necessary by contact-ing the first or corresponding authors of included studies. Toidentify any additional published or unpublished studies we con-tacted the following manufacturers: Abbott, AstraZeneca, Aven-

tis, Boehringer-Ingelheim, Bristol-Myers-Squibb, GlaxoSmithK-line Beecham, Hoffmann-LaRoche, Lilly, Merck, Merck Sharp &Dohme, Novartis, Pfizer, Pharmacia, Sanofi, and Yamanouchi. Nolanguage restrictions were applied to the search and selection pro-cesses. This search strategy yielded a total of 1828 references, someof which were double entries, due to the overlapping content ofdatabases.

Data collection and analysis

Selection of studies

Two review authors (MMK andLMB) used the titles and abstractsof the identified citations to exclude trials which clearly did notmeet the inclusion criteria of the review. If the reviewers felt thatthe trial might possibly fulfil the criteria, the full paper was ob-tained for further study. The most common reason for exclusionwas that studies were conducted exclusively in hospitalized pa-tients. Articles having passed this initial screen (n = 34) were thenreviewed independently by two reviewers (LMB and TJMV) todetermine whether they met the inclusion criteria of the review.The selection process is shown graphically in Figure 1.Studies could be excluded for any one of the following reasons: if they were not truly randomized;

if they only compared two doses or two application formsof the same substance; if the results were not reported separately for in- and out-

patients; if the indication for treatment consisted of a mix of

diagnoses (most commonly: acute bronchitis, exacerbation ofchronic bronchitis, and pneumonia) and the results were notreported separately for each diagnostic group.

Studies including only bacteriologically evaluated patients wereexcluded, because these studies typically included only patientswithpositivecultures of pathogenssusceptible to studyantibiotics.

A priori excluding patients with resistant strains as well as patientswith non-bacterial causes of CAP (such as Mycoplasma pneumo-niae) would falsely increase the treatment success rate to levels thatwould be unrealistic in real practice. Studies were also excludedif the diagnosis of pneumonia was not confirmed by chest x-ray.This exclusion criteria was necessary to ensure that only patientswith a very high likelihood of having pneumonia be included inthe review, since this was the patient population in which the ef-ficacy of various treatment alternatives was to be tested. Finally,studies were excluded if the total number of patients was less than




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30, because below this limit, the estimate of a binomial parameter(in this case, proportion of patients cured or improved) becomestoo unstable (Armitage 1994).

Data extraction and management

The following data were extracted from each study whenever pos-sible:- description of participants (outpatients over 12 years)- description of potential pathogens identified and their antimi-crobial resistance profiles- description of intervention- description of control therapy- total number of participants in each arm of the trial- study setting- mean duration of symptoms in each arm of the trial- clinical, radiographic and bacteriologic cure rates in each arm ofthe trial

- proportion of patients admitted to hospital in each arm of thetrial- mortality rates in each arm of the trial- study sponsorThe studies were assessed by two reviewers (LMB and TJMV).Disagreements were resolved by discussion and consensus. Therewereno unreconcilabledisagreements. Reviewerswerenot blindedto the identity and affiliation of the study authors.

Unit of analysis issues

For dichotomous outcome data, an estimate of the common oddsratios with approximate 95% confidence intervals was estimated

using the Mantel-Haenzel approach. This was done by means ofthe Cochrane Collaborations Review Manager software, version4.2.2.

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof excludedstudies.

Results of the search

See: Table of studiesNumber of trials and trial sizeThree randomized controlled trials involving a total of 622 pa-tientsaged12 years and older diagnosedwith communityacquiredpneumonia were included in the analysis (Anderson 1991;Chien

1993;Ramirez 1999). The trials included varying numbers of pa-tients, the largest having 342 patients (Ramirez 1999),thesmallest107 (Anderson 1991). The median trial size in the analysis was173 patients, the mean size 207.Diagnoses

All three trials exclusively enrolled outpatients with communityacquired pneumonia.Diagnostic criteriaIn all trials, the diagnosis of community acquired pneumonia wasbased on clinical signs and symptoms as well as radiographic find-ings in allpatients. The signs andsymptoms used as diagnostic cri-teria included combinations of the following: fever, chills, recentonset of productive cough, pleuritic chest pain, dyspnoea, pyrexia,tachypnoea, dullness to percussion, egophony, rales, localized re-duced breath sounds and bronchial breath sounds.Out- versus Inpatient treatmentIn all three trials, patients were treated exclusively as outpatients.Patient inclusion and exclusion criteria

Two trials included only adult patients, one (Chien 1993) also in-cluded adolescents (12 years of age and older). One trials reportedincluding patients asold as 90 and none used older age as an exclu-sion criterion. Overall, the trials excluded patients with conditionsthatcouldhave affected the treatmentor interferedwith follow-up.Exclusion criteria were reported in more or less detail in the studyreports. The most common criteria reported were: pregnancy andlactation, women not using adequate contraception (usually oralcontraceptives or a barrier method), history of allergic reaction tothe study drugs, recent treatment with or concommitant use ofan antimicrobial agent, concurrent medication with ergotamine,cyclosporin, antacids (except H2-antagonists) or digitalis, condi-tions affecting GI absorption, severe renal or hepatic impairment,

terminal illness or conditions precluding study completion, infec-tious mononucleosis, HIV/AIDS, and prior participation in thestudy.

AntibioticsThe trials varied with respect to the antibiotics studied (see Fig.2). Two trials (Anderson 1991;Chien 1993) studied the same an-tibiotic pair (clarithromycin and erythromycin). The other trial(Ramirez 1999) studied a different antibiotic pair, namely clar-ithromycin versus sparfloxacin.

Risk of bias in included studies

All three trials were randomized, double-blind evaluations com-paring two antibiotics. The extent of reporting was variable be-tween studies. None of the studies clearly statedthe randomizationmethod used. None of thearticles reported any test of effectivenessof the blinding procedures used. Compliance with treatment wasassessedbypillcountintwostudies(Anderson 1991; Chien1993);neither reported any difference in the number of pills remainingbetween the two groups, however in the Chien study, forty pa-tients were excluded because they received less than the mini-




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mumtherapy (sevendays)and these patients were distributed un-evenly across the two groups (10 in the clarithromycin group and30 in the erythromycin group). The third study (Ramirez 1999)reports having assessed patient compliance but does not state how.Regarding co interventions with other medications, most stud-

ies excluded patients whose co medication included certain drugssuch as other antibiotics, chemotherapeutics or anti retrovirals.Only one study (Chien 1993) reported how many patients wereexcluded because of forbidden co-medication. Withdrawals werereported by all studies with varying degree of detail as to the rea-sons for withdrawal. One study (Ramirez 1999) reported only thenumber of withdrawals without specifying any reason for these.The number of patients lost to follow-up was reported in all butone study (Ramirez 1999). In the other studies (Anderson 1991;Chien 1993), losses to follow-up appeared to be minor, amount-ing to a maximum of 10% of the initially randomized patients.One study (Chien 1993) did not present intention-to-treat anal-ysis results.

Effects of interventions

EfficacyThe success rates for each of the treatment arms of the three trialsare shown in Table 1. Success was defined as cure or improve-ment, be it clinical, bacteriological or radiological, as assessed at apredefined follow-up visit. None of the clinical, bacterial or radi-ological success rates differed significantly among treatment armswithin each of the studies, nor did they achieve clinical - or sta-tistical - significance when the results of the two studies of clary-thromycin vs erythromycin were pooled together (Fig. 3, 4 and5).

Comparisons across antibiotic groupsThe only comparison across antibiotic groups is provided by thestudy by Ramirez etal., whereby a macrolide (clarithromycin) anda quinolone (sparfloxacin) are compared. Again, there was no sig-nificant difference in clinical or bacteriological success; radiolog-ical outcomes were not reported separately for the two treatmentarms.Side-effectsThere were, however, significant differences in the occurrence ofside-effects attributed to the study drug in the two studies com-paring clarithromycin with erythromycin (Anderson 1991;Chien1993) (Table 2). In both cases, there were significantly more side-effects in the erythromycin group, the majority being gastroin-testinal side-effects. This was not, however, reflected in the rate ofside-effects leading to withdrawal from the study, which was notsignificantly different across treatment arms.Bacterial pathogenVarious pathogens were identified with varying frequency acrossstudies (see Table 3). The proportion of samples yielding an iden-tifiable pathogen ranged from 19% (Anderson 1991) to 43%(Ramirez 1999). Anderson reported on a majority of cases be-

ing positive for Haemophilus Influenzae (H. influenzae) (62% ofpositive cultures) with Streptococcus pneumoniae(S. pneumoniae)(18%)beingsecondmostcommon,whereasChienpredominantlyidentified S. pneumoniaeas causative organism in 56% of cul-tures, withH. influenzaetaking second place at 40%. On the con-

trary, Haemophilus parainfluenzae(H. parainfluenzae) (31%) wasthe most commonly identified pathogen in the study by Ramirez,withH. influenzae(23%) in second place.Serologically identified pathogensOnly two of the three studies carried out serologic tests to iden-tify putative pathogens (Anderson 1991;Chien 1993; see Table4). In both these studies, the most frequently identified pathogenwasMycoplasma pneumoniae(M. pneumoniae) which represented69%(Anderson 1991)and74%(Chien1993) of positive serologyresults.Chlamydia pneumonia(C. pneumonia) accounted for theremainder with 38% (Anderson 1991) and 26% (Chien 1993)respectively. There were no samples positive for Legionella pneu-moniae(L. pneumoniae) or forChlamydia psittaci (C. psittaci )in

either study.

D I S C U S S I O N

The overwhelming feature of this review is the utter paucity ofrelevant evidence that could be identified and included in thereview. Given this current state of affairs, it is not possible tomake evidence-based recommendations regarding the choice ofantibiotic to be used for the treatment of community acquiredpneumonia in ambulatory outpatients. One important reason for

this lack of evidence is that a large number of the trials originallyidentified were conducted in hospitalized patients and thereforeare not directly relevant to the treatment of ambulatory patients.

It could be argued that the inclusion/exclusion criteria for this re-view were too strict and that this is the reason why so few studieswere retained. We do, however, believe that the criteria we appliedwere necessary in order to validly address the question of the ef-ficacy of treatment of CAP in ambulatory patients. In particular,it could be argued that the decision to exclude studies based onsize is not desirable, since one aim of the review is to pool resultsand that each studytherefore would contribute some information.

We felt however that this criterion was necessary to exclude stud-ies where the number of patients with pneumonia was so smallthat randomization could no longer be expected to achieve a bal-anced distribution of confounders, both known and unknown,across study groups. Finally, arguing retrospectively, it can be seenthat dropping size as an exclusion criteria would not have mademuch difference to the results we obtained: the study by Fong etal. would have been excluded because it was not double-blindedand the two remaining studies would have contributed a total ofsix (Gris 1996) and eight (Tilyard 1992) patients respectively.




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As for the requirementthat the diagnosisof CAP be confirmed by achest radiograph, we felt that this wasnecessary to avoid diagnosticmisclassification, which could for example have led to inclusion ofpatients with bronchitisintothe review. This could have biasedtheestimation of the efficacy of various antibiotic treatments, either

differentially or non-differentially, depending on the distributionof non-CAP cases across treatment groups. Indeed, most recentclinical guidelines recommend the routine use of chest x-rays toconfirm a suspected pneumonia (ATS 2001, CCAPWG 2000,IDSA 2000), however, we are aware that this diagnostic test isoften not used in practice and that patients are therefore treatedempirically according to the severity of the clinical picture.

A U T H O R S C O N C L U S I O N S

Implications for practice

Currently available evidence from RCTs is insufficient to make ev-idence-based recommendations for choice of antibiotic to be used

in the treatment of community acquired pneumonia in ambula-tory patients. At most, it can be stated that individual study resultsdo not reveal significant differences in efficacy between variousantibiotics and antibiotic groups.

Implications for researchMulti-drug, multi-drug-group blinded comparisons using similaradministration schedules are needed to provide the evidence nec-essary for practice recommendations if these are to be applicablein the ambulatory setting. Study conditions should ensure thatdiagnosis and management of patients with community acquiredpneumonia is as similar as possible to real practice, while still en-suring that the study question is addressed in a valid way.

A C K N O W L E D G E M E N T S

Many thanks to Dr. Frederike Behn (Hamburg) for precious helpwith parts of the data extraction process.

R E F E R E N C E S

References to studies included in this review

Anderson 1991 {published data only} Anderson G, Esmonde TS, Coles S, Macklin J, CarnegieC. A comparative safety and efficacy study of clarithromycinand erythromycin stearate in community-acquiredpneumonia.Journal of Antimicrobial Chemotherapy1991;27

(Suppl A):11724.

Chien 1993 {published data only} Chien SM, Pichotta P, Siepman N, Chan CK andthe Canada-Sweden Clarithromycin-Pneumonia Group.Treatment of Community-Acquired Pneumonia: Amulticenter, double-blind, randomized study comparingclarithromycin with erythromycin. Chest1993;103:697701.

Ramirez 1999 {published data only} Ramirez J, Unowsky J, Talbot GH, Zhang H, TownsendL. Sparfloxacin vs clarithromycin in the treatment ofcommunity acquired pneumonia. Clinical Therapeutics1999;21(1):10317.

References to studies excluded from this review

Balgos 1999 {published data only} Balgos AA, Rodriguez-Gomez G, Nasnas R, MahasurAA, Margono BP, Tinoco-Favila JC. Efficacy of twice-daily amoxycillin/clavulanate in lower respiratory tractinfections.International Journal of Clinical Practice1999;53(5):32530.

Ball 1994 {published data only} Ball P. Efficacy and safety of cefprozil versus other beta-lactam antibiotics in the treatment of lower respiratory tractinfections. European Journal of Clinical Microbiology andInfectious Diseases1994;13(10):8516.

Balmes 1991 {published data only} Balmes P, Clerc G, Dupont B, Labram C, Pariente

P, Poirier R. Comparative study of azithromycin andamoxicillin/clavulanic acid in the treatment of lowerrespiratory tract infections. European Journal of Clinical

Microbiology and Infectious Diseases1991;10:4379.

Bantz 1987 {published data only} Bantz PM, Grote J, Peters-Haertel W, Stahmann J, TimmJ, Kasten R, et al.Low-dose ciprofloxacin in respiratory tractinfections: a randomized comparison with doxycycline ingeneral practice. American Journal of Medicine1987;82(Suppl 4A):20810.

Biermann 1988 {published data only} Biermann C, Loken A, Riise R. Comparison of spiramycinand doxycycline in the treatment of lower respiratory

infections in general practice. Journal of AntimicrobialChemotherapy1988;22(Suppl B):1558.

Chodosh 1991 {published data only} Chodosh S. Temafloxacin compared with ciprofloxacinin mild to moderate lower respiratory tract infections inambulatory patients. Chest1991;100:1497502.

Dark 1991 {published data only} Dark D. Multicenter evaluation of azithromycin andcefaclor in acute lower respiratory tract infections.American




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Journal of Medicine1991;91(Suppl 3A):315.

Dautzenberg 1992 {published data only} Dautzenberg B, Scheimberg A, Brambilla C, Camus P,Godard P, Guerin JC. Comparison of two oral antibiotics,roxithromycin and amoxicillin plus clavulanic acid, inlower respiratory tract infections. Diagnostic Microbiologyand Infectious Disease Diagnostic Microbiology and Infectious

Disease1992;15(Supplement):859.

De Cock 1988 {published data only} De Cock L, Poels R. Comparison of spiramycin witherythromycin for lower respiratory tract infections. Journalof Antimicrobial Chemotherapy1988;22(Suppl B):15963.

Fong 1995 {published data only} Fong IW, Laforge J, Dubois J, Small D, Grossman R,Zakhari R, et al.Clarithromycin versus cefaclor in lowerrespiratory tract infections. Clinical and Investigative

Medicine1995;18:1318.

Gris 1996 {published data only}

Gris P. Once-daily, 3-day azithromycin versus a three-times-daily, 10-day course of co-amoxiclav in the treatmentof adults with lower respriatory tract infections: results ofa randomized, double-blind comparative study.Journal of

Antimicrobial Chemotherapy1996;37(Suppl C):93101.

Higuera 1996 {published data only} Higuera F, Hidalgo H, Feris J, Giguere G, Collins JJ.Comparison of oral cefuroxime axetil and oral amoxycillin/clavulanate in the treatment of community-acquiredpneumonia. Journal of Antimicrobial Chemotherapy1996;37:55564.

Hoepelman 1993 {published data only} Hoepelman AIM, Sips AP, van Helmond JLM, vanBarneveld PWC, Neve AJ, et al.A single-blind comparison

of three-day azithromycin and ten-day co-amoxiclavtreatment of acute lower respiratory tract infections.Journalof Antimicrobial Chemotherapy1993;31(Suppl E):14752.

Hoepelman 1998 {published data only}Hoepelman IM, Mllers MJ, van Schie MH, GreefhorstAPM, Schlsser NJJ, Sinninghe Damst EJ, et al.A short(3-day) course of azithromycin tablets versus a 10-daycourse of amoxycillin-clavulanic acid (co-amoxiclav) in thetreatment of adults with lower respiratory tract infectionsand effects on long-term outcome. International Journal of

Antimicrobial Agents1998;9:1416.

Kammer 1991 {published data only} Kammer RB, Ress R. Randomized comparative study of

ceftibuten versus cefaclor in the treatment of acute lowerrespiratory tract infections. Diagnostic Microbiology andInfectious Disease1991;14:1015.

Kiani 1990 {published data only} Kiani R, Coulson L, Johnson D, Hammershaimb L.Comparison of once-daily and twice-daily cefixime regimenswith amoxicillin in the treatment of acute lower respiratorytract infections. Current Therapeutic Research, Clinical andExperimental1990;48(5):84152.

Lacny 1972 {published data only} Lacny J. A comparison of oral therapy with clindamycinand penicillin G in common gram-positive infections.Current Therapeutic Research, Clinical and Experimental

1972;14(1):2630.

Laurent 1996 {published data only} Laurent K. Efficacy, safety and tolerability of azithromycinversus roxithromycin in the treatment of acute lowerrespiratory tract infections. Journal of AntimicrobialChemotherapy1996;37(Suppl C):11524.

Liipo 1994 {published data only} Liippo K, Tala E, Puolijoki H, Brckner OJ, Rodrig J,Smits JPH. A comparative study of dirithromycin anderythromycin in bacterial pneumonia. Journal of InfectiousDiseases1994;28:1319.

Lode 1995 {published data only} Lode H, Garau J, Grassi C, Hosie J, Huchon G, LegakisN, et al.Treatment of community-acquired pneumonia:a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin. European Respiratory

Journal1995;8:19992007.

Lode 1998 {published data only} Lode H, Aubier M, Portier H, Ortqvist A and theSparfloxacin Study Group. Sparfloxacin as alternativetreatment to standard therapy for community-acquiredbacteremic pneumococcal pneumonia.Clinical Microbiologyand Infection1998;4(3):13543.

Mller 1992 {published data only} Mller O, Wettich K. Comparison of loracarbef(LY 163892) versus amoxicillin in the treatment ofbronchopneumonia and lobar pneumonia. Infection1992;20(3):17682.

NAPSG 1997 {published data only} The Nordic Atypical Pneumona Study Group. Atypicalpneumona in the Nordic countires: aetiology and clincalresults of a trial comparing fleroxacin and doxycyclin.

Journal of Antimicrobial Chemotherapy1997;39:499508.

Neu 1993 {published data only} Neu HC, Chick TW. Efficacy and safety of clarithromycincompared to cefixime as outpatient treatment of lowerrespiratory tract infections. Chest1993;104:13939.

ODoherty 1998 {published data only} ODoherty B, Muller O and the Azithromycin StudyGroup. Randomized, multicentre study of the efficacy and

tolerance of Azithromycin versus clarithromycin in thetreatment of adults with mild to moderate community-acquired pneumonia. European Journal of Clinical

Microbiology and Infectious Diseases1998;17:82833.

Peugeot 1991 {published data only} Peugeot RL, Lipsky BA, Hooton TM, Pecoraro RE.Treatment of lower respiratory infections in outpatientswith ofloxacin compred with erythromycin. Drugs inExperimental and Clinical Research1991;17(5):2537.




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Rayman 1996 {published data only} Rayman J, Krchnav M, Balciar P, Duchon J, FortunkJ, Faith L, et al.Ofloxacin once daily versus twice daily incommunity-acquired pneumonia and acute exacerbation ofchronic bronchitis. Chemotherapy1996;42:22730.

Salvarezza 1998 {published data only} Salvarezza CR, Mingrone H, Fachinelli H, KijanczukS. Comparison of roxithromycin with cefixime in thetreatment of adults with community-acquired pneumonia.

Journal of Antimicrobial Chemotherapy1998;41(Suppl B):7580.

Schleupner 1988 {published data only} Schleupner CJ, Anthony WC, Tan J, File TM, Lifland P,Craig W, Vogelman B. Blinded comparison of cefuroximeto cefaclor for lower respiratory tract infections. Archives ofInternal Medicine1988;148:3438.

Tilyard 1992 {published data only} Tilyard MW, Dovey SM. A randomized double-blindcontrolled trial of roxithromycin and cefaclor in the

treatment of acute lower respiratory tract infections ingeneral practice. Diagnostic Microbiology and InfectiousDisease1992;15:97101.

rtqvist 1996 {published data only} rtqvist A, Valtonen M, Cars O, Wahl M, Saikku P, JeanC, et al.Oral empiric treatment of community-acquiredpneumonia: a multicenter, double-blind, randomized studycomparing sparfloxacin with roxithromycin. Chest1996;110:1499506.

Additional references

Armitage 1994Armitage P, Berry G. Statistical Methods in Medical Research.3rd Edition. Oxford: Blackwell Scientific Publications,

1994.ATS 2001

American Thoracic Society. Guidelines for the managementof adults with community-acquired pneumonia. American

Journal of Critical Care2001;163:173054.

BTS 1992British Thoracic Society Research Committee and PublicHealth Laboratory Service. The aetiology, management andoutcome of severe community-acquired pneumonia on theintensive care unit. Respir Med1992;86:713.

BTS 2001British Thoracic Society. British Thoracic SocietyGuidelines for the management of adults with community-

acquired pneumonia. Thorax2001;56(Suppl IV):164.

CCAPWG 2000Canadian Community-Acquired Pneumonia WorkingGroup. Canadian guidelines for the initial managementof community-acquired pneumonia: an evidence-basedupdate by the Canadian Infectious Diseases Society andthe Canadian Thoracic Society. Clinical Infectious Diseases

2000;31:383421.Foy 1979

Foy HM, Cooney MK, Allan I, et al.Rates of pneumoniaduring influenza epidemics in Seattle, 1964 to 1975. JAMA1979;241:2538.

Guest 1997Guest JF, Morris A. Community-acquired pneumonia: theannual cost to the National Health Service in the UnitedKingdom.Eur Respir J1997;10:15304.

IDSA 2000Infectious Dieseases Society of America. Practice guidelinesfor the management of community-acquired pneumonia inadults. Clinical Infectious Diseases2000;31:34782.

IDSA 2003Infectious Dieseases Society of America. Update of practiceguidelines for the management of community-acquiredpneumonia in immunocompetent adults. Clinical InfectiousDiseases2003;37:140533.

Jokinen 1993Jokinen C, Heiskanen L, Juvonen H, et al.Incidence offcommunity-acquired pneumonia in the population of fourmunicipalities in eastern Finland. Am J Epidemiol1993;137:97788.

Loeb 2002Loeb M. Community-acquired pneumonia. ClinicalEvidence. Vol. 8 , London: BMJ Publishing Group, 2002.

Macfarlane 1984Macfarlane JT, Miller AC, Smith WHR, et al.Comparativeradiographic features of community-acquired legionnairesdisease, pneumococcal pneumonia, mycoplasma pneumoniaand psittacosis. Thorax1984;39:2833.

Torres 1991Torres A, Serra-Batlles J, Ferrer A, et al.Severe community-acquired pneumonia. Epidemiology and prognostic factors.

Am Rev Respir Dis1991;144:3128.

Woodhead 1987Woodhead MA, Macfarlane JT, McCracken JS, etal.Prospective study of the aetiology and outcome ofpneumonia in the community. Lancet1987;i:6714.

Indicates the major publication for the study




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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Anderson 1991

Methods Study period: ?Follow-up: 6 to 8 weeksParallel trialPatients were included from 57 general practitioners in the UKDouble-blind, double-dummy techniqueIntention-to-treat results providedDrop-outs: total: 48% (33% clarithro, 61% erythro) due to failure to confirm the diagnosis on the pre-treatment CXR, premature discontinuation, no post-treatment evaluation, less than minimum therapy,no post-treatment CXR, concomitant medication, lost of follow-upExclusion criteria clear3 of 5 authors from Abbott Laboratories

Participants Patients with CAP older than 18 yearsCAP diagnosis confirmed by:3 of the following features: pyrexia, dyspnoea, tachypnoea, rales, localized reduced breath sounds andcoughDiagnosis of CAP was later confirmed radiographicallyTotal: n = 208Evaluable for efficacy: n = 108(Exclusion usually due to failure to confirm initial Dx on CXR)n = 64 (clarithro),n = 44 (erythro)Mean age 53.5 yrsMale: 65%

Interventions Clarithromycin (clarithro)250 mg bid for 14 daysorErythromycin (erythro) 500 mg qid for 14 days,each given at least 1h before or 2h after mealsMean treatment duration: 13 days (clarithro), or 10 days (erythro)Compliance assessment: tablet count

Outcomes 1. Clinical cure rate2. Clinical success rate (cured and improved)3. Radiographic success rate4. Bacteriological cure rate

Clinical response at 2 weeks: cure: 52% (clarithro), 41% (erythro)success: 98% (clarithro), 91% (erythro)At 6 to 8 weeks: cure: 77% (clarithro), 80% (erythro), success: 89% (clarithro), 98% (erythro)

Notes

Risk of bias




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Anderson 1991 (Continued)

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Chien 1993

Methods Duration: January 1989 to June 1990Follow-up: 4-6 weeksParallel trialMulticenter study (15 centers of the Canada-Sweden Clarithromycin-Pneumonia Study Group)Double-blind, double-dummy techniqueNo intention-to-treat results providedDrop-outs: 35% (due to less than minimum therapy, premature discontinuation, unavailable for follow-

up, misdiagnosis, inadequate data collection, concomitant medication, underlying condition)Exclusion criteria clearResearch supported by Abbott Laboratories, Chicago

Participants Ambulatory patients older than 12 yrs with CAPCAP diagnosis basedon pretreatment CXR (new infiltrateconsistent with pneumonia), a positive bacterialculture of bronchopulmonary secretions before treatment or a history and clinical findings consistentwith a diagnosis of bacterial or atypical pneumonia to be confirmed subsequently by positive culture orserologic resultn = 268 all patients,exclusions, 173 evaluable patients:n = 92 (clarithro),n = 81 (erythro)

Patients with mild or moderate infectionMean age: 47.2 yrs (clarithro), 48.2 yrs (erythro)Male: 47% (clarithro),56% (erythro)

Interventions Clarithromycin: 250 mg every 12h,orErythromycin stearate: 500 mg every 6 hMean treatment duration not specified (minimum duration: 7 days, intended duration: 7-14 days)Compliance assessment: tablet count

Outcomes Clinical response:1. Cure: resolution of all signs and symptoms2. Improvement: partial resolution3. Failure: no improvement4. Relapse: deterioration observed at the first posttherapy visit after initial improvementRadiologic response:1. Resolution2. Improvement3. Unchanged4. Worsening




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Chien 1993 (Continued)

Bacteriologic responses:1. Cure: absence of the pretreatment pathogen in the posttreatment culture2. Failure: persistence of the pretreatment pathogen in the posttreatment culture3. Reinfection: presence of a pathogen in the posttreatment culture that was different from that in thepretreatment culture4. Recurrence: reappearance on the follow-up culture of a pathogen that was previously eradicatedClinical response: Success (cure and improvement) 97% clarithro, 96% erythroRadiological response: 96% in both groupsBacteriological response: 88% clarithro, 100% erythro (not significant)Overall adverse events: 31% clarithro, 59% erythro (p38C), cough, sputum production, evidence of pulmonaryconsolidation, hemoptysis, rigors, pleuritic chest painn = 167 (sparfloxacin)n = 175 (clarithromycin)Total = 342

150 sparflox and 162 clarithro clinically evaluable as per-protocol patients48 sparflox and 50 clarithro patients bacteriologically evaluable

Interventions Sparfloxacin 400 mg loading dose on day 1, then 200mg qd x 10 dorClarithromycin 250 mg bid x 10 dMean and median treatment duration not reportedCompliance not assessed




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Ramirez 1999 (Continued)

Outcomes Clinical response at visit 3 (10 days after end of treatment)1. cure: disappearance of all pretreatment clinical signs and symptoms; cxr resolved, improved or stable

compared to baseline2. improvement: resolution or reduction of most pretreatment clinical signs and symptoms; cxr resolved,improved or stable compared to baseline3. Failure: no resolution or reduction of most signs and symptoms of pneumonia, worsening of one ormore signs or sympt., new signs or sympt., or cxr worsened4. Indeterminate: it was not possible to assess signs and symptomsClinical results (intent-to-treat):1. cure or improv:Spar: 79.6%Clarithro: 82.9% no sig diff

Adverse events:Spar: 56.3%Clarithro: 65.1%

Notes

Risk of bias

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Balgos 1999 Mix of in- and outpatients (unspecified proportions)Mix of diagnoses (chron bronch and CAP), only about 50% with CAP; results reported separatelyComparison of two dosage regimens of the same drug (amoxycillin/clavulanic acid 875/125mg bid vs 500/125mg tid)

Ball 1994 Review of a series of unblinded trialsMix of patients of different studies

Balmes 1991 Mix of diagnoses (acute bronchitis and pneumonia)Only 8/110 (7%) patients had a diagnosis of pneumoniaMix of in- and out-patients (unspecified proportions)

Bantz 1987 Mix of diagnoses (bronchitis and pneumonia)Only 15/108 (14%) patients had a diagnosis of pneumoniaData not reported separately

Biermann 1988 No chest x-ray for every patient with suspected pneumonia




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(Continued)

Chodosh 1991 Only bacteriologically evaluable patients were included.

Dark 1991 Mix of diagnoses (bronchitis and pneumonia)Only 23/272 (8%) patients had a diagnosis of pneumoniaMix of in- and out-patients (unspecified proportions)

Dautzenberg 1992 Open-label study

De Cock 1988 Mix of diagnoses (acute bronchitis, acute superinfection of chronic bronchitis, pneumonia) and results reportedseparatelyOnly 42/198 (21%) patients had a diagnosis of pneumonia (results not specified for diagnosis groups)

Fong 1995 Too small (n


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(Continued)

Lode 1998 Combines patients from four other RCTs, including only those patients with strep pneumoniae pneumoniaconfirmed by blood culture, i.e. highly select sub-group, generalizability questionable. And the data from the

four studies can be obtained from the original reports (one of which is rtqvist 1996, already included in thereview)

Mller 1992 Only bacteriologically evaluable patients were included

NAPSG 1997 Study included both in- and out-patients, without providing any information on either of the sub-groups orcarrying out sub-group analyses

Neu 1993 Mix of diagnoses (acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis and bacterialpneumonia) but results not reported separatelyUnclear whether in- or outpatientsOnly 43/213 (20%) had a diagnosis of CAP

ODoherty 1998 Open-label study

Peugeot 1991 Open-label study

Rayman 1996 Comparison of different dosage regimens of the same drug.Included patients with either CAP or acute exacerbation of chronic bronchitis (i.e. mixed indications)Groups were not similar at baseline (more smokers and more failures of previous treatment in the twice dailygroup, for which more adverse reactions were reported)

Salvarezza 1998 Open-label study

Schleupner 1988 Mix of diagnoses (bronchitis, pneumonia)

Only 34/61 (56%) patients had a diagnosis of pneumoniaMix of in- and out-patients (unspecified proportions)

Tilyard 1992 Too small (n

ab for cap

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