antibiotic in CAP

8/7/2019 antibiotic in 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 in The Cochrane Library2009, Issue 4http://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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Erythromycin versus clarythromycin, Outcome 1 Clinical success. . . . . . . . . 29Analysis 1.2. Comparison 1 Erythromycin versus clarythromycin, Outcome 2 Bacteriological success. . . . . . . 30Analysis 1.3. Comparison 1 Erythromycin versus clarythromycin, Outcome 3 Radiological success. . . . . . . 30Analysis 1.4. Comparison 1 Erythromycin versus clarythromycin, Outcome 4 Drug-related adverse events. . . . . 31Analysis 2.1. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 1 Clinical success. . . . . 31Analysis 2.2. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 2 Bacteriological success. . . 32Analysis 2.3. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 3 Drug-related adverse events. 32Analysis 3.1. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 1 Clinical success. . . . 33Analysis 3.2. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 2 Bacteriological success. . 33Analysis 3.3. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 3 Drug-related adverse events. 34Analysis 4.1. Comparison 4 Telithromycin versus clarithromycin, Outcome 1 Clinical success. . . . . . . . . 34Analysis 4.2. Comparison 4 Telithromycin versus clarithromycin, Outcome 2 Bacteriological success. . . . . . . 35Analysis 4.3. Comparison 4 Telithromycin versus clarithromycin, Outcome 3 Drug-related adverse effects. . . . . 35Analysis 5.1. Comparison 5 Telithromycin versus levofloxacin, Outcome 1 Clinical success. . . . . . . . . . 36Analysis 5.2. Comparison 5 Telithromycin versus levofloxacin, Outcome 2 Bacteriological success. . . . . . . . 36Analysis 5.3. Comparison 5 Telithromycin versus levofloxacin, Outcome 3 Clinical efficacy against H. influenzae. 37Analysis 5.4. Comparison 5 Telithromycin versus levofloxacin, Outcome 4 Drug-related adverse effects. . . . . . 37

37APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .39INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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, Germany. [email protected]. [email protected]. (Editorial group: Cochrane Acute Respiratory InfectionsGroup.)

Cochrane Database of Systematic Reviews, Issue 4, 2009 (Status in this issue: New search for studies completed, conclusions not changed)Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD002109.pub3This version first published online: 7 October 2009 in Issue 4, 2009.Last assessed as up-to-date: 6 July 2009. (Help document - Dates and Statuses explained)

This record should be cited as: Bjerre LM, Verheij TJM, Kochen MM. Antibiotics for community acquired pneumonia in adultoutpatients. Cochrane Database of Systematic Reviews2009, Issue 4. Art. No.: CD002109. DOI: 10.1002/14651858.CD002109.pub3.

A B S T R A C T

BackgroundCommunity-acquired pneumonia (CAP), the sixth most common cause of death worldwide, is a common condition representing asignificant disease burden for the community, particularly in the elderly. Antibiotics are helpful in treating CAP and are the standardtreatment. CAP contributes significantly to antibiotic use, which is associated with the development of bacterial resistance and side-effects. Several studies have been published concerning treatment for CAP. Available data arises mainly hospitalized patients studies.This is an update of our 2004 Cochrane Review.

Objectives

To summarize current evidence from randomized controlled trials (RCTs) concerning the efficacy of different antibiotic treatments forCAP in participants older than 12.

Search strategy

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2009, issue 1) which containsthe Cochrane Acute Respiratory Infections Groups Specialized Register; MEDLINE (January 1966 to February week 2, 2009), andEMBASE (January 1974 to February 2009).

Selection criteria

RCTs in which one or more antibiotics were tested for the treatment of CAP in ambulatory adolescents or adults. Studies testing oneor more antibiotics and reporting the diagnostic criteria as well as the clinical outcomes achieved, were considered for inclusion.

Data collection and analysis

Two review authors (LMB, TJMV) independently assessed study reports in the first publication. In this update, LMB performed studyselection, which was checked by TJMV and MMK. Study authors were contacted to resolve any ambiguities in the study reports. Datawere compiled and analyzed. Differences between review authors were resolved by discussion and consensus.

Main results

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

mailto:[email protected]:[email protected]://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdfhttp://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdfmailto:[email protected]:[email protected]


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Six RCTs assessing five antibiotic pairs (1857 participants aged 12 years and older diagnosed with CAP) were included. The study

quality was generally good, with some differences in the extent of the reporting. A variety of clinical, radiological and bacteriologicaldiagnostic criteria and outcomes were reported. Overall, there was no significant difference in the efficacy of the various antibiotics.

Authors conclusions

Currently available evidence from RCTs is insufficient to make evidence-based recommendations for the choice of antibiotic to be usedfor the treatment of CAP in ambulatory patients. Pooling of study data was limited by the very low number of studies assessing thesame antibiotic pairs. 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

Antibiotics for community acquired pneumonia in adolescent and adult outpatients

Pneumonia, or infection involving the lungs, is the sixth most common cause of death worldwide. Pneumonia is especially life-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. This 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). Unfortunately, there were not enough trials to compare the effectsof different antibiotics 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), which includes pneu-monia acquired in the community at large, but excludes cases innursing and long-term care facilities, is a common condition thatcarries a high burden of mortality and morbidity, particularly inthe elderly. Prospective studies carried out in the UK, Finland andthe USA have estimated the annual incidence of CAP in commu-nity-dwellingadultsat5to11casesper1000adultpopulation;theincidence is known to vary markedly with age, being higher in thevery young and the elderly (Foy 1979; Jokinen 1993; Woodhead

1987).It is the most important cause of death from infectious causesin high-income countries and the sixth most important cause ofdeath overall (Mandell 2007).CAP can be caused by a broad rangeof pathogens including bacteria, atypical agents (Chlamydophilapneumoniae (C. pneumoniae), Mycoplasma pneumoniae (M. pneu-

moniae), Legionella pneumophilus (L. pneumophilus)) and viruses(Mandell 2007). In fact, more than 100 different microorgan-isms have been associated with CAP (Loeb 2002). Furthermore,a patient with CAP can be infected with more than one microbe,as in the case of a bacterial superinfection of an underlying in-fluenza infection. The most common pathogens include, depend-ing on the patient population tested, Streptococcus pneumoniae (S.

pneumoniae) (usually by far the most common), C. pneumoniae,Haemophilus influenzae (H. influenzae), M. pneumoniae and in-fluenza viruses (Loeb 2002; Mandell 2007).Significantcostsare associatedwith the diagnosisand managementof CAP. In the UK, 22% to 42% of adults with CAP are admittedto hospital (Guest 1997; Woodhead 1987), and of those, 5% to10% need to be admitted to an intensive care unit (BTS 1992;Torres 1991).

Description of the intervention

Antibiotics are the mainstay in the treatment of CAP, since thecausative organisms usually respond to them. Consequently, CAPcontributes significantly to antibiotic use, which is associated withthe development of bacterial resistance. In treating patients withCAP, the choice of antibiotic is a difficult one. Factors to be con-sidered are the possible etiologic pathogen, the efficacy of the sub-stance, potential side-effects, the treatment schedule and its effecton adherence to treatment, the particular regional resistance pro-file of the causative organism, and co-morbidities that might in-fluence the range of potential pathogens (such as in cystic fibrosis)or the dosage (as in the case of renal insufficiency).




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Why it is important to do this review

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 responseto treatment and their time to recovery. Consequently, it is un-clear as to what extent results comparing the efficacy of differentantibiotics in hospitalized patients can be extrapolated to outpa-tients. Numerous guidelines exist to aid clinicians with the treat-ment of CAP: in recent years, guidelines have been published,among others, by the American Thoracic Society (ATS 2001),the Infectious Diseases Society of America (IDSA 2000, updatedDecember 2003; IDSA 2003 and March 2007; Mandell 2007),the British Thoracic Society (BTS 2001, update: BTS 2004), theCanadian Community-Acquired Pneumonia Working Group (CCAPWG 2000), the European Respiratory Society (Woodhead2005), a German Guidelines Group (Hoeffken 2005), the GulfCooperation Council (Memish 2007), the Japanese RespiratorySociety (JRS 2005), the Latin American Thoracic Association (ALAT 2001, update: ALAT 2004), the South African ThoracicSociety (SATS 2007), and the Swedish Society of Infectious Dis-eases (Hedlund 2005; update: Strlin 2007). All these guidelinesinclude recommendations for the choice of antibiotic treatmentfor CAP in ambulatory patients. However, the evidence on whichthese recommendations are based are derived mainly from studies

carried out almost exclusively in hospitalized patients. Althoughmany studies have been published concerning CAP and its treat-ment, there is no concise summary of the available evidence con-cerning its treatment in unselected ambulatory outpatients.This review is an update of our first review (Bjerre 2004) and, likeit, addresses the comparative efficacy of antibiotic treatments forcommunity acquired pneumonia (CAP) in outpatients above 12years of age.

O B J E C T I V E S

1. To assess and compare the efficacy of individual antimi-

crobial therapies with respect to clinical, radiologicaland bacteriological outcomes in unselected adult out-patients with CAP.

2. To assess and compare the efficacy of antibiotic drugsacross drug groups.

M E T H O D S

Criteria for considering studies for this review

Types of studies

RCTs of antibiotics in adolescent and adult outpatients with CAPreporting on clinical parameters, cure rates and/or mortality wereconsidered for inclusion.

Types of participants

Outpatients of either gender over 12 years of age with the follow-ing:

1. Symptoms and signs consistent with an acute lowerrespiratory tract infection associated with new radio-graphic shadowing for which there is no other explana-tion (for example, not pulmonary edema or infarction);and

2. The illness is the primary clinical problem and is man-aged as pneumonia.(modified from the criteria for CAP as defined by the British Tho-racic Society (BTS 2001)).

Types of interventions

All double-blind randomized controlled comparisons of one an-tibiotic and a placebo or at least two antibiotics used to treat CAPwere considered. Trials comparing two doses, two treatment du-rations or two different application forms (intravenous versus oralfor example) of the same drug were not included. However, trialscomparing two different pharmacologic formulations of a samesubstance (for example, microspheres versus pure substance) were

included, as they are likely to differin their pharmacodynamic andpharmacokinetic properties, and thus may differ in their efficacy.Comparisons involving intravenous drugs are usually carried outin a hospital setting. However, as this might occasionally be per-formed in an ambulatory setting, we did not a priori exclude stud-ies dealing with intravenous drug applications.Trialsallowing concurrentuse of othermedicationssuchas antitus-sives, antipyretics, bronchodilators, or mucolytics were includedif they allowed equal access to such medications for participantsin both arms of the trial.

Types of outcome measures

1. Clinical response: improvement of signs andsymptoms,usually at a pre-defined test-of-cure (TOC)visit. Wherepossible, duration of clinical signs and symptoms wereused as outcome measures. We used a clinical definitionof cure as the primary outcome since radiographic res-olution lags behind clinical improvement (Macfarlane1984).

2. Radiologic response: resolution or improvement of anew finding on chest X-ray after antibiotic therapy.

3. Bacteriologic response: negative sputum culture in pa-tients previously found to have had pathogens in theirsputum.

4. Hospitalization.




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5. Mortality.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials(CENTRAL)(The CochraneLibrary,2009,issue1)whichcontainsthe Cochrane Acute Respiratory Infections Groups SpecialisedRegister; MEDLINE (January 1966 to February week 2, 2009),and EMBASE (January 1974 to February 2009).MEDLINE and CENTRAL were searched using the search strat-egyshown below. We combined the MEDLINE searchstring with

the Cochrane Highly Sensitive Search Strategy for identifying ran-domized trials in Medline: sensitivity maximizing version (2008revision) (Lefebvre 2008). The search string was adapted for EM-BASE, as shown in Appendix 1.MEDLINE (Ovid)1 exp Anti-Bacterial Agents/2 antibiotic$.mp.3 or/1-24 exp Pneumonia/5 exp Community-Acquired Infections/6 and/4-5 (3356)7 community acquired pneumonia.mp.8 or/6-7

9 3 and 8

Searching other resources

Studies were also identified by checking the bibliographies of stud-ies and review articles retrieved, and if necessary by contacting thefirstor correspondingauthorsof relevantstudies. In our first reviewof this topic, published in 2004 (Bjerre 2004) we had contactedthe following antibiotics manufacturers to identify any additionalpublished or unpublished studies: Abbott, AstraZeneca, Aventis,Boehringer-Ingelheim, Bristol-Myers-Squibb, GlaxoSmithKline,Hoffmann-LaRoche, Lilly, Merck, Merck Sharp & Dohme, No-vartis, Pfizer, Pharmacia, Sanofi, and Yamanouchi. This search

yielded no new studies.

We decided not to contact pharmaceutical companies for futurereview updates. This decision was made for two reasons: first,because of the very low yield of this search strategy, compared tothe significant amount of time it requires; andsecond, because thissearchstrategyprovides an unfair advantage to unpublished studiescarried out by industry, as opposed to government or academia,where an equivalent search strategy is not readily available.

For the same reason, we decided to only include studies that havebeen fully published in peer-reviewed journals. No language re-strictions were applied to the search and selection process.

Data collection and analysis

Selection of studies

Two review authors (LMB, TJMV) used the titles and abstracts ofthe identified citations to exclude trials that clearly did not meetour inclusion criteria in the first publication of this review (Bjerre2004). In this update, this was done by LMB. If the review authorfelt that a study might possibly fulfil the inclusion criteria, the fullpaper was obtained for further study.Two review authors (LMB, TJMV in the first review, LMB in thisupdatedreview)independentlyreviewedarticleshavingpassedthisinitial screen to determine whether they met the inclusion criteria

of the review.Studies could be excluded for any one of the following reasons:if they were not truly randomized; if they were conducted exclu-sively in hospitalized patients; if they only compared two doses ortwo application forms of the same substance; if the indication fortreatment consisted of a mix of diagnoses (most commonly: acutebronchitis, exacerbation of chronic bronchitis, and pneumonia)and the results were not reported separately for each diagnosticgroup.Another reason for exclusion was that some studies included a mixof in- and outpatients without reporting the data separately forthese two sub-groups. Whenever this was the case, we contactedthe trial authors to obtain separate data for outpatients only.

Studies including only bacteriologically evaluable patients werealso excluded, because these studies typically included only pa-tients with positive cultures of pathogens susceptible to study an-tibiotics or excluded patients with serologic confirmation of infec-tion with atypical agents (such as M. pneumoniaeor C. pneumo-niae). A priori exclusion of patients with resistant strains as wellas of patients with non-bacterial or atypical causes of CAP wouldfalsely increase the treatment success rate to levels that would beunrealistic in real practice. We chose to exclude these narrow-fo-cus studies because we are interested in the efficacy of treatmentin patients as they present to their general practitioner (GP), thatis, unselected and unfiltered. We consider this essential to the gen-eralizability of our results.

Studies were also excluded if the diagnosis of pneumonia was notconfirmed by chest X-ray. This exclusion criteria was necessary toensure that only participants with a very high likelihood of havingpneumonia be included in the review, since this was the patientpopulation in which the efficacy of various treatment alternativeswas to be assessed.Furthermore, studies were excluded if the total number of patientswas less than 30, because below this limit, the estimate of a bino-mial parameter (in this case, the proportion of patients cured orimproved) becomes too unstable (Armitage 1994).Finally, in this update, we added the following exclusion cri-terion: we excluded studies of antibiotics that have been with-drawn from the market or are no longer licensed for the treat-




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ment of outpatients with CAP, due to severe adverse effects. For

example, studies assessing the following fluoroquinolones were ex-cluded: gatifloxacin, grepafloxacin, sparfloxacin, temafloxacin andtrovafloxacin.Consequently, a study(Ramirez 1999)thathadbeenincluded in our first review (Bjerre 2004) was excluded from thepresent review.

Data extraction and management

The following data were extracted from each study, whenever pos-sible:

description of participants, in particular: age range andgender of participants, smoking status, co-morbidities;

description of potential pathogens identified and theirantimicrobial 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 of the trial; the number of patients lost to follow-up; types of adverse effects experienced and number of pa-

tients experiencing adverse effects the number of drop-outs due to adverse effects;

proportion of patients admitted to hospital in each armof the trial; mortality rates in each arm of the trial; study sponsor.

Therewere no unreconcilable disagreements. Review authors werenot blinded to the identity and affiliation of the study authors.

Assessment of risk of bias in included studies

The risk of bias tables in RevMan (version 5.0.18) were used tosystematically assessthe risk of bias inincluded studies. (See Char-acteristic of included studies table).

Measures of treatment effect

For dichotomous outcome data, an estimate of the common oddsratios with approximate 95% confidence intervals (CIs) was esti-mated using the Mantel-Haenzel approach. This was done usingRevMan software.

Unit of analysis issues

The unit of analysis was the individual patient. All included stud-ies were RCTs without any design particularities, such as cross-over design or multiple interventions, that would warrant specialattention to the units of analysis.

Dealing with missing data

Missing data arising, for example, from failure to report on out-comes such as radiological cure rates in some studies, were to bedealt with by excluding the specific outcome from the Data andanalysis section for the study in question. As for data missing fromindividual studies (more specifically, patients lost to follow-up),whenever possible, data from the clinical per-protocol populationwere used, because this excluded patients who had not been suffi-ciently exposed to the study drug to be able to potentially benefitfrom the drug.

Assessment of heterogeneity

The assessment of heterogeneity was carried out by means of the

Chi-square test for heterogeneity, available in RevMan software.

Assessment of reporting biases

If applicable, reporting/ publication bias wasassessed using funnelplots.

Data synthesis

Whenever possible, data was synthesizedusing a fixed-effect meta-analytic model (Mantel-Haenszel odds ratio, available in RevMansoftware).

Sensitivity analysis

Sensitivity analyses including and then excluding small studies(less than 30 patients) as well as, if relevant, excluding any lowquality studies were conducted, to assess the impact of such reviewdecisions on the outcome effect.

R E S U L T S

Description of studies

See: Characteristicsof includedstudies; Characteristicsof excluded

studies.

Results of the search

This search yielded a total of 1828 references in our first review(1966 to 2003) (Bjerre 2004), and the current updated search(2003 to 2009) yielded an additional 1298 records, for a grandtotal of 3126 records. Some records were double entries, due tothe overlapping content of databases.

Included studies

Six RCTs involving a total of 1857 patients aged 12 years andolderdiagnosed with community acquired pneumonia were included in




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erally good to very good. Compliance with treatment was explic-

itly assessed by pill count in three studies (Anderson 1991; Chien1993; Mathers Dunbar 2004). None reported any difference inthe number of pills remaining between the two groups. However,in the Chien 1993 study, 40 participants were excluded becausethey received less than the minimum therapy (seven days) andthese patients were distributed unevenly across the two groups (10in the clarithromycin group and 30 in the erythromycin group).In the two studies using azithromycin microspheres (DIgnazio2005; Drehobl 2005), the compliance in the azithromycin groupwas 100% in both studies, because the drug was administered ina single dose under directly observed therapy (DOT) at the initialtreatment visit.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.The risk of bias in included studies was systematically assessedusing RevMans risk of bias tables (see Characteristics of includedstudies table) as well as Figure 2 and Figure 3.

Figure 2. Risk of bias graph: review authors judgements about each methodological quality item presented

as percentages across all included studies.




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Figure 3. Risk of bias summary: review authors judgements about each methodological quality item for

each included study.




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Allocation

Only two of the studies clearly stated the randomization methodused (Drehobl 2005; Mathers Dunbar 2004).

Blinding

All trials were randomized, double-blind evaluations comparingtwo antibiotics. None of the articles reported any test of effective-ness of the blinding procedures used.

Follow up and exclusions

Withdrawals were generally reported in sufficient detail as to thereasons for withdrawal. The number of patients lost to follow-upwas reported in all studies. Losses to follow-up appeared to be mi-nor, amounting to a maximum of 10% of the initially randomizedpatients. One study (Chien 1993) did not present intention-to-treat analysis results.Since only two studies (Anderson 1991; Chien 1993) addressedthe efficacy of the same antibiotic pair, and both studies providedthe same information about outcomes, there were no missing dataissues in the combined analysis of the data arising from these twostudies.

Selective reporting

There were no concerns about the selective availability of data,or selective reporting of outcomes. However, because all includedstudies were supported by the pharmaceutical industry, there areconcerns that studies with results unfavourable to the drug underinvestigation may not have been published, thus potentially lead-

ing to publication bias.Other potential sources of bias

The main concern about other potential sources of bias was thatall included studies were sponsored by pharmaceutical companiesmanufacturing the antibiotics under study.

Effects of interventions

Efficacy

The success rates for each of the treatment arms of the six trialsare shown in the Data and analyses section of this review, Analyses1 to 5 (including sub-analyses). Success was defined as cure orimprovement, be it clinical, bacteriological or radiological, as as-

sessed at a predefined follow-up visit (Test-of-cure (TOC) visit).Overall, success rates, be they clinical, bacteriological or radiologi-cal , were very high, usually ranging from 87% to 96%. Except forbacteriological success in the study byKohno 2003, none of theclinical, bacterial or radiological success rates differed significantlyamong treatment arms within each of the studies, nor did theyachieve clinical - or statistical - significance when the results ofthe two studies of clarithromycin versus erythromycin (Anderson1991; Chien 1993) were pooled together. As for the Kohno 2003study, the bacteriological success rate (i.e. eradication of previouslyidentified pathogen) significantly favoured Levofloxacin (Analysis5.2). Most failures were due to failure to eradicate H. influenzae,so the authors looked at the clinical success rate of patients with

H. influenzaeat baseline, which turned out to not be significantly

different between levofloxacin and telithromycin (Analysis 5.3).Comparisons across antibiotic groups

The only comparisons across antibiotic groups are provided by thestudies byDIgnazio 2005 and Kohno 2003 whereby, in each ofthese studies, a macrolide and a quinolone are compared. Again,there was no significant difference in clinical or bacteriologicalsuccess, except in the Kohno 2003 study, as detailed above inthe Efficacy section; radiological outcomes were not reportedseparately for the two treatment arms.

Side effects

In all studies, the most common side effects attributable to thestudy drugs were gastrointestinal side effects. There were signifi-

cant differences in the occurrence of side effects attributed to thestudy drug in four of the six studies (Anderson 1991; Chien 1993;DIgnazio 2005; Mathers Dunbar 2004), affecting anywhere be-tween 12% and 38% of patients. In the two studies comparingclarithromycin with erythromycin (Anderson 1991; Chien1993),there were significantly more side effects in the erythromycingroup, the majority being gastrointestinal side effects. However,this was not reflected in the rate of side effects leading to with-drawal from the study, which was not significantly different acrosstreatment arms. However, as noted above, in the Chien 1993study, 40 patients were excluded because they received less thanthe minimum therapy (seven days) and these patients were dis-tributed unevenly across the two groups (10 in the clarithromycin

group and 30 in the erythromycin group). Although not listed asdrop-outs due to side effects, it is quite plausible that these dif-ferences in pre-study drop-out rates were due to the unfavourablegastrointestinal side effects of erythromycin.

Bacterial pathogen

Various pathogens were identified with varying frequency acrossstudies. The proportion of samples yielding an identifiablepathogen ranged from 19% (Anderson 1991) to 53% (DIgnazio2005). H. influenzaewas the most common pathogen identifiedbyAnderson 1991 (62% of positive cultures) and Kohno 2003(43% of positive cultures), whereas S. pneumoniaewas the maincausative organism in the Chien 1993 (56% of positive cultures)and Mathers Dunbar 2004 (52% of positive cultures) studies. Onthe contrary, DIgnazio 2005 and Drehobl 2005 reported C. pneu-moniaeas being the most common pathogen (20% and 23% ofpositive cultures, respectively).

Serologically identified pathogens

The most frequently identified pathogen in the studies byAnderson 1991, Chien 1993 and Kohno 2003 was M. pneumo-niaewhich represented 69%(Anderson 1991),74%(Chien1993)and 52% (Kohno 2003) of positive serology results, with C. pneu-moniae accounting for the remainder. In the study by DIgnazio2005, C. pneumoniaewas predominant, representing 61% of atyp-ical pathogens, with M. pneumoniae accounting for the remain-ing 39%. Likewise in the studies byDrehobl 2005 and Mathers




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Dunbar 2004, C. pneumoniaerepresented just over half of atypical

pathogens (53% and 52%, respectively). Only one patient testedpositive for Legionella pneumoniae(L. pneumoniae)inthe MathersDunbar 2004 study, and no samples were positive for Chlamydiapsittaci (C. psittaci ) in any of studies.

D I S C U S S I O N

Summary of main results

The overwhelming feature of this review update remains thepaucity of relevant evidence that could be identified and included

in the review. Nonetheless, in this update, four new studies wereincluded (DIgnazio 2005; Drehobl 2005; Kohno 2003; MathersDunbar 2004). Inclusion of these studies did not alter the conclu-sions of our previous review.Unfortunately, only two studies (Anderson 1991; Chien 1993),which had already been included in the previous version of thisreview, focused on the same antibiotic pair; all other studies dealtwith different antibiotic pairs, so that, once again, no formal meta-analysis of the data could be carried out. At most, it can be statedthat individual study results did not reveal significant differencesin efficacy between various antibiotics and antibiotic groups, butthat there were some significant differences with respect to thefrequency of side effects. Given this current state of affairs, it is

not possible to make strong evidence-based recommendations re-garding the choice of antibiotic to be used for the treatment ofcommunity acquired pneumonia in ambulatory outpatients. Un-der such circumstances, other factors such as tolerability, durationand frequency of treatment, and cost will take on more impor-tance in determining the choice of treatment.

Overall completeness and applicability ofevidence

One important reason for this lack of evidence is that a large num-ber of the trials originally identified were conducted in hospital-ized patients and therefore are not necessarily relevant to the treat-

ment of ambulatory patients. It could be argued that the inclu-sion/exclusion criteria for this review were too strict and that thisis the reason why so few studies were retained. However, we dobelieve that the criteria we applied are necessary in order to validlyaddress the question of the efficacy of treatment of CAP in ambu-latory patients. In particular, it could be argued that the decisionto exclude studies based on size is not desirable, since one aim ofthe review is to pool results and that each study therefore wouldcontribute some information. However, we felt that this criterionwasnecessary to exclude studies where the number of patients withpneumonia was so small that randomization could no longer beexpected to achieve a balanced distribution of confounders, bothknown and unknown, across study groups.

As for the requirement that the diagnosis of CAP be confirmed

by a chest radiograph, we felt that this was necessary to avoiddiagnostic misclassification, which could, for example, have led totheinclusionofpatientswithbronchitisintothereview.Thiscouldhave biased the estimation of the efficacy of various antibiotictreatments, either differentially or non-differentially, dependingon the distribution of non-CAP cases across treatment groups.Indeed, most recent clinical guidelines recommend the routineuse of chest X-rays to confirm a suspected pneumonia (ATS 2001;CCAPWG 2000; Mandell 2007). However, we are aware that thisdiagnostic test is often not used in practice and that patients aretherefore treated empirically according to the clinical findings andthe severity of the clinical picture. In such a situation, GPs shouldrealize that patients with an empirical diagnosis of pneumonia

(i.e. diagnosis without chest X-ray) are probably on average, lessseverely ill than the subjects in the trials we reviewed.The diversity of pathogens identified as most common causativeorganisms in our present review underscores the need for conduct-ing studies of CAP treatment in a variety of different geographicallocations, and also points to a possible limitation of such studies,namely their questionable generalizability to other clinical and,particularly, geographical situations than the ones under study.Finally, a lot of potentially useful information is lost because inves-tigators often included a mix of in- and outpatients in their studieswithout reporting results separately for each of these subgroups.Investigators and journal editors should be strongly encouragedto report such data separately, as these patients have different co-

morbidity profiles, and, potentially, respond to treatment differ-ently. Putting heterogenous patient groups into the same analyticbasket may reduce the generalizability and thus the usefulness ofsuch study results. Contacting trial authors after publication toget additional data, sometimes years after a study was published,is a time-consuming process with a very low yield, as was ourexperience, and that of other Cochrane reviewers (for example,Robenshtok 2008).

Quality of the evidence

Overall, the quality of the included studies was relatively good,although there were some differences in the completeness of re-porting. The fact that we chose to include only double-blind, con-trolled, prospective RCTs led to the a priori exclusion of studiesof lesser quality.

Potential biases in the review process

By choosing to include only studies published in peer-reviewedjournals and by choosing to no longer contact pharmaceuticalcompanies for information on unpublished studies, we believe thatwe have contributed to increasing study quality and reducing biasin our review to a minimum. Furthermore,by excluding data fromstudies focusing on selected sub-groups of ambulatory participants




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(such as participants with suspected bacterial pneumonia), we be-

lieve we have maximized the generalizability of our review resultsto unselected patients presenting to their GP.It is noteworthy that, once again, all studies meeting inclusion cri-teria for our review were sponsored by pharmaceutical companies.This could potentially introduce a publication bias, as it wouldbe in the interest of manufacturers not to publish studies yieldingunfavourable results about their products. We are of the opinionthat thereis an urgent need for industry-independent research intothe treatment of CAP in ambulatory patients.

Agreements and disagreements with otherstudies or reviews

As mentioned above, we feel that our decision to exclude studiesfocusing only on a subset of outpatients (forexample, onlybacte-riologically evaluable patients or excluding patients with atypicalpneumonia) is necessary to maintain the generalizability of ourresults to patients presenting to first-line physicians. In contrast,a recent meta-analysis we encountered in the process of searchingthe literature (Maimon 2008) was more inclusive. The object ofthis meta-analysis was different from that of our review. However,the target population (outpatient withCAP, treated as outpatients)wasthe same. Despite the authorsstated focus on the inclusionofonly randomised prospective double-blind studies using only oraltherapy exclusively in outpatients (p.1974), this work included anumber of open-label (non-blinded) studies, studies including a

mix of in- and outpatients (for which sub-group data was report-edly obtained from study authors) as well as narrow-focus studies(i.e. studies focusing exclusively on bacterial pneumonia, for ex-ample). Of the 13 studies included in this meta-analysis, none metthe inclusion criteria for our review, which leads us to question thegeneralizability of this meta-analysis results to unselected patientspresenting in general practice.Finally, a recent RCT confirmed that patients with CAP of mod-erate severity (Fine Score II or III) can be treated as safely andeffectively as outpatients than as inpatients (Carratala 2005), atonly a fraction of the cost. This further underscores the need forsolid, evidence-based data on the treatment of patients with CAPin the ambulatory care setting.

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 makeevidence-based recommendations for the choice of antibiotic to beused in the treatment of CAP in ambulatory patients. At most, itcan be stated that individual study results do not reveal significantdifferences in efficacy between various antibiotics and antibioticgroups.

Implications for research

Multi-drug, multi-drug-group, double-blind comparisons con-ducted in various geographical settings are needed to provide the

evidence necessary for practice recommendations if these are tobe applicable in the ambulatory setting. Study conditions shouldensure that diagnosis and management of patients with CAP isas similar as possible to real practice, while still ensuring that thestudy question is addressed in a valid way. Finally, in studies re-cruiting a mix of in- and outpatients, it is imperative that data bereported separately for these two sub-groups.

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

We thank the authors we contacted who kindly replied to our re-quests for additional information: Dr. Lorenzo Aguilar, Dr. ClaudeCarbon, Dr. LarsHagberg, Dr. KarenHiggins, Dr. Shigeru Kohno,Dr. Hartmut Lode, Dr. Lala Mathers Dunbar and Dr. Antoni Tor-res Mart. Many thanks to Dr. Frederike Behn for precious helpwith parts of the data extraction process in the first version of thisreview (Bjerre 2004). We also wish to thank the following peoplefor commenting on this updated draft: Clare Jeffrey, Anne Lyddi-att, Tina Tan, Mark Jones, and Roger Damoiseaux. Last but notleast, we thank the Acute Respiratory Infections Group editorialteam for enduring support and guidance, in particular Liz Dooley(Managing Editor), as well as Ruth Foxlee and Sarah Thorning(respectively, past and present Trials Search Co-ordinators).

R E F E R E N C E S

References to studies included in this review

Anderson 1991 {published data only} AndersonG, Esmonde TS,Coles S, Macklin J, Carnegie C. A com-parative safety and efficacy studyof clarithromycin and erythromycinstearate in community-acquired pneumonia. Journal of Antimicro-bial Chemotherapy1991;27(Suppl A):11724.

Chien 1993 {published data only} Chien SM, Pichotta P, Siepman N, Chan CK and the Canada-

Sweden Clarithromycin-Pneumonia Group. Treatment of commu-nity-acquired pneumonia: a multicenter, double-blind, randomizedstudy comparing clarithromycin with erythromycin. Chest 1993;103:697701.

DIgnazio 2005 {published data only} DIgnazioJ, Camere MA, LewisDE, Jorgensen D, Breen JD. Novel,single-dose microsphere formulation of azithromycin versus 7-daylevofloxacin therapy for treatment of mild to moderate community-acquired Pneumonia in adults. Antimicrobial Agents and Chemother-




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apy2005;49(10):403541.

Drehobl 2005 {published data only}Drehobl MA, De Salvo MC, Lewis DE, Breen JD. Single-doseazithromycin microspheres vs clarithromycin extended release for thetreatment of mild-to-moderate community-acquired pneumonia inadults. Chest2005;128(4):22307.

Kohno 2003 {published data only}Kohno S, Watanabe A, Aoki N, Niki Y. Clinical evaluation oftelithromycin for community-acquired pneumonia - Phase III dou-ble-blind comparative study of telithromycin versus levofloxacin[Japanese]. Japanese Journal of Chemotherapy2003;51(Suppl 1):25578.

Mathers Dunbar 2004 {published data only}Mathers Dunbar L, Hassman J, Tellier G. Efficacy and tolerability

of once-daily oral telithromycin compared with clarithromycin forthe treatment of community-acquired pneumonia in adults. ClinicalTherapeutics2004;26(1):4862.

References to studies excluded from this review

Balgos 1999 {published data only} Balgos AA, Rodriguez-Gomez G, Nasnas R, Mahasur AA, MargonoBP, Tinoco-Favila JC. Efficacy of twice-daily amoxycillin/clavulanatein lower respiratory tract infections. International Journal of ClinicalPractice1999;53(5):32530.

Ball 1994 {published data only} Ball P. Efficacy and safety of cefprozil versus other beta-lactam an-tibiotics in the treatment of lower respiratory tract infections. Euro-pean Journal of Clinical Microbiology and Infectious 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 and amoxicillin/clavulanic acidin the treatment of lower respiratory tract infections. European Jour-nal of Clinical Microbiology and Infectious Diseases 1991;10:4379.

Bantz 1987 {published data only} Bantz PM, Grote J, Peters-Haertel W, Stahmann J, Timm J, KastenR, et al.Low-dose ciprofloxacin in respiratory tract infections: a ran-domized comparison with doxycycline in general practice. AmericanJournal of Medicine1987;82(Suppl 4A):20810.

Biermann 1988 {published data only} Biermann C, Loken A, Riise R. Comparison of spiramycin and

doxycycline in the treatment of lower respiratory infections in generalpractice. Journal of Antimicrobial Chemotherapy1988;22(Suppl B):1558.

Bonvehi 2003 {published data only}Bonvehi P, Weber K, Busman T, Shortridge D, Notario G. Compar-ison of clarithromycin and amoxicillin/clavulanic acid for commu-nity-acquired pneumonia in an era of drug-resistant streptococcuspneumoniae. Clinical Drug Investigation 2003;23(8):491501.

Carbon 1999 {published data only}Carbon C, Ariza H, Rabie WJ, Salvarezza CR, Elkharrat D, Ran-garaj M, et al.Comparative study of levofloxacin and amoxy-cillin/clavulanic acid in adults with mild-to-moderate community-acquired pneumonia. Clin Microbiology and Infection 1999;5:72432.

Chodosh 1991 {published data only}

Chodosh S. Temafloxacin compared with ciprofloxacin in mild tomoderate lower respiratory tract infections in ambulatory patients.Chest1991;100:1497502.

Dark 1991 {published data only} Dark D. Multicenter evaluation of azithromycin and cefaclor inacute lower respiratory tract infections. American 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 andamoxicillin plus clavulanic acid, in lower respiratory tract infections.Diagnostic Microbiology and Infectious Disease1992;15(Suppl):859.

De Cock 1988 {published data only} De Cock L, Poels R. Comparison of spiramycin with erythromycinfor lower respiratory tract infections. Journal of Antimicrobial Che-motherapy1988;22(Suppl B):15963.

Dean 2006 {published data only}Dean NC, Sperry P, Wikler M, Suchyta MS, Hadlock C. Comparinggatifloxacin and clarithromycin in pneumonia symptom resolutionand process of care. Antimicrobial Agents and Chemotherapy2006;50(4):11649.

Donowitz 1997 {published data only}Donowitz GR, BrandonML, SalisburyJP, Harman CP, TippingDM,Urick AE, et al.Sparfloxacin versus cefaclor in the treatment of pa-tients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study. Clinical Therapeutics1997;

19(5):93653.File 1997 {published data only}

File TM Jr, Segreti J, Dunbar L, Player R, Kohler R, WilliamsRR, et al.A multicenter, randomized study comparing the efficacyand safety of intravenous and/or oral levofloxacin versus ceftriaxoneand/or cefuroxime axetil in treatment of adults with community-ac-quired pneumonia. Antimicrobial Agents and Chemotherapy1997;41(9):196572.

File 2001 {published data only}File TM Jr, Schlemmer B, Garau J, Cupo M, Young C, 049 ClinicalStudy Group. Efficacy and safety of gemifloxacin in the treatment ofcommunity-acquired pneumonia: a randomized, double-blind com-parison with trovafloxacin. Journal of Antimicrobial Chemotherapy

2001;48(1):6774.File 2004 {published data only}

File TM Jr, Lode H, Kurz H, Kozak R, Xie H, Berkowitz E, etal.Double-blind, randomized study of the efficacy and safety of oralpharmacokinetically enhanced amoxicillin-clavulanate (2,000/125milligrams) versus those of amoxicillin-clavulanate (875/125 mil-ligrams), both given twice daily for 7 days, in treatment of bacterialcommunity-acquired pneumonia in adults. Antimicrobial Agents andChemotherapy2004;48(9):332331.

Fogarty 1999 {published data only}Fogarty, C, Grossman C, Williams J, HaverstockD, Church D fortheCommutiy-Acquired Pneumonia Study Group. Efficacy and safetyof moxifloxacinvs clarithromycin for community-acquired pneumo-nia. Infections in Medicine1999;16:74863.




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Fogarty 2002 {published data only}

Fogarty CM, CyganowskiM, PaloWA,Hom RC, Craig WA. A com-parison of cefditoren pivoxil and amoxicillin/ clavulanatein the treat-ment of community-acquired pneumonia: a multicenter, prospec-tive, randomized, investigator-blinded, parallel-group study. Clini-cal Therapeutics2002;24(11):185470.

Fong 1995 {published data only} Fong IW, Laforge J, Dubois J, Small D, Grossman R, Zakhari R, etal.Clarithromycinversus cefaclor in lower respiratory tractinfections.Clinical and Investigative Medicine1995;18:1318.

Gotfried 2002 {published data only}GotfriedMH, Dattani D, Riffer E, Devcich KJ, Busman TA, NotarioGF, et al.A controlled, double-blind, multicenter study comparingclarithromycin extended-release tablets and levofloxacin tablets in the

treatment of community-acquired pneumonia. Clinical Therapeutics2002;24(5):73651.

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 treatment of adults with lowerrespriatory tract infections: results of a randomized, double-blindcomparative study. Journal of Antimicrobial Chemotherapy 1996;37(Suppl C):93101.

Hagberg 2002 {published data only}Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ru-uth E. Efficacy and tolerability of once-daily telithromycin comparedwith high-dose amoxicillin for treatment of community-acquiredpneumonia. Infection 2002;30(6):37886.

Higuera 1996 {published data only} Higuera F, Hidalgo H, Feris J, Giguere G, Collins JJ. Comparisonof oralcefuroxime axetil and oralamoxycillin/clavulanate in the treat-ment of community-acquired pneumonia. Journal of AntimicrobialChemotherapy1996;37:55564.

Hoeffken 2001 {published data only}Hoeffken G, Meyer HP, Winter J, Verhoef L, CAP1 Study Group.The efficacy and safety of two oral moxifloxacin regimens comparedtooral clarithromycinin the treatmentof community-acquired pneu-monia. Respiratory Medicine2001;95(7):55364.

Hoepelman 1993 {published data only} HoepelmanAIM,SipsAP,vanHelmondJLM,vanBarneveldPWC,Neve AJ, et al.A single-blind comparison of three-day azithromycin

and ten-day co-amoxiclav treatment of acute lower respiratory tractinfections. Journal of AntimicrobialChemotherapy1993;31(Suppl E):14752.

Hoepelman 1998 {published data only}Hoepelman IM, Mllers MJ, van Schie MH, Greefhorst APM,Schlsser NJJ, Sinninghe Damst EJ, et al.A short (3-day) course ofazithromycin tablets versusa 10-day courseof amoxycillin-clavulanicacid (co-amoxiclav) in the treatment of adults with lower respira-tory tract infections and effects on long-term outcome. InternationalJournal of Antimicrobial Agents1998;9:1416.

Kammer 1991 {published data only} Kammer RB, Ress R. Randomized comparative study of ceftibutenversus cefaclor in the treatment of acute lower respiratory tract infec-tions. Diagnostic Microbiology and Infectious Disease1991;14:1015.

Kiani 1990 {published data only}

Kiani R, Coulson L, Johnson D, Hammershaimb L. Comparisonof once-daily and twice-daily cefixime regimens with amoxicillin inthe treatment of acute lower respiratory tract infections. CurrentTherapeutic Research, Clinical and Experimental1990;48(5):84152.

Kinasewitz 1991 {published data only}Kinasewitz, WoodRG. Azithromycin versuscefaclorin the treatmentof acute bacterial pneumonia. European Journal of Clinical Microbi-ology and Infectious Diseases1991;10(10):8727.

Lacny 1972 {published data only} Lacny J. A comparison of oral therapy with clindamycin and peni-cillin G in common gram-positive infections. Current TherapeuticResearch 1972;14(1):2630.

Laurent 1996 {published data only}

Laurent K. Efficacy, safety and tolerability of azithromycin versusroxithromycin in the treatment of acute lower respiratory tract in-fections. Journal of Antimicrobial Chemotherapy 1996;37(Suppl C):11524.

Leophonte 2004 {published data only}Lophonte P, File T, Feldman C. Gemifloxacin once daily for 7 dayscompared to amoxicillin/clavulanic acid thrice daily for 10 days forthetreatment of community-acquired pneumonia of suspectedpneu-mococcal origin. Respiratory Medicine2004;98(8):70820.

Liipo 1994 {published data only} Liippo K, Tala E, Puolijoki H, Brckner OJ, Rodrig J, Smits JPH.A comparative study of dirithromycin and erythromycin in bacterialpneumonia. Journal of Infectious Diseases1994;28:1319.

Lode 1995 {published data only} Lode H, Garau J, Grassi C, Hosie J, Huchon G, Legakis N,et al.Treatment of community-acquired pneumonia: a randomizedcomparison of sparfloxacin, amoxycillin-clavulanic acid and ery-thromycin. European Respiratory Journal1995;8:19992007.

Lode 1998 {published data only} Lode H, Aubier M, Portier H, Ortqvist A and the SparfloxacinStudy Group. Sparfloxacin as alternative treatment to standard ther-apy for community-acquired bacteremic pneumococcal pneumonia.Clinical Microbiology and Infection 1998;4(3):13543.

Lode 2004a {published data only}Lode H, Magyar P, Muir JF, Loos U, Kleutgens K, International Gat-ifloxacin Study Group. Once-daily oral gatifloxacin vs three-times-

daily co-amoxiclav in the treatment of patients with community-ac-quired pneumonia. Clinical Microbiology and Infection 2004;10(6):51220.

Lode 2004b {published data only}Lode H, Aronkyto T, Chuchalin AG, Jaaskevi M, Kahnovskii I,KleutgensK, et al.Arandomised, double-blind,double-dummy com-parative study of gatifloxacin with clarithromycin in the treatmentof community-acquired pneumonia. Clinical Microbiology and In-fection 2004;10(5):4038.

Macfarlane 1996 {published data only}MacFarlane JT, Prewitt J, Gard P, Guion A. Comparison of amoxy-cillin and clarithromycin as initial treatment of community-acquiredlower respiratory tract infections. British Journal of General Practice1996;46(407):35760.




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Torres 2003 {published data only}

Torres A, Muir JF, Corris P, Kubin R, Duprat-Lomon I, Sagnier PP,et al.Effectiveness of oral moxifloxacin in standard first-line therapyin community-acquired pneumonia. European Respiratory Journal2003;21(1):13543.

Trmolires 1998 {published data only}Trmolires F, de Kock F, Pluck N, Daniel R. Trovafloxacin versushigh-dose amoxicillin (1 g three times daily) in the treatment of com-munity-acquired bacterial pneumonia. European Journal of ClinicalMicrobiology and Infectious Diseases1998;17(6):44753.

Trmolires 2005 {published data only}Trmolires F, Mayaud C, Mouton Y, Weber P, Dellatolas F, CaulinE. Efficacy and safety of pristinamycin vs amoxicillin in communityacquired pneumonia in adults [Essai comparatif de lefficacit et de latolrance de la pristinamycine vs amoxicilline dans le traitement des

pneumonies aigues communautaires de ladulte]. Pathologie-Biologie2005;53(8-9):50310.

van Zyl 2002 {published data only}van Zyl L, le Roux JG, LaFata JA, Volk RS, Palo WA, Flamm R,et al.Cefditoren pivoxil versus cefpodoxime proxetil for community-acquired pneumonia: results of a multicenter, prospective, random-ized, double-blind study. Clinical Therapeutics2002;24(11):184053.

Zuck 1990 {published data only}Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime prox-etil compared withceftriaxone in vulnerable patients with bronchop-neumonia. Journal of Antimicrobial Chemotherapy 1990;26(SupplE):717.

rtqvist 1996 {published data only} rtqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C, etal.Oral empiric treatment of community-acquired pneumonia: amulticenter, double-blind, randomizedstudy comparing sparfloxacinwith roxithromycin. Chest1996;110:1499506.

Additional references

ALAT 2001Grupo de trabajo de la Asociacin Latinoamericana del Trax(ALAT). Latin American Thoracic Association (ALAT) recommen-dations on community acquired pneumonia [RecomendacionesALAT sobre la neumona adquiridaen la comunidad(article in Span-ish)]. Archivos de Bronconeumologa 2001;37:3408.

ALAT 2004

Grupo de trabajo de la Asociacin Latinoamericana del Trax(ALAT). Updateto theLatin American Thoracic Association (ALAT)recommendationson communityacquiredpneumonia (article in En-glish). Archivos de Bronconeumologa 2004;40(8):36474.

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

ATS 2001American Thoracic Society. Guidelines forthe management of adultswith community-acquired pneumonia. American Journal of CriticalCare2001;163:173054.

BTS 1992BritishThoracic SocietyResearchCommitteeand PublicHealthLab-oratory Service. The aetiology, management and outcome of severe

community-acquired pneumonia on the intensive care unit. Respi-

ratory Medicine1992;86:713.

BTS 2001British Thoracic Society. British Thoracic Society Guidelines forthe management of adults with community-acquired pneumonia.Thorax2001;56(Suppl IV):164.

BTS 2004Macfarlane JT, Boldy D. 2004 update of BTS pneumonia guidelines:whats new? [www.britthoracic.org.uk/guidelines (Accessed March16th 2009)]. Thorax2004;59(5):3646. [: Macfarlane 2004]

Carratala 2005Carratal J, Fernndez-Sab N, Ortega L, Castellsagu X, Rosn B,Dorca J, et al.Outpatientcare comparedwith hospitalization for com-munity-acquired pneumonia: a randomized trialin low-riskpatients.

Annals of Internal Medicine2005;142(3):16572.

CCAPWG 2000Canadian Community-Acquired Pneumonia Working Group.Canadian guidelines for the initial management of community-ac-quired pneumonia: an evidence-based update by the Canadian In-fectious Diseases Society and the Canadian Thoracic Society. Clini-cal Infectious Diseases2000;31:383421.

Foy 1979Foy HM, Cooney MK, Allan I, et al.Rates of pneumonia duringinfluenza epidemics in Seattle, 1964 to 1975. JAMA 1979;241:2538.

Guest 1997Guest JF, Morris A. Community-acquired pneumonia: the annual

costtotheNationalHealthServiceintheUnitedKingdom. EuropeanRespiratory Journal1997;10:15304.

Hedlund 2005Hedlund J, Strlin K, Ortqvist A, Holmberg H, Community-Ac-quired Pneumonia Working Group of the Swedish Society of Infec-tious Diseases. Swedish guidelines for the management of commu-nity-acquired pneumonia in immunocompetent adults. Scandina-vian Journal of Infectious Diseases2005;37(11-12):791805.

Hoeffken 2005Hffken G, Lorenz J, Kern W, Welte T, Bauer T, Dalhoff K, etal.S3-guideline on ambulant acquired pneumonia and deep airwayinfections. Pneumologie2005;59(9):61264. [: German guidelines2005]

IDSA 2000Infectious Dieseases Society of America. Practice guidelines for themanagement of community-acquired pneumonia in adults. ClinicalInfectious Diseases2000;31:34782.

IDSA 2003Infectious Dieseases Society of America. Update of practice guide-lines for the management of community-acquired pneumonia in im-munocompetent adults. Clinical Infectious Diseases2003;37:140533.

Jokinen 1993Jokinen C, Heiskanen L, Juvonen H, et al.Incidence off community-acquired pneumonia inthe population of four municipalities in east-ern Finland. Am J Epidemiol1993;137:97788.




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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 Date and duration of study: not specified. Follow-up: 6 to 8 weeks. Patients were in-cluded from 57 general practitioners in the UK. Double-blind, double-dummy tech-nique, intention-to-treat results provided

Participants Patients with CAP older than 18 years. CAP diagnosis confirmed by 3 of the fol low-ing features: pyrexia, dyspnoea, tachypnoea, rales, localized reduced breath sounds andcough. Diagnosis of CAP was later confirmed radiographically. Total: n = 208. Evaluablefor efficacy: n = 108 (exclusion usually due to failure to confirm initial Dx on CXR), n= 64 (clarithromycin), n = 44 (erythromycin). Exclusion criteria clear

Interventions Clarithromycin 250 mg bid for 14 days or erythromycin 500 mg qid for 14 days, eachgiven at least 1 hour before or 2 hours after meals, mean treatment duration: 13 days(clarithromycin), or 10 days (erythromycin). Compliance assessment: tablet count

Outcomes Primary outcome: Clinical response at2 weeks(test-of-cure visit): 98% (clarithromycin),91% (erythromycin). Treatment-related adverse events: 16% (clarithromycin) versus33% (erythromycin), p = 0.004, mainly gastrointestinal side effects

Notes Three of 5 authors from Abbott Laboratories, source of funding not specified

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear Randomization method not specified

Allocation concealment? Unclear because randomization method not specified

Blinding?All outcomes

Yes Double-blind, double-dummy technique

Incomplete outcome data addressed?All outcomes

Yes Detailed list of reasons for exclusion fromefficacyanalyses, withnumber of patients affected

Free of selective reporting? Yes Pre-specified outcomes appear to be fully reported

Free of other bias? Unclear Three of 5 authors from Abbott Laboratories, source of fundingnot specified




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Chien 1993

Methods Dateanddurationofstudy:January1989toJune1990.Follow-up:4-6weeks.Multicen-ter study (15 centers of the Canada-Sweden Clarithromycin-Pneumonia Study Group,11 in Canada, 4 in Sweden). Double-blind, double-dummy technique, no intention-to-treat results provided

Participants Ambulatory patients older than 12 years with CAP. N = 268 all patients, after exclusions173 evaluable patients: n = 92 (clarithromycin), n = 81 (erythromycin). Patients withmild or moderate infection. Drop-outs: 35% (due to less than minimum therapy, pre-mature discontinuation, unavailable for follow-up, misdiagnosis, inadequate data col-lection, concomitant medication, underlying condition). Exclusion criteria clear

Interventions Clarithromycin: 250 mg every12 hours, or erythromycinstearate: 500 mg every 6 hours.Mean treatment duration not specified (minimum duration: 7 days, intended duration:7 to 14 days). Compliance assessment: tablet count

Outcomes Primary outcome: Clinical success (cure and improvement) 97% clarithromycin,96% erythromycin. Treatment-related adverse events: 31% clarithromycin, 59% ery-thromycin (p < 0.001)

Notes Research supported by Abbott Laboratories, Chicago

Risk of bias


Adequate sequence generation? Unclear Randomization method not specified

Allocation concealment? Yes Quote: The randomization was blinded to both the investiga-tors and the patients.






Free of other bias? Unclear Research supported by Abbott Laboratories, Chicago




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Drehobl 2005

Methods Date and duration of study: not specified. Double-blind, double-dummy, phase III trial,conductedin 58 outpatientcenters worldwide(UnitedStates,Canada,Argentina, Russia,India, Estonia, Lithuania)

Participants 501 outpatients, 16 years or older. Patients were eligible for enrollment if they had aclinical diagnosis of mild to moderate CAP (signs and symptoms) and radiographicevidence of new pulmonary infiltrate. Patients also had to have a modified Fine risk scoreof I or II (< 70 points).

Interventions Single 2 g dose of azithromycin microspheres administered as an oral suspension versusextended-release clarithromycin administered orally as two 500 mg capsules once daily

for 7 days

Outcomes Primary endpoint: clinical response in the clinical per protocol population, on the basisof signs and symptoms of CAP, assessed at test of cure visit (TOC; day 14 to 21): azi91.8% versus clari 94.7% (non-significant difference). Treatment-related adverse effects:azi 26.3% versus clari 24.6% (non-significant difference), mainly gastrointestinal sideeffects

Notes Study funded by Pfizer Inc., 2 of 4 authors are employees of Pfizer

Risk of bias


Adequate sequence generation? Yes Quote: Subjects were randomized according to computer-gen-erated pseudorandom code using the method of permutatedblocks, balanced within investigational site

Allocation concealment? Yes Quote: Randomization numbers were assigned by a centralWeb/telephone computer-based telerandomization system






Free of other bias? Unclear Study sponsored by Pfizer




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Kohno 2003

Methods Date and duration of study: December 2000 to June 2001. Double-blind, double-dummy, randomized phase III trial, conducted in 117 centers in Japan

Participants 270 patients (mix of in- and outpatients), aged 16 to 80 years. 123 outpatients wereincluded. Exclusion criteria are clearly stated and patient selection flow chart is provided

Interventions Telithromycin 600 mg (= 2 x 300 mg) once daily after breakfast versus levofloxacin 100mg three times daily for 7 days

Outcomes Results are reported separately for in- and outpatients. Primary endpoint: cl inical re-sponse in the clinical per protocol population, on the basis of signs and symptoms of

CAP, assessed at end of treatment (EOT; 7 days after treatment initiation) teli95.7% ver-sus clari 96.3% (non-significant difference). Treatment-related adverse effects:teli 33.6%versus levo 33.9% (non-significant difference), mostly gastrointestinal side effects

Notes Study report is in Japanese, but e xtensive fi gures and tables are p rovided in English, s o thatmost of the necessary information could be extracted. Missing information was kindlyprovided by the main author, Prof. Shigeru Kohno, MD, PhD, of Nagasaki University,Japan. Funding provided by Astellas (Fujisawa) Pharmaceutical Co. Ltd

Risk of bias


Adequate sequence generation? Unclear Text in Japanese; tables and figures in English

Allocation concealment? Unclear Text in Japanese; tables and figures in English




Yes Detailed flow chart of reasons for exclusion from efficacy anal-yses, with number of patients affected

Free of selective reporting? Unclear Text in Japanese; tables and figures in English

Free of other bias? Unclear Study sponsored by Fujisawa




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Mathers Dunbar 2004

Methods Date and duration of study: May 1998 to Sept. 1999. Double-blind, double-dummy,parallel-groupclinical trial conducted at 54 centers in 4 countries (UnitedStates, Canada,Argentiina and Chile)

Participants 493 outpatients aged 18 and over. Patients were eligible for enrollment if they had aclinical diagnosis of acute CAP (signs and symptoms) and chest radiographic findingssupporting the clinical diagnosis of bacterial pneumonia

Interventions Telithromycin 800 mg (= 2 x 400mg capsules) once daily in the morning versus clar-ithromycin 500 mg (= 2 x 250 mg capsules) twice daily for 10 days

Outcomes Primary endpoint: clinical response in the clinically assessable per protocol population,on the basis of signs and symptoms of CAP, assessed at test of cure visit (TOC; day17 to 24): teli 88.3% versus clari 88.5% (non-significant difference). Treatment-relatedadverse effects: teli 38.5% versus clari 27.9%, mostly gastrointestinal side effects

Notes Funded by an unrestricted educational grant from Aventis Pharmaceuticals

Risk of bias


Adequate sequence generation? Yes Quote: Patients.. . were randomized according to a schedulegenerated by the sponsor for each center. The schedule linkedsequential treatment assignment number to treatment codes al-located at random.

Allocation concealment? Yes Quote: Randomization schedules were held by the sponsor.


Yes Double-blind, double-dummy technique. Quote: Treatmentblinding was ensured by encapsulation of both active study med-ication and placebo within identical opaque capsules.




Free of other bias? Unclear Funded by a n unrestricted educational grant from Aventis Phar-maceuticals

Dx: diagnosisCXR: chest X-raybid: twice a dayqid: four times a day




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Characteristics of excluded studies [ordered by study ID]

Balgos 1999 Mix of in- and outpatients (unspecified proportions)Mix of diagnoses (chronic bronchitis and CAP), only about 50% with CAP; results reported separatelyComparison of two dosage regimens of the same drug (amoxycillin/clavulanic acid 875/125 mg bid versus500/125 mg 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

Bonvehi 2003 Focus on pneumococcal CAP; positive sputum cultures used as a selection criterion

Carbon 1999 Mix of in- and out-patients, data not reported separately; authors did not respond, or separate data could notbe provided by authors

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 reportedseparately.Only 42/198 (21%) patients had a diagnosis of pneumonia (results not reported separately for each diagnosticgroup)

Dean 2006 Open-label study

Donowitz 1997 Focus on bacterial pneumonia (acute onset, purulent sputum, Gram stain and chest X-ray consistent withbacterial pneumonia were required for inclusion into the study)

File 1997 Mix of in- and out-patients, data not reported separately, authors did not respond, or separate data could notbe provided by authors




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(Continued)

File 2001 Mix of in- and out-patients, data not reported separately, authors did not respond, or separate data could notbe provided by authors

File 2004 Focus on bacterial pneumonia

Fogarty 1999 Mix of in- and out-patients, data not reported separately, authors did not respond, or separate data could notbe provided by authors

Fogarty 2002 Focuson bacterialpneumonia.Serologic evidenceofM. pneumoniaeor C. pneumoniaewas an exclusioncriterion;serologic testing was systematically carried out pre-treatment as well as twice after treatment

Fong 1995 Too small (n < 30)

Gotfried 2002 Culture confirmation of bacterial CAP required

Gris 1996 Too small (n < 30)

Hagberg 2002 Mix of in and out-patients, data not reported separately, authors did not respond, or separate data could not beprovided by authors

Higuera 1996 Open-label study

Hoeffken 2001 Patients were recruited as outpatients, however, 30% were hospitalized in the course of the study, data for in-and outpatients are not reported separately, and hospitalization was not considered treatment failure

Hoepelman 1993 Mix of diagnoses (infective exacerbation of chronic obstructive pulmonary disease, purulent bronchitis andpneumonia) and results not reported separatelyOnly 9/99 (9%) patients had pneumoniaPneumonia not necessarily community acquired

Hoepelman 1998 Mix of diagnoses (infective exacerbation of chronic obstructive pulmonary disease, purulent bronchitis andpneumonia) and results not reported separately; only 3 of 144 patients had CAP

Kammer 1991 Only bacteriologically evaluable patients were included

Kiani 1990 Mix of in and out-patients, data not reported separatelyMix of diagnoses (acute bronchitis, pneumonia, acute exacerbation of chronic bronchopulmonary infection)but data reported separatelyOnly 10/110 (9%) patients had a diagnosis of pneumonia

Kinasewitz 1991 Focus on bacterialpneumonia (purulent sputumand leucocytosiswere required forinclusion into study, patientswithout sputum pathogens were excluded from efficacy analysis, etc.)




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(Continued)

Lacny 1972 Mix of diagnoses (infection of soft tissue, infection of the upper respiratory tract, otitis, skin infection, con-junctivitis, pneumonia) and results not reported separatelyOnly 2/121 (2.6%) patients had a diagnosis of pneumoniaCompletely institutionalized population32.5% patients were younger than 16 years

Laurent 1996 Mix of diagnoses (acute bronchitis, acute infectious exacerbations of chronic brochitis, or pneumonia) butresults reported separatelyOnly 43/204 (21%) patients had a diagnosis of pneumoniaMix of in- and outpatients (unclear in which proportions)

Leophonte 2004 Focus on pneumococcal pneumonia

Liipo 1994 Dirithromycin withdrawn from market

Lode 1995 Only inpatients (personal communication H. Lode), contrary to study report (Patients reportely treated aseither in- or outpatients)

Lode 1998 Combines patients from four other RCTs, including only those patients with S. pneumoniaepneumonia con-firmed by blood culture, i.e. highly select sub-group, generalizability questionable. The data from the fourstudies can be obtained from the original reports (one of which is rtqvist 1996, already excluded from thisreview because open-label)

Lode 2004a Gatifloxacin withdrawn from market

Lode 2004b Gatifloxacin withdrawn from market

Macfarlane 1996 Single-blind study, no chest X-ray required

Moola 1999 Grepafloxacin withdrawn from market

Mller 1992 Only bacteriologically evaluable patients were included

NAPSG 1997 Fleroxacin withdrawn from market

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

ODoherty 1997 Grepafloxacin withdrawn from worldwide market in October 1999 due to risk of severe arrhythmias

ODoherty 1998 Open-label study




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(Continued)

Pavie 2005 Descriptive study, no RCT

Petitpretz 2001 Focus on pneumococcal pneumonia

Peugeot 1991 Open-label study

Pullman 2003 Excluded because trovafloxacin no longer available for outpatients due to severe hepatotoxicity. Study recruit-ment was terminated because FDA restricted use of trovafloxacin to hospitalized patients with severe life- orlimb-threatening infections (1999)

Rahav 2004 Open-label study

Ramirez 1999 Sparfloxacin withdrawn from market due to increased risk of severe phototoxicity and rash, as well as rhab-domyolysis

Rayman 1996 Comparison of different dosage regimen 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)

Saito 2008 Mix of in- and out-patients, separate data for outpatients not available.Note: Article in Japanese. However, tables and figures in English; additional information obtained throughpersonal communication with one of the authors (Kohno S)

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)

Siquier 2006 Focus on pneumococcal pneumonia

Sokol 2002 Excluded because trovafloxacin no longer indicated for outpatients, later removed from market due to severehepatotoxicity. Study recruitment was terminated because FDA restricted use of trovafloxacin to hospitalizedpatients with severe life- or limb-threatening infections (1999)

Sopena 2004 Open-label study

Tellier 2004 Mix of in- and out-patients, data not reported separately, authors did not respond, or separate data could notbe provided by authors

Tilyard 1992 Too small (n < 30)




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(Continued)

Torres 2003 Mix of in- and out-patients, data not reported separately, authors did not respond, or separate data could notbe provided by authors

Trmolires 1998 Trovafloxacin withdrawn from market due to severe hepatotoxicity

Trmolires 2005 Focus on bacterial pneumonia

van Zyl 2002 Focuson bacterial pneumonia; purulent sputumsample required;patientswith serologic evidence ofMycoplasmapneumoniaeor Chlamydophila pneumoniaewere excluded

Zuck 1990 Open-label, unblinded study comparing oral administration twice daily versus intramuscular administrationonce daily. Included only high-risk patients; unclear whether treated as in- or outpatients

rtqvist 1996 Patients had CAP but were treated exclusively as inpatients

bid: twice a daytid: three times a day




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D A T A A N D A N A L Y S E S

Comparison 1. Erythromycin versus clarythromycin

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Clinical success 2 280 Odds Ratio (M-H, Fixed, 95% CI) 2.27 [0.66, 7.80]2 Bacteriological success 2 57 Odds Ratio (M-H, Fixed, 95% CI) 0.28 [0.03, 2.57]3 Radiological success 2 276 Odds Ratio (M-H, Fixed, 95% CI) 0.91 [0.33, 2.49]4 Drug-related adverse events 2 476 Odds Ratio (M-H, Fixed, 95% CI) 0.30 [0.20, 0.46]

Comparison 2. Azithromycin microspheres versus levofloxacin



1 Clinical success 1 363 Odds Ratio (M-H, Fixed, 95% CI) 0.59 [0.27, 1.26]2 Bacteriological success 1 237 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.32, 2.02]3 Drug-related adverse events 1 423 Odds Ratio (M-H, Fixed, 95% CI) 1.78 [1.04, 3.03]

Comparison 3. Azithromycin microspheres versus clarithromycin



1 Clinical success 1 411 Odds Ratio (M-H, Fixed, 95% CI) 0.69 [0.31, 1.55]2 Bacteriological success 1 303 Odds Ratio (M-H, Fixed, 95% CI) 1.17 [0.52, 2.61]3 Drug-related adverse events 1 499 Odds Ratio (M-H, Fixed, 95% CI) 1.09 [0.73, 1.64]

Comparison 4. Telithromycin versus clarithromycin



1 Clinical success 1 318 Odds Ratio (M-H, Fixed, 95% CI) 0.98 [0.49, 1.95]2 Bacteriological success 1 62 Odds Ratio (M-H, Fixed, 95% CI) 0.24 [0.03, 2.29]3 Drug-related adverse effects 1 443 Odds Ratio (M-H, Fixed, 95% CI) 1.61 [1.08, 2.40]




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Comparison 5. Telithromycin versus levofloxacin



1 Clinical success 1 123 Odds Ratio (M-H, Fixed, 95% CI) 0.85 [0.14, 5.25]2 Bacteriological success 1 86 Odds Ratio (M-H, Fixed, 95% CI) 0.03 [0.00, 0.60]

3 Clinical efficacy against H.influenzae

1 46 Odds Ratio (M-H, Fixed, 95% CI) 4.62 [0.38, 55.51]

4 Drug-related adverse effects 1 240

Documents

antibiotic in CAP