Antibiotics for community acquired pneumonia in adult ... · [Intervention Review] Antibiotics for community acquired pneumonia in adult outpatients Lise M Bjerre1, Theo JM Verheij2,

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 Library

2009, 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

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38WHAT’S 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)


[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 Göttingen, Göttingen, 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 Göttingen, Humboldtallee 38,Göttingen, 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 Reviews 2009, Issue 4. Art. No.: CD002109. DOI: 10.1002/14651858.CD002109.pub3.

A B S T R A C T

Background

Community-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 Group’s 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)


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Six RCTs assessing five antibiotic pairs (1857 participants aged 12 years and older diagnosed with CAP) were included. The studyquality 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-dwelling adults at 5 to 11 cases per 1000 adult population; theincidence is known to vary markedly with age, being higher in thevery young and the elderly (Foy 1979; Jokinen 1993; Woodhead1987).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 (Chlamydophila

pneumoniae (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).Significant costs are associated with the diagnosis and 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).



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: Strålin 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 studiescarried 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) wereincluded, as they are likely to differ in 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.Trials allowing concurrent use of other medications such as 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 and symptoms,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.



5. Mortality.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials(CENTRAL) (The Cochrane Library, 2009, issue 1) which containsthe Cochrane Acute Respiratory Infections Group’s 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-egy shown below. We combined the MEDLINE search string withthe 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/6-79 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 thefirst or corresponding authors of relevant studies. 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 searchyielded 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; and second, because thissearch strategy provides 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 thisupdated review) independently reviewed articles having passed thisinitial screen to determine whether they met the inclusion criteriaof 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. pneumoniae or 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-



ment of outpatients with CAP, due to severe adverse effects. Forexample, studies assessing the following fluoroquinolones were ex-cluded: gatifloxacin, grepafloxacin, sparfloxacin, temafloxacin andtrovafloxacin. Consequently, a study (Ramirez 1999) that had beenincluded 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 arm

of the trial;• mortality rates in each arm of the trial;• study sponsor.

There were 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 assess the risk of bias in included 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 theChi-square test for heterogeneity, available in RevMan software.

Assessment of reporting biases

If applicable, reporting / publication bias was assessed using funnelplots.

Data synthesis

Whenever possible, data was synthesized using 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: Characteristics of included studies; Characteristics of excludedstudies.

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 and olderdiagnosed with community acquired pneumonia were included in



this review: Anderson 1991 and Chien 1993, already included inour 2004 review (Bjerre 2004), and the new trials by D’Ignazio2005, Drehobl 2005, Kohno 2003, and Mathers Dunbar 2004.The trials included varying numbers of patients, the largest having499 patients (Drehobl 2005), the smallest 107 (Anderson 1991).The mean size of studies included in the analysis was 310 patients,the median size 315.All trials enrolled outpatients with CAP. In all trials, the diagnosisof CAP was based on clinical signs and symptoms as well as radio-graphic findings in all patients. The signs and symptoms used asdiagnostic criteria included combinations of the following: fever,chills, recent onset of productive cough, pleuritic chest pain, dysp-noea, pyrexia, tachypnoea, dullness to percussion, egophony, rales,localized reduced breath sounds and bronchial breath sounds. Inall six trials, patients were treated exclusively as outpatients.

Patient inclusion and exclusion criteria

Three trials included only adult patients, one trial (Chien 1993)also included adolescents 12 years of age and older, and two in-cluded adolescents 16 years of age and older (Drehobl 2005,Kohno 2003). One trial reported including patients as old as 91and only one used older age as an exclusion criterion (in the studyby Kohno 2003, patients were up to 80 years of age). Overall,

the trials excluded patients with conditions that could have af-fected the treatment or interfered with follow-up. Exclusion cri-teria were reported in sufficient detail in all study reports. Themost common criteria reported were: pregnancy and lactation,women not using adequate contraception (usually oral contracep-tives or a barrier method), history of allergic reaction to the studydrugs, recent treatment with or concomitant use of an antimicro-bial agent, concurrent medication with ergotamine, cyclosporin,antacids (except H2-antagonists) or digitalis, conditions affectingGI absorption, severe renal or hepatic impairment, terminal illnessor conditions precluding study completion, infectious mononu-cleosis, HIV/AIDS, and prior participation in the study.

Antibiotics

The trials varied with respect to the antibiotics studied (Figure1). Two trials (Anderson 1991; Chien 1993) studied the sameantibiotic pair (clarithromycin and erythromycin). All other tri-als studied different antibiotic pairs, namely clarithromycin versusazithromycin microspheres (Drehobl 2005), clarithromycin ver-sus telithromycin (Mathers Dunbar 2004), azithromycin micro-spheres versus levofloxacin (D’Ignazio 2005), and telithromycinversus levofloxacin (Kohno 2003).

Figure 1. Overview of included studies and antibiotic pairs studied. * indicates studies new to this review;

shaded ovals indicate quinolones (gyrase inhibitors), white ovals indicate macrolides

Excluded studies

A large number of studies were excluded because they were con-ducted exclusively in hospitalized patients. Furthermore, a numberof studies reported including a mix of in- and outpatients withoutreporting data separately for these two subgroups. For these stud-

ies, we contacted the trial authors to try to obtain separate data onoutpatients. Out of seven trial authors, only two responded, andboth were unable to provide us with the necessary data.

Risk of bias in included studies

The extent of reporting was variable between studies, but was gen-



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 (D’Ignazio2005; 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 RevMan’s 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.



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

each included study.



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 by Kohno 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. influenzae at baseline, which turned out to not be significantlydifferent between levofloxacin and telithromycin (Analysis 5.3).

Comparisons across antibiotic groups

The only comparisons across antibiotic groups are provided by thestudies by D’Ignazio 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;D’Ignazio 2005; Mathers Dunbar 2004), affecting anywhere be-tween 12% and 38% of patients. In the two studies comparingclarithromycin with erythromycin (Anderson 1991; Chien 1993),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 clarithromycingroup 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% (D’Ignazio2005). H. influenzae was the most common pathogen identifiedby Anderson 1991 (62% of positive cultures) and Kohno 2003(43% of positive cultures), whereas S. pneumoniae was the maincausative organism in the Chien 1993 (56% of positive cultures)and Mathers Dunbar 2004 (52% of positive cultures) studies. Onthe contrary, D’Ignazio 2005 and Drehobl 2005 reported C. pneu-

moniae as 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-

niae which represented 69% (Anderson 1991), 74% (Chien 1993)and 52% (Kohno 2003) of positive serology results, with C. pneu-

moniae accounting for the remainder. In the study by D’Ignazio2005, C. pneumoniae was predominant, representing 61% of atyp-ical pathogens, with M. pneumoniae accounting for the remain-ing 39%. Likewise in the studies by Drehobl 2005 and Mathers



Dunbar 2004, C. pneumoniae represented just over half of atypicalpathogens (53% and 52%, respectively). Only one patient testedpositive for Legionella pneumoniae (L. pneumoniae) in the MathersDunbar 2004 study, and no samples were positive for Chlamydia

psittaci (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 includedin the review. Nonetheless, in this update, four new studies wereincluded (D’Ignazio 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 isnot 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 criterionwas necessary 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 confirmedby a chest radiograph, we felt that this was necessary to avoiddiagnostic misclassification, which could, for example, have led tothe inclusion of patients with bronchitis into the review. This couldhave 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



(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 there is 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 (for example, “only bacte-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 with CAP, treated as outpatients)was the same. Despite the authors’ stated focus on “the inclusion ofonly 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 amix 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 theevidence 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. Lars Hagberg, Dr. Karen Higgins, Dr. Shigeru Kohno,Dr. Hartmut Lode, Dr. Lala Mathers Dunbar and Dr. Antoni Tor-res Martí. 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}∗ Anderson G, Esmonde TS, Coles S, Macklin J, Carnegie C. A com-parative safety and efficacy study of clarithromycin and erythromycinstearate in community-acquired pneumonia. Journal of Antimicro-

bial Chemotherapy 1991;27(Suppl A):117–24.

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;103:697–701.

D’Ignazio 2005 {published data only}∗ D’Ignazio J, Camere MA, Lewis DE, 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-



apy 2005;49(10):4035–41.

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. Chest 2005;128(4):2230–7.

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 Chemotherapy 2003;51(Suppl 1):255–78.

Mathers Dunbar 2004 {published data only}

Mathers Dunbar L, Hassman J, Tellier G. Efficacy and tolerabilityof once-daily oral telithromycin compared with clarithromycin forthe treatment of community-acquired pneumonia in adults. Clinical

Therapeutics 2004;26(1):48–62.

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 Clinical

Practice 1999;53(5):325–30.

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 Diseases 1994;13(10):851–6.

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;10:437–9.

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. American

Journal of Medicine 1987;82(Suppl 4A):208–10.

Biermann 1988 {published data only}∗ Biermann C, Loken A, Riise R. Comparison of spiramycin anddoxycycline in the treatment of lower respiratory infections in generalpractice. Journal of Antimicrobial Chemotherapy 1988;22(Suppl B):155–8.

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):491–501.

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;5:724–32.

Chodosh 1991 {published data only}∗ Chodosh S. Temafloxacin compared with ciprofloxacin in mild tomoderate lower respiratory tract infections in ambulatory patients.Chest 1991;100:1497–502.

Dark 1991 {published data only}∗ Dark D. Multicenter evaluation of azithromycin and cefaclor inacute lower respiratory tract infections. American Journal of Medicine

1991;91(Suppl 3A):31–5.

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 Disease 1992;15(Suppl):85–9.

De Cock 1988 {published data only}∗ De Cock L, Poels R. Comparison of spiramycin with erythromycinfor lower respiratory tract infections. Journal of Antimicrobial Che-

motherapy 1988;22(Suppl B):159–63.

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 Chemotherapy 2006;50(4):1164–9.

Donowitz 1997 {published data only}

Donowitz GR, Brandon ML, Salisbury JP, Harman CP, Tipping DM,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 Therapeutics 1997;19(5):936–53.

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 Chemotherapy 1997;41(9):1965–72.


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):67–74.


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 and

Chemotherapy 2004;48(9):3323–31.

Fogarty 1999 {published data only}

Fogarty, C, Grossman C, Williams J, Haverstock D, Church D for theCommutiy-Acquired Pneumonia Study Group. Efficacy and safetyof moxifloxacin vs clarithromycin for community-acquired pneumo-nia. Infections in Medicine 1999;16:748–63.



Fogarty 2002 {published data only}

Fogarty CM, Cyganowski M, Palo WA, Hom RC, Craig WA. A com-parison of cefditoren pivoxil and amoxicillin/ clavulanate in the treat-ment of community-acquired pneumonia: a multicenter, prospec-tive, randomized, investigator-blinded, parallel-group study. Clini-

cal Therapeutics 2002;24(11):1854–70.

Fong 1995 {published data only}∗ Fong IW, Laforge J, Dubois J, Small D, Grossman R, Zakhari R, etal.Clarithromycin versus cefaclor in lower respiratory tract infections.Clinical and Investigative Medicine 1995;18:131–8.

Gotfried 2002 {published data only}

Gotfried MH, 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 thetreatment of community-acquired pneumonia. Clinical Therapeutics

2002;24(5):736–51.

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):93–101.

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):378–86.

Higuera 1996 {published data only}∗ Higuera F, Hidalgo H, Feris J, Giguere G, Collins JJ. Comparisonof oral cefuroxime axetil and oral amoxycillin/clavulanate in the treat-ment of community-acquired pneumonia. Journal of Antimicrobial

Chemotherapy 1996;37:555–64.

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 comparedto oral clarithromycin in the treatment of community-acquired pneu-monia. Respiratory Medicine 2001;95(7):553–64.

Hoepelman 1993 {published data only}∗ Hoepelman AIM, Sips AP, van Helmond JLM, van Barneveld PWC,Neve AJ, et al.A single-blind comparison of three-day azithromycinand ten-day co-amoxiclav treatment of acute lower respiratory tractinfections. Journal of Antimicrobial Chemotherapy 1993;31(Suppl E):147–52.

Hoepelman 1998 {published data only}

Hoepelman IM, Möllers MJ, van Schie MH, Greefhorst APM,Schlösser NJJ, Sinninghe Damsté EJ, et al.A short (3-day) course ofazithromycin tablets versus a 10-day course of amoxycillin-clavulanicacid (co-amoxiclav) in the treatment of adults with lower respira-tory tract infections and effects on long-term outcome. International

Journal of Antimicrobial Agents 1998;9:141–6.

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 Disease 1991;14:101–5.

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. Current

Therapeutic Research, Clinical and Experimental 1990;48(5):841–52.

Kinasewitz 1991 {published data only}

Kinasewitz, Wood RG. Azithromycin versus cefaclor in the treatmentof acute bacterial pneumonia. European Journal of Clinical Microbi-

ology and Infectious Diseases 1991;10(10):872–7.

Lacny 1972 {published data only}∗ Lacny J. A comparison of oral therapy with clindamycin and peni-cillin G in common gram-positive infections. Current Therapeutic

Research 1972;14(1):26–30.

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):115–24.

Leophonte 2004 {published data only}

Léophonte P, File T, Feldman C. Gemifloxacin once daily for 7 dayscompared to amoxicillin/clavulanic acid thrice daily for 10 days forthe treatment of community-acquired pneumonia of suspected pneu-mococcal origin. Respiratory Medicine 2004;98(8):708–20.

Liipo 1994 {published data only}∗ Liippo K, Tala E, Puolijoki H, Brückner OJ, Rodrig J, Smits JPH.A comparative study of dirithromycin and erythromycin in bacterialpneumonia. Journal of Infectious Diseases 1994;28:131–9.

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 Journal 1995;8:1999–2007.

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):135–43.

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):512–20.

Lode 2004b {published data only}

Lode H, Aronkyto T, Chuchalin AG, Jaaskevi M, Kahnovskii I,Kleutgens K, et al.A randomised, 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):403–8.

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 Practice

1996;46(407):357–60.



Moola 1999 {published data only}

Moola S, Hagberg L, Churchyard GA, Dylewski JS, Sedani S, StaleyH. A multicenter study of grepafloxacin and clarithromycin in thetreatment of patients with community-acquired pneumonia. Chest

1999;116(4):974–83.

Müller 1992 {published data only}∗ Müller O, Wettich K. Comparison of loracarbef (LY 163892) ver-sus amoxicillin in the treatment of bronchopneumonia and lobarpneumonia. Infection 1992;20(3):176–82.

NAPSG 1997 {published data only}∗ The Nordic Atypical Pneumona Study Group. Atypical pneumonain the Nordic countires: aetiology and clincal results of a trial com-paring fleroxacin and doxycyclin. Journal of Antimicrobial Chemo-

therapy 1997;39:499–508.

Neu 1993 {published data only}∗ Neu HC, Chick TW. Efficacy and safety of clarithromycin com-pared to cefixime as outpatient treatment of lower respiratory tractinfections. Chest 1993;104:1393–9.

O’Doherty 1997 {published data only}

O’Doherty B, Dutchman DA, Pettit R, Maroli A. Randomized, dou-ble-blind, comparative study of grepafloxacin and amoxycillin in thetreatment of patients with community-acquired pneumonia. Journal

of Antimicrobial Chemotherapy 1997;40(Suppl A):73–81.

O’Doherty 1998 {published data only}∗ O’Doherty B, Muller O and the Azithromycin Study Group.Randomized, multicentre study of the efficacy and tolerance ofAzithromycin versus clarithromycin in the treatment of adults withmild to moderate community-acquired pneumonia. European Jour-

nal of Clinical Microbiology and Infectious Diseases 1998;17:828–33.

Pavie 2005 {published data only}

Pavie J, de la Prida JM, Diaz A, Saldias F. Assessment of the man-agement of commutiy-acquired pneumonia in adult outpatients[Manejo ambulatorio de la neumonía comunitaria del adulto en lasunidades de emergencia. Servicio de Salud Vina del Mar–Quillotade la V Región]. Revista Médica de Chile 2005;133:1322–30.

Petitpretz 2001 {published data only}

Petitpretz P, Arvis P, Marel M, Moita J, Urueta J, CAP5 Moxi-floxacin Study Group. Oral moxifloxacin vs high-dosage amoxi-cillin in the treatment of mild-to-moderate, community-acquired,suspected pneumococcal pneumonia in adults. Chest 2001;119(1):185–95.

Peugeot 1991 {published data only}∗ Peugeot RL, Lipsky BA, Hooton TM, Pecoraro RE. Treatmentof lower respiratory infections in outpatients with ofloxacin com-pred with erythromycin. Drugs in Experimental and Clinical Research

1991;17(5):253–7.

Pullman 2003 {published data only}

Pullman J, Champlin J, Vrooman PS Jr. Efficacy and tolerabil-ity of once-daily oral therapy with telithromycin compared withtrovafloxacin for the treatment of community-acquired pneumoniain adults. Internation Journal of Clinical Practice 2003;57(5):377–84.

Rahav 2004 {published data only}

Rahav G, Fidel J, Gibor Y, Shapiro M. Azithromycin versus compar-ative therapy for the treatment of community acquired pneumonia.International Journal of Antimicrobial Agents 2004;24(2):181–4.

Ramirez 1999 {published data only}

Ramirez J, Unowsky J, Talbot GH, Zhang H, Townsend L.Sparfloxacin vs clarithromycin in the treatment of community ac-quired pneumonia. Clinical Therapeutics 1999;21(1):103–17.

Rayman 1996 {published data only}∗ Rayman J, Krchnavý M, Balciar P, Duchon J, Fortuník J, Faith L,et al.Ofloxacin once daily versus twice daily in community-acquiredpneumonia and acute exacerbation of chronic bronchitis. Chemo-

therapy 1996;42:227–30.

Saito 2008 {published data only}

Saito A, Watanabe A, Aoki N, Niki Y, Kohno S, Kaku M, et al.PhaseIII double-blind comparative study of sitafloxacin versus tosufloxacinin patients with community-acquired pneumonia. Japanese Journal

of Chemotherapy 2008;56(Suppl 1):49–62.

Salvarezza 1998 {published data only}∗ Salvarezza CR, Mingrone H, Fachinelli H, Kijanczuk S. Compar-ison of roxithromycin with cefixime in the treatment of adults withcommunity-acquired pneumonia. Journal of Antimicrobial Chemo-

therapy 1998;41(Suppl B):75–80.

Schleupner 1988 {published data only}∗ Schleupner CJ, Anthony WC, Tan J, File TM, Lifland P, Craig W, etal.Blinded comparison of cefuroxime to cefaclor for lower respiratorytract infections. Archives of Internal Medicine 1988;148:343–8.

Siquier 2006 {published data only}

Siquier B, Sánchez-Alvarez J, García-Mendez E, Sabriá M, Santos J,Pallarés R, et al.Efficacy and safety of twice-daily pharmacokineticallyenhanced amoxicillin/clavulanate (2000/125 mg) in the treatmentof adults with community-acquired pneumonia in a country witha high prevalence of penicillin-resistant Streptococcus pneumoniae.Journal of Antimicrobial Chemotherapy 2006;57(3):536–45.

Sokol 2002 {published data only}

Sokol WN Jr, Sullivan JG, Acampora MD, Busman TA, NotarioGF. A prospective, double-blind, multicenter study comparing clar-ithromycin extended-release with trovafloxacin in patients with com-munity-acquired pneumonia. Clinical Therapeutics 2002;24(4):605–15.

Sopena 2004 {published data only}

Sopena N, Martínez-Vázquez C, Rodríguez-Suárez JR, Segura F, Va-lencia A, Sabrià M. Comparative study of the efficacy and toleranceof azithromycin versus clarithromycin in the treatment of commu-nity-acquired pneumonia in adults. Journal of Chemotherapy 2004;16(1):102–3.

Tellier 2004 {published data only}

Tellier G, Niederman MS, Nusrat R, Patel M, Lavin B. Clinicaland bacteriological efficacy and safety of 5 and 7 day regimens oftelithromycin once daily compared with a 10 day regimen of clar-ithromycin twice daily in patients with mild to moderate community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 2004;54(2):515–23.

Tilyard 1992 {published data only}∗ Tilyard MW, Dovey SM. A randomized double-blind controlledtrial of roxithromycin and cefaclor in the treatment of acute lowerrespiratory tract infections in general practice. Diagnostic Microbiol-

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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 Journal

2003;21(1):135–43.

Trémolières 1998 {published data only}

Trémolières 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 Clinical

Microbiology and Infectious Diseases 1998;17(6):447–53.

Trémolières 2005 {published data only}

Trémolières 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 l’efficacité et de latolérance de la pristinamycine vs amoxicilline dans le traitement despneumonies aigues communautaires de l’adulte]. Pathologie-Biologie

2005;53(8-9):503–10.

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 Therapeutics 2002;24(11):1840–53.

Zuck 1990 {published data only}

Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime prox-etil compared with ceftriaxone in vulnerable patients with bronchop-neumonia. Journal of Antimicrobial Chemotherapy 1990;26(SupplE):71–7.

Örtqvist 1996 {published data only}∗ Örtqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C, etal.Oral empiric treatment of community-acquired pneumonia: amulticenter, double-blind, randomized study comparing sparfloxacinwith roxithromycin. Chest 1996;110:1499–506.

Additional references

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ALAT 2004Grupo de trabajo de la Asociación Latinoamericana del Tórax(ALAT). Update to the Latin American Thoracic Association (ALAT)recommendations on community acquired pneumonia (article in En-glish). Archivos de Bronconeumología 2004;40(8):364–74.

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

ATS 2001American Thoracic Society. Guidelines for the management of adultswith community-acquired pneumonia. American Journal of Critical

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

ratory Medicine 1992;86:7–13.

BTS 2001British Thoracic Society. British Thoracic Society Guidelines forthe management of adults with community-acquired pneumonia.Thorax 2001;56(Suppl IV):1–64.

BTS 2004Macfarlane JT, Boldy D. 2004 update of BTS pneumonia guidelines:what’s new? [www.brit–thoracic.org.uk/guidelines (Accessed March16th 2009)]. Thorax 2004;59(5):364–6. [: Macfarlane 2004]

Carratala 2005Carratalà J, Fernández-Sabé N, Ortega L, Castellsagué X, Rosón B,Dorca J, et al.Outpatient care compared with hospitalization for com-munity-acquired pneumonia: a randomized trial in low-risk patients.Annals of Internal Medicine 2005;142(3):165–72.

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 Diseases 2000;31:383–421.

Foy 1979Foy HM, Cooney MK, Allan I, et al.Rates of pneumonia duringinfluenza epidemics in Seattle, 1964 to 1975. JAMA 1979;241:253–8.

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Respiratory Journal 1997;10:1530–4.

Hedlund 2005Hedlund J, Strålin 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 Diseases 2005;37(11-12):791–805.

Hoeffken 2005Höffken G, Lorenz J, Kern W, Welte T, Bauer T, Dalhoff K, etal.S3-guideline on ambulant acquired pneumonia and deep airwayinfections. Pneumologie 2005;59(9):612–64. [: German guidelines2005]

IDSA 2000Infectious Dieseases Society of America. Practice guidelines for themanagement of community-acquired pneumonia in adults. Clinical

Infectious Diseases 2000;31:347–82.

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Jokinen 1993Jokinen C, Heiskanen L, Juvonen H, et al.Incidence off community-acquired pneumonia in the population of four municipalities in east-ern Finland. Am J Epidemiol 1993;137:977–88.



JRS 2005Committee for The Japanese Respiratory Society guidelines for themanagement of respiratory infections. Guidelines for the manage-ment of community acquired pneumonia in adults, revised edition.Respirology 2006;11(Suppl 3):79–133.

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Systematic Reviews of Interventions. Chichester, UK: Wiley-Blackwell,2008.

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

Macfarlane 1984Macfarlane JT, Miller AC, Smith WHR, et al.Comparative radio-graphic features of community-acquired legionnaires’ disease, pneu-mococcal pneumonia, mycoplasma pneumonia and psittacosis. Tho-

rax 1984;39:28–33.

Maimon 2008Maimon N, Nopmaneejumruslers C, Marras TK. Antibacterial classis not obviously important in outpatient pneumonia: a meta-analysis.European Respiratory Journal 2008;31(5):1068–76.

Mandell 2007Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD,Dean NC, et al.Infectious Diseases Society of America/AmericanThoracic Society consensus guidelines on the management of com-munity-acquired pneumonia in adults. Clinical Infectious Diseases

2007;44(Suppl 2):S27–72.

Memish 2007Memish ZA, Arabi YM, Ahmed QA, Shibl AM, Niederman MS,GCC CAP Working Group. Executive summary of the Gulf Coop-eration Council practice guidelines for the management of commu-nity-acquired pneumonia. Journal of Chemotherapy 2007;19(Suppl1):7–11. [: Memish 2007]

Robenshtok 2008Robenshtok E, Shefet D, Gafter-Gvili A, Paul M, Vidal L,Leibovici L. Empiric antibiotic coverage of atypical pathogens

for community acquired pneumonia in hospitalized adults.Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI:10.1002/14651858.CD004418.pub3]

SATS 2007Working Group of the South African Thoracic Society. Managementof community-acquired pneumonia in adults. South African Medical

Journal 2007;97(12 Pt 2):1296–306.

Strålin 2007Strålin K, Goscinski G, Hedlund J, Lidman C, Spindler C, Or-tqvist A, et al.Management of adult patients with community-ac-quired pneumonia. Evidence-based guidelines from the Swedish In-fectious Diseases Association [Handläggning av samhälls–förvärvadpneumoni hos vuxna. Evidensbaserade riktlinjer från Svenska infek-tionsläkarföreningen. (Abridged version of the 2007 update; http://www.infektion.net/klinik/lunga/pneumoni/Vardprogram_Pneumoni_slutvers_2007.pdf (in Swedish). (Accessed March 23rd,2009)]. Lakartidningen 2008;105(38):2582–7.

Torres 1991Torres A, Serra-Batlles J, Ferrer A, et al.Severe community-acquiredpneumonia. Epidemiology and prognostic factors. American Review

of Respiratory Disease 1991;144:312–8.

Woodhead 1987Woodhead MA, Macfarlane JT, McCracken JS, et al.Prospectivestudy of the aetiology and outcome of pneumonia in the community.Lancet 1987;i:671–4.

Woodhead 2005Woodhead M, Blasi F, Ewig S, Huchon G, Leven M, Ortqvist A,et al.Guidelines for the management of adult lower respiratory tractinfections. European Respiratory Journal 2005;26(6):1138–80.

References to other published versions of this review

Bjerre 2004Bjerre LM, Verheij TJ, Kochen MM. Antibiotics for com-munity acquired pneumonia in adult outpatients. Cochrane

Database of Systematic Reviews 2004, Issue 2. [DOI:10.1002/14651858.CD002109.pub2]

∗ Indicates the major publication for the study



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 follow-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 at 2 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 from efficacy analyses, 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



Chien 1993

Methods Date and duration of study: January 1989 to June 1990. Follow-up: 4-6 weeks. 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 every 12 hours, or erythromycin stearate: 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



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



D’Ignazio 2005

Methods Date and duration of study: April 2003 to April 2004. Double-blind, double-dummy,non-inferiority trial, patients were recruited from 56 centers worldwide (Canada, Chile,India, Lithuania, Mexico, Peru, Russia, United States).

Participants 427 outpatients, 18 years or older, 423 patients received the study medication. Patientswere eligible for enrollment if they had a clinical diagnosis of mild to moderate CAP(signs and symptoms) and radiographic evidence of new pulmonary infiltrate. Patientsalso had to have a Fine Mortaliy risk class of I, II or III (< 90 points). Exclusion criteriaare clearly listed

Interventions Single, 2 g dose of azithromycin microspheres versus levofloxacin 500 mg once daily for7 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 13 to 21):azithro 89.7%, levo 93,7%, non significant difference. Treatment-related adverse effect:azi 19.9%, levo 12.3%, p = 0.0063, mainly gastrointestinal side effects

Notes Study funded by Pfizer Inc., 3 of 5 authors are employees of Pfizer

Risk of bias



Allocation concealment? Unclear because randomization method not specified






Free of other bias? Unclear Study funded by Pfizer Inc., 3 of 5 authors are employees ofPfizer



Drehobl 2005

Methods Date and duration of study: not specified. Double-blind, double-dummy, phase III trial,conducted in 58 outpatient centers worldwide (United States, 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 dailyfor 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



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: clinical re-sponse in the clinical per protocol population, on the basis of signs and symptoms ofCAP, assessed at end of treatment (EOT; 7 days after treatment initiation) teli 95.7% 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 extensive figures and tables are provided in English, so 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



Mathers Dunbar 2004

Methods Date and duration of study: May 1998 to Sept. 1999. Double-blind, double-dummy,parallel-group clinical trial conducted at 54 centers in 4 countries (United States, 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 an unrestricted educational grant from Aventis Phar-maceuticals

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



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



(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 Focus on bacterial pneumonia. Serologic evidence of M. pneumoniae or C. pneumoniae was an exclusion criterion;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 bacterial pneumonia (purulent sputum and leucocytosis were required for inclusion into study, patientswithout sputum pathogens were excluded from efficacy analysis, etc.)



(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. pneumoniae pneumonia 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 Örtqvist 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

Müller 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

O’Doherty 1997 Grepafloxacin withdrawn from worldwide market in October 1999 due to risk of severe arrhythmias

O’Doherty 1998 Open-label study



(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 daily”group, 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)



(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

Trémolières 1998 Trovafloxacin withdrawn from market due to severe hepatotoxicity

Trémolières 2005 Focus on bacterial pneumonia

van Zyl 2002 Focus on bacterial pneumonia; purulent sputum sample required; patients with serologic evidence of Mycoplasma

pneumoniae or Chlamydophila pneumoniae were 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

Örtqvist 1996 Patients had CAP but were treated exclusively as inpatients

bid: twice a daytid: three times a day



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]



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 Odds Ratio (M-H, Fixed, 95% CI) 0.99 [0.58, 1.68]

Analysis 1.1. Comparison 1 Erythromycin versus clarythromycin, Outcome 1 Clinical success.

Review: Antibiotics for community acquired pneumonia in adult outpatients

Comparison: 1 Erythromycin versus clarythromycin

Outcome: 1 Clinical success

Study or subgroup Clarythromycin Erythromycin Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Anderson 1991 63/64 39/43 21.2 % 6.46 [ 0.70, 59.94 ]

Chien 1993 89/92 78/81 78.8 % 1.14 [ 0.22, 5.82 ]

Total (95% CI) 156 124 100.0 % 2.27 [ 0.66, 7.80 ]Total events: 152 (Clarythromycin), 117 (Erythromycin)

Heterogeneity: Chi2 = 1.53, df = 1 (P = 0.22); I2 =35%

Test for overall effect: Z = 1.30 (P = 0.19)

0.001 0.01 0.1 1 10 100 1000

Favours erythromycin Favours clarythromycin



Analysis 1.2. Comparison 1 Erythromycin versus clarythromycin, Outcome 2 Bacteriological success.



Outcome: 2 Bacteriological success



Anderson 1991 8/9 5/5 27.5 % 0.52 [ 0.02, 15.06 ]

Chien 1993 23/26 17/17 72.5 % 0.19 [ 0.01, 3.96 ]


Heterogeneity: Chi2 = 0.19, df = 1 (P = 0.67); I2 =0.0%


0.001 0.01 0.1 1 10 100 1000


Analysis 1.3. Comparison 1 Erythromycin versus clarythromycin, Outcome 3 Radiological success.



Outcome: 3 Radiological success



Anderson 1991 55/61 38/42 55.1 % 0.96 [ 0.25, 3.65 ]

Chien 1993 88/92 78/81 44.9 % 0.85 [ 0.18, 3.90 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.4. Comparison 1 Erythromycin versus clarythromycin, Outcome 4 Drug-related adverse events.



Outcome: 4 Drug-related adverse events



Anderson 1991 15/96 37/112 33.9 % 0.38 [ 0.19, 0.74 ]

Chien 1993 34/133 76/135 66.1 % 0.27 [ 0.16, 0.45 ]



Test for overall effect: Z = 5.68 (P < 0.00001)

0.01 0.1 1 10 100

Favours clarithromycin Favours erythromycin

Analysis 2.1. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 1 Clinical success.


Comparison: 2 Azithromycin microspheres versus levofloxacin


Study or subgroup Azithromycin microspheres Levofloxacin Odds Ratio Weight Odds Ratio


D’Ignazio 2005 156/174 177/189 100.0 % 0.59 [ 0.27, 1.26 ]

Total (95% CI) 174 189 100.0 % 0.59 [ 0.27, 1.26 ]Total events: 156 (Azithromycin microspheres), 177 (Levofloxacin)

Heterogeneity: not applicable


0.1 0.2 0.5 1 2 5 10

Favours levofloxacin Favours azithromycin microspheres



Analysis 2.2. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 2 Bacteriological

success.






D’Ignazio 2005 97/107 120/130 100.0 % 0.81 [ 0.32, 2.02 ]




0.01 0.1 1 10 100

Favours levofloxacin Favours azithromycin microspheres

Analysis 2.3. Comparison 2 Azithromycin microspheres versus levofloxacin, Outcome 3 Drug-related

adverse events.






D’Ignazio 2005 42/211 26/212 100.0 % 1.78 [ 1.04, 3.03 ]




0.5 0.7 1 1.5 2

Favours azithromycin microspheres Favours levofloxacin



Analysis 3.1. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 1 Clinical success.


Comparison: 3 Azithromycin microspheres versus clarithromycin


Study or subgroup Azithromycin microspheres Clarithromycin Odds Ratio Weight Odds Ratio


Drehobl 2005 187/202 198/209 100.0 % 0.69 [ 0.31, 1.55 ]

Total (95% CI) 202 209 100.0 % 0.69 [ 0.31, 1.55 ]Total events: 187 (Azithromycin microspheres), 198 (Clarithromycin)



0.01 0.1 1 10 100

Favours clarithromycin Favours azithromycin microspheres

Analysis 3.2. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 2 Bacteriological

success.






Drehobl 2005 123/134 153/169 100.0 % 1.17 [ 0.52, 2.61 ]




0.01 0.1 1 10 100

Favours clarithromycin Favours azithromycin microspheres



Analysis 3.3. Comparison 3 Azithromycin microspheres versus clarithromycin, Outcome 3 Drug-related

adverse events.






Drehobl 2005 65/247 62/252 100.0 % 1.09 [ 0.73, 1.64 ]




0.5 0.7 1 1.5 2

Favours azithromycin microspheres Favours clarithromycin

Analysis 4.1. Comparison 4 Telithromycin versus clarithromycin, Outcome 1 Clinical success.


Comparison: 4 Telithromycin versus clarithromycin


Study or subgroup Telithromycin Clarithromycin Odds Ratio Weight Odds Ratio


Mathers Dunbar 2004 143/162 138/156 100.0 % 0.98 [ 0.49, 1.95 ]

Total (95% CI) 162 156 100.0 % 0.98 [ 0.49, 1.95 ]Total events: 143 (Telithromycin), 138 (Clarithromycin)



0.1 0.2 0.5 1 2 5 10

Favours clarithromycin Favours telithromycin



Analysis 4.2. Comparison 4 Telithromycin versus clarithromycin, Outcome 2 Bacteriological success.






Mathers Dunbar 2004 28/32 29/30 100.0 % 0.24 [ 0.03, 2.29 ]




0.002 0.1 1 10 500

Favours clarithromycin Favours telithromycin

Analysis 4.3. Comparison 4 Telithromycin versus clarithromycin, Outcome 3 Drug-related adverse effects.



Outcome: 3 Drug-related adverse effects



Mathers Dunbar 2004 85/221 62/222 100.0 % 1.61 [ 1.08, 2.40 ]




0.5 0.7 1 1.5 2

Favours telithromycin Favours clarithromycin



Analysis 5.1. Comparison 5 Telithromycin versus levofloxacin, Outcome 1 Clinical success.


Comparison: 5 Telithromycin versus levofloxacin


Study or subgroup Telithromycin Levofloxacin Odds Ratio Weight Odds Ratio


Kohno 2003 66/69 52/54 100.0 % 0.85 [ 0.14, 5.25 ]

Total (95% CI) 69 54 100.0 % 0.85 [ 0.14, 5.25 ]Total events: 66 (Telithromycin), 52 (Levofloxacin)



0.001 0.01 0.1 1 10 100 1000

Favours levofloxacin Favours telithromycin

Analysis 5.2. Comparison 5 Telithromycin versus levofloxacin, Outcome 2 Bacteriological success.






Kohno 2003 34/46 40/40 100.0 % 0.03 [ 0.00, 0.60 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 5.3. Comparison 5 Telithromycin versus levofloxacin, Outcome 3 Clinical efficacy against H.influenzae.



Outcome: 3 Clinical efficacy against H. influenzae



Kohno 2003 30/31 13/15 100.0 % 4.62 [ 0.38, 55.51 ]




0.001 0.01 0.1 1 10 100 1000


Analysis 5.4. Comparison 5 Telithromycin versus levofloxacin, Outcome 4 Drug-related adverse effects.



Outcome: 4 Drug-related adverse effects



Kohno 2003 42/125 39/115 100.0 % 0.99 [ 0.58, 1.68 ]




0.5 0.7 1 1.5 2

Favours telithromycin Favours levofloxacin



A P P E N D I C E S

Appendix 1. Embase.com search strategy

1. ’antibiotic agent’/exp AND [embase]/lim#2. antibiotic*:ti,ab AND [embase]/lim#3. #1 OR #2#4. ’pneumonia’/exp AND [embase]/lim#5. ’communicable disease’/exp AND [embase]/lim#7. ’community acquired pneumonia’/exp AND [embase]/lim#8. #4 AND #5#9. ’community acquired pneumonia’:ti,ab AND [embase]/lim#10. #7 OR #8 OR #9#11. #3 AND #10#12. ’randomized controlled trial’/exp OR ’double blind procedure’/exp OR ’single blind procedure’/exp OR’crossover procedure’/exp AND [embase]/lim#13. random*:ti,ab OR factorial*:ti,ab OR crossover*:ti,ab OR ’cross over’:ti,ab OR assign*:ti,ab OR allocat*:ti,ab OR volunteer*:ti,abOR ’single blind’:ti,ab OR ’single blinding’:ti,ab OR ’single blinded’:ti,ab OR ’double blind’:ti,ab OR ’double blinded’:ti,ab OR ’doubleblinding’:ti,ab AND [embase]/lim#14. #12 OR #13#15. #11 AND #14

W H A T ’ S N E W

Last assessed as up-to-date: 6 July 2009.

20 February 2009 New search has been performed Searches conducted.

20 February 2009 New citation required but conclusions have notchanged

Four new studies included.

H I S T O R Y

Protocol first published: Issue 2, 2000

Review first published: Issue 2, 2004

26 February 2004 New search has been performed Review first published, Issue 2, 2004



C O N T R I B U T I O N S O F A U T H O R S

Lise M. Bjerre (LMB) screened abstracts and full articles for inclusion into the review, decided, in agreement with Theo J. M. Verheij(TJMV), which articles to include, extracted the data from these articles, performed the quantitative analyses, wrote the text, tablesand figures of the review, and made modifications to the review based on the comments of peer and consumer referees.

Michael M. Kochen (MMK) co-wrote the protocol, defined the search strategy and did a preliminary screening of abstracts for inclusioninto the review. He also critically reviewed and edited the text of the review at various stages in its development.

Theo J. M. Verheij (TJMV) co-wrote the protocol, screened abstracts and full articles for inclusion into the study and decided, inagreement with LMB, which articles to include. He also critically reviewed and edited the text of the review at various stages in itsdevelopment.

D E C L A R A T I O N S O F I N T E R E S T

None of the authors have any potential conflicts of interest to declare.

S O U R C E S O F S U P P O R T

Internal sources

• None, Not specified.

External sources

• None, Not specified.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

In our first review of this topic published in 2004 (Bjerre 2004), as per protocol we contacted the following antibiotics manufacturers toidentify any additional published or unpublished studies: Abbott, AstraZeneca, Aventis, Boehringer-Ingelheim, Bristol-Myers-Squibb,GlaxoSmithKline, Hoffmann-LaRoche, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pharmacia, Sanofi, and Yamanouchi.This search yielded no new studies. Starting with this update, we decided to no longer contact pharmaceutical companies to ask aboutunpublished studies. 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; and second, because this search strategy provides an unfair advantage to unpublished studiescarried out by industry, as opposed to government or academia, where an equivalent search strategy is not readily available.

In this update, we excluded studies of antibiotics that have been withdrawn from the market or are no longer licensed for the treatmentof outpatients with CAP, due to severe adverse effects. For example, studies assessing the following fluoroquinolones were excluded:gatifloxacin, grepafloxacin, sparfloxacin, temafloxacin and trovafloxacin.

Finally, in this update, we applied the new risk of bias tools (tables, summary figures and graphs) newly made available in RevManVersion 5. These tools were not available at the time our protocol and our first review (Bjerre 2004) were written and published.



I N D E X T E R M S

Medical Subject Headings (MeSH)

Anti-Bacterial Agents [∗therapeutic use]; Community-Acquired Infections [drug therapy]; Pneumonia [∗drug therapy]; RandomizedControlled Trials as Topic

MeSH check words

Adult; Humans



Documents

Antibiotics for community acquired pneumonia in adult ... · [Intervention Review] Antibiotics for community acquired pneumonia in adult outpatients Lise M Bjerre1, Theo JM Verheij2,