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Cochrane Database of Systematic Reviews

Empiric antibiotic coverage of atypical pathogens for
community-acquired pneumonia in hospitalized adults
(Review)
Eliakim-Raz N, Robenshtok E, Shefet D, Gafter-Gvili A, Vidal L, Paul M, Leibovici L

Eliakim-Raz N, Robenshtok E, Shefet D, Gafter-Gvili A, Vidal L, Paul M, Leibovici L.
Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults.
Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD004418.
DOI: 10.1002/14651858.CD004418.pub4.

www.cochranelibrary.com

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Atypical versus non-aytpical, Outcome 1 Mortality per antibiotic (ABX) treatment. . .
Analysis 1.2. Comparison 1 Atypical versus non-aytpical, Outcome 2 Mortality per age. . . . . . . . . . .
Analysis 1.3. Comparison 1 Atypical versus non-aytpical, Outcome 3 Mortality - per geographical area. . . . . .
Analysis 1.4. Comparison 1 Atypical versus non-aytpical, Outcome 4 Mortality per allocation generation. . . . .
Analysis 1.5. Comparison 1 Atypical versus non-aytpical, Outcome 5 Mortality per allocation concealment. . . .
Analysis 1.6. Comparison 1 Atypical versus non-aytpical, Outcome 6 Mortality per blinding. . . . . . . . .
Analysis 1.7. Comparison 1 Atypical versus non-aytpical, Outcome 7 Mortality - ITT analysis. . . . . . . . .
Analysis 1.8. Comparison 1 Atypical versus non-aytpical, Outcome 8 Clinical failure per antibiotic (ABx) treatment.
Analysis 1.9. Comparison 1 Atypical versus non-aytpical, Outcome 9 Clinical failure per age. . . . . . . . .
Analysis 1.10. Comparison 1 Atypical versus non-aytpical, Outcome 10 Clinical failure per geographical area. . . .
Analysis 1.11. Comparison 1 Atypical versus non-aytpical, Outcome 11 Clinical failure per allocation generation. .
Analysis 1.12. Comparison 1 Atypical versus non-aytpical, Outcome 12 Clinical failure per allocation concealment. .
Analysis 1.13. Comparison 1 Atypical versus non-aytpical, Outcome 13 Clinical failure per blinding. . . . . . .
Analysis 1.14. Comparison 1 Atypical versus non-aytpical, Outcome 14 Clinical failure - ITT analysis. . . . . .
Analysis 1.15. Comparison 1 Atypical versus non-aytpical, Outcome 15 Clinical failure - pneumococcal pneumonia.
Analysis 1.16. Comparison 1 Atypical versus non-aytpical, Outcome 16 Clinical failure - atypical pathogens. . . .
Analysis 1.17. Comparison 1 Atypical versus non-aytpical, Outcome 17 Clinical failure - Legionella pneumophilae. .
Analysis 1.18. Comparison 1 Atypical versus non-aytpical, Outcome 18 Clinical failure per sponsorship. . . . . .
Analysis 1.19. Comparison 1 Atypical versus non-aytpical, Outcome 19 Bacteriological failure. . . . . . . . .
Analysis 1.20. Comparison 1 Atypical versus non-aytpical, Outcome 20 Bacteriological failure per allocation generation.
Analysis 1.21. Comparison 1 Atypical versus non-aytpical, Outcome 21 Adverse events - total. . . . . . . . .
Analysis 1.22. Comparison 1 Atypical versus non-aytpical, Outcome 22 Adverse events - gastrointestinal events. . .
Analysis 1.23. Comparison 1 Atypical versus non-aytpical, Outcome 23 Adverse events - requiring discontinuation of
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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i

[Intervention Review]

Empiric antibiotic coverage of atypical pathogens for
community-acquired pneumonia in hospitalized adults
Noa Eliakim-Raz1 , Eyal Robenshtok1 ,2 , Daphna Shefet1, Anat Gafter-Gvili1 , Liat Vidal1 , Mical Paul3 , Leonard Leibovici1
1 Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. 2 Sackler School of Medicine, Tel Aviv
University, Ramat Aviv and Endocrinology and Metabolism Institute, Petah Tikva, Israel. 3 Infectious Diseases Unit, Sackler Faculty of
Medicine, Tel Aviv, Israel

Contact address: Noa Eliakim-Raz, Department of Medicine E, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah
Tikva, 49100, Israel. noaeliakim@gmail.com.
Editorial group: Cochrane Acute Respiratory Infections Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2012.
Review content assessed as up-to-date: 16 April 2012.
Citation: Eliakim-Raz N, Robenshtok E, Shefet D, Gafter-Gvili A, Vidal L, Paul M, Leibovici L. Empiric antibiotic coverage of
atypical pathogens for community-acquired pneumonia in hospitalized adults. Cochrane Database of Systematic Reviews 2012, Issue 9.
Art. No.: CD004418. DOI: 10.1002/14651858.CD004418.pub4.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Community-acquired pneumonia (CAP) is caused by various pathogens, traditionally divided into ’typical’ and ’atypical’. Initial
antibiotic treatment of CAP is usually empirical, customarily covering both typical and atypical pathogens. To date, no sufficient
evidence exists to support this broad coverage, while limiting coverage is bound to reduce toxicity, resistance and expense.
Objectives
The main objective was to estimate the mortality and proportion with treatment failure using regimens containing atypical antibiotic
coverage compared to those that had typical coverage only. Secondary objectives included the assessment of adverse events.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2012 which includes the Acute Respiratory
Infection Group’s Specialized Register, MEDLINE (January 1966 to April week 1, 2012) and EMBASE (January 1980 to April 2012).
Selection criteria
Randomized controlled trials (RCTs) of adult patients hospitalized due to CAP, comparing antibiotic regimens with atypical coverage
(quinolones, macrolides, tetracyclines, chloramphenicol, streptogramins or ketolides) to a regimen without atypical antibiotic coverage.
Data collection and analysis
Two review authors independently assessed the risk of bias and extracted data from included trials. We estimated risk ratios (RRs) with
95% confidence intervals (CIs). We assessed heterogeneity using a Chi2 test.
Main results
We included 28 trials, encompassing 5939 randomized patients. The atypical antibiotic was administered as monotherapy in all but three
studies. Only one study assessed a beta-lactam combined with a macrolide compared to the same beta-lactam. There was no difference
in mortality between the atypical arm and the non-atypical arm (RR 1.14; 95% CI 0.84 to 1.55), RR < 1 favors the atypical arm.
Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Clinical success for the atypical arm was significantly higher for Legionella pneumophilae (L. pneumoniae) is the leading cause of CAP. Mycoplasma pneumoniae (M. The main ’typical’ agent causing CAP is Streptococcus pneumoniae (S. Ltd.70. PLAIN LANGUAGE SUMMARY Initial antibiotic treatment for coverage of ’atypical’ pathogens for community-acquired pneumonia in hospitalized adults Pneumonia is a serious lung infection and is usually treated with antibiotics. There are limitations to this review in that a single study compared the addition of the atypical antibiotic to a typical antibiotic. There was no significant difference between the groups in the frequency of total adverse events. especially those designated ’atypical pathogens’ (Legionella pneumophilae (L. by which 30-day mortality has been estimated up to 17%. respiratory rate. gastrointestinal events were less common in the atypical arm.1% for pa- tients stratified to risk class IV and V. BACKGROUND Description of the condition Community acquired pneumonia (CAP) is a common clinical disease with considerable mortality and overwhelming economic burden. 95% CI 0. We included 28 trials. Authors’ conclusions No benefit of survival or clinical efficacy was shown with empirical atypical coverage in hospitalized patients with CAP.92). pneumonia contracted outside healthcare settings) are traditionally divided into ’typical’ and ’atypical’. While typical coverage is essential. It is usually not possible to determine which of the many potential agents is the cause of CAP. the major question in clinical practice. four or five risk factors.3% and 31. gastrointestinal events were less common in the atypical arm (RR 0. 21 of the 27 studies were sponsored by pharmaceutical companies of which all but one was conducted by the manufacturer of the atypical antibiotic. pneumophila). customarily covering both typical and atypical bacteria. For the regimens tested. Given the persisting inconsistency between current guidelines for treatment of pneumonia and the available evidence. involving 5939 patients. respectively (Fine 1997). comparing beta-lactam monotherapy to the same combined with a macrolide. urea. blood pressure and age).mortality and clinical efficacy. Atypical bacteria include. The Pneumonia Patient Outcomes Research Team (PORT) has developed a prediction scheme utilizing clinical variables to stratify CAP patients into five mortality risk classes. no advantage was found for regimens covering atypical bacteria in the major outcomes tested . pneumophilae) and non-significantly lower for pneumococcal pneumonia. respectively (Lim 2003). most compared a single atypical antibiotic to a single typical antibiotic. varies with geographical area. so that antibiotic treatment is empirical. no significant heterogeneity was detected in the analyses. However. pneumophilae). Although Streptococcus pneumoniae (S. pneumoniae).5% and 57% for patients with three. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. should be performed. This Cochrane review looked at trials comparing antibiotic regimens with atypical coverage to those without. There was no significant difference between the groups in the frequency of (total) adverse events. Seventeen of the 27 trials were open label. limited to hospitalized adults with CAP. The CURB-65 score is based on five easily measurable factors (confusion. Published by John Wiley & Sons. pneumoniae) and Chlamydia pneumoniae (C. In the previous version of this review we showed that there was no advantage to the atypical arm.53 to 0. Bacteria which cause community-acquired pneumonia (CAP. frequency of other agents. which disappeared when evaluating methodologically high quality studies alone. pneumoniae). However. pneumoniae) and Chlamydia pneumoniae (C. pneumoniae)). or those requiring discontinuation of treatment. by which 30day mortality has been estimated up to 9. This conclusion relates mostly to the comparison of quinolone monotherapy to beta-lactams. or those requiring discontinuation of treatment. we undertook to update this systematic review. each dictating a different antibiotic treatment. 2 . Further trials. the necessity of the atypical coverage has not been proven.The atypical arm showed an insignificant trend toward clinical success and a significant advantage to bacteriological eradication. Mycoplasma pneumoniae (M. Legionella pneumophila (L. 41. Although the trials assessed different antibiotics.

i. in hospitalized patients in the UK (higher.85). a lower failure rate in L. pneumophilae. we undertook to update this systematic review of hospitalized adults with CAP. Published by John Wiley & Sons.age groups and diagnostic means available. in order to evaluate the efficacy and need of atypical coverage in this subset of patients.e. 3 . No trials comparing an atypical antibiotic in combination with a non-atypical antibiotic (the regimen currently recommended in all guidelines) versus the non-atypical antibiotic alone were found. To evaluate mortality and proportion with treatment failure using regimens containing atypical antibiotic coverage compared to those without (typical coverage only). or a single agent with broad coverage. The American Thoracic Society (ATS) reserves recommendation of atypical coverage to clinical circumstances. Lim 2009.97. Moreover. hospitalized patients on a general ward and hospitalized patients in intensive care units (ICUs). this broad coverage might be at the expense of efficacy of pneumococcal coverage (Johansen 2000). Why it is important to do this review How the intervention might work Most trials comparing different treatment arms were performed to evaluate a specific drug. and equivalence for M. Hedlund 2005. frequently a macrolide or a fluoroquinolone. The British Thoracic Society (BTS) guidelines support this recommendation in view of a high percentage of atypical pathogens. Description of the intervention All major guidelines for treatment of CAP divide patients into three subgroups: outpatients. a RCT by Malhotra-Kumar 2007 showed by obtaining pharyngeal swabs from patients before and after treatment with macrolides versus placebo. Expanding coverage to atypical pathogens is bound to increase toxicity. should this coverage be routinely included? Furthermore. Niederman 2001. The atypical arm showed an insignificant trend toward clinical success and a significant advantage to bacteriological eradication. particularly L. In view of these data. Ltd. All guidelines support extensive antibiotic coverage for ICU patients. Suggested regimens include extended spectrum cephalosporins. we showed that the major pitfall of such observational studies is the marked difference between patients prescribed non-atypical coverage and those prescribed a regimen including atypical coverage. The causing agent cannot be clearly sorted to either group by any clinical. Woodhead 2011). Admittedly. beta-lactams (BLs) or beta-lactam/beta-lactamase inhibitors (BL/BLIs). A large systematic review that included observational studies. 0. all combined with macrolides. Tremolieres 1998). There was no difference in mortality between the atypical arm and the non-atypical arm. Mandell 2000. Major guidelines recommend in general. If patients improve regardless of atypical coverage. initial antibiotic treatment of CAP is largely empirical. pneumoniae and C. radiological or laboratory parameter (Donowitz 2000. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. OBJECTIVES 1. ical agents in the treatment of pneumonia really is. as there have been only few randomized controlled trials (RCTs) assessing CAP treatment protocols. and therefore the effect of prescribing macrolides is of ecological importance. A metaanalysis by Mills 2005 compared typical antibiotic coverage with BL to atypical coverage in non-severe pneumonia and found no advantage of antibiotics with atypical coverage over BLs (risk ratio (RR) 0. one must wonder what the true role of atyp- Given the persisting inconsistency between current guidelines and the available evidence. that macrolide use is the single most important driver of the emergence of macrolide resistance. a large percentage of atypical pneumonia cases have been shown to be dual infections. Mandell 2007. which disappeared when evaluating methodologically high quality studies alone. Furthermore. As the microbiological diagnosis is often unknown. However. an antibiotic regimen covering both typical and atypical pathogens in hospitalized CAP patients (BTS 2001. as the latter share intracellularity and are treated with specific antibiotic drugs.07). Significant reduction in mortality with atypical coverage was found in six of the eight selected studies. resistance and cost. Levison 2001). these guidelines are based on insufficient evidence. In the previous version of this systematic review (Robenshtok 2008).87 to 1. evaluated the superiority of atypical coverage to non-atypical coverage regimens (Oosterheert 2003). Distinctions between typical and atypical organisms is significant. pneumoniae.19 to 0. usually in combination with a typical pathogen (Donowitz 2000). although conceding elsewhere that clinical presentation cannot establish etiology. incidentally. Several of these trials (incidentally) compared regimens with and without atypical antibiotic coverage and found results to be generally equal (Aubier 1998.4. noting the prevalence as well as high mortality rates of pneumonia caused by L. Using propensity analysis. pneumophilae in that population. Woodhead 2005. a difference that precludes the comparison of these treatment regimens in observational studies (Paul 2007). these studies were nonexperimental cohort studies and outcomes showed several inconsistencies. fluoroquinolones. The review encompassed all trials which compared treatment regimens with versus without atypical antibiotic coverage. than in North America or Europe). 25 RCTs were found comparing a treatment regimen with atypical antibiotic coverage to one without such coverage. 95% CI 0. pneumophilae (RR 0.

Fluoroquinolone: including ciprofloxacin. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity. 2. 2012) and EMBASE (June 2007 to April 2012).com (accessed 16 April 2012). Issue 3. 2. 2. Published by John Wiley & Sons. Search methods for identification of studies Electronic searches For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012. We included other drugs within the antibiotic classes listed above. 6. azithromycin and clarithromycin. life-threatening. Types of outcome measures Primary outcomes 1. 2. 4. 1. We adapted the search for EMBASE (Appendix 2). Tetracyclines: including tetracycline.and precision-maximizing version (2008 revision) Ovid format (Lefebvre 2011). Ketolides: including telithromycin (ketek. defined as isolation of a pathogen or a colonizing micro-organism resistant to the study drug. Streptogramins: including pristinamycin and quinupristindalfopristin. We did not consider patients with major immunosuppressive state(s) (i. We used the search strategy in Appendix 1 to search CENTRAL and MEDLINE. Overall mortality at the end of the study and up to 30 days following the end of treatment. To evaluate mortality and treatment failure of regimens containing atypical antibiotic coverage for patients with identified S. roxithromycin. To evaluate the frequency of adverse effects associated with different types of antibiotic treatment. Regimens containing the following drugs. Number of patients who needed mechanical ventilation during hospital stay. Adverse events 1. as defined in the study. Any serious adverse events that were fatal. 3. HIV) for inclusion on this review. IV to oral or IV to IV). which includes the Acute Respiratory Infection Group’s Specialized Register. 5. www. We considered regimens lacking the above drugs as non-atypical coverage. we reviewed both oral and intravenous (IV) therapies (whether comparing oral to oral. 7. 6.thecochranelibrary. Mean duration to regaining previous functional capacity. We excluded trials with a dropout rate of over 30%. Any adverse events that required discontinuation of medication. Types of interventions Studies comparing antibiotic therapy with atypical coverage to antibiotic therapy without atypical coverage. moxifloxacin and grepafloxacin. Types of participants Adult patients hospitalized due to suspected CAP. recently withdrawn from Food and Drug Administration (FDA) approval) (Ross 2007. Secondary outcomes 1. Soreth 2007). ofloxacin. 5. Mean duration of hospital stay. malignancy. Number of patients excluded from outcome assessment after randomizations. Number of patients who developed superinfection or resistance to the studied drug. or requiring prolongation of existing hospitalization. pneumoniae. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. cystic fibrosis.Secondary objectives 1. Chloramphenicol. part of The Cochrane Library.e. To evaluate mortality and treatment failure of regimens containing atypical antibiotic coverage for patients with identified atypical pathogens. if identified by our searches. tigecycline and minocycline. To evaluate treatment failure with regimens containing atypical antibiotic coverage compared to those without (typical coverage only). Number of patients in whom bacteriological eradication was achieved. 4 . 3. 4. levofloxacin. trovafloxacin. MEDLINE (June 2007 to April Week 1. doxycycline. Macrolides: including erythromycin. Ltd. METHODS Criteria for considering studies for this review Types of studies Randomized controlled trials (RCTs) or quasi-RCTs. were considered atypical coverage. Number of patients with treatment failure. 4. 3. during or after antibiotic treatment.

2012). 5 . NER. ER in this current update) independently extracted data from the included trials. we searched ClinicalTrials. Data extraction and management Two review authors (DS. 6. dose and route of administration. ER. events requiring cessation of treatment. 2. 17. 3. Published by John Wiley & Sons. Measures of outcome. allocation concealment. events necessitating specific medical treatment. NER. Bacteriological eradication. abstract/proceeding. 21. ER. Mechanical ventilation. 9. or in cases of disagreement between the two review authors. Patients with S.table of random numbers. Intention-to-treat (ITT) analysis: performed.gov/) and FDA new drug approval documents for ongoing or unpublished trials (last searched 1 May. concealment. blinding. pneumococcus. with and without treatment modifications. per group. Severity of the disease (as classified by PORT). unclear. Adverse events: life-threatening events.We inspected the references of all identified studies for more trials.gov (www. Number of patients with documented typical pathogen. Assessment of risk of bias in included studies Two review authors (DS. 20. ER in this current update) assessed the risk of bias in trials fulfilling the review inclusion criteria. Overall mortality at end of study follow-up.clinicaltrials. Treatment failure: as defined in study. 19. Trial characteristics 1.e. 4. We discussed the data extraction. we contacted the first or corresponding author of each included trial and researchers active in the field for information regarding unpublished trials or complementary information on their own trial. we obtained the full article and inspected it independently. high risk of bias . Failure definition: including time of failure assessment. AG in the 2008 update (Robenshtok 2008). Number of patients with documented atypical pathogen. Searching other resources In addition. computer generated or coin tossing. high risk Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. ER in the original review (Shefet 2005). documented decisions and. A third review author (MP) extracted the data in case of disagreement between the two review authors. ER. We documented justifications for excluding studies from the review. Infection characteristics 10. Patient characteristics 8. Antibiotics type. unclear allocation concealment. 13. For possible relevant articles. 11. L. pneumophilae and Mycoplasma infections. ER in this current update) independently inspected each reference identified by the search and applied the inclusion criteria. efficacy analysis. 22. Trial sponsor. ER in the original review (Shefet 2005). 5. AG in the 2008 update (Robenshtok 2008). i. We identified trials by the name of the first author and year in which the trial was first published and ordered chronologically. We imposed no language or publication restrictions. AG in the 2008 update (Robenshtok 2008). free of selective reporting and free of other bias. 14. Treatment duration. Ltd. We used the ’Risk of bias’ tool (Higgins 2011) to assess methodological quality according to: sequence generation. checked and recorded the following data. Intervention characteristics 15. Publication status: published in journal. We graded randomization similarly (low risk . quasirandomized studies). we contacted the trial authors of the study for clarification. In addition to this. 16. unpublished. We assessed risk of bias by allocation concealment (low risk of bias adequate allocation concealment. Treatment modifications. Study follow-up duration. A third review author (MP) checked the article in cases where resolving disagreement by discussion was not possible. 7. Number of patients with infections caused by bacteria resistant to the administered antibiotic regimen. NER. A third review author (MP) was responsible for resolving disagreements. Year(s) and country/countries of study.inadequate allocation concealment. Data collection and analysis Selection of studies Two review authors (DS. We extracted. incomplete outcome data addressed. ER in the original review (Shefet 2005). extracted as number of patients per group 18. When required. blinding. possible to extract. 12. Age: mean or median. we contacted the trial authors for clarification. Number of patients randomized and evaluated. See Appendix 3 for details of previous searches. where necessary. Randomization methods: allocation generation.

blinding. Continuous data were not available for analysis in this review. sample size (up to 100 or more than 100 patients). 4. blinding. combination of quinolones and macrolides. Sensitivity analysis We performed sensitivity analyses in order to assess the robustness of the findings to different aspects of the trials’ methodology: allocation concealment (adequate or unclear). randomizations. North America. to analyze treatment effects on particular patient groups. Unit of analysis issues We analyzed studies with non-standard designs as follows.patient-blinded or no blinding. Geographical area: Europe. Cluster-randomized trials: this design would not be appropriate to evaluate antibiotic treatment for CAP. Characteristics of excluded studies. 1. Ltd. high risk . We did not include the data in the meta-analysis in cases of missing standard deviations.tripleblinded or double-blinded. non-sponsored. Results of the search In this 2012 update we retrieved 1301 records from the electronic database searches. We noted missing data in the ’Risk of bias’ table and performed a sensitivity analysis. 3. 6 . 2. and others..10). MEDLINE identified 594 records and the EMBASE search identified 823 records. and unclear when there was not enough data). Assessment of reporting biases We examined a funnel plot estimating the precision of trials (plots of logarithm of the RR for efficacy against the sample size) in order to estimate potential asymmetry. We evaluated all records for this update. We compared the fixed-effect model to a random-effects model when we observed significant heterogeneity between the trials (P < 0. 1. and others. Sponsoship: sponsored. exclusions after randomizations (reported or not reported). and legionella. We planned to analyze mortality and clinical failure only on the following subgroups. Dealing with missing data We contacted the original trial authors for missing data and requested additional information. RESULTS Description of studies See: Characteristics of included studies. Published by John Wiley & Sons. allocation concealment. 3. We did not evaluate further any studies in which the abstract suggested comparator antibiotic regimens incompatible with the inclusion Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Type of bacteria: S. Subgroup analysis and investigation of heterogeneity We performed subgroup analysis to assess the impact of the various treatment regimens. 6. 5. Assessment of heterogeneity We initially assessed heterogeneity in the results of the trials by inspection of graphical presentations and by calculating a test of heterogeneity (Chi2 test). If more than two groups were relevant. Age: under or over 65 years. Methodology: allocation generation. atypical pathogens. we combined groups to create a single pair-wise comparison. We assumed the data to be missing at random if additional data were unavailable. The CENTRAL search identified 304 records. We performed subgroup analyses in order to assess the impact of these possible sources of heterogeneity on the main results. Cross-over trials: this design would not be appropriate to evaluate antibiotic treatment for CAP. Studies with multiple treatment groups: we assessed intervention groups for relevance for our review. if trials were performed in different geographical areas and among different age groups or if per different drug regimens were assessed. macrolides. pneumoniae. Measures of treatment effect We analyzed dichotomous data by calculating the RR for each trial with the uncertainty in each result being expressed using 95% CIs. Type of antimicrobial agent in the atypical arm: quinolones. We had anticipated between-trial variation in estimation of morbidity and mortality for those patients who were hospitalized on a general ward or in ICU. and ITT analysis. and unclear sponsorship.anything else) and did the same for blinding (low risk . Data synthesis We used a fixed-effect model throughout the review. and to investigate for heterogeneity. and length of follow-up (up to one month or one to 12 months). 2.

In all but three studies. Pneumonia was defined by a combination of clinical signs. Petitpretz 2001. and in one case above 16 years (Tremolieres 1998). seven of whom responded. Kobayashi 1984) results were given and analyzed separately for the CAP population. Jardim 2003 of Petitpretz 2001). The atypical arm consisted of a quinolone in 21 studies. Eleven studies provided the percentage of patients with chronic obstructive pulmonary disease (COPD) (most others included the data in combination with other major co morbidities). without further clarification. The adjusted mean rate of bacteriological documentation was 47% in 20 studies that reported on the number of patients with bacteriological confirmation. Two studies were carried out in nursing homes (Hirata-Dulas 1991. Included studies Thirty publications fulfilled our inclusion criteria. Nine of 24 studies included patients with either nosocomial pneumonia (three studies) or bronchitis (six studies). Kalbermatter 2000. in addition to patients with CAP. Fifteen were performed in Europe. cephalosporin or a BL/BLI. The drugs were administered orally in all but eight studies. BL/BLI in three cases. The studies encompassed 5939 randomized patients. Miki 1984. In eight studies. Romanelli 2002). cephalosporin and AG (Fourrier 1986). Lephonte 2004). Ltd. macrolide was combined with either cephalosporin or an aminoglycoside (AG) (the two arms evaluated together. In one case quinolone was combined with teicoplanin (Rizzato 1997) and in the second. cephalosporin (nine. We similarly excluded studies of outpatients.criteria. Five studies did not report the mean age. cephalosporin (one) or to carbapenems (two. laboratory (white blood count. Lephonte 2004. a fifth study excluded suspected cases of atypical pneumonia (Tremolieres 1998). chest X-ray (sole criteria in two studies . three studies excluded severe infections (Carbon 1992. However. Vanderdonckt 1990 . the latter was done exclusively in gold-miners and subsequently evaluated only the proven cases. of which most switched to oral administration within a few days. 7 . three in Japanese. the excellent results in a senior population suggest a low rate of nosocomial pneumonia. one of which was probably originally in Chinese). Peterson 1988). the atypical arm was given as a monotherapy. Zeluff 1988). eight as quinolone monotherapy).Bohte 1995. Four studies included suspected pneumococcal infection (Bohte 1995. antistaphylococcal drugs.5%. In three. Twenty-one of the included trials were in English (including two abstracts. Rizzato 1997. Two were published as abstracts only. Vanderdonckt 1990). The specific antibiotic regimens used are detailed in the Characteristics of included studies table. Peterson 1988) and one was restricted per definition to patients over 70 (Romanelli 2002). Argentina and South Africa) or multicontinental. the third is an abstract assessing the addition of an atypical antibiotic to a BL (Hatipoglu 2010). Norrby 1998. Three trials included outpatients (Chuard 1989. In the ninth study (Khan 1989).quinolone. including BL. Sixteen were multicentered. patients were randomized to one of three arms . respiratory tract infections other than pneumonia and non-randomized studies. A fourth study (Lode 1995) stated that most patients were hospitalized. carbapenems in two cases and penicillin in one. two of which were preformed in nursing homes (Hirata-Dulas 1991. macrolide to penicillin (one). two in French. BL/BLI (one). Four studies were restricted to severe pneumonia (Fourrier 1986. The inclusion criteria in most studies were adults hospitalized with CAP. In two studies (Gleadhill 1986. nosocomial (hospital-acquired) infections. Thus. We identified three new studies in the 2012 update (Hatipoglu 2010. In contrast. In the remaining study. The number of participants was 100 or lower in nine trials and over 100 in 19 trials (range 40 to 808 participants). which were evaluated together (Kalbermatter 2000). Petitpretz 2001. a macrolide in five and pristinamycine in one study. Kohno 2011). The non-atypical arm consisted of BLs or cephalosporins: BL in nine cases. three in North America and ten in other countries (Japan. of whom 5444 patients could be evaluated for our primary outcome analysis (overall mortality). of which we excluded 38. Hirata-Dulas 1991. In six studies (Carbon 1992. Published by John Wiley & Sons. The mean age in 14 studies was under 65 and in nine studies over 65. over 90%) of the patients.and absent in five). carbapenem (one) or various non-atypical drugs (two). Another study compared the atypical arm to ’customary antibiotic therapy’. 12 studies) and/or bacteriological evidence (six studies. macrolide and a nonatypical regimen. Comparisons included: quinolone to BL (eight). and the two former arms were evaluated together (Lode 1995). quinolone and macrolide to BL/BLI (one). Hong-yun 2007. one cephalosporin was given intra-muscularly and the remaining drugs (15 studies) were administered intravenously. we included 28 trials in the review. Peterson 1988). cephalosporin in 11 cases. Two were substudies of a parallel publication (Allegra 1995 of Rizzato 1997. one in Spanish and one in German. the distribution of nosocomial pneumonia versus CAP was unclear. BL/BLI (one). Khan 1989. in one as a necessary condition) (Zeluff 1988). CAP patients consisted of over 60% (and in three of which. None of the studies included a comparison of COPD patients and/or smokers to non-COPD patients and/or non-smokers. One study had two non-atypical arms. Feldman 2001. one as macrolide monotherapy). We requested additional information from nearly all the trial authors. one cephalosporin and two BL/BLI (12 studies) were administered orally. All BLs. Tremolieres 1998). One study compared pristinamycine Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. All trials were restricted to adults (defined as aged above 18 years. We retrieved 66 publications for full-text inspection. The studies were performed between 1982 and 2011. Rizzato 1997). who comprised less than 25% of patients. up to a quarter of the patients were previously diagnosed with COPD. the number of COPD patients exceeded 30% (up to 52. Study details can be found in the Characteristics of included studies table.

defined by eradication. One was a retrospective observational cohort study. Twenty-one trials assessed bacteriological failure. Risk of bias in included studies The overall risk of bias is presented graphically in Figure 1 and summarized in Figure 2. The main outcome measure in all studies was clinical failure. including but not exclusively. Adverse events were addressed in all studies but the two abstracts. pneumonia. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Reasons for exclusion (occasionally more than one per study) included: studies addressing outpatients (11). Figure 1. double publication or pooled data (5). Excluded studies We retrieved 66 publications for full-text inspection. None of the studies named mortality as a primary outcome. allowance of atypical antibiotics in the non-atypical arm (12). some may have been nosocomial and the data were not always given separately per site of infection. Therefore. one of which found all tests negative (Vogel 1991). Only 10 studies performed serology tests for atypical pathogens. The percentage of pneumonia cases was usually small. Seven studies assessed duration of hospital stay. Six excluded studies investigated general severe infections. none reported standard deviations. Two studies failed to report the number of events per treatment arm (Hirata-Dulas 1991. Most took follow-up bacteriological specimens only from those patients found initially positive. One comparison of combination cephalosporinmacrolide to cephalosporin monotherapy was found. Ltd. Data relating specifically to antibiotic-associated diarrhoea were scarce and did not permit reliable evaluation. studies addressing only patients with bronchitis (2) and a dropout rate of over 30% (1). nosocomial infections (5). Some reported results per patients. Published by John Wiley & Sons. Six studies mandated radiological resolution for success definition and one asked for bacteriological eradication. Four studies were evaluated for atypical pathogens eradication rate while the other six did not fully report bacteriological success rates.with amoxycillin. of which we excluded 38 (Characteristics of excluded studies table). continuous data was not available for analysis in this review. the latter reporting the number of events in the comparator arms alone. whereas others by pathogens (occasionally more than one pathogen per patient). 8 . Two of these studies reported mean deviations. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies. Lode 1995). In four studies definition of success was unclear.

Figure 2. Ltd. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Published by John Wiley & Sons. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 9 .

No heterogeneity was seen for the overall comparison (Chi2 test = 8. while 11 provided data per-protocol. 12 reported a mortality rate between 0. Mortality was not a primary outcome and was usually reported in the safety analysis. Published by John Wiley & Sons. Rizzato 1997). The difference remained nonsignificant when evaluating quinolone therapy (RR 0. two of these reported mean duration stay (Hirata-Dulas 1991. permitting re-analysis by ITT assuming failure for all dropouts. As mentioned above. North America or other). Twenty studies reported bacteriological eradication rates.7) Twenty-five of the 27 studies could be evaluated for mortality. encompassing 5444 of 5939 randomized patients (91. 95% CI 0. continuous data were not available for analysis in this review. one was single-blinded and the remaining (17 out of 28) were open label.Allocation Adequate allocation concealment was reported in 7 out of 28 studies. All trials defined clinical success or failure as their primary outcome and reported on it. Six studies did not refer to dropouts (type 3) and were analyzed by evaluated patients only in the sensitivity analysis. Only one study (Rizzato 1997) reported standard deviation. Incomplete outcome data We separated between three levels of possible bias as follows. Per-protocol studies. Hong-yun 2007. one reported median duration (Norrby 1998). Romanelli 2002). All studies of adequate allocation concealment were also of adequate allocation generation. Twenty-five of the 27 studies could be evaluated for mortality.69 to 1. Studies performed by ITT. Two of the studies included in this review were abstracts.14. Seven studies reported results by ITT (type 1). Ltd.25.52 to 3. 95% CI 0. Kobayashi 1984). Per-protocol studies. Allocation generation was adequate in 10 out of 28 studies. df =17. Mortality was further analyzed by patient characteristics: age (mean age older or younger than 65 years). Five studies assessed duration of hospital stay. Fifteen additional studies reported the number of dropouts per study arm (type 2). Mortality was not reported as a separate outcome in methods but was reported in results as a safety measure or otherwise. In three studies. Six studies reported no deaths. two of which were abstracts.39) and macrolide therapy (RR 1. Randomization and allocation concealment procedures in these trials are unknown. Follow-up ranged from immediately after completion of treatment to three months after. 1. Blinding Ten studies were double-blind. Specific data are reported for each study in the Characteristics of included studies tables. and the rest reported the total number of days in hospital (Chuard 1989. in which the number of dropouts was given per study arm. and geographical area (Europe. One study does not specifically mention deaths (Kobayashi 1984). Hong-yun 2007). mortality was not mentioned (Hatipoglu 2010.98. We failed to contact the authors of this abstract. 95% CI 0.1). encompassing 5444 of 5939 randomized patients (91. No information was available for 18 studies.55.4% to 5%. 2. One of the abstracts was published in the Chinese journal Chinese Journal of Antibiotics (Hong-yun 2007) but we could not obtain its full-text. Insufficient information was available for the other studies. Follow-up duration was specified in 22 studies (81%). encompassing 2310 patients/isolates. There was no significant difference between the atypical arm and the non-atypical arm in the overall mortality rate (RR 1.6%). None of the trials mentioned duration to regaining previous functional capacity. Therefore. Effects of interventions Overall mortality (Analyses 1. 3. all but one of these manufactured the atypical drug. I2 statistic = 0%). nor were there sufficient data regarding the number of patients who required mechanical ventilation. 10 . Analysis 1. Thirteen studies recounted information regarding overall mortality by ITT (type 1). and therefore we have no detailed information about randomizations and allocation concealment in this study. All but five trials reported on adverse events per treatment arm.34. Other potential sources of bias At least 21 of the 27 studies were sponsored by pharmaceutical companies. of which 16 studies (59%) defined a specific time for outcome measurement. in which the number of dropouts was reported or could be calculated but not given per study arm. Selective reporting We did not find any specific concerns over selective.96. None of the deaths according to the authors were related to the drug treatment.84 to 1. as is the case for the two abstracts (Hatipoglu 2010. P = 0. and one study reported a 25% mortality rate (Fourrier 1986). with data extracted only from the abstracts and no further data were available.01) alone. The adjusted mean mortality rate was 3. the primary outcome in all studies was clinical success. including 4918 patients. Neither comparison disclosed a Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.6%). six reported a rate of 5% to 8%.5%.1 to 1.

10).98) but not in studies carried out elsewhere (Analysis 1.11. 95% CI 0. I2 statistic = 18. Rates of clinical failure were similar in trials sponsored by pharmaceutical companies (RR 0.5 and Analysis 1. which included 19 trials in which mortality was more than zero.12).75 to 1. 95% CI 0. Ltd.91. 95% CI 0. allocation concealment and blinding (Analysis 1. No heterogeneity for the total results was seen (Chi2 test = 29.79 to 1. 95% CI 0.81 to 1. A non-significant trend toward an advantage to the atypical arm was observed combining all studies (RR 0. 95% CI 0. Overall mortality in both arms was similar when analyzing studies by randomizations generation.19).9). respectively).93.08. In the funnel plot for overall mortality.11.99.2. 11 . P = 0.8 to 1.53. quinolone monotherapy showed non-significant advantage (RR 0.3. Studies of B score accentuated an advantage toward the atypical arm (Analysis 1. Analysis 1. There was no advantage to atypical treatment in studies of high methodological quality.84 to 1. 95% CI 0.18) Clinical failure was the primary outcome in all 28 studies.86 to 1. 95% CI 0. as in the non-sponsored trials there was no mortality.7).99.significant difference (Analysis 1.85. The effect of sponsorship by pharmaceutical companies could not be evaluated. 21 trials) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.62).82 to 1. Clinical failure (Analyses 1.6. Analysis 1.74 to 0. The non-significant advantage of the atypical arm was seen in young patients (mean age < 65 years: RR 0.19) or allocation concealment (RR 0. Published by John Wiley & Sons.97.04) (Analysis 1.93. Figure 3. When evaluating the different atypical regimens.7%). respectively).02) while macrolide monotherapy showed non-significant disadvantage (RR 1.89.06) as well as older patients (mean age older than 65 years: RR 0. comprising 5419 patients (of 5939 randomized).8). results are symmetrically centered around the combined RR (Figure 3). There was no difference in clinical efficacy when combining studies that scored A in randomizations generation (RR 0. df = 24.10) (Analysis 1.76 to 1. 95% CI 0.82 to 1.2 and Analysis 1.4. 95% CI 0. as well as in the ITT analysis (Analysis 1. The advantage was statistically significant in the European studies (RR 0.

e. Perhaps this prevalence diminishes in the hospitalized population.52.41.68. 12 .05) or type 3 (RR 0.23).32.84 to 1. I2 statistic = 0%).61 to 1. These endpoints are subjective and should therefore be studied with care.62. although only 43 cases were available (Analysis 1.6% of randomized patients. no significant difference was detected in bacteriological eradication between the two treatment arms (RR 0. with a RR of 0. A significant advantage in bacteriological eradication was detected in the atypical arm. there was a nonsignificant advantage to the non-atypical arm (RR 1. given a higher prevalence of atypical pneumonia in this age group.05 to 0.21) were similar in both treatment arms (RR 1. 95% CI 0. Overall completeness and applicability of evidence Mortality data were obtained for 91.19). Published by John Wiley & Sons.93. 95% CI 0. There was no difference between the atypical arm and the non-atypical arm with respect to this outcome. The similar response of the young and old is somewhat surprising. especially as many are non-blinded.16). Only five studies reported super-infections.02.88 to 1.4. None of the trials mentioned duration to regaining previous functional capacity.0% (Fine 1997)). with numbers too small for statistical assessment.63). 3 trials) (Analysis 1. Failure was commonly defined as lack of clinical improvement.5%) was lower than reported in the literature (MedisGroups overall mortality of 10.23) All but five trials reported on adverse events per treatment arm. The overall mortality in included studies (adjusted mean 3. Analysis 1. accentuated with quinolone monotherapy. although type 3 studies showed a higher effect estimate for atypical treatment. Analysis 1. The advantage disappeared when evaluating high-quality methodological studies alone (i.64 to 1. counting all dropouts as failures in the ITT group (Analysis 1.08.24 to 1. No significant differences between type 1 (RR 0.22) were reported in 16 studies and were significantly less common in the atypical arm (RR 0.80.21 to 1. No heterogeneity was seen (Chi2 test = 12.13). the point estimate for sponsored and non-sponsored trials for clinical failure is similar. When considering only the high quality studies (’A’ score in allocation generation). although less gastrointestinal events were noted in the atypical arm. definition of gastrointestinal events differed. Clinical failure rates were evaluated per pathogens isolated. P = 0. no heterogeneity was seen (Chi2 test = 1. Clinical failure with macrolide antibiotic treatment was the only comparison in which heterogeneity was detected (Chi2 test = 6. df = 3.10. Total adverse events (Analysis 1. Although pharmaceutical companies producing the atypical antibiotic sponsored most studies.22. thereby excluding an accurate comparison of the frequency of antibiotic-associated diarrhoea. We performed an ITT versus per-protocol design sensitivity analysis.90.17). encompassing 2310 patients/isolates (mixed results. one ex- Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Eradication of L.53 to 0. Analysis 1. 95% CI 0. df = 21.72 to 1. However.15) studies. This did not change when analyzing results per population characteristics or methodology. 95% CI 0.17 and a narrow CI (0. Adverse events (Analyses 1.92. Re-analysis done by the random-effects model did not alter results.02. No heterogeneity was seen (Chi2 test = 39. There was a statistically significant advantage to bacteriological eradication in the atypical treatment arm (RR 0. especially in reference to L.35.and non-sponsored trials (RR 1. there was a non-significant advantage to the atypical arm in the treatment of atypical pathogens (RR 0.92).65 to 0.6% (Iezzoni 1988). type 2 (RR 0.1%). df = 6. including 4918 patients. with no difference between the arms.97. Bacteriological failure (Analyses 1.12). Analysis 1.14). 95% CI 0. pneumophilae prevalence in the elder population may also explain the similarity. P = 0. Again. studies that had a low risk of selection bias).7. 95% CI 0.85. PORT validation cohort inpatient mortality of 8. Data were insufficient to distinctively analyze cases of pneumococcal bacteraemia. I2 statistic = 0%).7. A higher L. Both arms were nearly equal with regard to adverse events requiring discontinuation (RR 1. DISCUSSION Summary of main results The primary outcome we assessed was overall mortality. 95% CI 0. 95% CI 0. pneumophilae in particular was highly significant. Of the 1021 pneumococcal pneumonia cases reported. pneumoniae.0. relapse and/or modifications of the antibiotic treatment.01. 95% CI 0. This is surprising in view of the fact that 12 of the 27 studies target relatively severe pneumonia cases (two studies conducted in nursing homes. In contrast to S.93 to 1. I2 statistic = 55. Analysis 1. deterioration. as each study used different measures. P = 0. 95% CI 0.20). pneumophilae eradication. Ltd. There was no statistically significant difference in the frequency of total adverse events between the two groups. some including abdominal pain and some diarrhoea alone.94.20) Twenty studies reported bacteriological eradication rates. nor were there sufficient data regarding the number of patients who required mechanical ventilation.15). 95% CI 0.19 to 1. df = 18.76 to 1. see above). as one might anticipate that younger people would benefit more from atypical coverage. Other outcomes Treatment duration was conveyed in 14 studies and was almost uniformly 10 days. I2 statistic = 29.63 to 1.8%). P = 0. Gastrointestinal events (Analysis 1.98.83. This advantage was not demonstrated in an analysis restricted to studies with adequate allocation generation.18). There was a non-significant trend toward clinical success in the atypical arm.009.

which found no positive effect on treatment success rates with the addition of atypical coverage (Hatipoglu 2010). A large systematic review that included observational studies. Hedlund 2005. Potential biases in the review process Inclusion of abstracts and studies with missing data might have introduced bias. Furthermore. Regarding this comparison. compared to the typical arm which comprised of BL or cephalosporins. an antibiotic regimen covering both typical and atypical pathogens in hospitalized CAP patients (BTS 2001. these guidelines are based on insufficient evidence. Lim 2009. It is interesting to note that cases of atypical pneumonia (including L. in terms of mortality and successful treatment. one excluding suspected atypical cases. since it became insignificant in the evaluation of high quality studies. as there have been only few randomized controlled trials assessing CAP treatment protocols. Woodhead 2005). using mortality as its primary outcome. One should note that the atypical arm was usually a new drug (tested by the manufacturer) and therefore expected resistance rates were small. Using propensity analysis. Expanding coverage to atypical pathogens is bound to increase toxicity. evaluated the superiority of atypical coverage to non-atypical coverage regimens (Oosterheert 2003). Quality of the evidence The atypical arm’s advantage in bacteriological eradication could not be explained by the coverage of atypical pathogens alone: results of clinical success in those cases were equivocal and their proven share of events was small. Most trials comparing different treatment arms were performed to evaluate a specific drug. Mandell 2000. comparing BL or cephalosporins therapy to BL or cephalosporins combined with a macrolide in this population. AUTHORS’ CONCLUSIONS Implications for practice No benefit of survival or clinical efficacy was shown to empirical atypical coverage in hospitalized patients with CAP. 13 . further limits our conclusion. resistance and cost. The relatively low mortality rates in the existing hospitalized CAP trials included in the mortality analysis. most publications date to the early 1990s. Ltd. three including suspected or proven pneumococcal pneumonia (the fourth excluded severe cases). Moreover. as mortality data were almost complete. All major guidelines for treatment of CAP recommend in general. pneumophilae) often resolved even in the treatment arm lacking atypical coverage. We had set off to investigate the contribution of atypical coverage to empiric treatment of CAP in hospitalized patients. The last update found no such trials. should be performed. frequently a macrolide or a fluoroquinolone. these studies were non-randomized cohort studies and outcomes showed several inconsistencies. Our meta-analysis is therefore chiefly based on comparison of BL or cephalosporin regimens to atypical monotherapy. However. The clinical advantage of L. although it is obviously the most significant outcome in a potentially lethal infectious episode. we found no advantage to atypical coverage in terms of mortality or clinical success. Gastrointestinal side effects were studied separately in order to try and assess frequency of antibiotic-associated diarrhoea after BL or cephalosporin treatment and were found to be significantly more prevalent in the non-atypical arm. Only a minority were co-infections with typical pathogens. The total of adverse events did not differ significantly between treatment arms. the trials differed in definition of events to a point that precludes this assessment. Agreements and disagreements with other studies or reviews The objective of our study was to assess the efficacy and need of adding antibiotic coverage for atypical pathogens in hospitalized patients with CAP. The most suitable study for our purpose is one comparing a BL or cephalosporin with the same BL or cephalosporin combined with a macrolide or a quinolone. Mortality was not a primary outcome in any of the studies. Published by John Wiley & Sons. This conclu- Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. mainly quinolone monotherapy.cluding patients under 70 years of age. As demonstrated above. However. Admittedly. In this update we found only a single abstract assessing directly the addition of an atypical antibiotic to a BL. we showed that the major pitfall of such observational studies is the marked difference between patients prescribed nonatypical coverage and those prescribed a regimen including atypical coverage. Niederman 2001. Further randomized controlled trials. Mandell 2007. its reliability is questionable. We conclude that no benefit of survival or clinical efficacy was shown to empirical atypical coverage in hospitalized patients with CAP. Several of these trials (incidentally) compared regimens with and without atypical antibiotic coverage and found results to be generally equal (Aubier 1998. a difference that precludes the comparison of these treatment regimens in observational studies (Paul 2007). while new resistant trends have emerged since then (for example increasing pneumococcal resistance to quinolones). Significant reduction in mortality with atypical coverage was found in six of the eight selected studies. The need to add a macrolide to a BL therapy is a common dilemma manifested within the guidelines themselves. four restricted to clinically severe pneumonia and one restricted to moderate-severe pneumonia (see above). Tremolieres 1998). this broad coverage might be at the expense of efficacy of pneumococcal coverage (Johansen 2000). The low mortality rate is not a result of under-reporting. pneumophilae coverage is not surprising.

et al. Feldman 2001 {published data only} Feldman C. Guay DR. Barcelona. Gleadhill 1986 {published data only} Gleadhill IC. Tabakoglu E. Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxycillin. We would like to thank Dr. Lowry RC. Managing Editor) and the help devising and conducting the search (Sarah Thorning. Gruninger RP. Hirata-Dulas 1991 {published data only} Hirata-Dulas CA. Petitpretz P. the major regimen recommended in current guidelines remains unsubstantiated by evidence.15(26):1240. Randomized study of a new quinolone: pefloxacin.18(Supp D):133–8. International Journal of Antimicrobial Agents 2001. Richard Taggart. REFERENCES References to studies included in this review Aubier 1998 {published data only} Aubier M. Lobatto S. Altiay G. Savage C. The trial should have adequate randomizations generation and concealment and should report patient relevant outcomes (FDA 2009) and mortality. (5). Observation of the therapeutic effects of gatifloxacin on community acquired pneumonia. compatible (as regards severity) to those observed in sound observational studies. Sut N. Vercken JB.119(52):1913–6. Hatipoglu 2010 {unpublished data only} Hatipoglu ON. Gabriel Izbicki for his translation from German and to Ms. Hartmut Lode. Nauta EH. Lephonte P. Clarithromycin versus amoxicillin-clavulanic acid in the treatment of community-acquired pneumonia. Dr. Flitcroft A. Bohte 1995 {published data only} Bohte R. Ltd. Stein DJ. Hong-yun 2007 {published data only} ∗ Hong-yun L. Daniel Genne. O’Grady J. Jose Sifuentes Osornio. The trial should include patients with severe pneumonia. Karla SoaresWeiser for her guidance. van’t Wout JW. Claude Carbon.16(11):783–8. Nelcy Rodriguez and Allen Cheng. Until then. Clinical Infectious Diseases 1998.26 (6):1312–20. An open. multi-centre study comparing the safety and efficacy of sitafloxacin and imipenem/cilastatin in the intravenous treatment of hospitalised patients with pneumonia. Briggs A. Humair L. Phillip Peterson. Francois Fourrier. 2010 September 18-22. Verster R.sion relates mostly to the comparison of quinolone monotherapy with BL monotherapy. Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. 14 . Chao Q. Ferguson WP. A randomized study of ciprofloxacin versus ceftriaxone in the treatment of nursing home-acquired lower respiratory tract infections. Geslin P. The effect of addition of macrolide to a beta-lactam antibiotic on treatment success in patients with moderately severe community acquired pneumonia (Abstract). Chopin C. Siegrist HH. Chauvin JP. randomised. 2010. Sparfloxacin European Study Group. We wish to thank the following people for commenting on this latest updated draft: Linda Hornbeek. Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired. Antimicrobial Agents and Chemotherapy 1992.Efficacy and safety of azithromycin versus benzylpenicillin or erythromycin in community-acquired pneumonia. Genne 1997 {published data only} Genné D. Uysal S. Dr. Lestavel P. Published by John Wiley & Sons. Qun F. We are indebted to Dr. Journal of Antimicrobial Chemotherapy 1986. Blusse van Oud Alblas A. European Journal of Clinical Microbiology and Infectious Diseases 1997. Chinese Journal of Antibiotics 2007. Peterson PK. European Journal of Clinical Microbiology and Infectious Diseases 1995. Theo Verheij. La Presse Medicale 1986. Qian L. Boekhout M. Proceedings of the European Respiratory Society Annual Congress.14(3): 182–7. Implications for research A RCT of a BL monotherapy compared to the same BL combined with a macrolide or a quinolone in hospitalized patients with CAP should be performed. Regamey C. Regamey C. ACKNOWLEDGEMENTS We thank the trial authors who responded to our requests: Dr.39(10):979–85. Richards G. Carbon 1992 {published data only} Carbon C. Dr. Patrick Petitpretz and Dr. Spain. White H. Effect and tolerance of ofloxacin in bronchopulmonary infections in comparison with amoxicillin. Journal of the American Geriatrics Society 1991. de Torrenté A. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Chuard 1989 {published data only} Chuard C. Hazebroucq J.17(3):177–88. Warm thanks to the Cochrane Acute Respiratory Infections Group editorial team for their guidance throughout the review (Liz Dooley. Rika Fujia for obtaining and translating the Japanese articles. Schweizerische Medizinische Wochenschrift 1989. 36(4):833–9. Janin-Jaquat B. Dr. Dr. suspected pneumococcal pneumonia in adults. Initial antibiotherapy in severe bacterial bronchopneumopathies. Fourrier 1986 {published data only} Fourrier F. Trials Search Co-ordinator).

26(Suppl B):111–6. et al. et al. Boisisio E. Mayaud C. Rizzato 1997 {published data only} Allegra L. Stein D. Chest 1989. CAP5 Moxifloxacin Study Group. Cravarezza P.58(10): 1083–113. European Respiratory Journal 1993. Berni F. et al. The teicoplanin-ciprofloxacin combination versus ceftriaxone in community acquired pneumonia of elderly and patients with underlying diseases. Arvis P. Franchino L. Takashima T. Urueta J. Garau J. Caulin E. Niki Y. Kadota J. Trovafloxacin versus high-dose amoxicillin (1g three times daily) in the treatment of community-acquired bacterial pneumonia. Obaid S. Grassi C. Nagahama F. Weber P. Scandinavian Journal of Infectious Diseases 1998. Moita J. Rizzato G.Prospective study of lower respiratory tract infections in an extended-care nursing home program: potential role of oral ciprofloxacin. Legakis N. Rizzato G. Bagilet D. A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia.8(12):1999–2007.7(Supp 18):170. 15 . Saito A. Aoki N. Petitpretz P.14(6):609–17. Nakayama I. Mouton Y. File T. Oral levofloxacin versus intravenous ceftriaxone and amoxicillin/ clavulanic acid in the treatment of community-acquired pneumonia that requires hospitalization. Koorhof HJ. Japanese Journal of Chemotherapy 2011. Basir R. Urueta J. Kohno 2011 {published data only} Kohno S. Diab M. Feldman C. Peterson 1988 {published data only} Peterson PK. Dellatolas F. et al.17(6):447–53.31:39–43. Comparison of pefloxacin with ceftazidime in severe bronchopulmonary infections. Guay DR. Javkin E. Salewski E. Vanderdonckt 1990 {published data only} Vanderdonckt J.85(2):164–71. The use of oral temafloxacin compared with a parenteral cephalosporin in hospitalized patients with pneumonia. Tremolieres 2005 {published data only} Tremolieres F.115(15):561–3. Efficacy and safety of pristinamycin vs amoxicillin in community acquired pneumonia in adults. Romanelli 2002 {published data only} Romanelli G. Sasaki N. Journal of Antimicrobial Chemotherapy 1991. Miki 1984 {published data only} Miki F.59:32–45. Journal of Chemotherapy 2002. Norrby 1998 {published data only} Norrby SR. Ltd. Zeluff 1988 {published data only} Zeluff BJ.30(4): 397–404. Vogel 1991 {published data only} Vogel F. Zulli R. Marel M. Sequential intravenous-oral administration of ciprofloxacin vs ceftazidime in serious bacterial respiratory tract infections. Huchon G. Pozzi A. Willcox PA. Lode H. Kansenshogaku Zasshi 1984. et al. de Kock F. Internista 1995.98(8):708–20. European Journal of Clinical Microbiology and Infectious Diseases 1988. Tomizawa M. community-acquired. Allegra L: Multicentre Italian Study Group (coordinated by Centro Thorax).28 (Supp C):81–6. Oral moxifloxacin vs highdosage amoxicillin in the treatment of mild-to-moderate. Watanabe A. European Respiratory Journal 1995. Gentry LO. suspected pneumococcal pneumonia in adults. Rico G. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Tremolieres 1998 {published data only} Tremolieres F. Takebe K. Kansenshogaku Zasshi 1984. Archives de Bronchoneumologia 2003. Logan G.Kalbermatter 2000 {published data only} Kalbermatter V. et al.58(6):525–55.96(3): 453–6. Dal Negro R. Petitpretz 2001 {published data only} Jardim JR.Clinical phase III comparative study of intravenous levofloxacin and ceftriaxone in community-acquired pneumonia treatment. Ravizzola G. Clini V.Comparison of DL-8280 and amoxicillin in the treatment of respiratory tract infections.119(1):185–95. Chest 2001. et al.39(9):387–93. Gruninger R. et al. Obispo E. Damato S. Kobayashi 1984 {published data only} Kobayashi H. Hosie J. Efficacy and tolerability of teicoplanin-ciprofloxacin combination in severe community-acquired pneumonia.53(8-9):503–10. amoxycillinclavulanic acid and erythromycin.Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin. Comparison with ceftriaxone in a multicentre Italian study.A comparison of moxifloxacin and amoxicillin in the treatment of community-acquired pneumonia in Latin America: results of a multicenter clinical trial. Multicenter Study Group. Lowe P. European Journal of Clinical Microbiology and Infectious Diseases 1998. Journal of Antimicrobial Chemotherapy 1990. Kono K. Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin. Takamura K. Clinical Drug Investigation 1997. Vetter N. Evaluation of roxithromycin (RU-965) versus cephradine in pneumococcal pneumonia. Medicina Clinica 2000.Comparative study of the effectiveness of enoxacin and amoxicillin in bacterial pneumonia by a double blind method. Daniel R. Petermann W.7(1):69–71. Pluck N. American Journal of Medicine 1988.Efficacy of the teicoplanin-ciprofloxacin combination in high risk community acquired pneumonia: Comparison to ceftriaxone in a multicenter study. Lephonte 2004 {published data only} Leophonte P. de la Roza C. Fujita J. Montemurro L. Lode 1995 {published data only} Lode H.Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy.14(5):337–45. Published by John Wiley & Sons. Onodera S. Khan 1989 {published data only} Khan FA. Respiratory Medicine 2004. Pathologiebiologie (Paris) 2005. Wolff M.

Neve AJ. Kinasewitz 1991 {published data only} Kinasewitz G. et al. open-label study. Gomez Criado C. Garreltes J. Brandon ML. Clinical efficacy and safety of a short regimen of azithromycin sequential therapy vs standard cefuroxime sequential therapy in the treatment of community-acquired pneumonia: an international. Harman CP.v.30(6):378–86. et al. Mortensen EM.17(6):636–42. Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia. Segreti J. double-blind trial comparing intravenous ciprofloxacin with imipenemcilastatin.28(36):1975–9. Khajotia 1990 {published data only} Khajotia R. Zwinkels M. 16 . van Barneveld PW. Antimicrobial Agents and Chemotherapy 1997. Kohler R. Grossman R. Agastya G. et al. et al.31(Suppl E):147–52.87(5A):164–8. Anzueto A. Veyssier P. Aubier 1996 {published data only} Aubier M. Tipping DM. Laforge J.38 (3):547–57. Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia. Fogarty CM. et al. randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 1999.v. Plouffe JF. Published by John Wiley & Sons. 26(7):447–51. Ruuth E. Kuzman 2005 {published data only} Kuzman I. Dakovic-Rode O. Intravenous and oral mono. Johnson RH. Lerner SA. Niederman MS. Torres A. Journal of Emergency Medicine 2004. randomized. 10(10):872–7. Legakis N. Fink 1994 {published data only} Fink MP. Hamed K. Song J. Haverstock D. Zakhari R. Krumpe 1999 {published data only} Krumpe PE. Dunbar L.27(4):395–405. Fong 1995 {published data only} Fong IW. comparative. American Journal of Medicine 1989. Leeper KV Jr. Katz 2004 {published data only} Katz E. Levofloxacin in the treatment of community-acquired pneumococcal pneumonia. Randomized. Wood RG. Frei CR. Chokshi 2007 {published data only} Chokshi R. Ltd.A multicenter.Ciprofloxacin Study Group. randomized. European Journal of Clinical Microbiology and Infectious Diseases 2007.26(Suppl D):83–91.37 (Suppl A):73–82. doubleblind comparative study of intravenous ciprofloxacin versus Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Levofloxacin versus beta-lactamic therapy in community acquired pneumonia that requires hospitalisation [Levofloxacino frente a betalactamicos en el tratamiento de la neumonia adquirida en la comunidad con ingreso hospitalario]. multicenter study. to p. et al. Vetter N. Restrepo MI. Weeratunge N. A comparative study of ofloxacin and amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections. Williams RR. Fass 1989 {published data only} Fass RJ. et al. Hoepelman 1993 {published data only} ∗ Hoepelman AI. Banaszak AM. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i. Gialdroni-Grassi G.or combination-therapy in the treatment of severe infections: ciprofloxacin versus standard antibiotic therapy. Leophonte 1999 {published data only} Leophonte P. Dubois J. File 1997 {published data only} File TM. Journal of Antimicrobial Chemotherapy 1990. Anales de Medicina Interna 2002. Salisbury JP. Heard SO. Small D. Mukunda BN.A single-blind comparison of three-day azithromycin and ten-day co-amoxiclav treatment of acute lower respiratory tract infections. Dimas Nunez JF. Choudhri S. Treatment of severe pneumonia in hospitalized patients: results of a multicenter. Hosie J.18(2):131–8. Journal of Chemotherapy 2005. IV/oral ciprofloxacin vs ceftazidime in the treatment of serious infections. Snydman DR. Geijo Martinez 2002 {published data only} Geijo Martinez MP. Sips AP.Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized. Oremus M. Monotherapy versus combination antibiotic therapy for patients with bacteremic Streptococcus pneumoniae community-acquired pneumonia. Clarithromycin versus cefaclor in lower respiratory tract infections.19(12): 609–11. Clinical Therapeutics 1997. McNeil P. Lode H. Clinical and Investigative Medicine. van Rensburg D. The Canadian Bronchitis Study Group. Ailani RK. Journal of Antimicrobial Chemotherapy 1996. Diaz de Tuesta. Donowitz 1997 {published data only} Donowitz GR. Drlicek M. Safety and efficacy of sequential i. therapy. Coulter H. La Presse Medicale 1999. van Helmond JL. Azithromycin versus cefaclor in the treatment of acute bacterial pneumonia. Chow-Quan AM.41(9):1965–72. Huchon G. Infection 2002.o.43(Supp A):117–28. Médecine Clinique et Experimentale 1995.Sparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies. Russell JA.References to studies excluded from this review Ailani 1999 {published data only} Ailani RK. Archives of Internal Medicine 1999. Shekar R. Ramirez J. Herranz CR. Journal of Antimicrobial Chemotherapy 1993. Player R. Levine 1989 {published data only} Levine D. Rangaraju M.The Severe Pneumonia Study Group. Cohn S.19(5): 936–53. European Journal of Clinical Microbiology and Infectious Diseases 1991. Larsen LS. double-masked. Antimicrobial Agents and Chemotherapy 1994. Urick AE. Hagberg 2002 {published data only} Hagberg L.159(3):266–70. Leroy B.

Mouton 1991 {published data only} Mouton Y. RuizPalacios GM. Prospective. double blind. Lorenz J.87(Supp 5A):116S–8S. Treatment with sequential intravenous or oral Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Ofloxacin versus standard therapy in treatment of community-acquired pneumonia requiring hospitalization.21(1): 135–43.36(1): 23–30.10(6):512–20. Lode 2004 {published data only} Lode H. Parsons JN. Wintermantel M. Results of a multicentre trial comparing i. File TM Jr. Welte 2005 {published data only} Welte T. Reimnitz P. Ltd. Fidel J.49(Supp 2):439–41. Evaluation of ciprofloxacin versus amoxicillin + clavulanic acid or erythromycin for the empiric treatment of community-acquired pneumonia. Magyar P. Peacock 1987 {published data only} Peacock J Jr. Scandinavian Journal of Infectious Diseases 1990. Stocks 1989 {published data only} Stocks JM. Torres 2003 {published data only} Torres A. Niederman M.49(Supp 2):436–8. Once-daily oral gatifloxacin vs three-times-daily co-amoxiclav in the treatment of patients with community-acquired pneumonia. Yamaguti A. Garcia JG.Prospective randomized clinical trials of new quinolones versus beta-lactam antibiotics in lower respiratory tract infections. Pathologie-Biologie 1991. Fink F. Siami 1995 {published data only} Siami GA. Muir JF. Ofloxacin in community-acquired lower respiratory infections. Gvazdinskas LC. Baetz R. Aubier M. Ott 2008 {published data only} Ott SR. Randomized. Randomized study of intravenous/oral ciprofloxacin versus ceftazidime in the treatment of hospital and nursing home patients with lower respiratory tract infections. Wiley E. Kubin R. et al. O’Doherty 1997 {published data only} O’Doherty BO.Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia. Maroli A. Sparfloxacin as alternative treatment to standard therapy for community-acquired bacteremic pneumococcal pneumonia. Portier H. Weber SF. Muir JF. Hoffken G. Clinical Microbiology and Infection 1998.Prospective randomized controlled study of ciprofloxacin versus imipenem-cilastatin in severe clinical infections. Schmitt BA. Macias A. Bess DT. Comparison of ciprofloxacin with imipenem in the treatment of severe pneumonia in hospitalised geriatric patients. Clinical Microbiology and Infection 2004. Beuscart C. Shapiro M. Herbert MT.ceftazidime in the treatment of serious infections. Mendoca 2004 {published data only} Mendonca JS. Wilkins WT.24(2):181–4. American Journal of Medicine 1989. Lode 1998 {published data only} Lode H. Kahn JB. Wallace RJ Jr. European Respiratory Journal 2003. with or without macrolides.87(6C):52–6. International Gatifloxacin Study Group. et al. Leone PA. Badaro R. Petermann W. Lode H. Sievers H. American Journal of Medicine 1989. Schurmann D. Pettit R. Reimnitz P. comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia. Lode 1990 {published data only} Lode H. in hospitalized adult patients with mild to moderately severe pneumonia. Plouffe 1996 {published data only} Plouffe JF. Journal of Antimicrobial Chemotherapy 1997. Groupe Multicentrique. Cost-effectiveness of oral gemifloxacin versus intravenous ceftriaxone followed by oral cefuroxime with/without a macrolide for the treatment of hospitalized patients with community-acquired pneumonia. Sifuentes 1989 {published data only} Sifuentes-Osornio J.68(Suppl):50–5. Kohler RB. Loos U.v. Sparfloxacin Study Group. Correa JC.40(Supp A):73–81. Duprat-Lomon I. Antimicrobial Agents and Chemotherapy 1987. Drugs 1995. A prospective. Snydman 1995 {published data only} Snydman D. Lode 1987 {published data only} Lode H. Ambrose PG. Kleutgens K. American Journal of Medicine 1989. Gatifloxacin in the treatment of community-acquired pneumonias: a comparative trial of ceftriaxone.39(1):34–7. Wagner J. Charrel J. Spear J. Drugs 1995. Baird I. Dutchman DA. Gibor Y. A comparison with amoxicillin or erythromycin. Azithromycin versus comparative therapy for the treatment of community acquired pneumonia. Ajana F. Wiley R. Treatment of severe pneumonia in hospitalised patients. Leroy O. Brazilian Journal of Infectious Diseases 2004. the treatment of serious infections.40(5):1175–9. Griffith DE.4(3):135–43. Bauer TT. Pegram SP. Corris P. American Journal of Medicine 1989. Ortquist A. randomized comparison of sequential intravenous followed by oral ciprofloxacin with intravenous ceftazidime in Rahav 2004 {published data only} Rahav G. Reinhart H. Ramos A. et al. Trenholme 1989 {published data only} Trenholme GM. American Journal of Medicine 1989. Allewelt M. Antimicrobial Agents and Chemotherapy 1996.87(5A):185S–90S. Amieva RI.31 (10):1491–6. Christman JW.8(1):90–100. ciprofloxacin with imipenem/cilastatin. 17 . Olschewski P. et al. International Journal of Antimicrobial Agents 2004.87(5A):160–3. Intravenous ciprofloxacin and ceftazidime in serious infections. Diagnostic Microbiology and Infectious Disease 2008. Infection 2008.87(5A):202S–5S. Published by John Wiley & Sons. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Sujata 2008 {published data only} Bhavnani SM. Sagnier PP. controlled clinical trial with third-party blinding.60(1): 59–64. Borner K. Lode H.

Thorax 2003.fda. Boersma WG. Bartlett JG. www. Pneumonia.37:791–805. Version 5. Dolin R editor(s). Jensen TG. Clinical Infectious Diseases 2005. 18 . Jamieson C. New England Journal of Medicine 1997. In: Braunwald E. Chow AW. Additional references Lefebvre 2011 Lefebvre C. Khan FA. et al. Hyland RH. Holmberg H. Campbell GD.369(9560): 482–90.Infectious Diseases Society of America/American Thoracic Society. Chapter 6: Searching for studies. Levison 2001 Levison M.cochrane-handbook.0 [updated March 2011].moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy. Harrison’s Principles of Internal Medicine. Mandell LA. Broughton WA. et al. Lammens C. 15th Edition.cochrane-handbook.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM193282. Philadelphia: Churchill Livingstone. Lundgren B. 5th Edition. Grossman RF. In: Higgins JPT. Le Jeune I.64 (Suppl 3):1–55. The Cochrane Collaboration. Frimodt-Moller N. Lancet 2007. Town GI. Wollschlager 1987 {published data only} Wollschlager CM. Vol.BTS guidelines for the management of community acquired pneumonia in adults. Fauci AS. Fine 1997 Fine MJ. et al. Singer DE.260(21):3159–63. Niederman 2001 Niederman MS. FDA 2009 FDA. Thorax 2001. Baudouin SV. Principles and Practice of Infectious Diseases. Wunderink RG. Mandell 2000 Mandell LA. 2011. Guidelines for the management of adults with Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 58(5):377–82.336(4):243–50. Guidance for industry. BMJ 2005. Mandell G.Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Yealy DM. Goossens H. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. 46:973–80.41(12): 1697–705. Oehley MR. placebo-controlled study. Acute Pneumonia. comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Swedish guidelines for the management of community-acquired pneumonia in immunocompetent adults. Iezzoni 1988 Iezzoni LI. Anzueto A. Available from www. Arrol B. van der Eerden MM. Clinical Infectious Diseases 2000. Lim 2009 Lim WS. Dessau RB. A clinical assessment of MedisGroups. Journal of Antimicrobial Chemotherapy 2000. Moskowitz MA. 1. doubleblind. Hill AT. Campbell GD.44 (Suppl 2):27–72.1. Bennet JE. Van Herck K. Johansen 2000 Johansen HK. Anzueto A. Hauser SL. Ortqvist A. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised. Mills 2005 Mills DG. Bass JB. BTS guidelines for the management of community acquired pneumonia in adults. George RC. Hanusa BH. LaBombardi V. Jameson JL editor(s). Mandell 2007 Mandell LA. et al. 2. Stralin K. Thorax 2009.330(7489):456. Longo DL. Auble TE.1. Malhotra-Kumar 2007 Malhotra-Kumar S. Coenen S. New York: McGraw-Hill.A prediction rule to identify lowrisk patients with community-acquired pneumonia.56(Suppl 4:IV):1–64.0 [updated March 2011]. The Canadian Community-Acquired Pneumonia Working Group. Dean NC.82(4A):164–8.pdf (accessed May 2010) (accessed May 2010). Donowitz 2000 Donowitz G. Weissfeld LA. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Guarneri JJ. JAMA 1988. Cochrane Handbook for Systematic Reviews of Interventions Version 5. Ltd. Lim 2003 Lim WS. Clinical Infectious Diseases 2007. Manheimer E. Scandinavian Journal of Infectious Diseases 2005. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo. Laing R. The Cochrane Collaboration. Afzal Q. Higgins 2011 Higgins JPT. In: Mandell GL. 2001:1475–85. BTS 2001 British Thoracic Society. Raoof S. 2000:717–43. Controlled. Patient-reported outcome measures: use in medical product development to support labeling claims. Cochrane Handbook for Systematic Reviews of Interventions. Vol.org 2011.31:383–421. Karalus N. et al. Marrie TJ. Hedlund 2005 Hedlund J. Green S (editors). Published by John Wiley & Sons. Kasper DL. including necrotizing pulmonary infections (lung abscess). Available from www.org.American Thoracic Society. Green S (editors). Glanville J. American Journal of Medicine 1987. Effectiveness of beta-lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis.

Oosterheert 2003 Oosterheert JJ. How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review. Blasi F. Hoepelman IM. Leibovici L. Woodhead 2005 Woodhead M. Ortqvist A. Leven M. Cochrane Database of Systematic Reviews 2005. et al. Journal of Antimicrobial Chemotherapy 2003. Published by John Wiley & Sons. Hak E. Blasi F. Nielsen AD. Paul M. Robenshtok E. Paul 2007 Paul M. Gafter-Gvili A. Issue 2. New England Journal of Medicine 2007. Cox E.pub3] ∗ Indicates the major publication for the study Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.17(6):1–24. [DOI: 10. Ltd. References to other published versions of this review Robenshtok 2008 Robenshtok E. Woodhead 2011 Woodhead M.the FDA perspective.1002/14651858.26:1138–80.The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis. 356(16):1675–6.pub3] Shefet 2005 Shefet D. Cochrane Database of Systematic Reviews 2008. Soreth 2007 Soreth J. Kweder S. Diagnosis.CD004418.356(16):1601–4.CD004418. Paul M. Clinical Microbiology infections 2011. Huchon G. Ross 2007 Ross DB.community-acquired pneumonia. Bonten MJM.163 (7):1730–54. Empiric antibiotic coverage of atypical pathogens for communityacquired pneumonia in hospitalized adults. Gafter-Gvili A. assessment of severity. Galson S. 19 . and prevention. Jenkins J. Ieven M. [DOI: 10. Ortqvist A. The FDA and the case of Ketek.1002/ 14651858. European Respiratory Journal 2005. American Journal of Respiratory and Critical Care Medicine 2001. Leibovici L. Schneider MM. et al. Shefet D. Ewig S.52(4):555–63. Ketek . Huchon G. Issue 1.Guidelines for the management of adult lower respiratory tract infections.Guidelines for the management of adult lower respiratory tract infections. European Respiratory Journal 2007 May 30 [Epub ahead of print]. et al. Andreassen S. antimicrobial therapy. Vidal L. Ewig S. Tacconelli E. New England Journal of Medicine 2007. Almanasreh N. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults.

CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Aubier 1998 Methods Randomized Multicenter Participants Adults (mean age: 42) Hospitalized CAP Interventions Atypical: PO sparfloxacin 400 mg X 1/d followed by 200 mg X 1/d Non-atypical: PO amoxacillin 1 G X /d Outcomes Success: resolution of signs and symptoms Modification = failure Notes Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure High risk 266/329 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Low risk Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons. Ltd. 20 .

000. followed by PO azithromycin 500 mg X 1/d Non-atypical: IV benzylpenicillin 1. 21 . Ltd. aureus) and Klebsiella pneumonia (K. pneumophilae) Staphylococcus aureus (S. which was excluded from analysis Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure Unclear risk 64/66 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias High risk Not ITT (4/108 lost) Sponsored: grant from Pfizer Inc.Bohte 1995 Methods Randomized Multicenter Participants Adults (18 to 75. pneumonia) excluded) Hospitalized Interventions Atypical: PO azithromycin 500 mg X 2/d loading dose. age ~ 53) CAP . change of antibiotics Notes Study included a second comparison between erythromycin and azithromycin. Published by John Wiley & Sons.clinically suspected pneumococcal pneumonia (suspected Legionella pneumophilae (L. radiological. Blinding of participants and personnel High risk (performance bias) All outcomes None (open label) Blinding of outcome assessment (detection High risk bias) All outcomes None Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.000 IU X 4/d Outcomes Failure = clinical.

treatment modification Modification = failure Notes Severe pneumonia excluded Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure High risk 243/246 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias High risk Not ITT Sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Ltd.Carbon 1992 Methods Randomized Multicenter Participants Adults (mean age: 55) Hospitalized CAP (severe pneumonia excluded) Interventions Atypical: PO temafloxacin 600 mg X 2/d Non-atypical: PO amoxicillin 500 mg X 3/d Outcomes Failure = persistence of symptoms or signs. 22 . Published by John Wiley & Sons.

Published by John Wiley & Sons. 23 . including non-pneumonia Study in German Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None (open label) Blinding of outcome assessment (detection High risk bias) All outcomes None Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Chuard 1989 Methods Randomized Multicenter Participants Adults (mean ~ 66) 95% hospitalized 58% CAP (42% bronchitis or COPD exacerbation) Interventions Atypical: PO ofloxacin 200 mg X 2/d (several 400 mg X 2/d) Non-atypical: PO amoxicillin 750 mg X 3/d (several 375 mg X 4/d) Outcomes Clinical Notes Another trial reported in same study of non-randomized CAP suspected of atypical infection. relationship to this trial unclear Results given are for all patients. Ltd.

Feldman 2001
Methods

Randomized
Multicentered

Participants

Adults 18 to 70 (mean age: 43)
Hospitalized
~ 90% CAP; ~ 10% nosocomial

Interventions

Atypical: IV sitafloxacin 400 mg X 1/d
Non-atypical: IV imipenem/cilastatin 500 mg X 3/d

Outcomes

Clinical success (as defined by investigator)

Notes

Phase II trial

Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk
bias)

Computer-generated randomization code designed to
allocate equal numbers of patients to the 2 treatment
groups using the method of random-permutated blocks
of 4

Allocation concealment (selection bias)

Low risk

Sealed, serially-numbered envelopes, each containing details of the treatment allocation for a single patient

Incomplete outcome data (attrition bias)
Mortality

Low risk

All patients evaluated

Incomplete outcome data (attrition bias)
Failure

Low risk

All patients evaluated

Selective reporting (reporting bias)

Low risk

Not identified

Other bias

Unclear risk

Sponsored

Blinding of participants and personnel High risk
(performance bias)
All outcomes

None (open label)

Blinding of outcome assessment (detection High risk
bias)
All outcomes

None (open label)

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

24

Fourrier 1986
Methods

Randomized
Allocation A/B

Participants

Adults (no age mentioned)
Hospitalized
CAP; severe (per clinical)

Interventions

Atypical: PO pefloxacine 1200 mg/d
Non-atypical: customary antibiotics:
• beta lactam
• cephalosporin - AG
• anti-staphylococcal ABX

Outcomes

Failure = opposite of complete recovery

Notes

A lot of data missing (letter), even after correspondence with author
Study in French

Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk
bias)

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
Mortality

Low risk

All patients evaluated

Incomplete outcome data (attrition bias)
Failure

Low risk

All patients evaluated

Selective reporting (reporting bias)

High risk

Number of patients with bacteriologically documented
pathogen and pneumococcal pneumonia was lost (correspondence with author)

Other bias

Unclear risk

Sponsored

Blinding of participants and personnel High risk
(performance bias)
All outcomes

Maybe single-blinded - simple randomization

Blinding of outcome assessment (detection High risk
bias)
All outcomes

None

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

25

Genne 1997
Methods

Randomized

Participants

Adults (mean age: 70)
Hospitalized
CAP

Interventions

Atypical: IV clarythromycin 500 mg X 2/d 3 to 5/d , followed by PO clarythromycin
500 mg X 2/d
Non-atypical: IV amoxicillin-clavulanate 1.2 G X 4/d 3-5/d, followed by PO amoxicillinclavulanate 625 mg X 3/d

Outcomes

Failure = change of ABX, persistence or progression of sx/radiological finding, death, s/
e enabling completion of trial

Notes
Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk
bias)

Randomization was performed using sealed envelopes with random numbers

Allocation concealment (selection bias)

Low risk

Sealed opaque envelopes with numbers

Incomplete outcome data (attrition bias)
Mortality

High risk

112/127 patients evaluated

Incomplete outcome data (attrition bias)
Failure

Unclear risk

112/127 patients evaluated

Selective reporting (reporting bias)

Low risk

Not identified

Other bias

Unclear risk

Sponsored

Blinding of participants and personnel High risk
(performance bias)
All outcomes

None

Blinding of outcome assessment (detection High risk
bias)
All outcomes

None

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

26

bacteriological eradication • partial success = clinical improvement.Gleadhill 1986 Methods Randomized Participants Adults (mean 71) 46% CAP. bacteriological reduction/indeterminate • unsuccessful = clinical failure. 27 . 50% COPD exacerbation. Published by John Wiley & Sons. Ltd. regardless of bacteriological response • undetermined (assessment impossible) • moderation = ? Notes Less than 50% CAP Data analyzed only for pneumonia patients (given separately) Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality High risk 48/52 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 48/52 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsor? Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 4% acute bronchitis Hospitalized Interventions Atypical: PO ciprofloxacin 500 mg X 2/d Non-atypical: PO amoxicillin 250 mg X 3/d Outcomes Clinical and bacteriological: • complete success = clinical recovery.

Hatipoglu 2010 Methods Randomized Participants Adults (no age mentioned) Hospitalized CAP. Ltd. no correspondence Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Unclear risk Not described Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Unclear risk Not described Other bias Unclear risk Not enough data Blinding of participants and personnel Unclear risk (performance bias) All outcomes Not enough data Blinding of outcome assessment (detection Unclear risk bias) All outcomes Not enough data Hirata-Dulas 1991 Methods Randomized Participants Adults (mean age: 79) Nursing home residents Hospitalized Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. moderately-severe Interventions Atypical: ceftriaxone + clarithromycin Non-atypical: ceftriaxone Outcomes Success rate Incremental cost-effectiveness analysis Notes Data extracted from abstract. 28 . Published by John Wiley & Sons.

29 . early termination due to lack of improvement. Ltd.Hirata-Dulas 1991 (Continued) Nursing home-acquired lower respiratory tract infection (54 pneumonia. followed by IM ceftriaxone 1 G X 1/d Outcomes Success = resolution or marked improvement in clinical signs and symptoms of lower RTI and completion of 14 d treatment course Failure = all cause death. adverse event or superinfection Indeterminate = withdrawal due to protocol specification or to other factors unrelated to study drug administration Moderation = failure Notes Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None (unknown) Blinding of outcome assessment (detection High risk bias) All outcomes None (unknown) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. followed by PO ciprofloxacin 750 mg X 2/d (* protocol changed from 200 mg to 400 mg on 4/1989. Published by John Wiley & Sons. 6 acute bronchitis) Interventions Atypical: IV ciprofloxacin 200 mg/400 mg* X 2/d. 5/24 P in new protocol) Non-atypical: IV ceftriaxone 2 G X 1/d.

Ltd. no correspondence Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection High risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Unclear risk Not described Incomplete outcome data (attrition bias) Failure Unclear risk Not described Selective reporting (reporting bias) Unclear risk Not described Other bias Unclear risk Not enough data Blinding of participants and personnel Unclear risk (performance bias) All outcomes Not enough data Blinding of outcome assessment (detection Unclear risk bias) All outcomes Not enough data Kalbermatter 2000 Methods Randomized Participants Adults (mean age: 69 years) Hospitalized CAP. 30 .Hong-yun 2007 Methods Randomized Participants Adults (no age mentioned) Hospitalized CAP Interventions Atypical: iv gatifloxacin (400 mg) Non-atypical: iv cefuroxime (2 G) Outcomes Success: clinical and bacteriological Adverse reactions Notes Data extracted from abstract. Published by John Wiley & Sons. severe pneumonia was excluded Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.

Kalbermatter 2000 (Continued) Interventions Atypical: PO levofloxacin 500 mg X 2/d Non-atypical: IV amoxicillin/clavulanate 1 G X 3/d IV ceftriaxone 1 G X 2/d Outcomes Success = clinical and radiological Modification = failure Notes 3 arms. 31 . Ltd. Published by John Wiley & Sons. no isolation) CAP + nursing home-acquired + nosocomial Interventions Atypical: IV ciprofloxacin 200 mg X 2/d (5 patients received 300 mg X 2/d) Non-atypical: IV ceftazidime 1 to 2 G X 2/d to 3/d Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. amoxicillin/clavulanate and ceftriaxone calculated together as non-atypical arm Study in Spanish Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Not identified Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Khan 1989 Methods Randomized Participants Adults (mean age: 58) Severe bacterial respiratory tract infection (34/122 presumed bacterial.

good results suggest low rate of nosocomial pneumonia Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) Antibiotics were administered with a computer-generated.Khan 1989 (Continued) Outcomes Failure = continuation/worsening of signs and symptoms Notes Distribution of nosocomial pneumonia versus CAP unclear. randomized code Allocation concealment (selection bias) Low risk Antibiotics were administered in a sequential manner Incomplete outcome data (attrition bias) Mortality High risk 122/140 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 122/140 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Manufacturer/Pharmaceutical company sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Kobayashi 1984 Methods Randomized Participants Adults CAP + COPD (results given separately) Interventions Atypical: PO levofloxacin 200 mg X 3/d Non-atypical: PO amoxicillin 250 mg X 4/d Outcomes Notes Study in Japanese Risk of bias Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Ltd. 32 . Published by John Wiley & Sons.

radiological and laboratory Notes Study in Japanese Risk of bias Bias Authors’ judgement Random sequence generation (selection Low risk bias) Support for judgement Central. registration control system Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Ltd. Published by John Wiley & Sons. non-inferiority study Multicenter Participants Adults (mean age: 58. open-label.5) CAP mild to severe (70% moderate) Interventions Atypical: IV levofloxacin 500 mg X 1/d for 7 to 14 days Non-atypical: IV ceftriaxone 1 G X 2/d for 7 to 14 days Outcomes Success: clinical.Kobayashi 1984 (Continued) Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) High risk Inadequate Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure High risk 74/76 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Kohno 2011 Methods Randomized. 33 .

randomly allocated patients Incomplete outcome data (attrition bias) Mortality High risk 200/260 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 200/260 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Low risk Not identified Blinding of participants and personnel High risk (performance bias) All outcomes Open label trial Blinding of outcome assessment (detection Low risk bias) All outcomes A separate party committee evaluated the effects of the drugs. Ltd. not knowing which drug had been used Lephonte 2004 Methods Randomized Multicenter Participants Adults (mean age: 54) CAP Suspected pneumococcal pneumonia > 90% hospitalized Interventions Atypical: PO gemifloxacin 320 mg X 1/d for 1 week Non-atypical: amoxicillin/clavulanate 1 G/125 mg X 3/d for 10 days Outcomes Failure = clinical. bacteriological and radiological Notes Phase III Suspected pneumococcal pneumonia Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Not described Unclear risk Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Kohno 2011 (Continued) Allocation concealment (selection bias) Low risk Evaluator center. 34 . Published by John Wiley & Sons.

Lephonte 2004 (Continued) Incomplete outcome data (attrition bias) Mortality High risk 249/324 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 249/324 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Manufacturer/Pharmaceutical company sponsored No ITT analysis Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Lode 1995 Methods Randomized Multicenter Participants Adults (mean age: 54) Hospitalized and outpatients CAP Interventions Atypical: PO sparfloxacin 400 mg loading dose.no further data. radiological. short of stating the majority of patients were hospitalized Risk of bias Bias Authors’ judgement Random sequence generation (selection Unclear risk bias) Support for judgement Not described Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. in comparison to the non-atypical arm Note: also outpatients . Published by John Wiley & Sons. followed by PO sparfloxacin 200 mg X 1/d PO erythromycin 1 G X 2/d Non-atypical: PO amoxicillin-clavulanic acid 500/125 mg X 3/d Outcomes Failure = clinical. 35 . the two atypical arms were calculated as one. Ltd. change of antibiotics Modification = failure Notes 3 arms in 2:1:1 randomizations (sparfloxacin: amoxicillin-clavulanic acid: erythromycin) .

Published by John Wiley & Sons.Lode 1995 (Continued) Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Miki 1984 Methods Randomized Participants Adults Hospitalized Suspected bacterial pneumonia (CAP). small percentage of upper RTI Interventions Atypical: PO enoxacin 600 mg/d Non-atypical: PO amoxicillin 1 G/d Outcomes Notes Study in Japanese Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality High risk 145\147 patients evaluated Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Ltd. 36 .

drug study discontinued. followed by PO levofloxacin 500 mg X 2/d Non-atypical: IV ceftriaxone 4 G X 1/d Outcomes Cure = all infection related signs and symptoms disappeared or returned to pre-infection state and chest X-ray findings at least improved Failure = all infection related signs and symptoms unchanged or worsened. Ltd. nosocomial 6%) Interventions Atypical: IV levofloxacin 500 mg X 2/d. 37 . patient died due to the infection. patients developed new clinical findings consistent with active infection.Miki 1984 (Continued) Incomplete outcome data (attrition bias) Failure High risk 139/147 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Norrby 1998 Methods Randomized Multicenter Participants Adults (mean 65) Hospitalized Pneumonia (CAP 94%. computerized telephone system Allocation concealment (selection bias) Low risk Evaluator-blinded for selected patients Incomplete outcome data (attrition bias) Mortality High risk 619/625 patients evaluated Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons. one or more antibiotics added to drug due to treatment failure Notes CAP and nosocomial infection Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) Central.

Ltd. investigator. conducted by computer. conducted by an external evaluator for selected patients using blinded data Peterson 1988 Methods Randomized Participants Adults > 60 years old (mean: 81 years) Nursing home residents Hospitalized CAP/RTI Interventions Atypical: PO ciprofloxacin 750 mg X 2/d Non-atypical: IM cefamandole 1 G X 4/d Outcomes Success = improvement in signs and symptoms and patient not given another course of drug treatment for RTI within 6 weeks of discharge Notes 2/3 CAP. most data combined Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) Computer-generated random assignment code Allocation concealment (selection bias) Low risk Sealed envelopes Incomplete outcome data (attrition bias) Mortality Low risk All patients evaluated Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Norrby 1998 (Continued) Incomplete outcome data (attrition bias) Failure High risk 619/625 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored No ITT Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection Unclear risk bias) All outcomes Three types of assessments were performed according to the study protocol: protocol. conducted by the investigator and evaluator-blinded. Published by John Wiley & Sons. 38 . 1/3 RTI.

multicenter Participants Adults (mean age: 51) CAP: suspected pneumococcal pneumonia 79% hospitalized Interventions Atypical: PO moxifloxacin 400 mg X 1/d Non-atypical: PO Amoxicillin 1 G X 3/d Both for 10 days Outcomes Clinical response Failure = insufficient resolution of symptoms/death Notes Presumed pneumococcal pneumonia Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) Author confirmed in correspondence adequate methods Allocation concealment (selection bias) Low risk Author confirmed in correspondence adequate methods Incomplete outcome data (attrition bias) Mortality High risk 408/411 patients evaluated Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons. 39 . Ltd.Peterson 1988 (Continued) Incomplete outcome data (attrition bias) Failure Low risk All patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Petitpretz 2001 Methods Randomized Multinational.

Petitpretz 2001 (Continued) Incomplete outcome data (attrition bias) Failure High risk 408/411 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Rizzato 1997 Methods Randomized Multicenter Participants Age > 65 or 18 to 65 years + comorbidities (mean age: 68. followed by 400/200 mg X 1/d (per investigator’s discretion) + PO ciprofloxacin 500 mg X 2/d Non-atypical: IV ceftriaxone 2 G X 1/d Outcomes Clinical response: success (cure. improvement). Published by John Wiley & Sons. Ltd. failure and data could not be evaluated Notes Severe CAP. 40 . elderly or comorbidities Allegra 1995 is a double publication of this study Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality High risk 225/240 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 225/240 patients evaluated Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.5) Severe CAP: exclusion: “risk of death within 48h of study start” Hospitalized Interventions Atypical: IV teicoplanin 400 mg LD.

Published by John Wiley & Sons. 41 . Ltd.Rizzato 1997 (Continued) Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Romanelli 2002 Methods Randomized Multicenter Participants Elderly > 70 (mean age: 76) CAP Hospitalized Interventions Atypical: IV clarythromycin 500 mg + IV ceftriaxone 1 G X 2/d IV clarythromycin 500 mg + IV amikacin 250 mg X 2/d versus Non-atypical: IV meropenem 500 mg X 3/d IV imipenem/cilastatin 500 mg X 3/d Outcomes Clinical response Failure = no improvement or deterioration of signs and symptoms OR relapse Notes Elderly Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality High risk 204/226 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 204/226 patients evaluated Selective reporting (reporting bias) Low risk Not identified Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.

42 . Ltd. Secondary = bacteriological response Failure = lack of resolution of signs and symptoms/radiological failure/additional ABX given to patient Notes Adult defined as age > 16 years old (rather than 18 years old. as in other studies) Only 75% hospitalized Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Unclear risk bias) Not described Allocation concealment (selection bias) Unclear risk Not described Incomplete outcome data (attrition bias) Mortality High risk 335/344 patients evaluated Incomplete outcome data (attrition bias) Failure High risk 285/344 patients evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk Sponsored Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.Romanelli 2002 (Continued) Other bias Unclear risk Sponsored Blinding of participants and personnel High risk (performance bias) All outcomes None Blinding of outcome assessment (detection High risk bias) All outcomes None Tremolieres 1998 Methods Randomized Multicenter Participants Adults > 16 years old (mean age: 52) 75% hospitalized CAP: exclusion: high probability of atypical pneumonia Interventions Atypical: PO trovafloxacin 200 mg X 1/d Non-atypical: PO amoxicillin 1 G X 3/d Outcomes Primary = clinical response. Published by John Wiley & Sons.

Tremolieres 1998

(Continued)

Blinding of participants and personnel Low risk
(performance bias)
All outcomes

Double-blind

Blinding of outcome assessment (detection Low risk
bias)
All outcomes

Double-blind

Tremolieres 2005
Methods

Randomized
Multicenter

Participants

Adults > 18 years old (mean age: 48)
CAP

Interventions

Atypical: PO pristinamycin 1 G x 3
Non-atypical: amoxacillin 1 G x 3

Outcomes

Clinical failure, bacteriological failure, pneumococcal treatment failure, mortality, s/e

Notes

20% with COPD; 6.5% asthma

Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk
bias)

Not identified

Allocation concealment (selection bias)

Unclear risk

Not identified

Incomplete outcome data (attrition bias)
Mortality

High risk

285/342 patients evaluated

Incomplete outcome data (attrition bias)
Failure

High risk

285/342 patients evaluated

Selective reporting (reporting bias)

Low risk

Not identified

Other bias

Unclear risk

sponsored by Pfizer Center Research

Blinding of participants and personnel Low risk
(performance bias)
All outcomes

Double-blind, double dummy

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

43

Tremolieres 2005

(Continued)

Blinding of outcome assessment (detection Low risk
bias)
All outcomes

Double-blind

Vanderdonckt 1990
Methods

Randomized
Multicentre

Participants

Adults (mean 60)
Severe bronchopulmonary infections
Hospitalized

Interventions

Atypical: PO pefloxacin 400 mg X 2/d
Non-atypical: IV ceftazidime 2 G X 2/d

Outcomes

Success not defined in study
Bacteriological outcome

Notes

Severe infection = failure on previous treatment, multi-resistant pathogens, severe underlying disease, poor general condition

Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk
bias)

Not identified

Allocation concealment (selection bias)

Unclear risk

Not identified

Incomplete outcome data (attrition bias)
Mortality

Low risk

All patients evaluated

Incomplete outcome data (attrition bias)
Failure

High risk

156/170 patients evaluated

Selective reporting (reporting bias)

Low risk

Not identified

Other bias

Unclear risk

Unknown sponsorship

Blinding of participants and personnel High risk
(performance bias)
All outcomes

None

Blinding of outcome assessment (detection High risk
bias)
All outcomes

None

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
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44

Vogel 1991
Methods

Randomized
Multicenter

Participants

Adults (mean age: 62)
Hospitalized
CAP

Interventions

Atypical: PO temafloxacin 600 mg X 2/d
Non-atypical: IV cefotaxime 2 G X 3/d

Outcomes

Cure: all signs and symptoms resolved
Improvement: reduction of severity or numbers of signs and symptoms
Failure: evidence of fever or worsening of signs, symptoms or chest X-ray after 3 treatment
days
Modification = ?

Notes
Risk of bias
Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk
bias)

Not identified

Allocation concealment (selection bias)

Unclear risk

Not identified

Incomplete outcome data (attrition bias)
Mortality

Low risk

All patients evaluated

Incomplete outcome data (attrition bias)
Failure

High risk

75/100 patients evaluated

Selective reporting (reporting bias)

Low risk

Not identified

Other bias

Unclear risk

Sponsored

Blinding of participants and personnel High risk
(performance bias)
All outcomes

None

Blinding of outcome assessment (detection High risk
bias)
All outcomes

None

Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review)
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45

Zeluff 1988 Methods Randomized Participants Adults (mean age: 31. Ltd. all South-African black gold miners) Hospitalized Pneumococcal pneumonia per chest X-ray and sputum (analyzed only culture positive) Interventions Atypical: PO roxithromycin 150 mg X 2/d Non-atypical: PO cephradine 1 G X 2/d Outcomes Clinical response (= improvement of signs and symptoms and resolution of lung infiltrate) Notes Pneumococcal pneumonia in a young homogenous group Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) An allocation schedule of random numbers Allocation concealment (selection bias) Unclear risk Not identified Incomplete outcome data (attrition bias) Mortality High risk 158/160 participants evaluated Incomplete outcome data (attrition bias) Failure High risk 90/160 participants evaluated Selective reporting (reporting bias) Low risk Not identified Other bias Unclear risk ? sponsored Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind ABX: antibiotics CAP: community-acquired pneumonia COPD: chronic obstructive pulmonary disease IM: intramuscular ITT: intention-to-treat IV: intravenous LD: loading dose PO: per oral Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 46 . Published by John Wiley & Sons.

After consulting with the third review author (MP). including erythromycin The results of studies are combined.latter arm not differentiated to regimens with atypical coverage and those without such coverage Aubier 1996 Pooled analysis of 2 studies (1 = this paper) Sparfloxacin versus comparator arm. Ltd.RTI: respiratory tract infection s/e: side effects 1/d: once a day 2/d: two times a day 3/d: three times a day 4/d: four times a day Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Ailani 1999 Doxycycline versus standard therapy . data not given separately Katz 2004 In the typical arm. some may be nosocomial File 1997 Atypical coverage (macrolide or doxycycline) could be added to non-atypical arm at investigator’s discretion (if atypical pathogens were suspected or proven) Fink 1994 Of 402 participants randomized. 29 were non-randomized but included with randomized participants in the analysis Only 21/98 participants with pneumonia. follow-up setting and results. 47 . thus no differentiation between atypical and non-atypical coverage Note: very large study (N = 1137 Chokshi 2007 Retrospective observational cohort study Donowitz 1997 Outpatients Fass 1989 Study of general serious infections Of 98 participants. both in antibiotic regimen. Most probably outpatients. we had decided it was most probably outpatients and therefore excluded it 2. patients could receive azithromycin or/and flagyl Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 78% were diagnosed with nosocomial pneumonia Fong 1995 Outpatients Geijo Martinez 2002 Non-atypical group were given a macrolide optionally Hagberg 2002 Outpatients Hoepelman 1993 1. The data is consistent with outpatients (rather than hospitalized patients). not stated specifically in the text. Trial author did not reply to further enquires. Published by John Wiley & Sons. 9 of 99 patients with pneumonia. however.

Relevant studies were extracted and analyzed separately Lode 2004 Both ambulatory and hospitalized patients could be included in the study but that information was not recorded. the proportion of hospitalized patients is unknown Mendoca 2004 In the typical arm 11% received a macrolide antibiotic Mouton 1991 Non-atypical group were given amoxicillin and/or erythromycin O’Doherty 1997 Outpatients Ott 2008 Study of aspiration pneumonia and lung abscess Peacock 1987 Study of general serious infections. 89% were diagnosed with nosocomial pneumonia and only 11% diagnosed with CAP Sifuentes 1989 Study of general severe infections. Pneumonia patients 25/66. 310 were diagnosed with pneumonia. The first is included in our study and the second compares two quinolones. Ltd. concentrating on CAP patients with pneumococcal bacteraemia.(Continued) Khajotia 1990 Over 80% lower respiratory tract infection without parenchymal involvement per chest X-ray. Small number of pneumonia patients (7 and 4) Plouffe 1996 Ofloxacin versus standard therapy . the fifth is yet to be located Levine 1989 > 30% dropout rate (45/113 patients) Lode 1987 Study of general severe clinical infections. The third and the forth have insufficient data regarding the study populations and outcomes. Not published elsewhere Lode 1998 Retroactive analysis of 4 randomized clinical trials. Data of mortality not given separately Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Small number of pneumonia patients. No separate information given for the (15 + 7) patients with CAP Kinasewitz 1991 Outpatients Krumpe 1999 Study of treatment of severe infections: of 540 patients enrolled. some may be nosocomial (no response from trial author) Lode 1990 Reports 4 trials. Published by John Wiley & Sons. out of which 2 are included and 2 are excluded in this study. 48 . of whom more than 50% (57% of original patients) were diagnosed with nosocomial pneumonia Kuzman 2005 In the typical arm 30% received doxycycline Leophonte 1999 Meta-analysis of 5 trials. Therefore.latter arm not differentiated to regimens with atypical coverage and those without such coverage Rahav 2004 Outpatients Siami 1995 Of 54 randomized patients.

(Continued) Snydman 1995 Previously published (Fink 1994. Ltd. 49 . patients could receive erythromycin Wollschlager 1987 1. patients could receive macrolide Torres 2003 Outpatients Trenholme 1989 1. Bacterial bronchitis CAP: community-acquired pneumonia Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. excluded due to a high percentage of nosocomial pneumonia in enrolled patients) Stocks 1989 Outpatients Sujata 2008 In the typical arm. Over 50% of treated patients (27/44) were diagnosed with nosocomial pneumonia 2. Ciprofloxacin versus ceftazidime .when feasible. patients in latter group were switched to ANY alternative oral therapy Welte 2005 In the typical arm. Outpatients 2. Published by John Wiley & Sons.

83] 0.3 C 5 Mortality per allocation concealment 5.04] 21 5 1 3704 536 808 Risk Ratio (M-H. Fixed.69] 25 15 5444 3820 Risk Ratio (M-H. 1.1 Quinolone (atypical arm) 8. 95% CI) 1. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.70.66. 95% CI) Risk Ratio (M-H.3 Combined quinolone and macrolide (atypical arm) 8. Fixed. Fixed. 95% CI) 0.60] 1.84. Fixed.89 [0.0.34.37 [0. 2. Fixed. Fixed.99 [0.3 Combined quinolone and macrolide (atypical arm) 1. 95% CI) Risk Ratio (M-H. of studies No. 1. 1.62] 0. 95% CI) Risk Ratio (M-H.04] Statistical method Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 95% CI) 1.14 [0. Fixed. 95% CI) 1. 95% CI) Risk Ratio (M-H. Fixed.81.22 [0.0. 1.55] 7 18 0 25 16 0 9 12 12 28 1590 3854 0 5444 2290 0 3154 2143 2143 5419 Risk Ratio (M-H.2 Macrolide (atypical arm) 1.02] 1. 1.79.1 A 4.10 [0.14 [0. 95% CI) Risk Ratio (M-H.2 Macrolide (atypical arm) 8. 1.1 Non-blinded 6. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.89] 1.42 [0.81.29 [0.2 B 4. Fixed.79. 3. Fixed.2 Single-blind 6. 3.52.44] 1 398 Risk Ratio (M-H. 95% CI) 1.79.23 [0. Fixed.93 [0.per geographical area 3.55] 1.0] 1.93] 1. 95% CI) 1. 0.05 [0. 95% CI) 1. 1. Fixed.84.55] 1.0 [0.3 Double or triple-blind 7 Mortality . 1.81] 28 5419 Risk Ratio (M-H. 1.84.93 [0.14 [0. Ltd. 2. Effect size 50 .14 [0.65] 1.55] 1.62. 1. Fixed.81] 0.04 [0. 0.17] 1 371 Risk Ratio (M-H.84.0 [0. of participants 25 5444 Risk Ratio (M-H.25 [0.52. 1.98 [0.76.93 [0.15] 1.77.94] 8 1439 Risk Ratio (M-H.98 [0. 2.23 [0. 6.0] 1. Fixed.DATA AND ANALYSES Comparison 1. 1. 1. Published by John Wiley & Sons.20 [0. 95% CI) Risk Ratio (M-H. Fixed. 95% CI) Risk Ratio (M-H. Fixed. Fixed.07 [0.69.0.4 Pristinamycine (atypical arm) 9 Clinical failure per age No.01] 2. 95% CI) Risk Ratio (M-H.70. 1.14 [0. Fixed. 95% CI) Risk Ratio (M-H.2 North America 3. Fixed.11 [0.86] 0. Fixed. 95% CI) Risk Ratio (M-H. 2. Fixed.39] 1.50] 0.18 [0.2 Mean age over 65 years old 2. Fixed.2 B 5.ITT analysis 7.84.15] 0.84. Fixed. 95% CI) Risk Ratio (M-H. 0.72.0 [0. Fixed. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.22 [0. Fixed. 1.1 A 5.1 Quinolone (atypical arm) 1. 1. 1. 95% CI) 0. 95% CI) Risk Ratio (M-H. 1.0] 1.75. 95% CI) Risk Ratio (M-H.3 Other 4 Mortality per allocation generation 4.69] 2 25 14 3 8 25 185 5444 3209 232 2003 5444 Risk Ratio (M-H. Fixed. 1.14 [0. Fixed. 95% CI) 1.55] 19 4 1 3698 540 808 Risk Ratio (M-H. 1.21 [0. Fixed. 95% CI) 1.4 Pristinamycine (atypical arm) 2 Mortality per age 2. 10.3 Data unavailable 3 Mortality .68] 1. 95% CI) Risk Ratio (M-H.1 Europe 3.84. 95% CI) 0. 1.55] 10 15 0 25 1953 3491 0 5444 Risk Ratio (M-H.75. Fixed.72. 95% CI) Risk Ratio (M-H.37.3 C 6 Mortality per blinding 6.1 ITT (type 1) 8 Clinical failure per antibiotic (ABx) treatment 8.0 [0.68. Fixed. 1. Fixed.1 Mean age under 65 years old 2.79.38] 1. Atypical versus non-aytpical Outcome or subgroup title 1 Mortality per antibiotic (ABX) treatment 1.84. Fixed. Fixed.

Fixed.85 [0. 1.70 [0.80 [0. Fixed. Fixed.ITT analysis 14.41. 0.98] 8 13 24 16 708 1602 4918 4129 Risk Ratio (M-H.requiring discontinuation of treatment 15 3554 Risk Ratio (M-H. Fixed. 1.02] 7. Fixed.3 Double or triple-blind 14 Clinical failure .22 [0. 95% CI) 0.1 Overall 20 Bacteriological failure per allocation generation 20.05] 0. 0.06] 8 1439 Risk Ratio (M-H. 51 . Fixed. 0.91 [0. 1. 95% CI) Risk Ratio (M-H.97 [0.53.12] 0. 95% CI) 0. 1. 95% CI) Risk Ratio (M-H.63. 1.02] 0. 0. 95% CI) 1.02 [0.0 [0.49. Fixed. 1.64] 0. Fixed.01 [0. 1.0] 0. 0.75. 95% CI) Risk Ratio (M-H.59. 95% CI) Risk Ratio (M-H. Fixed. 1. Fixed.04] 15 3 10 28 3084 232 2103 5419 Risk Ratio (M-H.97 [0.10] 5 43 Risk Ratio (M-H. 0. 95% CI) Risk Ratio (M-H.1 A 11. Fixed.50] 0.52 [0.99 [0.90.88.93 [0.05.59.02] 7.77. 1.2 Non-sponsored trials 18.85 [0. Fixed.19] 0.2 B 12. 1.1 Europe 10.61.98] 0.80 [0.3 Data unavailable 10 Clinical failure per geographical area 10. 95% CI) Risk Ratio (M-H.3 Unclear sponsorship 19 Bacteriological failure 19. Fixed.1 A 20. Fixed.82.3 C 13 Clinical failure per blinding 13. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.93 [0. Fixed. 1. Fixed. 95% CI) Risk Ratio (M-H. Fixed. Fixed. 1.98] 0.92 [0. 95% CI) 0.74.1 Sponsored trials 18.1 A 12.13] 0. 95% CI) 0. Fixed. Fixed. 95% CI) 0. Fixed.29 [0.3 Other 11 Clinical failure per allocation generation 11. 1. 95% CI) Risk Ratio (M-H.90 [0.02 [0.05] 6 601 Risk Ratio (M-H.2 B 21 Adverse events .93 [0. 95% CI) 1. 1.90 [0. 95% CI) 0.0.79. Fixed.92] 12 3806 Risk Ratio (M-H. 1. Fixed. Fixed.93 [0. Published by John Wiley & Sons.76. 1.84.84.17 [0.98] 0. 95% CI) Risk Ratio (M-H.81.84.3 Non-ITT. 95% CI) Risk Ratio (M-H. 1.total 22 Adverse events .41] Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Fixed.15] 18 1021 Risk Ratio (M-H.2 Single-blind 13.3 C 12 Clinical failure per allocation concealment 12. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.86. 1.24] 0. 95% CI) 0.65. 95% CI) 0. 95% CI) 0. 95% CI) Risk Ratio (M-H.65.84.29 [0.19] 0.84. 95% CI) Risk Ratio (M-H. Ltd. 95% CI) Risk Ratio (M-H. Fixed. 1. Fixed.1 ITT studies (type 1) 14. 95% CI) Risk Ratio (M-H. Fixed. 1. Fixed. 0. 95% CI) 1.2 Mean age over 65 years old 9.pneumococcal pneumonia 16 Clinical failure .99 [0.85. 95% CI) Risk Ratio (M-H. 130.04] 0. 0.1 Mean age under 65 years old 9.93 [0.1 Non-blinded 13.08] 1. dropouts cannot be calculated (type 3) 15 Clinical failure .93 [0. 1.04] 10 17 1 28 1878 3467 74 5419 Risk Ratio (M-H.93] 0.04] 7 20 1 28 18 0 10 28 7 15 1583 3762 74 5419 2415 0 3004 5682 1232 3849 Risk Ratio (M-H.82.41.80 [0. 95% CI) 0.76 [0. 95% CI) Risk Ratio (M-H. Fixed.77.64.90 [0. Fixed. Fixed.2 North America 10. Fixed. 1.04] 0. 0. Fixed. 95% CI) Risk Ratio (M-H.atypical pathogens 17 Clinical failure .32] 0.90 [0. Fixed. 130.63] 28 21 3 4 21 21 21 5419 4540 288 591 2310 2310 2310 Risk Ratio (M-H.06 [0. Fixed.80.24.11] 0.07 [0.72. 1.10] 5 28 426 5419 Risk Ratio (M-H.93 [0.93. 1.67 [0. 95% CI) Risk Ratio (M-H.84.70] 4 158 Risk Ratio (M-H.45] 1. 1.gastrointestinal events 23 Adverse events .96] 1.2 Dropouts assumed as failure (type 2) 14.9. 1.64] 0.94 [0.84. 95% CI) Risk Ratio (M-H. 95% CI) Risk Ratio (M-H.Legionella pneumophilae 18 Clinical failure per sponsorship 18.2 B 11.62] 0. 95% CI) Risk Ratio (M-H.65. 1.93 [0. Fixed. Fixed.

33.46 [ 0. 2.95% CI 1 Quinolone (atypical arm) Subtotal (95% CI) Total events: 57 (Atypical ABX).19.0 % 0.48.13 [ 0. . Ltd.1 Favors atypical 1 10 500 Favors non-atypical (Continued . 7.20 ] Peterson 1988 3/30 1/30 1.93 ] Norrby 1998 21/314 22/305 29.5 % 0.5 % 1.47 ] Feldman 2001 1/35 0/34 0.01. df = 13 (P = 0.95% CI Risk Ratio M-H.1. 52 .93 [ 0.00 [ 0.22 [ 0. 27.30 [ 0. Published by John Wiley & Sons.78 [ 0. 1.39 ] Petitpretz 2001 3/200 4/208 5.6 % 0.Analysis 1.85 ] Aubier 1998 1/159 3/170 3.34.84 ] Lephonte 2004 4/167 3/153 4.2 % 0.8 % 0.69. 5.93 ] Hirata-Dulas 1991 2/24 2/26 2.26. 5.28.15 [ 0.52. 4.04. 57 (Non-atypical ABX) Heterogeneity: Chi2 = 5.97).73 ] Rizzato 1997 7/110 5/115 6. 7.3 % 3.65 ] Fourrier 1986 5/20 5/20 6. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 1 Mortality per antibiotic (ABX) treatment Study or subgroup Atypical ABX Non-atypical ABX n/N n/N Risk Ratio Weight Vanderdonckt 1990 0/82 0/88 Not estimable Gleadhill 1986 0/26 0/22 Not estimable Miki 1984 0/73 0/72 Not estimable Kalbermatter 2000 0/28 0/56 Not estimable Chuard 1989 0/59 0/62 Not estimable Vogel 1991 0/49 3/51 4.85 [ 0.18. 3.08 [ 0.0% Test for overall effect: Z = 0.12. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.1 % 1.39 ] M-H. Comparison 1 Atypical versus non-aytpical.98 [ 0.6 % 1.36 [ 0. 5.Fixed.11 (P = 0.37 ] Tremolieres 1998 4/173 3/169 4.3 % 1. 1.10 ] Khan 1989 4/66 3/56 4.91) 2 Macrolide (atypical arm) Bohte 1995 0/36 0/30 Not estimable 0. 4.9 % 0.5 % 1.17.002 0. Outcome 1 Mortality per antibiotic (ABX) treatment. 2.92 [ 0.7 % 2. 3.44 ] Kohno 2011 2/108 2/92 2.12. 69. I2 =0.Fixed.80 ] Carbon 1992 0/125 1/121 2.00 [ 0.30.2 % 0.01.0 % 1. .23 ] 1848 1850 78.32 [ 0.

002 0.81. 10.81.69 ] Subtotal (95% CI) 200 198 2.44 ] 609 199 8.80 ] Genne 1997 2/56 1/56 1. df = 18 (P = 0. 53 .0% Test for overall effect: Z = 0. 21. 8 (Non-atypical ABX) Heterogeneity: Chi2 = 0.(. 6. 2.43 ] Zeluff 1988 1/80 0/78 0. 3.3 % 2.58.7 % 2.01 ] 28/609 4/199 8.79 (P = 0.98 [ 0.39) Test for subgroup differences: Chi2 = 2. I2 =0.0 % 1. df = 2 (P = 0. .0 % 2. Study or subgroup Atypical ABX Non-atypical ABX Risk Ratio Weight n/N n/N 7/101 7/103 9.98 [ 0.57 (P = 0.88.37.00 [ 0. 2 (Non-atypical ABX) Heterogeneity: not applicable Test for overall effect: Z = 0.12) 4 Pristinamycine (atypical arm) Tremolieres 2005 4/200 2/198 2.97). 6.55 ] Total events: 4 (Atypical ABX).41). I2 =0.42.2 % 1. df = 3 (P = 0.0% 0. 1. Ltd.52.62) 3 Combined quinolone and macrolide (atypical arm) Lode 1995 Subtotal (95% CI) Total events: 28 (Atypical ABX).7 % 1.69 ] 2514 100.75).95% CI Total events: 10 (Atypical ABX).14 [ 0.29 [ 0. 4 (Non-atypical ABX) Heterogeneity: not applicable Test for overall effect: Z = 1.12.85 (P = 0.43) Total (95% CI) 2930 Total events: 99 (Atypical ABX).75 ] 273 267 11.Fixed. .19. I2 =0. Published by John Wiley & Sons. 71 (Non-atypical ABX) Heterogeneity: Chi2 = 8. 70.29 [ 0.1 Favors atypical 1 10 500 Favors non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.37.37.95% CI Continued) Risk Ratio M-H.7 % 1.02 [ 0.0 % 2.25 [ 0.84.93 [ 0. 10.Fixed.2 % 1.50 (P = 0.0% Test for overall effect: Z = 0.44 ] Romanelli 2002 Subtotal (95% CI) M-H.

3 % 1.32 [ 0.85 [ 0.83).00 [ 0.8 % 0.12.7 % 1. Outcome 2 Mortality per age. 1.80 ] Zeluff 1988 1/80 0/78 0.95% CI Risk Ratio M-H.Analysis 1.Fixed.20 ] Kalbermatter 2000 0/28 0/56 Khan 1989 4/66 3/56 4.7 % 2.12.15 [ 0. 54 . 2. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.7 % 2.73 ] Tremolieres 2005 4/200 2/198 2. 21.2 % 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 2 Mortality per age Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 1/159 3/170 Bohte 1995 0/36 0/30 Carbon 1992 0/125 1/121 2.17.19.05 0. 70.6 % 0. Published by John Wiley & Sons. 1.30.0 % 2.92 [ 0.29 [ 0.65 ] 3/30 1/30 1.08 [ 0.30 [ 0. 3.18.37.13 [ 0.37 ] 28/609 4/199 8.85 ] Feldman 2001 1/35 0/34 0.0 % 1. .44 ] Petitpretz 2001 3/200 4/208 5. 28 (Non-atypical ABx) Heterogeneity: Chi2 = 6. .22 [ 0.98 [ 0.52.3 % 3. 5. 5.12.0% Test for overall effect: Z = 0.9 % 0. Ltd.Fixed.95% CI 1 Mean age under 65 years old Lode 1995 Subtotal (95% CI) 3.2 Favours atypical 1 5 20 Favours non-atypical (Continued . 3.36 [ 0.28. 6.33.10 ] 21/314 22/305 29.26. df = 11 (P = 0. 27.3 % 2.44) 2 Mean age over 65 years old Chuard 1989 0/59 0/62 Genne 1997 2/56 1/56 Gleadhill 1986 0/26 0/22 Hirata-Dulas 1991 2/24 2/26 2. 4.5 % 0.93 ] Lephonte 2004 4/167 3/153 4.43 ] Not estimable 0.9 % 1.93 [ 0. 69. 10.75.39 ] Not estimable Not estimable Not estimable Total events: 52 (Atypical ABx).81.78 [ 0. I2 =0.93 [ 0. 7.5 % 1.0 % 0.60.01.78 (P = 0. 5.69 ] Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 4.75 ] 2117 1703 42.94 ] M-H.23 ] Norrby 1998 Peterson 1988 Not estimable 1.84 ] Kohno 2011 2/108 2/92 2.04.01.21 [ 0. Comparison 1 Atypical versus non-aytpical.2.1 % 1.00 [ 0. 7.44 ] Tremolieres 1998 4/173 3/169 4.

0 % 1.84. Ltd.00 [ 0.Fixed. 55 .80 ] 720 719 50. .0% 0.90).69 ] 6.72. 4.55 ] Subtotal (95% CI) Not estimable Total events: 5 (Atypical ABx).2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.2 % 1.14.93 ] Subtotal (95% CI) M-H.97).37.6 % 1. df = 2 (P = 0. I2 =0.42.5 % 1.02 [ 0.Fixed. 38 (Non-atypical ABx) Heterogeneity: Chi2 = 1.0 (P = 1.93 ] 2514 100.0) Total (95% CI) 2930 Total events: 99 (Atypical ABx).85 (P = 0.48.05 0.39) Test for subgroup differences: Chi2 = 0.93).4 % 1.10 [ 0. Published by John Wiley & Sons.34.34.95% CI Continued) Risk Ratio M-H.47 ] Romanelli 2002 7/101 7/103 9.0% Test for overall effect: Z = 0.0% Test for overall effect: Z = 0.65) 3 Data unavailable Fourrier 1986 5/20 5/20 Miki 1984 0/73 0/72 93 92 6.6 % 1. 1. df = 5 (P = 0. I2 =0.46 [ 0. 2.95% CI Total events: 42 (Atypical ABx). . 2.46 (P = 0. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N Rizzato 1997 7/110 5/115 6. 71 (Non-atypical ABx) Heterogeneity: Chi2 = 8. 1. I2 =0.00 [ 0.65. df = 18 (P = 0. 5 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: Z = 0.(.14 [ 0. 2.

per geographical area Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 1/159 3/170 Bohte 1995 0/36 0/30 Carbon 1992 0/125 1/121 Chuard 1989 0/59 0/62 Fourrier 1986 5/20 5/20 6. 10.81.84 ] Peterson 1988 3/30 1/30 1.13 [ 0.7 % 2. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 3 Mortality .93 ] Genne 1997 2/56 1/56 1.17. 5.32 [ 0. I2 =0.01.34. 7. 2.04. 4.10 ] Khan 1989 4/66 3/56 4.86 ] 0/34 0.33.5 % 1. 34 (Non-atypical ABx) Heterogeneity: Chi2 = 6.7 % 1.Fixed.2 % 1. 21.95% CI Risk Ratio M-H.0 % 0. Ltd. df = 9 (P = 0. 7.3.12.2 Favours atypical 1 5 20 Favours non-atypical (Continued . Outcome 3 Mortality .89 ] M-H.36 [ 0.8 % 0.37. I2 =0.52.05 0.23 ] 120 112 8.44 ] Rizzato 1997 7/110 5/115 6.3 % 1.00 [ 0.80 ] 1805 1404 48.92 [ 0.48. .43 ] Gleadhill 1986 0/26 0/22 28/609 4/199 8.Analysis 1.39 ] Not estimable 2.08 [ 0.73 ] Tremolieres 2005 4/200 2/198 2.19.79.3 % 3.26.47 ] Romanelli 2002 7/101 7/103 9. df = 2 (P = 0. 27.05.46 [ 0.0 % 1.62. 6.29 [ 0.30.30 [ 0. Published by John Wiley & Sons.0% Test for overall effect: Z = 0. 2.74).49) 3 Other Feldman 2001 1/35 0. 3. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.98 [ 0. 56 .42 [ 0.36) 2 North America Hirata-Dulas 1991 2/24 2/26 2.01. 4.0% Test for overall effect: Z = 0.69 (P = 0. Comparison 1 Atypical versus non-aytpical.37. 1. 2.69 ] Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 4.5 % 1.7 % 1.95% CI 1 Europe Lode 1995 Subtotal (95% CI) 3.02 [ 0.5 % 0.74).00 [ 0.0 % 2.00 [ 0.2 % 1.92 (P = 0. 69.3 % 2.22 [ 0.15 [ 0.80 ] Tremolieres 1998 4/173 3/169 4. 3.per geographical area.20 ] Subtotal (95% CI) Total events: 9 (Atypical ABx).Fixed.85 ] Not estimable Not estimable Not estimable Total events: 58 (Atypical ABx). 6 (Non-atypical ABx) Heterogeneity: Chi2 = 0. .6 % 1.

44 ] 1/80 0/78 0.14 [ 0.0% Test for overall effect: Z = 0.98) Total (95% CI) 2930 Total events: 99 (Atypical ABx).37 ] 0/73 0/72 21/314 22/305 29.18.0 % 1. df = 2 (P = 0. 3.Fixed. I2 =0.12.61. df = 5 (P = 0. 1.1 % 0.02 (P = 0.85 [ 0.95% CI M-H.60 ] 2514 100. 57 .65 ] 3/200 4/208 5.6 % 0.95% CI Not estimable Not estimable Total events: 32 (Atypical ABx).62.9 % 0.75 ] 1005 998 43. Ltd.28. I2 =0. 5. .(.22 [ 0.99 [ 0. 1.0% Test for overall effect: Z = 0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.93 ] Lephonte 2004 4/167 3/153 4.97).Fixed. Published by John Wiley & Sons.74).85 (P = 0. Atypical ABx n/N n/N Kalbermatter 2000 0/28 0/56 Kohno 2011 2/108 2/92 2.2 % 0.05 0.39) Test for subgroup differences: Chi2 = 0.93 [ 0. df = 18 (P = 0.14.7 % 2.12. 71 (Non-atypical ABx) Heterogeneity: Chi2 = 8. 1. .78 [ 0.93 [ 0. 5.52.84. 31 (Non-atypical ABx) Heterogeneity: Chi2 = 1.0% 0.95).55 ] Miki 1984 Norrby 1998 Petitpretz 2001 Zeluff 1988 Subtotal (95% CI) Non-atypical ABx Risk Ratio Weight Continued) Risk Ratio Study or subgroup M-H. 70.42.1 % 1. I2 =0.

6.5 % 1.28.19.92 [ 0. 27.4. df = 7 (P = 0.36 [ 0. 3.95% CI Risk Ratio M-H.05 0.46 [ 0.01. 4.07 [ 0. 4.Fixed.12. 5.6 % 1.95% CI 1A Zeluff 1988 Subtotal (95% CI) Not estimable Not estimable Total events: 37 (Atypical ABx). ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.34.84 ] Kohno 2011 2/108 2/92 2. 21.Analysis 1. 1.37 ] 28/609 4/199 8.75 ] 976 977 45. Outcome 4 Mortality per allocation generation.33.00 [ 0.1 % 1. 3.22 [ 0.39 ] M-H.80 ] Lephonte 2004 Lode 1995 Miki 1984 Not estimable Not estimable Not estimable 0.12.9 % 0.52.93 [ 0.23 ] Petitpretz 2001 3/200 4/208 5.18.Fixed.0% Test for overall effect: Z = 0. I2 =0. 69. .7 % 2.44 ] 0/73 0/72 Rizzato 1997 7/110 5/115 6.47 ] Romanelli 2002 7/101 7/103 9.94).76) 2B Aubier 1998 1/159 3/170 Bohte 1995 0/36 0/30 Carbon 1992 0/125 1/121 2. . 2. 58 .0 % 0.68.65 ] Peterson 1988 3/30 1/30 1.3 % 1.2 Favours atypical 1 5 20 Favours non-atypical (Continued .04.6 % 0.9 % 1.13 [ 0.37.93 ] Norrby 1998 21/314 22/305 29. 7.85 ] Fourrier 1986 5/20 5/20 6.78 [ 0.29 [ 0.5 % 1.8 % 0. Published by John Wiley & Sons.00 [ 0. Ltd. 33 (Non-atypical ABx) Heterogeneity: Chi2 = 2.08 [ 0.93 ] Gleadhill 1986 0/26 0/22 Hirata-Dulas 1991 2/24 2/26 2.31 (P = 0.93 [ 0. 2. 7. 5.3 % 3.32 [ 0.2 % 0.12.68 ] 3.26.81. Comparison 1 Atypical versus non-aytpical. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 4 Mortality per allocation generation Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Chuard 1989 0/59 0/62 Feldman 2001 1/35 0/34 0.20 ] Genne 1997 2/56 1/56 1.17. 70.43 ] Kalbermatter 2000 0/28 0/56 Khan 1989 4/66 3/56 4.48. 1.35.85 [ 0.00 [ 0.10 ] 4/167 3/153 4.44 ] 1/80 0/78 0.02 [ 0.2 % 1.0 % 2.7 % 2.3 % 2.

0 % 1.97). . 5.0% Test for overall effect: Z = 0.82).89. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N Tremolieres 1998 4/173 3/169 4. .98 [ 0. Ltd.79. df = 1 (P = 0.55 ] Total events: 99 (Atypical ABx).0 % 1. Published by John Wiley & Sons.20 [ 0.95% CI Continued) Risk Ratio M-H.01.73 ] Tremolieres 2005 4/200 2/198 2. 2.1 % 1.80 ] 1954 1537 54.14 [ 0.0% 0.86 (P = 0.Fixed.0% Test for overall effect: Z = 0.84.(.95% CI Not estimable Total events: 62 (Atypical ABx).5 % 0.37.69 ] Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 4. 71 (Non-atypical ABx) Heterogeneity: Chi2 = 8.85 (P = 0.12. 1. 38 (Non-atypical ABx) Heterogeneity: Chi2 = 5.7 % 1.30 [ 0.39) 3C Subtotal (95% CI) 0 0 Not estimable Total events: 0 (Atypical ABx). 59 . 10. 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: not applicable Total (95% CI) 2930 2514 100.81 ] Subtotal (95% CI) M-H. df = 10 (P = 0.39) Test for subgroup differences: Chi2 = 0.42.15 [ 0.Fixed. df = 18 (P = 0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. I2 =0.73). I2 =0.05 0. I2 =0.30. 1.

6.92 [ 0.28.5 Favours atypical 1 2 5 10 Favours non-atypical (Continued .19.00 [ 0.85 ] Not estimable 6.3 % 2.84 ] Kohno 2011 2/108 2/92 2.94. Ltd.12.18.36 [ 0.3 % 3. 3.7 % 2.34.93 ] Norrby 1998 21/314 22/305 29.33.01.65 ] Peterson 1988 3/30 1/30 1. 5.0 % 0.8 % 0. 5. 21.93).85 [ 0. I2 =0.Fixed. 4. Comparison 1 Atypical versus non-aytpical.00 [ 0.9 % 0.44 ] 809 781 45.73 ] Lephonte 2004 Lode 1995 Miki 1984 Not estimable 2.Analysis 1. 69. 1.0 % 1.95% CI Risk Ratio M-H.37 ] 28/609 4/199 8.32 [ 0. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.39 ] M-H.37.05 [ 0.5 % 1.66.0 % 2.95% CI 1A Subtotal (95% CI) Total events: 36 (Atypical ABx).6 % 1.81.23 ] Petitpretz 2001 3/200 4/208 5.0% Test for overall effect: Z = 0.2 % 1.12.20 (P = 0.2 % 0.02 [ 0. Published by John Wiley & Sons.43 ] Khan 1989 4/66 3/56 4.3 % 1.6 % 0.1 % 1.04.10 ] Not estimable Not estimable 0.78 [ 0.48.47 ] Romanelli 2002 7/101 7/103 9. 60 .84) 2B Aubier 1998 1/159 3/170 Bohte 1995 0/36 0/30 Carbon 1992 0/125 1/121 Chuard 1989 0/59 0/62 Fourrier 1986 5/20 5/20 Gleadhill 1986 0/26 0/22 Hirata-Dulas 1991 2/24 2/26 Kalbermatter 2000 0/28 0/56 4/167 3/153 4. 2.Fixed. 7.65 ] 3.29 [ 0.46 [ 0.5.20 ] Genne 1997 2/56 1/56 1.30 [ 0. 33 (Non-atypical ABx) Heterogeneity: Chi2 = 1. . Outcome 5 Mortality per allocation concealment.08 [ 0.44 ] 0/73 0/72 Rizzato 1997 7/110 5/115 6. 3.93 [ 0.1 0.17. 7. 27. 5.5 % 1.30.52. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 5 Mortality per allocation concealment Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Feldman 2001 1/35 0/34 0.80 ] Tremolieres 1998 4/173 3/169 4.93 ] Not estimable 2. 2.13 [ 0. 4.22 [ 0. 1. .2 0.00 [ 0.3 % 1. df = 6 (P = 0.26.

93 [ 0. df = 1 (P = 0.80 ] Zeluff 1988 1/80 0/78 0.(.0% Test for overall effect: Z = 0.97). .1 0. 38 (Non-atypical ABx) Heterogeneity: Chi2 = 6.34) 3C Subtotal (95% CI) 0 0 Not estimable Total events: 0 (Atypical ABx). 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: not applicable Total (95% CI) 2930 2514 100. .85 (P = 0.62).39) Test for subgroup differences: Chi2 = 0.95% CI 2. df = 11 (P = 0. Ltd.75 ] 2121 1733 54. 70. df = 18 (P = 0.81.19.7 % 1.Fixed.24.95% CI Continued) Risk Ratio M-H. I2 =0.5 Favours atypical 1 2 5 10 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.0 % 1. 61 . I2 =0.5 % 0.2 0.14 [ 0.69 ] Not estimable Total events: 63 (Atypical ABx). 2.95 (P = 0. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N 4/200 2/198 Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 4. I2 =0.7 % 1.7 % 2.37.84.55 ] Total events: 99 (Atypical ABx). 10.0% Test for overall effect: Z = 0.42.83 ] Tremolieres 2005 Subtotal (95% CI) M-H.0% 0.Fixed. 71 (Non-atypical ABx) Heterogeneity: Chi2 = 8.15 [ 0. 1.22 [ 0. Published by John Wiley & Sons.86).12.98 [ 0.01. 1.

df = 10 (P = 0.37.92 [ 0.95).93 ] Norrby 1998 21/314 22/305 29.Analysis 1.21 (P = 0. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.3 % 3.5 % 0.04 [ 0.15 [ 0.12.01.9 % 0. 62 .20 ] Fourrier 1986 5/20 5/20 6. 21. 7.05 0.34. 4. 1.95% CI Risk Ratio M-H. 69.10 ] Not estimable Not estimable Total events: 54 (Atypical ABx).26. Comparison 1 Atypical versus non-aytpical.84 ] Kohno 2011 2/108 2/92 2. 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: not applicable 3 Double or triple-blind Aubier 1998 1/159 3/170 3.52. .3 % 2. Published by John Wiley & Sons.93 ] Genne 1997 2/56 1/56 1.0% Test for overall effect: Z = 0. 51 (Non-atypical ABx) Heterogeneity: Chi2 = 3.19.2 Favours atypical 1 5 20 Favours non-atypical (Continued .43 ] Gleadhill 1986 0/26 0/22 Hirata-Dulas 1991 2/24 2/26 Kalbermatter 2000 0/28 0/56 Khan 1989 4/66 3/56 4.3 % 1.33. I2 =0.93 [ 0.85 ] 0.Fixed.8 % 0.48. 2.32 [ 0.00 [ 0.47 ] Romanelli 2002 7/101 7/103 9.5 % 1.72.17.6 % 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 6 Mortality per blinding Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Bohte 1995 0/36 0/30 Not estimable Chuard 1989 0/59 0/62 Not estimable Feldman 2001 1/35 0/34 0. 2.04.02 [ 0. 4.65 ] 3/30 1/30 1. 7.39 ] Carbon 1992 0/125 1/121 2. . 27.80 ] 1144 1146 69. Outcome 6 Mortality per blinding. 2.6 % 1.12.6.84. Ltd.23 ] Rizzato 1997 7/110 5/115 6.13 [ 0.83) 2 Single-blind Subtotal (95% CI) 0 0 Not estimable Total events: 0 (Atypical ABx).01.80 ] Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 4.0 % 0.95% CI 1 Non-blinded Peterson 1988 Subtotal (95% CI) Not estimable 2. 5.4 % 1.5 % 1.08 [ 0. 1.00 [ 0.00 [ 0. 3.36 [ 0.46 [ 0.50 ] M-H.2 % 1.85 [ 0.Fixed.7 % 2.

6 % 1. 6.30.22 [ 0.14 [ 0.44 ] 0/73 0/72 Petitpretz 2001 3/200 4/208 5.7 % 1.28. df = 18 (P = 0.78 [ 0.77). Published by John Wiley & Sons. I2 =0.79.30 [ 0. 3.37. I2 =0.85 (P = 0.0% Test for overall effect: Z = 0.67.(.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.38 ] 2514 100.93 [ 0.44 ] Tremolieres 1998 4/173 3/169 4.95% CI Continued) Risk Ratio M-H.37 ] 28/609 4/199 8. Ltd.84. 10.05 0. 70. df = 7 (P = 0.0 % 1.0 % 1.08.75 ] 1786 1368 30.42. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N 4/167 3/153 4.29 [ 0.98 [ 0.81.26) Total (95% CI) 2930 Total events: 99 (Atypical ABx).Fixed.12. df = 1 (P = 0.39) Test for subgroup differences: Chi2 = 0.7 % 2.0% 0.Fixed. I2 =0. 2.0 % 2.1 % 1.73 ] Tremolieres 2005 4/200 2/198 2. 20 (Non-atypical ABx) Heterogeneity: Chi2 = 4. 1.12 (P = 0.0% Test for overall effect: Z = 1.97). .2 % 0. 71 (Non-atypical ABx) Heterogeneity: Chi2 = 8. 5.69 ] 1/80 0/78 0.37 [ 0.41). 63 .55 ] Lephonte 2004 Lode 1995 Miki 1984 Zeluff 1988 Subtotal (95% CI) M-H.18.95% CI Not estimable Total events: 45 (Atypical ABx). 5. .

15 ] M-H.4 % 1.72 (P = 0.23 ] Vanderdonckt 1990 0/82 0/88 Vogel 1991 0/49 3/51 15.20 ] Fourrier 1986 5/20 5/20 22. 2. 64 .04.23 [ 0.Fixed.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Outcome 7 Mortality .70.Analysis 1.93 ] Hirata-Dulas 1991 2/24 2/26 8.39 ] Not estimable 6. 3.85 ] Not estimable Not estimable Not estimable Total events: 40 (Atypical ABx).80 ] 1256 887 100. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 7 Mortality . 6.0 % 0.36 [ 0.08 [ 0.44 ] Peterson 1988 3/30 1/30 4. Ltd.00 [ 0.0 % 1. I2 =0.17.15 [ 0. 7.5 % 3.4 % 0.00 [ 0.32 [ 0.8 % 0. Published by John Wiley & Sons.05 0.Fixed. 19 (Non-atypical ABx) Heterogeneity: Chi2 = 6.0% Test for overall effect: Z = 0.01.33.12.3 % 2. Comparison 1 Atypical versus non-aytpical.92 [ 0. 69.51).01.0 % 2.47) Test for subgroup differences: Not applicable 0.ITT analysis.ITT analysis Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 1/159 3/170 Bohte 1995 0/36 0/30 Carbon 1992 0/125 1/121 Chuard 1989 0/59 0/62 Feldman 2001 1/35 0/34 2.95% CI Risk Ratio M-H.29 [ 0.28.81. df = 7 (P = 0.34. 7. 2. 2. 27.6 % 1.10 ] Kalbermatter 2000 0/28 0/56 28/609 4/199 27.95% CI 1 ITT (type 1) Lode 1995 Total (95% CI) 13.7.

130. .4 % 0.65 [ 0.091) 0.50 [ 0.10 ] Gleadhill 1986 5/26 4/22 0.9 % 1. 1.Analysis 1.67 ] 1849 1855 68.41.8.25 ] Peterson 1988 7/30 9/30 1.49 [ 0.48 ] Kobayashi 1984 4/41 0/33 0. 1. I2 =6% Test for overall effect: Z = 1.3 % 1. 0.26 [ 0.33. 4.65 ] 11/71 7/68 1. Comparison 1 Atypical versus non-aytpical.5 % 0.29 [ 0.08 [ 0.12.11.77 [ 0.09 [ 0.2 0.72 ] Feldman 2001 3/35 3/34 0.85 [ 0.1 % 1. Outcome 8 Clinical failure per antibiotic (ABx) treatment.27.06 [ 0.61.22. Ltd. Published by John Wiley & Sons.1 % 0.72.64.47.5 Favours atypical 1 2 5 10 Favours non-atypical (Continued .69 (P = 0.33 ] Chuard 1989 5/59 6/62 1.66 ] 85/314 85/305 15. 1.4 % 0.94 [ 0.95% CI 1 Quinolone (atypical arm) Miki 1984 Norrby 1998 Rizzato 1997 Tremolieres 1998 Vanderdonckt 1990 Vogel 1991 Subtotal (95% CI) Total events: 340 (Atypical ABx). 2. 2.26 ] Lephonte 2004 38/167 32/153 6.6 % 0. 1.29.62.86 [ 0.9 % 0. 379 (Non-atypical ABx) Heterogeneity: Chi2 = 21.38).3 % 0.89 [ 0. df = 20 (P = 0.78 [ 0. 3.5 % 0.38. 3.75. 2.79. 1. 1.1 % 0.64 ] Kohno 2011 12/104 10/89 1.08 [ 0.32 ] Carbon 1992 19/123 24/120 4.Fixed.8 % 1.5 % 0.2 % 0.5 % 0.57 ] 7/110 28/115 4.28. 1.6 % 1.57 ] 13/138 28/147 4.82 ] Petitpretz 2001 46/200 44/208 7. 2. .32. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 8 Clinical failure per antibiotic (ABx) treatment Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 14/126 22/140 3.97 [ 0. 3.21.Fixed.75. 1. 0.1 % 7.0 % 1.97 [ 0. 4.71 [ 0.06.92 ] 21/75 21/81 3.88 [ 0.95% CI Risk Ratio M-H.1 0.9 % 0.46 ] Hirata-Dulas 1991 12/24 12/26 2.81 ] 2/38 3/37 0.02 ] M-H.48 ] Fourrier 1986 6/20 7/20 1.27 ] Khan 1989 6/66 6/56 1.44 ] Kalbermatter 2000 1/28 4/56 0. 1.8 % 0.93 ] Hong-yun 2007 23/54 24/53 4.61. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.45.8 % 1. 65 .09 [ 0.51 [ 0.35.03 [ 0. 1.

36.77. 126.95% CI M-H.7 % 1. Published by John Wiley & Sons. df = 3 (P = 0.93 [ 0.81 ] 189 182 5.61 (P = 0. 1.81 ] 2500 100. 31 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: Z = 0. 1.84.Fixed.77. 2.14 ] Hatipoglu 2010 6/34 7/32 1.60) 3 Combined quinolone and macrolide (atypical arm) Lode 1995 Subtotal (95% CI) Total events: 197 (Atypical ABx).51).07 ] 3/46 0/44 0.7 % 0.30.91.18 [ 0.62 ] 197/609 69/199 18. 2.33. 1.0 % 0. Ltd.93 [ 0. I2 =43% Test for overall effect: Z = 0.7 % 1.21.04. 1.29 (P = 0.70 [ 0.17 ] 609 199 18. . I2 =0.89 [ 0.0 % 0.Fixed.5 % 1.95% CI 2 Macrolide (atypical arm) Zeluff 1988 Subtotal (95% CI) Total events: 46 (Atypical ABx). df = 27 (P = 0. df = 4 (P = 0.1 % 6.04 ] M-H.68 [ 0. 69 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: Z = 0.75.75. Study or subgroup Risk Ratio Weight Continued) Risk Ratio Atypical ABx Non-atypical ABx n/N n/N Bohte 1995 6/35 10/29 2.0% 0.76.13).7 % 0.5 Favours atypical 1 2 5 10 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.76 (P = 0. 40 (Non-atypical ABx) Heterogeneity: Chi2 = 7.6 % 0.2 0. 1. 3.50 [ 0.37.81 [ 0. 1. 1. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29.45) Total (95% CI) 2919 Total events: 621 (Atypical ABx).1 0.14 ] Romanelli 2002 23/101 14/103 2.5 % 1.54) 4 Pristinamycine (atypical arm) Tremolieres 2005 Subtotal (95% CI) Total events: 38 (Atypical ABx).20) Test for subgroup differences: Chi2 = 2.3 % 0. . 66 . I2 =9% Test for overall effect: Z = 1.93 [ 0.17 ] 38/189 31/182 5.11 [ 0.13 ] 272 264 7.20 ] Genne 1997 8/56 9/56 1.18 [ 0.67.52 (P = 0.(.33).

0 % 0.75. 1.1 % 6.0 % 1.85 [ 0.7 % 1. 4. 1. I2 =0.2 Favours atypical 1 5 20 Favours non-atypical (Continued .36.49 [ 0.47.71 [ 0.08 [ 0.78 [ 0. Ltd.93 [ 0.5 % 0.06 [ 0.81 ] Vogel 1991 2/38 3/37 0.93 [ 0.97 [ 0. 0.6 % 0.6 % 0.03 [ 0. 67 . df = 14 (P = 0.81 ] 21/75 21/81 3.77 [ 0.Fixed.18 [ 0. 1.67 ] Zeluff 1988 3/46 0/44 0.09 [ 0. Published by John Wiley & Sons.95% CI 1 Mean age under 65 years old Aubier 1998 Bohte 1995 Carbon 1992 Lode 1995 Vanderdonckt 1990 Subtotal (95% CI) Total events: 419 (Atypical ABx). 4.28.14 ] Gleadhill 1986 5/26 4/22 0.07 (P = 0.1 % 1.09 [ 0.38.45.27.32 ] 6/35 10/29 2. 1.75.9 % 0. 2.48 ] Kohno 2011 12/104 10/89 1. Outcome 9 Clinical failure per age.0% Test for overall effect: Z = 1.1 % 0.88 [ 0.2 % 0. 2. 1. 2. 1.29.8 % 1.23.11.06.21.72. 1.06 ] M-H.33 ] Feldman 2001 3/35 3/34 0.37.5 % 0.57 ] Tremolieres 1998 13/138 28/147 4.65 [ 0.97 [ 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 9 Clinical failure per age Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight 14/126 22/140 3. 1.70 [ 0.08 [ 0.82 ] Hirata-Dulas 1991 Norrby 1998 Peterson 1988 0.46 ] 12/24 12/26 2.17 ] Petitpretz 2001 46/200 44/208 7. 1. 1.20 ] 19/123 24/120 4. 307 (Non-atypical ABx) Heterogeneity: Chi2 = 12. 126.75. 1.81.6 % 1.61.64.9 % 1.95% CI Risk Ratio M-H.9.92 ] Tremolieres 2005 38/189 31/182 5.25 ] 7/30 9/30 1. .Analysis 1.26 ] Lephonte 2004 38/167 32/153 6.5 % 0. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.50 [ 0.50 [ 0.65 ] 197/609 69/199 18.8 % 1.5 % 0.72 ] Genne 1997 8/56 9/56 1.4 % 0.Fixed.48 ] Kalbermatter 2000 1/28 4/56 0. Comparison 1 Atypical versus non-aytpical. .27 ] Khan 1989 6/66 6/56 1.28) 2 Mean age over 65 years old Chuard 1989 5/59 6/62 1. 3.93 ] 85/314 85/305 15. 3.77.6 % 0.32.59).13 ] 1979 1575 61.7 % 0.89 [ 0.05 0. 1.33. 2.8 % 0.21.

2.12.(.1 % 7. 1.10 ] Hatipoglu 2010 6/34 7/32 1.69). I2 =9% Test for overall effect: Z = 1.20) Test for subgroup differences: Chi2 = 0.62.04 ] Miki 1984 Subtotal (95% CI) Total events: 50 (Atypical ABx).10 ] Total events: 152 (Atypical ABx). .67.3 % 0.Fixed.02 (P = 0.61.69) Total (95% CI) 2919 Total events: 621 (Atypical ABx). 167 (Non-atypical ABx) Heterogeneity: Chi2 = 14.41.Fixed.5 % 1.33).64 ] 11/71 7/68 1.95% CI 0.86 [ 0.05 0.53). I2 =0.29 [ 0.04). Ltd.3 % 1.17.14 ] Hong-yun 2007 23/54 24/53 4.0% 0.81 [ 0. I2 =52% Test for overall effect: Z = 1.84.91.91 [ 0. 68 .31) 3 Data unavailable Fourrier 1986 6/20 7/20 1. 130. 1. I2 =0.44 ] Kobayashi 1984 4/41 0/33 0. df = 27 (P = 0. Published by John Wiley & Sons.75.93 [ 0. 1.57 ] 23/101 14/103 2.66 ] 220 206 8. 0.29 (P = 0. df = 7 (P = 0.0 % 0.94 [ 0. df = 4 (P = 0.40 (P = 0.1 % 0.3 % 0.4 % 0.30.9 % M-H.07 ] 720 719 30.51 [ 0. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29. Study or subgroup Rizzato 1997 Romanelli 2002 Subtotal (95% CI) Atypical ABx Non-atypical ABx Risk Ratio Weight M-H. 2.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. .26 [ 0.0% Test for overall effect: Z = 0. 1.77.43.35. 3. 45 (Non-atypical ABx) Heterogeneity: Chi2 = 3.95% CI Continued) Risk Ratio n/N n/N 7/110 28/115 4.3 % 1.75. df = 2 (P = 0.07 [ 0. 3.68 [ 0.50 ] 2500 100.

1.0 % 0.0% Test for overall effect: Z = 0.50 [ 0.61.78 [ 0. 0.38.21. 1. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 10 Clinical failure per geographical area Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight 14/126 22/140 3.3 % 0.49 [ 0.75.3 % 0.27. 1.06 [ 0.35.95% CI 1 Europe Aubier 1998 Bohte 1995 Lode 1995 Rizzato 1997 Vanderdonckt 1990 Vogel 1991 Subtotal (95% CI) Total events: 370 (Atypical ABx).48 ] Peterson 1988 7/30 9/30 1.12.6 % 0.57 ] Romanelli 2002 23/101 14/103 2.81 ] 2/38 3/37 0.14 ] 197/609 69/199 18.8 % 1.88 [ 0.81 ] 21/75 21/81 3.0 % 0. 69 .8 % 0.07 ] Tremolieres 1998 13/138 28/147 4. 1.74.59.7 % 1. 1.32.73) 0.65 [ 0. I2 =37% Test for overall effect: Z = 2. I2 =0.9 % 0.85 [ 0. 1. 27 (Non-atypical ABx) Heterogeneity: Chi2 = 0. Comparison 1 Atypical versus non-aytpical.07).71 [ 0. 2. 0.67 ] 1739 1345 57.79).20 ] Carbon 1992 19/123 24/120 4.08 [ 0.30.2 Favours atypical 1 5 20 Favours non-atypical (Continued . 2.Fixed.6 % 1. 1. 2.4 % 0.91.18 (P = 0.33 ] Chuard 1989 5/59 6/62 1.9 % 0.95% CI Risk Ratio M-H.27. .34 (P = 0.93 ] Khan 1989 6/66 6/56 1. 0.89 [ 0. 1. 2.029) 2 North America Hirata-Dulas 1991 Subtotal (95% CI) Total events: 25 (Atypical ABx). Published by John Wiley & Sons.81 [ 0.05 0.93 [ 0.85 [ 0.93 [ 0.77 [ 0. df = 2 (P = 0.47.68 [ 0. 2.32 ] 6/35 10/29 2.6 % 0.45.17 ] 7/110 28/115 4.5 % 1.2 % 0.10. 3.1 % 0.18 [ 0.92 ] Tremolieres 2005 38/189 31/182 5.08 [ 0.33.77. Ltd.26 [ 0. 3.Analysis 1.5 % 0. Outcome 10 Clinical failure per geographical area.11.28. 3. .1 % 1.46 ] Hatipoglu 2010 6/34 7/32 1.72 ] Fourrier 1986 6/20 7/20 1.98 ] 12/24 12/26 2. 283 (Non-atypical ABx) Heterogeneity: Chi2 = 22.86 [ 0. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.9 % 0.82 ] 120 112 4.10 ] Genne 1997 8/56 9/56 1.64.7 % 0.45 ] M-H.14 ] Gleadhill 1986 5/26 4/22 0.37. 1.Fixed. df = 14 (P = 0.29.

Study or subgroup Risk Ratio Weight Continued) Risk Ratio Atypical ABx Non-atypical ABx n/N n/N Feldman 2001 3/35 3/34 0.97 [ 0.Fixed.5 % 0. df = 27 (P = 0. 4.44 ] Kalbermatter 2000 1/28 4/56 0. 1.36.3 % 1.47.83). 1. 4.75.95% CI M-H.67.05 0. 1.9 % 1.72. .0 % 1. I2 =46% 0.61.97 [ 0.13 ] 1060 1043 38. Published by John Wiley & Sons.0% Test for overall effect: Z = 0. df = 9 (P = 0.29 (P = 0. 1.06 [ 0. df = 2 (P = 0. 130.1 % 1.65 ] 11/71 7/68 1. I2 =9% Test for overall effect: Z = 1.52) Total (95% CI) 2919 Total events: 621 (Atypical ABx).27 ] Kobayashi 1984 4/41 0/33 0.07.94 [ 0. 126.06.64 (P = 0.(.68.66 ] Norrby 1998 85/314 85/305 15.33). I2 =0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 1.24 ] 2500 100.95% CI 3 Other Miki 1984 Zeluff 1988 Subtotal (95% CI) Total events: 226 (Atypical ABx).41.Fixed.09 [ 0.50 [ 0. 1.20) Test for subgroup differences: Chi2 = 3. 3.16).09 [ 0.93 [ 0.8 % 1.26 ] Lephonte 2004 38/167 32/153 6.25 ] Petitpretz 2001 46/200 44/208 7.51 [ 0. Ltd.4 % 0. 2. 70 .57 ] 3/46 0/44 0. . 209 (Non-atypical ABx) Heterogeneity: Chi2 = 5.0 % 0.90.75.1 % 6.21.1 % 7.04 ] M-H.48 ] Hong-yun 2007 23/54 24/53 4.03 [ 0.62.5 % 0.64 ] Kohno 2011 12/104 10/89 1.70 [ 0.84.5 % 0. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29.29 [ 0.

26 ] Norrby 1998 85/314 85/305 15.36. 2.75.48 ] Genne 1997 8/56 9/56 1.29.93 [ 0. Ltd.92) 2B Aubier 1998 Bohte 1995 Lode 1995 Miki 1984 0.37.21.27 ] Khan 1989 6/66 6/56 1. 2.33 ] Fourrier 1986 6/20 7/20 1. 2.14 ] Kalbermatter 2000 1/28 4/56 0.Fixed.8 % 0.3 % 0.6 % 0.95% CI 1A Zeluff 1988 Subtotal (95% CI) Total events: 176 (Atypical ABx). 1.32 ] 6/35 10/29 2. 1. 2. df = 9 (P = 0. 2. 4.82. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.47. 1.6 % 0.71 [ 0.38.77 [ 0.0% Test for overall effect: Z = 0.2 % 0.95% CI Risk Ratio M-H.5 % 0.8 % 1.02 0.61.5 % 0.44 ] Lephonte 2004 38/167 32/153 6.45.1 % 1.09 [ 0.70 [ 0.4 % 0.51 [ 0.48 ] Kohno 2011 12/104 10/89 1. Comparison 1 Atypical versus non-aytpical.78 [ 0.10 (P = 0.25 ] Peterson 1988 7/30 9/30 1.46 ] Hatipoglu 2010 6/34 7/32 1.06. 1.5 % 0. 176 (Non-atypical ABx) Heterogeneity: Chi2 = 2.14 ] Hirata-Dulas 1991 12/24 12/26 2. .28.82 ] Petitpretz 2001 46/200 44/208 7.75.1 % 6.30.7 % 0.62.97 [ 0.65 ] 197/609 69/199 18.32.8 % 1.20 ] Carbon 1992 19/123 24/120 4.72 ] Feldman 2001 3/35 3/34 0. 2.Analysis 1.89 [ 0.66 ] M-H.85 [ 0. 126.21.94 [ 0. 1.97). Published by John Wiley & Sons.97 [ 0.13 ] 938 940 31.50 [ 0.19 ] 14/126 22/140 3. I2 =0. Outcome 11 Clinical failure per allocation generation.8 % 0.08 [ 0.9 % 1.99 [ 0.4 % 0.1 % 0.1 Favours atypical 1 10 50 Favours non-atypical (Continued .33.75. 71 . 3. 1.Fixed.0 % 1. 1.03 [ 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 11 Clinical failure per allocation generation Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Chuard 1989 5/59 6/62 1.0 % 0.11.61. 3.06 [ 0.35.10 ] Gleadhill 1986 5/26 4/22 0.3 % 1.72.80.88 [ 0.86 [ 0. 1. 4.57 ] 3/46 0/44 0. .93 ] Hong-yun 2007 23/54 24/53 4.17 ] 11/71 7/68 1. 1. 1.81 [ 0.09 [ 0. 1.50 [ 0.3 % 0.

1 % 7. Ltd. 0.1 Favours atypical 1 10 50 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.29 [ 0.18 [ 0.7 % 1. df = 2 (P = 0.04 ] Rizzato 1997 Vanderdonckt 1990 Vogel 1991 Subtotal (95% CI) M-H.20) Test for subgroup differences: Chi2 = 2.5 % 0.92 ] Tremolieres 2005 38/189 31/182 5. 0.73.81 ] 21/75 21/81 3.5 % 1.95% CI Continued) Risk Ratio M-H. I2 =26% 0. 3.Fixed. Published by John Wiley & Sons.29 (P = 0.64. 3.93 [ 0.1 % 7.49 [ 0.12. I2 =35% Test for overall effect: Z = 1. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29.1 % 0.02 0.57 ] Romanelli 2002 23/101 14/103 2.26).08 [ 0.90 [ 0.27.35 (P = 0.81 ] 2/38 3/37 0. df = 27 (P = 0.79.29 [ 0.64 ] 2500 100.26 [ 0. 130.07).84.18) Total (95% CI) 2919 Total events: 621 (Atypical ABx). Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N 7/110 28/115 4. . 130.66 (P = 0.9 % 0.67.91.95% CI Total events: 441 (Atypical ABx).65 [ 0.9 % 0.096) 3C Kobayashi 1984 Subtotal (95% CI) Total events: 4 (Atypical ABx). 343 (Non-atypical ABx) Heterogeneity: Chi2 = 24. 72 .6 % 1. df = 16 (P = 0. 1.77. 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: Z = 1. .64 ] 41 33 0.(. I2 =9% Test for overall effect: Z = 1.0 % 0.41.67 ] 1940 1527 68. 1.Fixed.68 [ 0. 1. 1.70.33).02 ] 4/41 0/33 0.11.41.07 ] Tremolieres 1998 13/138 28/147 4.

95% CI 1A Subtotal (95% CI) Total events: 167 (Atypical ABx). 1.Fixed. 1.5 % 0.95% CI Risk Ratio M-H.75. 1.94 [ 0. 73 .81 [ 0. 0.46 ] Hatipoglu 2010 6/34 7/32 1.66 ] Rizzato 1997 7/110 28/115 4.4 % 0.97 [ 0.1 % 1.82 ] Petitpretz 2001 46/200 44/208 7. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.5 % 0.3 % 0.17 ] Miki 1984 11/71 7/68 1.50 [ 0. 1.7 % 0.97 [ 0.88 [ 0.0 % 0.1 % 0.61.9 % 1.10 ] Gleadhill 1986 5/26 4/22 0.72 ] Fourrier 1986 6/20 7/20 1.82.25 ] Peterson 1988 7/30 9/30 1. . 2. 1.05 0. 1.26 [ 0. 2.88) 2B Aubier 1998 Bohte 1995 Kalbermatter 2000 Lephonte 2004 Lode 1995 0.6 % 0.75.48 ] Kohno 2011 12/104 10/89 1.78 [ 0.03 [ 0.9 % 0.21.12.Analysis 1.2 % 0.37. Outcome 12 Clinical failure per allocation concealment.44 ] 1/28 4/56 0.6 % 0.8 % 1. 2.51 [ 0. Ltd.30. 2.93 ] Hong-yun 2007 23/54 24/53 4.65 ] 197/609 69/199 18.47. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 12 Clinical failure per allocation concealment Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Feldman 2001 3/35 3/34 0.14 ] Hirata-Dulas 1991 12/24 12/26 2.62.09 [ 0.85 [ 0.75. 2.0% Test for overall effect: Z = 0.21.93 [ 0.Fixed.8 % 0. 1. I2 =0. 3.27 ] 38/167 32/153 6. .77 [ 0.26 ] Norrby 1998 85/314 85/305 15.89 [ 0.33 ] Chuard 1989 5/59 6/62 1. 4.57 ] M-H.32 ] 6/35 10/29 2.12.16 (P = 0. Comparison 1 Atypical versus non-aytpical.33.32.09 [ 0. 1. 166 (Non-atypical ABx) Heterogeneity: Chi2 = 0.99 [ 0.72.35.38. 1.99).57 ] 805 778 30. 3.2 Favours atypical 1 5 20 Favours non-atypical (Continued . 1.19 ] 14/126 22/140 3.29.14 ] Khan 1989 6/66 6/56 1. 2. df = 6 (P = 0.45. 1.20 ] Carbon 1992 19/123 24/120 4. 4.48 ] Genne 1997 8/56 9/56 1.61.0 % 1.4 % 0.3 % 1.06.73.06 [ 0.2 % 0.3 % 0.28.50 [ 0.08 [ 0.8 % 1.5 % 0.71 [ 0.86 [ 0. Published by John Wiley & Sons.

11) 3C Kobayashi 1984 Subtotal (95% CI) Total events: 4 (Atypical ABx).Fixed. I2 =9% Test for overall effect: Z = 1.53.9 % 0.36.80.76.95% CI Total events: 450 (Atypical ABx).77.13 ] 2073 1689 69.84.27.11).Fixed.6 % 1. 1.64. Published by John Wiley & Sons.41.7 % 0.05 0. I2 =21% 0.1 % 6.08 [ 0.35 (P = 0.29 [ 0.60 (P = 0. Ltd.02 ] 4/41 0/33 0.90 [ 0.18 [ 0.41. 74 . df = 19 (P = 0.65 [ 0. 3. I2 =29% Test for overall effect: Z = 1.81 ] Vogel 1991 2/38 3/37 0.04 ] Vanderdonckt 1990 Subtotal (95% CI) M-H.67.95% CI Continued) Risk Ratio M-H. 130.81 ] 21/75 21/81 3.1 % 7.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.67 ] Zeluff 1988 3/46 0/44 0. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29.0 % 0.49 [ 0.64 ] 2500 100. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N Romanelli 2002 23/101 14/103 2.1 % 7.7 % 1. .92 ] Tremolieres 2005 38/189 31/182 5. 130.29 (P = 0. 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: Z = 1. 1. 3.33). df = 2 (P = 0.68 [ 0. df = 27 (P = 0.91.5 % 0.29 [ 0.18) Total (95% CI) 2919 Total events: 621 (Atypical ABx). 353 (Non-atypical ABx) Heterogeneity: Chi2 = 26.07 ] Tremolieres 1998 13/138 28/147 4.93 [ 0.5 % 1. 1.64 ] 41 33 0.28). . 0.11. 126.(.70 [ 0.20) Test for subgroup differences: Chi2 = 2. 1.

3 % 0.0 % 0.Fixed. 4. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.21.35.21.37.06 [ 0. df = 17 (P = 0.48 ] Kohno 2011 12/104 10/89 1.38 (P = 0.43).Analysis 1. 75 .67 ] 1209 1206 47.1 % 1. Outcome 13 Clinical failure per blinding.06.50 [ 0.50 [ 0.46 ] Hatipoglu 2010 6/34 7/32 1.85 [ 0.5 % 0.5 % 0.26 [ 0.93 ] Hong-yun 2007 23/54 24/53 4.78 [ 0. . 2.65 [ 0.Fixed.28.25 ] 7/30 9/30 1. 4.95% CI Risk Ratio M-H.64. 2.86 [ 0.20 ] Chuard 1989 5/59 6/62 1.26 ] Norrby 1998 85/314 85/305 15. 1. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 13 Clinical failure per blinding Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Bohte 1995 6/35 10/29 2.81 [ 0. Ltd.14 ] Gleadhill 1986 5/26 4/22 0.5 % 0. 262 (Non-atypical ABx) Heterogeneity: Chi2 = 17.97 [ 0.44 ] Kalbermatter 2000 1/28 4/56 0. 3. 1.68 [ 0.17) 2 Single-blind Subtotal (95% CI) 0 0 Not estimable Total events: 0 (Atypical ABx). . 1.13.1 % 0.03 [ 0.6 % 0.05 0.6 % 0.3 % 0.48 ] Fourrier 1986 6/20 7/20 1.32.89 [ 0.75. Published by John Wiley & Sons. 2.61. 3.27 ] Khan 1989 6/66 6/56 1.95% CI 1 Non-blinded Peterson 1988 Rizzato 1997 Romanelli 2002 Vanderdonckt 1990 Vogel 1991 Subtotal (95% CI) Total events: 238 (Atypical ABx). 0.9 % 1.81 ] 2/38 3/37 0.90 [ 0.77.72 ] Feldman 2001 3/35 3/34 0.88 [ 0.5 % 0.2 Favours atypical 1 5 20 Favours non-atypical (Continued . 0 (Non-atypical ABx) Heterogeneity: not applicable Test for overall effect: not applicable 0.08 [ 0.4 % 0.3 % 0.47.07 ] 21/75 21/81 3. 1.30.2 % 0.82 ] 7/110 28/115 4.6 % 1.5 % 1. 1.10 ] Genne 1997 8/56 9/56 1.94 [ 0.57 ] 23/101 14/103 2. I2 =2% Test for overall effect: Z = 1. 1.11. Comparison 1 Atypical versus non-aytpical.29.8 % 1. 2.14 ] Hirata-Dulas 1991 12/24 12/26 2. 2.37.33.61. 3.91.08 [ 0.9 % 0.05 ] M-H.12. 1.97 [ 0. 2.

Published by John Wiley & Sons. 1.97 [ 0. I2 =0.7 % 0.27.84. Ltd. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29.41. df = 1 (P = 0.70 [ 0.92 ] Tremolieres 2005 38/189 31/182 5.57 ] Tremolieres 1998 13/138 28/147 4.75.7 % 1.47.66 ] Petitpretz 2001 46/200 44/208 7.93 [ 0.49 [ 0.Fixed.33).Fixed. 1.49). I2 =27% Test for overall effect: Z = 0.1 % 7.05 0.20) Test for subgroup differences: Chi2 = 0.4 % 0. 3.71 [ 0.95% CI 3 Double or triple-blind Lode 1995 Miki 1984 Zeluff 1988 Subtotal (95% CI) Total events: 383 (Atypical ABx).29 [ 0.81 ] 3/46 0/44 0.77.62.31. df = 27 (P = 0. 130. 126.47 (P = 0.8 % 1.18 [ 0.0% 0. . 1. 257 (Non-atypical ABx) Heterogeneity: Chi2 = 12.8 % 0. 1. 76 .38.51 [ 0. Study or subgroup Risk Ratio Weight Continued) Risk Ratio Atypical ABx Non-atypical ABx n/N n/N Aubier 1998 14/126 22/140 3.32 ] Carbon 1992 19/123 24/120 4.17 ] 11/71 7/68 1.93 [ 0.64 ] Lephonte 2004 38/167 32/153 6.72.0 % 1. 1. 1.7 % 0.13 ] 1710 1294 52.04 ] M-H.36.20).75.65 ] 197/609 69/199 18.45.9 % 0. df = 9 (P = 0.(.95% CI M-H. 1.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 1.77 [ 0.0 % 0. 0. I2 =9% Test for overall effect: Z = 1.09 [ 0.3 % 1.64) Total (95% CI) 2919 Total events: 621 (Atypical ABx).29 (P = 0.33 ] Kobayashi 1984 4/41 0/33 0.67. .84.11 ] 2500 100.1 % 6.09 [ 0.

8 % 1.Fixed.2 % 4. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 1.33.93 [ 0. 1.ITT analysis Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Chuard 1989 5/59 6/62 0. .72 ] Feldman 2001 3/35 3/34 0.78.95% CI Risk Ratio M-H.78 [ 0. 1.95% CI 1 ITT studies (type 1) Lode 1995 Peterson 1988 Subtotal (95% CI) Total events: 231 (Atypical ABx).61. 2.93 ] Kalbermatter 2000 1/28 4/56 0.03 [ 0.98 [ 0.02 ] Kohno 2011 28/136 32/124 4.14.69.0 % 0.8 % 0.1 % 0.05 [ 0. 33. 1.3 % 0.55 ] 14/74 12/73 1.06. 1.99). 1.4 % 0.82. Outcome 14 Clinical failure .50. 1.51.14 [ 0.33.6 % 1.8 % 0.17 ] 7/30 9/30 1.70.92 [ 0. Ltd.Analysis 1.23. 1.67.3 % 0.31 ] Tremolieres 2005 49/189 48/182 7.57.20 ] 21/125 25/121 3.Fixed.75.35.12 ] 47/159 52/170 7.7 % 0.80 [ 0.82 (P = 0. 4.0% Test for overall effect: Z = 0.81 [ 0.5 % 1.88 [ 0.34 ] 7/36 11/30 1.6 % 0.29 ] Petitpretz 2001 49/203 44/208 6.80.70. df = 6 (P = 0.65 ] M-H. 77 .53 [ 0.44 ] 5/42 1/34 0.48 ] Fourrier 1986 6/20 7/20 1.63 ] Rizzato 1997 18/121 32/119 4. 0.05 0.2 % 0. Published by John Wiley & Sons.37 ] 14/76 16/66 2.7 % 1. 1. 1. 110 (Non-atypical ABx) Heterogeneity: Chi2 = 0.2 % 1.07 [ 0.4 % 0.93 ] Tremolieres 1998 48/173 50/169 7.41) 2 Dropouts assumed as failure (type 2) Aubier 1998 Bohte 1995 Carbon 1992 Khan 1989 Kobayashi 1984 Miki 1984 Vanderdonckt 1990 0. 1.40.ITT analysis.76 [ 0.21. 1.2 % 1.27 ] 197/609 69/199 14.10 ] Hirata-Dulas 1991 12/24 12/26 1. .4 % 0.55 [ 0.15 [ 0.2 Favours atypical 1 5 20 Favours non-atypical (Continued .50 [ 0.6 % 0.76. 2.97 [ 0.97 [ 0.86 [ 0. 1.8 % 0. 1. Comparison 1 Atypical versus non-aytpical. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 14 Clinical failure .0 % 0.94 [ 0.28. 1.38 ] 28/82 28/88 3. 4.32 ] Norrby 1998 90/319 86/306 12. 2.24 ] Lephonte 2004 39/168 35/156 5. I2 =0.69.48.00 [ 0.08 [ 0.82 ] 805 427 20.

3 % 0.36.0 % 0.61).59.15 ] 2622 100. 65 (Non-atypical ABx) Heterogeneity: Chi2 = 3.83). I2 =0.3 % 0.60 [ 0. 7.43.26) 3 Non-ITT.70 [ 0.52.44 ] Romanelli 2002 14/103 23/101 3.14 ] Hong-yun 2007 23/54 24/53 3.4 % 0.3 % 1.02 ] Zeluff 1988 Subtotal (95% CI) Total events: 56 (Atypical ABx).61.09 ] 3/46 0/44 0.13 ] 303 298 9.63.69.89 [ 0.63).93 [ 0.81 [ 0.0% Test for overall effect: Z = 1. 1. . 1.37.62 (P = 0.05 ] Hatipoglu 2010 6/34 7/32 1. 1. I2 =0.94 [ 0.30. 1. df = 14 (P = 0.(.05 (P = 0.20 [ 0. .33.95% CI Continued) Risk Ratio n/N n/N 13/49 17/51 2.94 [ 0. I2 =0.0% 0. 126.85 [ 0. 664 (Non-atypical ABx) Heterogeneity: Chi2 = 16.0% Test for overall effect: Z = 1.Fixed. 1.1 % 6. 1.85. dropouts cannot be calculated (type 3) Genne 1997 8/56 9/56 1.20. I2 =0. 2. df = 2 (P = 0. 78 . df = 5 (P = 0. df = 27 (P = 0.94). 2.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.0 % 0.05 0. Published by John Wiley & Sons.Fixed.80 [ 0.4 % 0.12 (P = 0.3 % 0.38. 489 (Non-atypical ABx) Heterogeneity: Chi2 = 11.0% Test for overall effect: Z = 1.4 % M-H.29) Total (95% CI) 3060 Total events: 757 (Atypical ABx).95% CI 0.14 ] Gleadhill 1986 2/10 2/12 0.10) Test for subgroup differences: Chi2 = 0. Study or subgroup Vogel 1991 Subtotal (95% CI) Atypical ABx Non-atypical ABx Risk Ratio Weight M-H. Ltd.84.05 ] Total events: 470 (Atypical ABx).46 ] 1952 1897 70.

21 ] Vanderdonckt 1990 1/6 0/10 0.17 [ 0. 4. 109. 64.83 [ 0.13 ] 549 472 100.70 ] Lode 1995 Miki 1984 Total (95% CI) Risk Ratio Weight M-H.Fixed.23 ] Norrby 1998 5/59 4/66 7.5 % 1.96 ] Petitpretz 2001 7/49 6/49 11.46.00 [ 0.46.44 [ 0.95% CI Not estimable Total events: 67 (Atypical ABx). 18. 18.75 [ 0. 79 .12. Ltd.22 [ 0. 67.26 ] Gleadhill 1986 0/5 0/7 Hirata-Dulas 1991 1/3 3/4 4.2 % 1.Fixed. 2.25 ] Vogel 1991 1/4 0/8 0. 48 (Non-atypical ABx) Heterogeneity: Chi2 = 10.8 % 0.pneumococcal pneumonia.05.94 [ 0. 2.95% CI Risk Ratio M-H.Analysis 1.0 % 0. 1.01.0 % 2.42.5 % 1. Comparison 1 Atypical versus non-aytpical.7 % 4. Published by John Wiley & Sons.22.70 [ 0.20.0 % 1. 3.22 [ 0. 3. 6.7 % 5.88.1 % 1.36.81 ] 3/6 2/7 3.13 [ 0.05 0.32 ] Tremolieres 2005 6/27 4/35 6. I2 =0. 100.00 [ 0.60 [ 0.4 % 1.9 % 3.65 ] Tremolieres 1998 0/20 4/24 7.pneumococcal pneumonia Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Aubier 1998 9/80 6/65 12.25 ] Carbon 1992 12/56 11/49 22.14.7 % 0.43 ] Kobayashi 1984 1/8 0/2 1. 1.61.96 ] Lephonte 2004 2/23 1/21 2.71 [ 0. 126.40 [ 0.19 (P = 0. 1.42.08. df = 16 (P = 0.3 % 1.70 ] 9/105 4/28 11. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 15 Clinical failure . 6.89 [ 0.27.95 [ 0.39.22 ] Romanelli 2002 5/17 3/19 5.0 % 6.18.57 ] Kohno 2011 1/27 0/26 1.79.0% Test for overall effect: Z = 1. Outcome 15 Clinical failure .8 % 0.52.35 ] Zeluff 1988 3/46 0/44 1. 7.97 ] Chuard 1989 1/8 0/8 0.82).4 % 1.86 [ 0.40 [ 0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.15.24) Test for subgroup differences: Not applicable 0.0 % 1.

Fixed.087) Test for subgroup differences: Not applicable 0.2 % 0.19 ] Carbon 1992 0/7 1/5 10.95% CI Risk Ratio M-H. I2 =0. Published by John Wiley & Sons.88 [ 0. 1. 17 (Non-atypical ABx) Heterogeneity: Chi2 = 2.32. Outcome 16 Clinical failure .32 [ 0. Ltd.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Comparison 1 Atypical versus non-aytpical.52 [ 0.05.0 % 0. 1.56).4 % 0.07.Analysis 1.0% Test for overall effect: Z = 1. 3.Fixed.0 % 0.13 ] Lode 1995 2/24 5/19 32.95% CI Total events: 8 (Atypical ABx).02.01. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 16 Clinical failure . 5.71 (P = 0.16.atypical pathogens.05 0. df = 3 (P = 0.46 ] Tremolieres 1998 6/46 7/47 40. 80 .41 ] Total (95% CI) 80 78 100.atypical pathogens Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 0/3 4/7 17.22 [ 0.25 [ 0.10 ] M-H.24. 2.4 % 0.

21 ] Carbon 1992 0/3 1/2 15.17 [ 0.03 ] Tremolieres 1998 0/6 3/6 31.88. 1. 4.0081) Test for subgroup differences: Not applicable 0.6 % 0. 4.Fixed.63 ] M-H.65 (P = 0.Fixed.2 % 0. I2 =0.01.95% CI Not estimable Total events: 0 (Atypical ABx).0 % 0.1 Favours atypical 1 10 50 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.23 ] Lephonte 2004 0/5 0/6 Lode 1995 0/8 2/2 34.02 0. 9 (Non-atypical ABx) Heterogeneity: Chi2 = 0. 0.2 % 0.Analysis 1. Comparison 1 Atypical versus non-aytpical.Legionella pneumophilae.17. Ltd. 2.01.05.07 [ 0.95% CI Risk Ratio M-H.83).0% Test for overall effect: Z = 2.36 [ 0.9 % 0. Outcome 17 Clinical failure .25 [ 0. 81 .14 [ 0.03.28 ] Total (95% CI) 23 20 100.Legionella pneumophilae Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 0/1 3/4 18.00. df = 3 (P = 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 17 Clinical failure . Published by John Wiley & Sons.

48 ] Kobayashi 1984 4/41 0/33 0.49 [ 0.29 [ 0. Published by John Wiley & Sons. I2 =0.33 ] Chuard 1989 5/59 6/62 1.1 % 7.82 ] Petitpretz 2001 46/200 44/208 7.07 ] Tremolieres 1998 13/138 28/147 4.62.Analysis 1.72.18.20 ] Carbon 1992 19/123 24/120 4. 1.29. 1. 4.57 ] Romanelli 2002 23/101 14/103 2.08 [ 0. Ltd.3 % 1. 2.46. 1.10 ] Genne 1997 8/56 9/56 1.21.48 ] Fourrier 1986 6/20 7/20 1. 2.75.2 Favours atypical 1 5 20 Favours non-atypical (Continued .41. 1.1 % 1.11.75. 1.09 [ 0.08 ] M-H.92 ] Tremolieres 2005 38/189 31/182 5.50 [ 0. 2. 1.0 % 1.93 ] Khan 1989 6/66 6/56 1. Outcome 18 Clinical failure per sponsorship.6 % 0.5 % 1. 1.4 % 0.7 % 1. 1.17 ] 11/71 7/68 1.97 [ 0.Fixed.89 [ 0.8 % 0.97 [ 0.6 % 0.56).77.3 % 0.33.28.9 % 0. 126.2 % 0. 2. 1.58) 2 Non-sponsored trials 0.95% CI 1 Sponsored trials Aubier 1998 Bohte 1995 Hirata-Dulas 1991 Lode 1995 Miki 1984 Norrby 1998 Subtotal (95% CI) Total events: 546 (Atypical ABx).38. 1.66 ] 85/314 85/305 15.97 [ 0.09 [ 0.51 [ 0.21.35. 3.37.72 ] Feldman 2001 3/35 3/34 0.77 [ 0.65 [ 0.1 % 0.45.32 ] 6/35 10/29 2. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.68 [ 0.1 % 6.88 [ 0. 1. 130. 3.14 ] 12/24 12/26 2.85 [ 0.71 [ 0.64 ] Lephonte 2004 38/167 32/153 6.67 ] Zeluff 1988 3/46 0/44 0.0 % 0.93 [ 0.95% CI Risk Ratio M-H. df = 20 (P = 0.5 % 0. 0.86.13 ] 2488 2052 82.5 % 0.78 [ 0. .55 (P = 0. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 18 Clinical failure per sponsorship Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight 14/126 22/140 3.6 % 0.61.25 ] Peterson 1988 7/30 9/30 1.05 0. Comparison 1 Atypical versus non-aytpical.81 ] Vogel 1991 2/38 3/37 0.8 % 1.91.Fixed.7 % 0.18 [ 0.5 % 0.70 [ 0.0% Test for overall effect: Z = 0.86 [ 0.65 ] 197/609 69/199 18.36. 3.27. .75. 421 (Non-atypical ABx) Heterogeneity: Chi2 = 18. 82 .

57 ] 302 289 12. 519 (Non-atypical ABx) Heterogeneity: Chi2 = 29. .6 % 1.46 ] Kalbermatter 2000 1/28 4/56 0.04 ] Subtotal (95% CI) Total events: 48 (Atypical ABx).8 % M-H.9 % 0.0 % 0.02 [ 0.4 % 0.30.95% CI Continued) Risk Ratio n/N n/N Gleadhill 1986 5/26 4/22 0.Fixed.27 ] Vanderdonckt 1990 21/75 21/81 3. I2 =67% Test for overall effect: Z = 2.64. Ltd.93 [ 0.33).84.44 ] Kohno 2011 12/104 10/89 1.93 ] 2500 100.93) 3 Unclear sponsorship Hatipoglu 2010 6/34 7/32 1. 69 (Non-atypical ABx) Heterogeneity: Chi2 = 9.03 [ 0.47.Fixed. 1.50 [ 0.5 % 0.08 (P = 0.42 (P = 0. df = 3 (P = 0. 29 (Non-atypical ABx) Heterogeneity: Chi2 = 0.3 % 0.81 [ 0.67.03).9 % 1. 2.62 ] Total events: 27 (Atypical ABx). 4. 1.29 (P = 0. 1.5 % 0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.06. I2 =9% Test for overall effect: Z = 1.79). 2.95% CI 1.9 % 1.49.26 ] Rizzato 1997 7/110 28/115 4.32. I2 =56% 0. .64.81 ] Subtotal (95% CI) 129 159 4. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight M-H.08 [ 0. df = 2 (P = 0. 3. I2 =0. 0.14 ] Hong-yun 2007 23/54 24/53 4.10).14.12.26 [ 0. 1. Published by John Wiley & Sons.016) Total (95% CI) 2919 Total events: 621 (Atypical ABx).20) Test for subgroup differences: Chi2 = 4.06 [ 0.61.67 [ 0.53.48. df = 2 (P = 0. df = 27 (P = 0. 83 .0% Test for overall effect: Z = 0.(. 0.05 0.94 [ 0.

95% CI Risk Ratio M-H.48 [ 0.36 [ 0.96 [ 0.45 ] Vanderdonckt 1990 7/93 11/89 6.85 [ 0.49 [ 0.50 ] Vogel 1991 2/23 1/23 0.25.33 ] Genne 1997 4/35 4/28 2. Ltd.0 % 0.13. 3.01. 1.19.80 [ 0. 2.02 0.50 ] Hong-yun 2007 6/54 3/53 1.13 ] Petitpretz 2001 9/58 12/65 6. 156 (Non-atypical ABx) Heterogeneity: Chi2 = 14. 2.41.81).12.14.7 % 1.Analysis 1.44 ] Khan 1989 3/46 3/41 1.1 Favours atypical 1 10 50 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons.96 ] Miki 1984 11/39 8/25 5.10 ] Tremolieres 2005 11/62 8/67 4.7 % 0.Fixed. 1. 7.58. 0. 15.00 [ 0.6 % 0.77 [ 0.76 ] 1251 1059 100.9 % 0.0 % 0.02 ] Chuard 1989 2/20 4/23 2.5 % 1.20.7 % 0.81 ] Feldman 2001 1/20 0/22 0.6 % 1.8 % 0. 3.2 % 0.52 [ 0. 1.33.45.64.58 [ 0.14.029) Test for subgroup differences: Not applicable 0.89 [ 0. 76.47 [ 0.55 [ 0.2 % 0.09.5 % 1.91 ] Lode 1995 26/201 16/68 14.3 % 3. 1.77 ] 18/72 15/63 9. Comparison 1 Atypical versus non-aytpical.2 % 0.19. 20. 1. 4.88 [ 0.0 % 0.80 [ 0.88 ] Norrby 1998 12/69 14/85 7. df = 20 (P = 0. I2 =0.05 [ 0. 0.98 ] M-H.52.19. 1.Fixed.55 ] Zeluff 1988 8/46 10/44 6.65.59 ] Tremolieres 1998 7/86 15/87 8.17 ] Kobayashi 1984 2/18 5/16 3.13 [ 0.84 [ 0.38.85 ] Romanelli 2002 13/50 15/49 9.54 ] Carbon 1992 2/94 3/73 2. 1. 2.59 ] Kohno 2011 2/61 1/45 0.2 % 0.52. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 19 Bacteriological failure Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Aubier 1998 0/86 3/80 2. 1.22. 2.08. Outcome 19 Bacteriological failure. 84 .31.95% CI 1 Overall Lephonte 2004 Total (95% CI) Total events: 149 (Atypical ABx).19 (P = 0.5 % 0.0% Test for overall effect: Z = 2. 1.06 [ 0.8 % 1.43 [ 0.61 [ 0.45.29 [ 0.1 % 0.92 ] Gleadhill 1986 3/18 5/13 3.6 % 2.9 % 0.

Published by John Wiley & Sons. Outcome 20 Bacteriological failure per allocation generation.59 ] Lephonte 2004 18/72 15/63 9.32 ] M-H. 15.09.89 [ 0.13 ] Petitpretz 2001 9/58 12/65 6.45 ] 0.61.2 Favours atypical 1 5 20 Favours non-atypical (Continued . 4. 3.19.59) 2B Aubier 1998 0/86 3/80 2.0 % 0.53.14.05 [ 0.0 % 0.8 % 0.01.0 % 0. Ltd.13 [ 0.43 [ 0.88 ] Romanelli 2002 13/50 15/49 9.0% Test for overall effect: Z = 0.54 ] Carbon 1992 2/94 3/73 2.52.36 [ 0.98). 1.47 [ 0. 1. . I2 =0. 1.22. df = 7 (P = 0.29 [ 0. 1.38.54 (P = 0. 85 . 1.84 [ 0.96 ] Miki 1984 11/39 8/25 5.33 ] Genne 1997 4/35 4/28 2. 0.76 ] 355 353 28.10 ] Tremolieres 2005 11/62 8/67 4. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.52 [ 0.88 [ 0.02 ] Gleadhill 1986 3/18 5/13 3.9 % 0.77 [ 0.91 ] Lode 1995 26/201 16/68 14.41.7 % 1. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 20 Bacteriological failure per allocation generation Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Risk Ratio Weight Chuard 1989 2/20 4/23 2.96 [ 0.64.58. 2.1 % 0.6 % 1.20.2 % 0.12. 1. 1.33. 1.5 % 0.17 ] Kohno 2011 2/61 1/45 0.92 ] Khan 1989 3/46 3/41 1.5 % 1.55 [ 0. 7.49 [ 0.44 ] Kobayashi 1984 2/18 5/16 3.Analysis 1.95% CI Risk Ratio M-H.77 ] Norrby 1998 12/69 14/85 7.59 ] Tremolieres 1998 7/86 15/87 8.14.6 % 0.58 [ 0.05 0.Fixed.52.5 % 1.81 ] Feldman 2001 1/20 0/22 0.8 % 1. 3.06 [ 0. . Comparison 1 Atypical versus non-aytpical.08. 48 (Non-atypical ABx) Heterogeneity: Chi2 = 1.2 % 0.13. 1. 2.50 ] Hong-yun 2007 6/54 3/53 1.90 [ 0.80 [ 0.95% CI 1A Subtotal (95% CI) Total events: 41 (Atypical ABx).9 % 0. 2.7 % 0. 76.45. 2.2 % 0.85 [ 0.48 [ 0.Fixed.20.3 % 3.31.2 % 0.85 ] Zeluff 1988 8/46 10/44 6.

58 [ 0.01 ] Carbon 1992 30/125 19/119 3. Published by John Wiley & Sons. ) Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 21 Adverse events . Comparison 1 Atypical versus non-aytpical. 86 .95% CI 0.08 ] Aubier 1998 Bohte 1995 Gleadhill 1986 Risk Ratio Weight M-H.74. 0. df = 12 (P = 0.33. 0.90.50 [ 0.60 ] Genne 1997 19/56 12/56 2.029) Test for subgroup differences: Chi2 = 0.2 % 1. 1.8 % 0.05 0.85.00 ] Feldman 2001 15/35 14/34 2.0% Test for overall effect: Z = 2. 20.2 1 Favours atypical 5 20 Favours non-atypical Analysis 1. df = 20 (P = 0. 1.Fixed. 3. 2. .6 % 1. 108 (Non-atypical ABx) Heterogeneity: Chi2 = 12.65.81).6 % 0. I2 =0.2 Favours atypical 1 5 Risk Ratio M-H. Ltd.023) Total (95% CI) 1251 Total events: 149 (Atypical ABx).0% 0.56 [ 0.58.21.50 [ 0.05 0.04 [ 0.59.81 ] Fourrier 1986 0/20 3/20 0.98 ] Subtotal (95% CI) M-H.Fixed.01.46.45. .60. .52 ] Chuard 1989 4/59 3/62 0.76 [ 0.19.6 % 1.total. 6.49.5 % 1. 2.96 ] 1059 100.94 ] 2/26 3/22 0.95% CI Continued) Risk Ratio M-H. I2 =4% Test for overall effect: Z = 2.(.35 ] 7/35 0/29 0.25.1 % 12. 2.Fixed.28 (P = 0.95% CI 20 Favours non-atypical (Continued . df = 1 (P = 0. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N Vanderdonckt 1990 7/93 11/89 6.total Study or subgroup Atypical ABx Non-atypical ABx n/N n/N 20/159 27/170 4.55 ] 896 706 72.95% CI Total events: 108 (Atypical ABx). I2 =0. Outcome 21 Adverse events .41).61 [ 0. 210. 1.19 (P = 0.10.Fixed.14 [ 0.45).0 % 0.40 [ 0.6 % 0.6 % 2.7 % 0. 156 (Non-atypical ABx) Heterogeneity: Chi2 = 14. .0 % 0.80 [ 0.00 [ 0.79 [ 0.50 ] Vogel 1991 2/23 1/23 0.

68 [ 0.3 % 1.95% CI Continued) Risk Ratio M-H.42 ] Tremolieres 1998 29/173 18/169 3.12 [ 0. 2.31.6 % 1.70 [ 0.67 [ 0.Fixed.15 ] Peterson 1988 4/30 6/30 1.9 % 0. Ltd.11). 536 (Non-atypical ABx) Heterogeneity: Chi2 = 30. 1. 87 .7 % 0. 1.7 % 1.95% CI Not estimable Total events: 564 (Atypical ABx).97 ] Rizzato 1997 8/121 7/119 1.13 ] Kobayashi 1984 Miki 1984 Norrby 1998 Vanderdonckt 1990 Total (95% CI) M-H.21. 1.5 % 0. 3.76.32.17 ] Lephonte 2004 31/167 42/153 8. I2 =28% Test for overall effect: Z = 0. 1.8 % 0.2 Favours atypical 1 5 20 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. 5.5 % 0.44 [ 0.48 ] Vogel 1991 9/49 14/51 2.40 ] Zeluff 1988 9/80 20/78 3.00 ] Romanelli 2002 7/101 6/103 1.41.94 [ 0.93 ] Kohno 2011 73/136 70/123 13.1 % 0. 3.00 ] 13/82 18/88 3. 1. 1. 0.2 % 0. 6.79 [ 0. 1.19 [ 0.3 % 1.05 0.67 ] 169/314 165/305 30.02 [ 0.1 % 0.43. 2.67 [ 0.48 ] 8/132 10/130 1. 1.(.02 ] 4/73 3/72 0.1 % 1.72 ] Tremolieres 2005 41/200 31/198 5.44.99 [ 0.42.0 % 1.90 ] 2467 2451 100.6 % 1.78 [ 0.13 ] Petitpretz 2001 56/200 42/208 7.32.48 (P = 0.57 [ 0.31 [ 0.Fixed.39 [ 0.6 % 1.21. .86. .41. Study or subgroup Atypical ABx Non-atypical ABx Risk Ratio Weight n/N n/N Kalbermatter 2000 0/28 0/56 Khan 1989 6/66 3/56 0. 2.63) Test for subgroup differences: Not applicable 0.91.93. Published by John Wiley & Sons.98.86. df = 22 (P = 0.45.32 [ 0.

45 ] Chuard 1989 2/59 1/62 0.10 [ 0. 88 .60 [ 0.3 % 0.20. 0.20 [ 0. Outcome 22 Adverse events .78.6 % 1.45 ] Vogel 1991 0/49 3/51 3.86 [ 0.01 ] Kobayashi 1984 3/132 3/130 2.4 % 0.18.50 [ 0. 92 (Non-atypical ABx) Heterogeneity: Chi2 = 23. 3.Analysis 1.94 [ 0. 1.20.80 ] 2279 1850 100.78 ] Carbon 1992 1/125 0/119 0.53.0 % 0.07 ] Petitpretz 2001 14/200 8/208 7.15 [ 0.5 % 2.8 % 0.5 % 7.58 ] Bohte 1995 4/35 0/29 0.01 0.42 [ 0.22.20.98 [ 0.89.Fixed. Comparison 1 Atypical versus non-aytpical.Fixed.01.33 [ 0. 5. 13.8 % 2. 69.7 % 0. 8.01. 1.3 % 0. 8.8 % 0.07).54 (P = 0.54.45 ] Fourrier 1986 0/20 2/20 2.10 ] Lephonte 2004 10/167 17/153 16. 20.95% CI Total events: 83 (Atypical ABx).79 ] Kohno 2011 8/136 15/123 14.48 [ 0.9 % 2.25.25 ] Vanderdonckt 1990 5/82 2/88 1.4 % 0.42.70 [ 0.gastrointestinal events. Ltd.14 ] Lode 1995 22/609 20/199 28. 1. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 22 Adverse events .0 % 1.95% CI Risk Ratio M-H.54 [ 0.01.1 Favours atypical 1 10 100 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.16. 4.57 ] Feldman 2001 2/35 1/34 1.82 [ 0.4 % 1.92 ] Norrby 1998 Total (95% CI) Risk Ratio Weight M-H.gastrointestinal events Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Aubier 1998 6/159 4/170 3.2 % 0.64 ] 6/314 14/305 13. 2.46. 4. df = 15 (P = 0.68 [ 0. 22. 0. Published by John Wiley & Sons. 133.12.34 [ 0.3 % 0.21.24 ] Romanelli 2002 0/101 1/103 1.01. I2 =37% Test for overall effect: Z = 2.36 [ 0.011) Test for subgroup differences: Not applicable 0.92 ] Genne 1997 0/56 1/56 1.

3 % 1.14 [ 0.4 % 0.95% CI Risk Ratio M-H.1 Favours atypical 1 10 50 Favours non-atypical Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.40. 3.56 [ 0.04. 4. 5.19 ] Lode 1995 19/609 5/199 11.98 [ 0.Analysis 1. 89 .04 [ 0.6 % 1.91 [ 0.8 % 2.01 [ 0.requiring discontinuation of treatment Study or subgroup Atypical ABx Non-atypical ABx n/N n/N Aubier 1998 4/159 2/170 2.Fixed.5 % 0.14 [ 0. Comparison 1 Atypical versus non-aytpical.31. 2.22 ] Petitpretz 2001 8/200 8/208 11. Review: Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults Comparison: 1 Atypical versus non-aytpical Outcome: 23 Adverse events .61.40 ] Peterson 1988 1/30 2/30 3.14.requiring discontinuation of treatment.56.11 ] Gleadhill 1986 2/26 3/22 4.90).87 ] Tremolieres 1998 4/173 1/169 1.15 [ 0.02 0.0 % 0. 6.05 (P = 0.44 ] 5/167 4/153 6.28 ] Norrby 1998 15/314 20/305 30.73 [ 0.34 ] Total (95% CI) 2121 1685 100.40. 2.72.5 % 3.8 % 1.47.51 ] Genne 1997 1/56 3/56 4. 34. 3.96) Test for subgroup differences: Not applicable 0.23. df = 11 (P = 0. Ltd.60 ] Tremolieres 2005 15/200 13/198 19.08 ] Khan 1989 1/66 0/56 0.Fixed. Outcome 23 Adverse events .38.41 ] Lephonte 2004 Risk Ratio Weight M-H. 63 (Non-atypical ABx) Heterogeneity: Chi2 = 5.44. I2 =0.50 [ 0.0% Test for overall effect: Z = 0. 1.9 % 2.0 % 0.11. Published by John Wiley & Sons. 3. 61.95% CI Total events: 77 (Atypical ABx). 11.9 % 0.55 [ 0.0 % 1.72 ] Rizzato 1997 2/121 2/119 3.10.3 % 1.05.24 [ 0. 1.33 [ 0.

antibiotic*:ab. random*:ab. #4 OR #5 OR #6 OR #7 788. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp AND [embase]/lim 242.680 1 Jun 2011 #6.ti OR fluoroquinolon*:ab.ti OR quinupristin*:ab.385 1 Jun 2011 #2. Ltd.ti OR grepafloxacin*:ab.ti OR trovafloxacin*:ab.ti OR cap:ab. 6 exp Quinolones/ 7 exp Macrolides/ 8 exp Tetracyclines/ 9 exp Chloramphenicol/ 10 exp Streptogramins/ 11 Ketolides/ 12 (quinolon* or fluoroquinolon* or macrolid* or doxycyclin* or tetracyclin* or chloramphenicol* or streptogramin* or ketolid* or erythromycin* or roxithromycin* or azithromycin* or clarithromycin* or ciprofloxacin* or ofloxacin* or levofloxacin* or trovafloxacin* or moxifloxacin* or grepafloxacin* or tigecyclin* or minocyclin* or pristinamycin* or quinupristin* or telithromycin*).097 1 Jun 2011 #8.nm. 3 1 or 2 4 exp Anti-Bacterial Agents/ 5 antibiotic*. 90 . #1 OR #2 169.ti AND [embase]/lim 176.808 1 Jun 2011 #4.ti OR streptogramin*:ab.ti OR ciprofloxacin*:ab.ti OR levofloxacin*:ab.ti OR factorial*:ab.ti OR chloramphenicol*: ab.926 1 Jun 2011 #9.993 1 Jun 2011 #12.ti OR assign*:ab.ti OR ((singl* OR doubl*) NEAR/1 blind*):ab.ti OR ’cross over’:ab.ti AND [embase]/lim 95.523 1 Jun 2011 #10.809 1 Jun 2011 #3. EMBASE search strategy #13.APPENDICES Appendix 1. #10 OR #11 866. #9 AND #12 3.ti OR volunteer*: ab. CENTRAL and MEDLINE search strategy MEDLINE (PUBMED) 1 exp Pneumonia/ 2 (pneumon* or cap).ti OR telithromycin*:ab.ti OR ’cross-over’:ab.ti AND [embase]/lim 826.ti OR tigecyclin*:ab.834 1 Jun 2011 #1.ti OR placebo*:ab.698 1 Jun 2011 #5.tw. 13 or/4-12 14 3 and 13 Appendix 2.ti OR azithromycin*:ab. ’quinolone derivative’/exp OR ’macrolide’/exp OR ’tetracycline derivative’/exp OR ’chloramphenicol’/exp OR ’streptogramin derivative’/exp OR ’ketolide’/exp AND [embase]/lim 230.ti OR ofloxacin*:ab.ti OR crossover*:ab. #3 AND #8 54. ’antibiotic agent’/exp AND [embase]/lim 706.ti OR erythromycin*:ab.ti OR tetracyclin*:ab.ti OR pristinamycin*:ab. Published by John Wiley & Sons.ti OR doxycyclin*:ab.ti OR clarithromycin*: ab.tw.ti OR moxifloxacin*:ab.353 1 Jun 2011 #11.ti OR roxithromycin*:ab.ti OR minocyclin*:ab.ti OR macrolid*:ab.217 1 Jun 2011 #7. pneumon*:ab.tw.ti OR ketolid*:ab. quinolon*:ab.ti OR allocat*:ab.ti AND [embase]/lim 122. ’pneumonia’/de OR ’infectious pneumonia’/exp AND [embase]/lim 92.744 1 Jun 2011 Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration.

23 or/17-20 24 13 and 18 and 23 We inspected the references of all identified studies for more trials. Published by John Wiley & Sons. In addition to this. Date Event Description 16 April 2012 New search has been performed Searches updated. 21 exp Hospitalization/ 22 ((hospitaliz$ or hospitalis$) adj patient$).ti. 91 . WHAT’S NEW Last assessed as up-to-date: 16 April 2012. 13 or/1-12 14 exp Community-Acquired Infections/ 15 exp Pneumonia/ 16 and/14-15 17 (community acquired pneumonia or CAP). we contacted the first or corresponding author of each included trial and researchers active in the field for information regarding unpublished trials or complementary information on their own trial. Ott 2008. Three new trials were included (Hatipoglu 2010.ti. Previous search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007. Our conclusions and recommendations for further research remain unchanged Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. We imposed no language or publication restrictions.ab.ab.ab. MEDLINE (PUBMED) 1 exp Anti-Bacterial Agents/ 2 exp Quinolones/ 3 exp Fluoroquinolones/ 4 exp Macrolides/ 5 exp Doxycycline/ 6 exp Tetracycline/ 7 exp Chloramphenicol/ 8 exp Streptogramins/ 9 exp Ketolides/ 10 (Quinolon$ or Fluoroquinolon$ or Macrolide$ or Doxycycline$ or Tetracycline$ or Chloramphenicol$). no significant changes were noted in any of the comparisons evaluated. and EMBASE (January 1980 to June 2007).ti. Hong-yun 2007.ti. 18 16 or 17 19 exp Inpatients/ 20 inpatient$. MEDLINE (January 1966 to June 2007). After integrating the data from the new included studies.mp. Kohno 2011) and three new trials were excluded (Chokshi 2007. Ltd.ab. Issue 2) which includes the Acute Respiratory Infection Group’s specialized register.mp. We ran the following search strategy over MEDLINE and CENTRAL and adapted it for EMBASE. Sujata 2008). 11 empirical antibiotic$. 12 empiric antibiotic$.Appendix 3.

NER.(Continued) 14 September 2011 New citation required but conclusions have not A new author joined the team to lead the update of changed this review HISTORY Protocol first published: Issue 4. ER. Daphna Shefet (DS). Anat Gafter-Gvili (AG) and Mical Paul (MP) were responsible for screening search results. NER was responsible for entering data into Review Manager 5 (RevMan). 2005 Date Event Description 22 June 2008 Amended Converted to new review format. 92 . guided by Leonard Leibovic (LL). writing to trial authors for additional information and organizing retrieval of papers. no significant changes were noted in all comparisons evaluated. one new study was included and six new studies were excluded. Ltd. 12 November 2007 New search has been performed In the 2007 update. CONTRIBUTIONS OF AUTHORS Noa Eliakim Raz (NER) co-ordinated this updated review. NER and ER were responsible for undertaking searches. All review authors participated in analysis and interpretation of data. Our conclusions and recommendations for further research remain unchanged 20 January 2005 New search has been performed Searches conducted. 2003 Review first published: Issue 2. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. After integrating the data from the new included study. NER and Eyal Robenshtok (ER) were responsible for data collection. screening retrieved papers against inclusion criteria and appraising quality of papers (the latter review author was incharge in case of disagreement). abstracting data from papers. Published by John Wiley & Sons. NER and ER were responsible for writing the review.

microbiology. Combination. External sources • EU 5th Framework: TREAT project (grant number: 1999-11459). mortality]. Humans Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons. • The Rothschild-Caesarea Foundation “Optimal antibiotic treatment of moderate to severe infections: Integration of PCR technology and medical informatics/artificial intelligence”. microbiology. Not specified. Randomized Controlled Trials as Topic. 93 . mortality]. INDEX TERMS Medical Subject Headings (MeSH) ∗ Antibiotic Prophylaxis. ∗ Hospitalization. Not specified. Anti-Bacterial Agents [∗ therapeutic use]. Treatment Failure MeSH check words Adult. Community-Acquired Infections [drug therapy. Pneumonia [∗ drug therapy.Beilinson Campus.DECLARATIONS OF INTEREST None known. Israel. SOURCES OF SUPPORT Internal sources • Rabin Medical Center . Ltd. Drug Therapy.