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Macrolides and Mortality in Critically Ill Patients With Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis*

Sligl, Wendy I. MD, MSc1,2; Asadi, Leyla MD2; Eurich, Dean T. PhD3; Tjosvold, Lisa MLIS4; Marrie, Thomas J. MD5; Majumdar, Sumit R. MD, MPH6

doi: 10.1097/CCM.0b013e3182a66b9b
Review Articles

Objective: Some studies suggest better outcomes with macrolide therapy for critically ill patients with community-acquired pneumonia. To further explore this, we performed a systematic review of studies with mortality endpoints that compared macrolide therapy with other regimens in critically ill patients with community-acquired pneumonia.

Data Sources: Studies were identified via electronic databases, grey literature, and conference proceedings through May 2013.

Study Selection: Using prespecified criteria, two reviewers selected studies; studies of outpatients and hospitalized noncritically ill patients were excluded.

Data Extraction: Two reviewers extracted data and evaluated bias using the Newcastle-Ottawa Scale. Random effects models were used to generate pooled risk ratios and evaluate heterogeneity (I2).

Data Synthesis: Twenty-eight observational studies (no randomized control trials) were included. Average age ranged from 58 to 78 years and 14–49% were women. In our primary analysis of 9,850 patients, macrolide use was associated with statistically significant lower mortality compared with nonmacrolides (21% [846 of 4,036 patients] vs 24% [1,369 of 5,814]; risk ratio, 0.82; 95% CI, 0.70–0.97; p = 0.02; I2 = 63%). When macrolide monotherapy was excluded, the macrolide mortality benefit was maintained (21% [737 of 3,447 patients] vs 23% [1,245 of 5,425]; risk ratio, 0.84; 95% CI, 0.71–1.00; p = 0.05; I2 = 60%). When broadly guideline-concordant regimens were compared, there was a trend to improved mortality and heterogeneity was reduced (20% [511 of 2,561 patients] mortality with beta-lactam/macrolide therapy vs 23% [386 of 1,680] with beta-lactam/fluoroquinolone; risk ratio, 0.83; 95% CI, 0.67–1.03; p = 0.09; I2 = 25%). When adjusted risk estimates were pooled from eight studies, macrolide therapy was still associated with a significant reduction in mortality (risk ratio, 0.75; 95% CI, 0.58–0.96; p = 0.02; I2 = 57%).

Conclusions: In observational studies of almost 10,000 critically ill patients with community-acquired pneumonia, macrolide use was associated with a significant 18% relative (3% absolute) reduction in mortality compared with nonmacrolide therapies. After pooling data from studies that provided adjusted risk estimates, an even larger mortality reduction was observed. These results suggest that macrolides be considered first-line combination treatment in critically ill patients with community-acquired pneumonia and support current guidelines.

1Division of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada.

2Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada.

3Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, AB, Canada.

4John W. Scott Health Sciences Library, University of Alberta, Edmonton, AB, Canada.

5Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.

6Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

* See also p. 475.

Dr. Sligl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. All authors participated in study conception, design, interpretation, critical revisions, and approved the final article. Drs. Sligl and Asadi undertook data abstraction. Dr. Sligl performed the analyses and drafted the initial article. Drs. Sligl, Eurich, Marrie, and Majumdar obtained funding, and Dr. Majumdar supervised the study. All authors have seen and approved the final version.

Supported, in part, by grants from the Canadian Institutes of Health Research; the Alberta Heritage Foundation for Medical Research; and the University Hospital Foundation (University of Alberta).

Dr. Eurich receives salary support awards from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research (AHFMR). Dr. Marrie consulted for the Government of Alberta. Dr. Majumdar holds the Endowed Chair in Patient Health Management from the Faculties of Medicine and Dentistry and Pharmacy and Pharmaceutical Sciences (University of Alberta) and receives salary support awards from AHFMR (Health Scholar). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: wsligl@ualberta.ca

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins