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A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study

Kumar, Anand MD; Safdar, Nasia MD; Kethireddy, Shravan MD; Chateau, Dan PhD

doi: 10.1097/CCM.0b013e3181e96b91
Continuing Medical Education Articles

Objective: To assess whether a potential benefit with combination antibiotic therapy is restricted to the most critically ill subset of patients, particularly those with septic shock.

Data Sources: OVID MEDLINE (1950–October 2009), EMBASE (1980–October 2009), the Cochrane Central Register of Controlled Trials (to third quarter 2009), the ClinicalTrial.gov database, and the SCOPUS database.

Study Selection: Randomized or observational studies of antimicrobial therapy of serious bacterial infections potentially associated with sepsis or septic shock. Fifty studies met entry criteria.

Data Extraction: Study design, mortality/clinical response, and other variables were extracted independently by two reviewers. When possible, study datasets were split into mutually exclusive groups with and without shock or critical illness.

Data Synthesis: Although a pooled odds ratio indicated no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856; 95% confidence interval, 0.71–1.03; p = .0943; I2 = 45.1%), stratification of datasets by monotherapy mortality risk demonstrated substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51; 95% confidence interval, 0.41–0.64; I2 = 8.6%). Of those datasets that could be stratified by the presence of shock/critical illness, the more severely ill group consistently demonstrated increased efficacy of a combination therapy strategy (odds ratio, 0.49; 95% confidence interval, 0.35–0.70; p < .0001; I2 = 0%). An increased risk of death was found in low-risk patients (risk of death ≤15% in the monotherapy arm) exposed to combination therapy (odds ratio, 1.53; 95% confidence interval, 1.16–2.03; p = .003; I2 = 8.2%). Meta-regression indicated that efficacy of combination therapy was dependent only on the risk of death in the monotherapy group.

Conclusion: Combination antibiotic therapy improves survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients.

Associate Professor of Medicine (AK), Medical Microbiology and Pharmacology/Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada; Attending ICU Physician (AK), Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada; Associate Professor (NS), School of Medicine & Public Health, Section of Infectious Diseases, University of Wisconsin, Madison, WI; Fellow (SK), Department of Critical Care Medicine, University of Manitoba Health Sciences, Winnipeg, Manitoba, Canada; Research Scientist (DC), Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

Dr. Kumar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Kethireddy and Kumar served as the reviewers. Dr. Safdar performed the meta-analysis and Dr. Chateau performed the meta-regression.

For information regarding this article, E-mail: akumar61@yahoo.com

© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins