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.
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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.