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

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; I-2 = 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; I-2 = 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; I-2 = 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; I-2 = 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. (Crit Care Med 2010; 38: 1651-1664)