The Effectiveness of Combination Therapy for Treating Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Literature Review and a Meta-Analysis

Background: This meta-analysis aims to evaluate the effectiveness of combination therapy for treating MSSA bacteremia. Methods: We searched Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and clinicaltrials.gov for studies including adults with MSSA bacteremia. The monotherapy group used a first-line antibiotic active against MSSA and the combination group used a first-line antibiotic plus additional antibiotic/s. The primary outcome was all-cause mortality. Secondary outcomes included persistent bacteremia, duration of bacteremia, relapse, and adverse events. Random-effects models with inverse variance weighting were used to estimate pooled risk ratios (pRR). Heterogeneity was assessed using the I-2 value and the Cochrane's Q statistic. Results: A total of 12 studies (6 randomized controlled trials [RCTs]) were included. Combination therapy did not significantly reduce 30-day mortality (pRR 0.92, 95% CI, 0.70-1.20), 90-day mortality (pRR 0.89, 95% CI, 0.74-1.06), or any-time mortality (pRR 0.91, 95% CI, 0.76-1.08). Among patients with deep-seated infections, adjunctive rifampicin may reduce 90-day mortality (3 studies with moderate-high risk of bias; pRR 0.62, 95% CI, 0.42-0.92). For secondary outcomes, combination therapy decreased the risk of relapse (pRR 0.38, 95% CI, 0.22-0.66), but this benefit was not maintained when pooling RCTs (pRR 0.54, 95% CI, 0.12-2.51). Combination therapy was associated with an increased risk of adverse events (pRR 1.74, 95% CI, 1.31-2.31). Conclusions: Combination therapy not only did not decrease mortality in patients with MSSA bacteremia, but also increased the risk of adverse events. Combination therapy may reduce the risk of relapse, but additional high-quality studies are needed.