The Effect of Combination Therapy on Mortality and Adverse Events in Patients with Staphylococcus aureus Bacteraemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

INTRODUCTION: The findings of randomized controlled trials (RCTs), observational studies, and meta-analyses vary regarding the effectiveness and safety of combination therapy for patients with Staphylococcus aureus bacteraemia (SAB). We aimed to identify the effectiveness and safety of combination therapy in patients with SAB compared with those of monotherapy. METHODS: We performed a systematic review and meta-analysis to compare combination therapy versus monotherapy in patients with SAB. Two authors independently searched PubMed, Embase, and the Cochrane Library of clinical trials until 17 February 2021. Any RCT comparing mortality or adverse events (AEs) of combination therapy versus monotherapy for patients with SAB was eligible. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were evaluated using a random-effects model. The primary outcome was all-cause mortality at any time point. This meta-analysis is registered with the PROSPERO database (CRD42020188176) and reported according to PRISMA guidelines. RESULTS: In total, 1906 articles were identified and screened, and 14 studies (2367 patients) were included in the meta-analysis. There was no significant difference in the risk of all-cause mortality between the two groups (RR = 1.00; 95% CI 0.83–1.20; P = 0.99; I(2) = 0%). Similar results were obtained by subgroup analysis of mortality recording time, endocarditis, pathogen resistance, article publication time, number of patients, and adjuvant antibiotics. Notably, combination treatment might significantly increase the risk of drug-related AEs (RR = 1.68; 95% CI 1.06–2.66; P = 0.03; I(2) = 67%) and nephrotoxicity (RR = 2.30; 95% CI 1.68–3.16; P < 0.00001; I(2) = 0%), although the occurrences of AEs leading to treatment discontinuation and serious AEs were not significantly different between the two groups. CONCLUSIONS: The meta-analysis suggested that combination therapy could not reduce mortality but might increase the risk of drug-related AEs and nephrotoxicity and should be applied very cautiously. Future studies on combined drug therapy for SAB need careful and rigorous design for specific antibiotic combinations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40121-021-00539-y.