Combination therapy with fosfomycin for Staphylococcus aureus bacteraemia or endocarditis: a systematic review and meta-analysis of randomized trials.

Background and objectives: Fosfomycin combination therapy for Staphylococcus aureus bacteraemia or endocarditis has been evaluated, but studies were limited by small sample sizes. We sought to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to establish robust efficacy and safety estimates of fosfomycin combination therapy in this patient population.

Data sources: MEDLINE, Embase, Cochrane Library and Web of Science databases were searched from inception through September 2024 (PROSPERO CRD42024583822).

Study eligibility: RCTs comparing fosfomycin combination with standard-of-care antibiotics in patients with S. aureus bacteraemia or endocarditis were included. Two independent reviewers screened studies for inclusion.

Assessment of risk of bias: Risk of bias was assessed using the revised Cochrane RoB 2 tool.

Data synthesis and analysis: Treatment effects were estimated with pooled risk ratios (RRs) using random effects meta-analysis. Heterogeneity between studies was assessed with Cochran's Q-statistic and I ² test.

Results: Of 437 articles identified, three RCTs met inclusion criteria. Primary outcome of treatment success or cure was not meta-analysed due to clinical heterogeneity. Combination therapy did not significantly improve mortality (RR 0.85; 95% CI, 0.28-2.52; I²  = 27.8%) or persistent bacteraemia (RR 0.34; 95% CI, 0.04-2.59; I²  = 0%). Participants receiving combination therapy had more adverse events leading to treatment discontinuation, but this was not statistically significant (RR 1.84; 95% CI, 0.36-9.36; I²  = 18%).

Conclusions: In this meta-analysis of three RCTs, fosfomycin combination therapy for S. aureus bacteraemia or endocarditis did not significantly improve patient outcomes and may be associated with higher rates of adverse events.