Efficacy and safety of vancomycin versus 13 alternatives in MRSA-confirmed skin and soft tissue infections: a meta-analysis of 39 randomized controlled trials

Vancomycin is the standard therapy for suspected or confirmed Methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI). Although newer anti-MRSA agents claim improved efficacy and safety, evidence in microbiologically confirmed MRSA-SSTI remains limited and heterogenous. Thus, this study aimed to systematically compare the efficacy and safety of alternative agents versus vancomycin in adults with confirmed MRSA-SSTI. Three databases were searched until August 05, 2025, to retrieve randomized controlled trials (RCTs) from published meta-analyses evaluating vancomycin versus alternatives involving patients with MRSA-confirmed SSTI. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using random-effects model. The study is registered in PROSPERO (CRD420251119756). From 28 meta-analyses, 39 RCTs (n = 20,285; 2,662 patients with MRSA-confirmed SSTI receiving alternative agents and 2,322 receiving vancomycin) were included. No significant difference in clinical success was observed between groups (RR: 1.012, 95% CI: 0.992–1.032; prediction interval: 0.994–1.030). Although alternatives showed modestly higher microbiological success (RR: 1.058, 95% CI 1.001–1.119; prediction interval: 0.895–1.250), the effect lost significance after publication bias adjustment. Alternative agents had significantly lower dermatologic but higher gastrointestinal and hematological risk. Tigecycline had higher adverse events (RR: 1.090, 95% CI: 1.019–1.166), and telavancin had higher drug discontinuation (RR: 1.405, 95% CI: 1.105–1.786). Despite the growth of newer anti-MRSA agents, vancomycin remains clinically comparable for MRSA-confirmed SSTI, with apparent microbiological advantages of alternatives tempered by potential publication bias. Varying safety and pharmacological profiles of these agents emphasize the importance of individualized treatment selection.