Comparative effectiveness of cefazolin versus antistaphylococcal penicillins in methicillin-susceptible Staphylococcus aureus infective endocarditis: a systematic review of observational studies

Abstract

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) is a leading cause of infective endocarditis (IE), associated with high morbidity and mortality. While antistaphylococcal penicillins (ASPs) are considered the standard treatment, cefazolin has emerged as a potential alternative due to its pharmacokinetic advantages and lower toxicity profile. Objectives: To assess the efficacy and safety of cefazolin compared with ASPs in adult patients with MSSA infective endocarditis. Design: Systematic review and meta-analysis. Data sources and methods: We systematically searched MEDLINE, Embase, CENTRAL, Scopus, and Web of Science up to 2024. We included cohort studies and non-randomized trials comparing cefazolin and ASPs in adult patients with MSSA IE. Risk of bias was evaluated using the ROBINS-I tool. Meta-analyses were performed using random-effects models to estimate pooled odds ratios (ORs) and standardized mean differences (SMDs). Results: Seven cohort studies involving 1685 patients (305 cefazolin; 1380 ASPs) were included. Thirty-day mortality, reported in two studies (n = 1083), was lower with cefazolin (OR 0.49; 95% CI 0.29–0.83; I² = 0%). Ninety-day mortality (three studies, n = 475) showed no significant difference (OR 1.00; 95% CI 0.63–1.57; I² = 0%). No significant differences were observed in relapse rates (OR 1.01; 95% CI 0.34–3.02; I² = 12.5%), hospital stay duration (SMD –0.06; 95% CI –0.27 to 0.14), or bacteremia duration (SMD –0.96; 95% CI –1.93 to 0.01). Safety data suggested a lower incidence of adverse events with cefazolin, although definitions varied across studies. Risk of bias was moderate in most studies. Conclusion: Cefazolin demonstrated comparable efficacy to ASPs for the treatment of MSSA IE, with a potential reduction in short-term mortality and a favorable safety profile. These findings support cefazolin as a viable therapeutic alternative, but randomized controlled trials are needed to confirm its effectiveness and safety. Trial registration: PROSPERO registration number: CRD42024593515.