Effectiveness and safety of cefazolin vs antistaphylococcal penicillins for methicillin-susceptible Staphylococcus aureus bacteremia: a multicenter real-world evaluation using the international TriNetX database

This study aimed to evaluate the effectiveness and safety of cefazolin vs antistaphylococcal penicillins (ASPs) in the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. This phase IV, retrospective, comparative-effectiveness, multicenter study used data extracted from the international TriNetX analytics platform. Eligible patients developed monomicrobial MSSA bacteremia during hospitalization between 1 January 2015 and 31 December 2025 and received treatment with either cefazolin or ASPs. The primary outcome was all-cause mortality within 90 days. Safety outcomes included Clostridioides difficile infection within 90 days and renal, liver, allergic, and hematological disorders within 30 days. Survival analyses were conducted after propensity score matching. Among 110,275 patients with MSSA bacteremia identified, 3,908 (3.5%) met the inclusion criteria. After propensity score matching, 1,954 patients were included in each group. Treatment with cefazolin was associated with significantly reduced all-cause mortality within 90 days (9.7% vs 14.7%, HR = 0.620 [0.515–0.748]). Among the safety outcomes, Clostridioides difficile infection occurred less frequently in the cefazolin group (4.9% vs 7.20%, HR = 0.631 [0.482–0.827]). This real-world evaluation using the international TriNetX database suggests that, compared with ASPs, cefazolin is more effective and safer for the management of MSSA bacteremia. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT07186894 .