Cefazolin Versus Flucloxacillin for Methicillin-Susceptible Staphylococcus aureus Bone and Joint Infections: A Retrospective Single-Center Comparative Study of Effectiveness and Renal Safety of Intravenous Monotherapy

Background/Objectives: In methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, randomized evidence indicates comparable efficacy of cefazolin and antistaphylococcal penicillins with less nephrotoxicity; whether this extends to bone and joint infection (BJI) is unknown. We compared both agents in MSSA BJI. Methods: We retrospectively analyzed all adults at a single center with culture-confirmed, monomicrobial MSSA BJI treated with inpatient intravenous cefazolin or flucloxacillin monotherapy (January 2022–January 2025)—a selected population excluding rifampicin-based combination therapy, outpatient parenteral therapy, polymicrobial infection, and concurrent bacteremia/endocarditis. Endpoints, a priori exploratory, comprised effectiveness (mortality; clinical success) and renal safety (peri-treatment acute kidney injury [AKI]); the AKI comparison was additionally adjusted for confounders. Results: Among 110 patients (64 cefazolin, 46 flucloxacillin), baseline characteristics were comparable except for more frequent nephrotoxic co-medication with cefazolin (56.2% vs. 26.1%; p = 0.002). No statistically significant differences in effectiveness were detected: 30-day clinical success was 89.1% versus 80.4% (ARD 8.6 percentage points, 95% CI −4.7 to +23.3) and one-year clinical success 79.7% versus 65.2% (ARD 14.5, 95% CI −2.2 to +31.0); these imprecise estimates are compatible with effects ranging from no difference to a clinically relevant benefit of cefazolin. Peri-treatment AKI occurred in 19.0% versus 30.4% (ARD 11.4, 95% CI −4.7 to +27.7; adjusted odds ratio 2.27, 95% CI 0.87–5.91); the difference was confined to stage 1. Conclusions: In this selected inpatient monotherapy cohort, cefazolin was associated with numerically fewer AKI events, without statistically significant differences in any comparison. These exploratory findings support cefazolin as a rational targeted option for MSSA BJI, pending prospective confirmation.