Cefazolin Versus Antistaphylococcal Penicillins in Methicillin-Susceptible Staphylococcus aureus Bone and Joint Infections: A Narrative Review

Methicillin-susceptible Staphylococcus aureus (MSSA) is among the most common pathogens causing bone and joint infections (BJI), which require adequate source control combined with prolonged antimicrobial therapy. For decades, intravenous antistaphylococcal penicillins (ASP) have generally been preferred over cefazolin for MSSA bacteremia, although this practice was based more on convention and historical concerns than on robust comparative evidence. Two recent randomized controlled trials—CloCeBa (2025) and the MSSA domain of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial (2026)—have now established that cefazolin is noninferior to ASP for MSSA bacteremia, with an overall more favorable safety profile. Whether these findings extend to BJI remains uncertain: osteoarticular infection was the most common focus in SNAP, yet no focus-specific analyses have been published, and direct comparative evidence in BJI is limited to a few retrospective cohorts. This narrative review summarizes the randomized and observational evidence with emphasis on osteoarticular populations and discusses the cefazolin inoculum effect, bone pharmacokinetics, the safety of prolonged therapy, outpatient practicality and current guidelines. We conclude that cefazolin is a rational first-line option for most patients with MSSA BJI, outline the remaining uncertainties in high-inoculum and implant-associated infection, and propose a focus-specific research agenda.