Cefazolin vs. antistaphylococcal penicillins for the treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a systematic review and meta-analysis

Authors:

• Prosty, Connor
• Noutsios, Dean
• Lee, Todd C.
• Daneman, Nick
• Davis, Joshua S.
• Jager, Nynke G.L.
• Ghanem-Zoubi, Nesrin
• Goodman, Anna L.
• Kaasch, Achim J.
• Kouijzer, Ilse
• McMullan, Brendan J.
• McDonald, Emily G.
• Tong, Steven Y.C.
• Ong, Sean W.X.

Details:

Clinical Microbiology and Infection, Volume 31, Issue 8, 2025-08-31

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Background There is debate on whether cefazolin or antistaphylococcal penicillins should be the first-line treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Ongoing trials are investigating whether cefazolin is non-inferior to (flu)cloxacillin, but it remains uncertain whether these findings apply to other antistaphylococcal penicillins. Objectives We conducted a systematic review and meta-analysis comparing cefazolin with each of the individual antistaphylococcal penicillins for MSSA bacteraemia. Methods Data sources: We updated a 2019 systematic review but specifically focused on evaluating outcomes by individual antistaphylococcal penicillins. Study eligibility criteria Study eligibility criteria include comparative observational studies. Participants Participants include patients with MSSA bacteraemia. Interventions Interventions include cefazolin vs. the antistaphylococcal penicillins. Assessment of risk of bias Assessment of risk of bias involved the risk of bias in non-randomized studies of interventions tool. Methods of data synthesis The primary outcome was 30-day all-cause mortality and we assessed for non-inferiority of cefazolin using a pre-specified non-inferiority margin of a pooled OR <1.2 using raw unadjusted data. Secondary outcomes were 90-day mortality, treatment-related adverse events (TRAEs), discontinuation due to toxicity, and nephrotoxicity. Results No randomized data have been published. A total of 30 observational studies at moderate or high risk of bias were included, which comprised 3869 patients who received cefazolin and 11 644 patients who received antistaphylococcal penicillins (flucloxacillin = 6721, unspecified = 2440, nafcillin = 1305, cloxacillin = 1258, and oxacillin = 120). Cefazolin was associated with a reduced odds of 30-day all-cause mortality (OR = 0.73, 95% CI: 0.62–0.85) compared with antistaphylococcal penicillins, meeting pre-specified non-inferiority. This effect was consistent vs. flucloxacillin (OR = 0.92, 95% CI: 0.73–1.16), nafcillin (OR = 0.58, 95% CI: 0.28–1.17), cloxacillin (OR = 0.42, 95% CI: 0.11–1.58), and oxacillin (OR = 0.31, 95% CI: 0.03–2.75). Point estimates favoured cefazolin for 90-day mortality, TRAEs, nephrotoxicity, and discontinuation due to toxicity overall and in each comparison with individual antistaphylococcal penicillins, except for TRAEs vs. cloxacillin. Discussion In moderate-to low-quality observational data, cefazolin was non-inferior for mortality and potentially superior for safety as compared with antistaphylococcal penicillins overall and across most individual comparisons.