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

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.