IntroductionMethicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of infection in humans. Beta-lactam antibiotics are the preferred agents, with anti-staphylococcal penicillins (ASPs) or the first-generation cephalosporin, cefazolin, favored by clinicians. Recent studies comparing the two strategies suggest similar outcomes between the agents. The purpose of this meta-analysis was to explore differences between cefazolin and ASPs for the treatment of MSSA infections.MethodsWe performed a meta-analysis with trial sequential analysis (TSA) of observational or cohort studies using a random-effects model. Two blinded reviewers independently assessed studies for inclusion, risk of bias, and data extraction. The primary outcome was all-cause mortality. Secondary outcomes included clinical failure, infection recurrence, and antibiotic discontinuation due to adverse events. Subgroup analyses were conducted for the primary outcome by type of ASP, studies with a high percentage of deep-seated infections, and studies of low to moderate risk of bias.ResultsAfter performing a comprehensive search of the literature, and screening for study inclusion, 19 studies (13,390 patients) were included in the final meta-analysis. Fifteen of the 19 studies (79%) were judged as having a low or moderate risk of bias. Use of cefazolin was associated with lower all-cause mortality [odds ratio (OR) 0.71, 95% confidence interval (CI) 0.56–0.91, p = 0.006, I2 = 28%], clinical failure (OR 0.55, 95% CI 0.41–0.74, p < 0.001, I2 = 0%), and antibiotic discontinuation due to adverse events (OR 0.25, 95% CI 0.16–0.39, p < 0.001, I2 = 23%). Infection recurrence was higher in the cefazolin patients (OR 1.41, 95% CI 1.04–1.93, p = 0.03, I2 = 0%).ConclusionThis meta-analysis demonstrated that the use of cefazolin was associated with significant reductions in all-cause mortality, clinical failure, and discontinuation due to adverse events, but was associated with an increased risk of infection recurrence.FundingUniversity of Florida Open Access Publishing Fund funded the Rapid Service Fees.Trial registrationPROSPERO International Prospective Register of Systematic Reviews (study ID: CRD42018106442).Electronic supplementary materialThe online version of this article (10.1007/s40121-019-00259-4) contains supplementary material, which is available to authorized users.

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