Cefazolin Inoculum Effect and Cefazolin Microbiological Treatment Failure in Serious Methicillin-Susceptible <i>Staphylococcus aureus</i> Infections: A Multicenter Retrospective Cohort Study

BACKGROUND: It remains unclear if cefazolin inoculum effect (CzIE) translates to poorer clinical outcomes in patients with methicillin-susceptible Staphylococcus aureus (MSSA) infections who were treated with cefazolin. METHODS: This retrospective cohort study across five hospitals in Ontario, Canada from 2021 to 2025 included adult patients who received cefazolin treatment for serious MSSA infection based on blood or deep sterile site culture growth. CzIE was defined as a ≥4 fold increase in cefazolin minimum inhibitory concentration to ≥16 μg/mL at a high inoculum based on broth microdilution assay. Patients were followed to 90 days. Primary outcome was all-cause mortality. Secondary outcome was microbiological treatment failure based on culture growth of MSSA after one week of cefazolin treatment. Potential confounders were adjusted using propensity score weighting and a competing risk model for microbiological treatment failure was used to account for mortality as a competing event. RESULTS: Of 259 patients, 92 (35.5%) patients had an MSSA isolate that displayed CzIE. The 90-day mortality rate was 19/92 (20.7%) and 37/167 (22.2%) in the CzIE positive and negative group respectively with adjusted risk difference of 0.6% (95% CI -9.0% to 10.2%, p=0.9060). Microbiological treatment failure occurred in 19/92 (20.7%) and 10/167 (6.0%) from the CzIE positive and negative group respectively with adjusted sub-distribution hazard ratio of 3.12 (95% CI 1.38 to 7.08, p=0.0065) in a competing risk model. CONCLUSIONS: CzIE was associated with a significantly increased risk of microbiological treatment failure. CzIE testing may be useful in guiding antibiotic treatment for serious MSSA infections.