Clinical implications of cefazolin inoculum effect and β-lactamase type on methicillin-susceptible staphylococcus aureus bacteremia

Background: Cefazolin is a common antibiotic for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Type A or C β-lactamase-producing MSSA frequently shows the cefazolin inoculum effect (CIE). However, the clinical implication of the CIE for MSSA bacteremia is obscure. Methods: MSSA bacteremic patients treated with cefazolin were included in a retrospective cohort study. The blaZ gene of the isolates was sequenced to identify the type of β-lactamase. The patients whose isolates showed a ≥4-fold increase in cefazolin, the minimal inhibitory concentration (MIC) at the high inoculum (∼5×10⁷ CFU/ml), were assigned to the CIE-positive group and the remainder to the CIE-negative group. Treatment failure was assessed at 12 weeks after cefazolin was initiated. Results: A total of 113 MSSA bacteremic patients were included. Among the 113 isolates, 57.5% showed the CIE and 77.9% carried the blaZ gene; type A β-lactamase was 15.0% and type C was 40.7%. Persistent bacteremia was more common in the CIE-positive group (9% vs. 0%, p=0.04). Treatment failure rates were higher in the CIE-positive group with high bacterial burden infection, but the difference was not significant (48% vs. 25%, p=0.13). There was no significant difference of failure between groups with high-inoculum MIC ≥16 and ≤1μg/ml (13% vs. 5%, p=0.31). In the multivariable analysis, underlying cardiovascular diseases, pneumonia, osteoarticular infections, and endocarditis were significant risk factors for treatment failure and the CIE was not significantly associated with treatment failure. Conclusion: The CIE might be associated with persistent bacteremia if cefazolin is used for MSSA bacteremia with a high burden of infections. However, the sites of infections are more important factors for the clinical outcome than the CIE.