Genomic determinants of penicillin G susceptibility and cefazolin inoculum effect in methicillin-susceptible Staphylococcus aureus bloodstream isolates.

BACKGROUND: This study aimed to describe penicillin G susceptibility, blaZ diversity, and genetic determinants of the cefazolin inoculum effect (CfzIE) among MSSA bloodstream isolates. METHODS: The first three non-duplicate MSSA isolates recovered each month from blood cultures at our French university hospital between January 2010 and December 2023 were selected. Whole-genome sequencing was performed using the Illumina NextSeq platform to characterize blaZ and its genetic context. Susceptibility to penicillin G and the CfzIE were assessed using phenotypic methods. RESULTS: Among 488 MSSA isolates, 373 (76.5%) carried blaZ, of which 119 (31.9%) exhibited CfzIE. Thirty BlaZ allotypes were identified overall; 26 were included in the genetic determinant analysis after exclusion of isolates with multiple or truncated blaZ. In multivariable analysis, BlaZA3 was strongly associated with CfzIE (aOR, 15.72; 95% CI, 3.33-74.24; P < 0.001), as was CC7 (aOR, 5.48; 95% CI, 1.45-20.69; P = 0.011). Among BlaZA3 isolates, CfzIE was mainly observed with complete blaR1. Among 122 isolates with a penicillin G inhibition zone ≥26 mm, seven carried blaZ, including six with sharp zone edges and truncated blaZ sequences. CONCLUSION: CfzIE was mainly associated with a BlaZA3-related genetic background, particularly in the presence of complete blaR1, rather than with blaZ type alone. Approximately one-quarter of MSSA bloodstream isolates were susceptible to penicillin G, and rare phenotype-genotype discrepancies were associated with truncated blaZ sequences.