Frequency of Cefazolin Inoculum Effect among Bacteremic Methicillin-Susceptible Staphylococcus aureus, is it a cause of concern?

Resumen

Background: Recent studies suggest that cefazolin (Cz) has clinical efficacy similar to isoxazolyl penicillins for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia with a lower rate of adverse events and greater ease of administration. However, the Cz inoculum effect (CzIE), mediated by staphylococcal beta-lactamases, could limit the therapeutic efficacy of Cz. In this study the presence of CzIE was analyzed in 55 bloodstream MSSA isolates recovered consecutively from 55 patients in a Spanish hospital during 2020-2021. Methods: The identification of the isolates was performed by MALDI-TOF. Cz MICs were determined at standard (105 CFU/mL) and high (107 CFU/mL) inoculum by broth microdilution. The CzIE was defined as an increase of MIC to ≥16 mg/L when tested at high inoculum. S. aureus ATCC 29213, a producer of BlaZ type A beta-lactamase lacking the CzIE, was used as control strain.The characterization of the blaZ gene was performed in all isolates by PCR (using new designed primers to amplify the complete gene) and sequencing; BlaZ variants and allotypes were stablished according to Carvajal et al (AAC 2020; 64:e02511-19). Results: The Cz MIC90 for all isolates when tested at standard inoculum was 1 mg/L. The overall prevalence of the CzIE was 20% (11/55). Among the 55 BlaZ sequences, type B was the most predominant beta-lactamase (n=32; 58%), followed by type A (n=11; 25%), and type C (n=9; 16%). Most isolates with type A (10/14; 71.4%) showed CzIE; however, none of the type B isolates, and only one isolate with type C beta-lactamase showed CzIE. We found 10 allotypes in BlaZ, being BlaZ-1, -2, -3 and -7 predominants (83%). A single allotype, designated BlaZ-2, was present in 72.7% (8/11) of isolates showing CzIE. All BlaZ-2 isolates presented three critical amino acid substitutions (A9V, E112A, and G145E). Two other allotypes (BlaZ-3 and BlaZ-7) were associated with a lack of the CzIE. Conclusion: Among recent bloodstream MSSA isolates, the prevalence of the CzIE was 20% and was mostly associated with type A beta-lactamase. The presence of type A beta-lactamase could predict the CzIE among MSSA clinical isolates.