Cefiderocol Susceptibility in Japanese Clinical Enterobacterales Isolates and the Effect of IMP-Type Carbapenemases on Resistance.

Objectives: Carbapenem-resistant Enterobacterales (CRE) limit treatment options, and cefiderocol's efficacy can be compromised by regional carbapenemases. In this study, we aimed to characterize cefiderocol susceptibility distribution among Enterobacterales in Japan-specifically endemic strains producing IMP-type carbapenemases (IMP)-and explore the effect of IMP in mediating resistance. Methods: The susceptibility of 556 evaluable Enterobacterales isolates (from an initial 560 screened) to cefiderocol was assessed using disk diffusion and broth microdilution methods based on Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) distributions across groups were compared using Kruskal-Wallis and Mann-Whitney U tests. Results: A total of 556 isolates yielded evaluable results. The cefiderocol susceptibility rate was 99.5 and 98.7% based on CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints, respectively. Notably, under both criteria, IMP-producing isolates exhibited a susceptibility rate of 99.6%, whereas non-CRE and non-extended-spectrum β-lactamase (ESBL) exhibited a susceptibility rate of 99.4%. Statistical analysis revealed that the ESBL-only group had higher MICs than the non-CRE/non-ESBL and IMP-only groups (both p < 0.001), whereas no significant difference was observed between the latter two (p = 0.083). Notably, the ESBL-only group exhibited higher MICs than those of isolates harboring both IMP and ESBL. Conclusions: These findings indicate a non-additive effect, in which the coexistence of multiple resistance enzymes does not necessarily increase cefiderocol resistance. The association between IMP and cefiderocol resistance may be limited. In specific enzyme combinations, its presence was even associated with lower MICs.