The global spread of extended-spectrum beta-lactamase (ESBL) producing Enterobacterales represents a major clinical challenge often requiring carbapenem use with the consequent risk of selecting carbapenemase-producing strains. Recently, new beta-lactam plus beta-lactamase inhibitor formulations available could provide effective carbapenem-sparing alternatives. Among these, cefepime/enmetazobactam (FEP-ET) is tailored for ESBL infection treatment. Here, we tested cefepime/enmetazobactam against a multicentric collection of 112 CTX-M producing E. coli and K. pneumoniae isolated in Northern Italy in order to evaluate the performance of gradient strip and disk diffusion (DD) test compared to broth microdilution, and to assess the in vitro antimicrobial activity of this new formulation. Molecular testing for bla genes and CTX-M typing were also performed. The results showed 100% of categorical agreement and no major error or very major error. All strains were susceptible to cefepime/enmetazobactam while resistance was observed only in carbapenemase-producing strains. CTX-M-1 was predominant and several strains carried blaTEM and blaSHV. These data demonstrate a good in vitro activity of cefepime/enmetazobactam against CTX-M producing E. coli and K. pneumoniae . Moreover, DD proved reliable and reproducible for routine testing while gradient strips underestimated MIC values which could be critical for isolates near the breakpoint.