Blanco Martín, TaniaGuzmán-Puche, JuliaHernández-García, MartaMuñoz-Rosa, MontserratElías-López, CristinaRiazzo, CristinaTorre-Cisneros, JuliánArca-Suárez, JorgeCausse, ManuelBou, GermánCantón, RafaelMartínez-Martínez, Luis2026-03-052026-03-052025-09-29Blanco-Martín T, Guzmán-Puche J, Hernández-García M, Muñoz-Rosa M, Elías-López C, Riazzo C, Torre-Cisneros J, Arca-Suárez J, Causse M, Bou G, Cantón R, Martínez-Martínez L. Mechanisms of resistance to ceftazidime/avibactam in mutants derived in vitro from Klebsiella pneumoniae producing OXA-48-like enzymes. J Antimicrob Chemother. 2025 Dec 2;80(12):3265-3272.1460-2091https://hdl.handle.net/2183/47586[Abstract] Objectives: To generate in vitro ceftazidime-avibactam-resistant mutants derived from Klebsiella pneumoniae producing OXA-48 or OXA-48 derivatives OXA-131 and OXA-232 carbapenemases, to define their antimicrobial susceptibility phenotype and to analyse mutations potentially involved in resistance to ceftazidime-avibactam. Methods: Mutants were obtained by plating overnight bacterial cultures on Mueller-Hinton agar plates containing increasing concentrations of ceftazidime-avibactam (0.5/4-32/4 mg/L). MICs were determined using Sensititre™ DKMNG panels. Whole-genome sequencing of 8 parental strains and 31 mutant derivatives was performed with Illumina. Results: All parental strains were susceptible to ceftazidime-avibactam (MIC ≤ 0.5/4-2/4 mg/L) and either susceptible or resistant to meropenem (MIC 0.5 to >16 mg/L) and imipenem (MIC ≤ 0.5 to >16 mg/L). MICs of ceftazidime-avibactam for the mutants increased up to 4 to >16 mg/L, while MICs of meropenem and imipenem for most mutants either increased up to >16 mg/L or remained unchanged. Whole-genome sequencing of the mutants identified alterations in genes coding for proteins related to AcrAB-TolC (AcrB, AcrR), PBPs (PBP2, PBP3), porins (OmpK36, EnvZ) or the stress or stringent responses (RseB, CpxA, SpoT). No mutations were detected in genes coding for OXA-48-like enzymes or other β-lactamases. Conclusions: Ceftazidime-avibactam can select in vitro mutants of OXA-48-like carbapenemase-producing K. pneumoniae resistant to this combination and, in some cases, also to carbapenems. No mutations related to ceftazidime-avibactam resistance were found in genes coding OXA-48-like enzymes, but they were detected in genes related to active efflux, PBPs, permeability or proteins of the stress and stringent responses.engThis is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record is available online at Oxford Academic web.Anti-bacterial agentsAzabicyclo compoundsCeftazidimeDrug resistance, BacterialKlebsiella pneumoniaebeta-Lactamasesjournal articleembargoed access10.1093/JAC/DKAF360