Genomic Characteristics and β-Lactam/β-Lactamase Inhibitor Susceptibility Profiles of Ceftazidime–Avibactam-Resistant KPC-Producing Klebsiella pneumoniae

Background/Objectives: Ceftazidime–avibactam (CZA) resistance in KPC-producing Klebsiella pneumoniae is frequently associated with variant KPC enzymes, but the resulting susceptibility to other β-lactam/β-lactamase inhibitor combinations remains difficult to predict. We investigated the genomic characteristics and collateral susceptibility profiles of CZA-resistant KPC-producing K. pneumoniae colonizing isolates. Methods: This retrospective study included a selected collection of 38 isolates recovered from rectal screening samples between 2019 and 2023, with only one isolate per patient included. Isolates underwent whole-genome sequencing and susceptibility testing to aztreonam–avibactam (AZT–AVI), meropenem–vaborbactam (MEM–VAB), imipenem–relebactam (IMI–REL), and meropenem. MICs were interpreted according to EUCAST 2026 criteria. Results: Twelve blaKPC alleles were identified. The most frequent were blaKPC-31 (17/38, 44.7%) and blaKPC-66 (7/38, 18.4%), while the remaining 14 isolates carried ten less frequent alleles. Most KPC variants involved the Ω-loop. OmpK35 and OmpK36 alterations were common and frequently occurred together. AZT–AVI was active against all isolates, whereas susceptibility to MEM–VAB, IMI–REL, and meropenem was 89.5%, 81.6%, and 44.7%, respectively. Marked MIC variability was observed among isolates carrying the same blaKPC allele, including isolates with identical OmpK35 and OmpK36 profiles. Resistance to MEM–VAB and IMI–REL showed incomplete overlap across allelic backgrounds. Conclusions: Within this collection, isolates carrying the same blaKPC allele and porin profile could exhibit different collateral susceptibility patterns, supporting direct susceptibility testing of individual β-lactam/β-lactamase inhibitor combinations.