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 38 isolates recovered from rectal screening samples between 2019 and 2023, with only the first 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 bla_KPC alleles were identified. The most frequent were bla_KPC-31 (17/38, 44.7%) and bla_KPC-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 bla_KPC allele, including isolates with identical OmpK35 and OmpK36 profiles. Resistance to MEM-VAB and IMI-REL showed incomplete overlap across allelic backgrounds. Conclusions: Neither the bla_KPC allele nor the porin genotype reliably predicted collateral susceptibility, supporting direct testing of each β-lactam/β-lactamase inhibitor combination, including in colonizing isolates with restored carbapenem susceptibility.