@article{Di:2024:10.1016/j.ijantimicag.2023.107030,
author = {Di, Pilato V and Codda, G and Niccolai, C and Willison, E and Wong, JLC and Coppo, E and Frankel, G and Marchese, A and Rossolini, GM},
doi = {10.1016/j.ijantimicag.2023.107030},
journal = {Int J Antimicrob Agents},
title = {Functional features of KPC-109, a novel 270-loop KPC-3 mutant mediating resistance to avibactam-based β-lactamase inhibitor combinations and cefiderocol.},
url = {http://dx.doi.org/10.1016/j.ijantimicag.2023.107030},
volume = {63},
year = {2024}
}

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TY  - JOUR
AB  - OBJECTIVES: To investigate a ceftazidime/avibactam (CZA)-resistant Klebsiella pneumoniae (NE368), isolated from a patient exposed to CZA, expressing a novel K. pneumoniae carbapenemase (KPC)-3 variant (KPC-109). METHODS: Antimicrobial susceptibility testing was performed by reference broth microdilution. Whole-genome sequencing (WGS) analysis of NE368 was performed combining a short- and long-reads approach (Illumina and Oxford Nanopore Technologies). Functional characterization of KPC-109 was performed to investigate the impact of KPC-109 production on the β-lactam resistance phenotype of various Escherichia coli and Klebsiella pneumoniae strains, including derivatives of K. pneumoniae with OmpK35 and OmpK36 porin alterations. Horizontal transfer of the KPC-109-encoding plasmid was investigated by conjugation and transformation experiments. RESULTS: K. pneumoniae NE368 was isolated from a patient after repeated CZA exposure, and showed resistance to CZA, fluoroquinolones, piperacillin/tazobactam, expanded-spectrum cephalosporins, amikacin, carbapenems and cefiderocol. WGS revealed the presence of a large chimeric plasmid of original structure (pKPN-NE368), encoding a novel 270-loop mutated KPC-3 variant (KPC-109; ins_270_KYNKDD). KPC-109 production mediated resistance/decreased susceptibility to avibactam-based combinations (with ceftazidime, cefepime and aztreonam) and cefiderocol, with a trade-off on carbapenem resistance. However, in the presence of porin alterations commonly encountered in high-risk clonal lineages of K. pneumoniae, KPC-109 was also able to confer clinical-level resistance to carbapenems. Resistance of NE368 to cefiderocol was likely contributed by KPC-109 production acting in concert with a mutated EnvZ sensor kinase. The KPC-109-encoding plasmid did not appear to be conjugative. CONCLUSIONS: These findings expand current knowledge about the diversity of emerging KPC enzyme variants with 270-loop alterations that can be encountered in the
AU  - Di,Pilato V
AU  - Codda,G
AU  - Niccolai,C
AU  - Willison,E
AU  - Wong,JLC
AU  - Coppo,E
AU  - Frankel,G
AU  - Marchese,A
AU  - Rossolini,GM
DO  - 10.1016/j.ijantimicag.2023.107030
PY  - 2024///
TI  - Functional features of KPC-109, a novel 270-loop KPC-3 mutant mediating resistance to avibactam-based β-lactamase inhibitor combinations and cefiderocol.
T2  - Int J Antimicrob Agents
UR  - http://dx.doi.org/10.1016/j.ijantimicag.2023.107030
UR  - https://www.ncbi.nlm.nih.gov/pubmed/37931849
VL  - 63
ER  - 

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