Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect
Abstract
Objectives Ceftazidime–avibactam (CZA) and cefiderocol are recently commercialized molecules active against highly drug-resistant bacteria, including carbapenem-resistant members of the Enterobacteriaceae. Mutants resistant to CZA have been described, notably in Klebsiella pneumoniae carbapenemase (KPC) producers. Considering the structural similarities between ceftazidime and cefiderocol, we hypothesized that resistance to CZA in KPC-producing members of the Enterobacterales may lead to cross-resistance to cefiderocol. Methods CZA-resistant mutants from three clinical isolates of the Enterobacterales carrying either bla KPC-2 or bla KPC-3 were selected in vitro . Mutants with increased MIC to CZA compared to the ancestral allele were cloned in a pBR322 plasmid and expressed in Escherichia coli TOP10. We evaluated the impact of these mutations on cefiderocol MICs and minimal bactericidal concentrations (MBCs), and we assessed the impact of bacterial inoculum size on cefiderocol MICs. Results We used 37 KPC mutants with increased CZA MICs. Of these, six have been described previously in clinical isolates. Compared to the wild-type alleles, increases in the cefiderocol MICs of 4- to 32-fold were observed for 75.6% of tested mutants (28/37), MICs reaching up to 4 mg/L in E. coli TOP10 for KPC-31 (D179Y–H274Y mutations). MBCs and MICs of cefiderocol were similar, confirming the bactericidal activity of this drug. Finally, when using higher inocula (10 7 CFU/mL), a large increase in cefiderocol MIC was observed, and all isolates were categorized as resistant. Conclusion We observed that most of the CZA-resistant KPC variants have a possible impact on cefiderocol by increasing the cefiderocol MICs. In addition, cefiderocol is greatly impacted by the inoculum effect, suggesting that precautions should be taken when treating infections with a suspected high inoculum.
Related
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BibTeX
@article{hobson2026crossresistance,
title = {{Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect}},
author = {Claire Amaris Hobson and Aurélie Cointe and Hervé Jacquier and Alaksh Choudhury and Mélanie Magnan and Céline Courroux and Olivier Tenaillon and Stéphane Bonacorsi and André Birgy},
journal = {Clinical Microbiology and Infection},
year = {2026},
month = sep,
doi = {10.1016/j.cmi.2021.04.016},
url = {https://hal.science/hal-05771478v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect
AU - Claire Amaris Hobson
AU - Aurélie Cointe
AU - Hervé Jacquier
AU - Alaksh Choudhury
AU - Mélanie Magnan
AU - Céline Courroux
AU - Olivier Tenaillon
AU - Stéphane Bonacorsi
AU - André Birgy
PY - 2026
DA - 2026/09/30
JO - Clinical Microbiology and Infection
DO - 10.1016/j.cmi.2021.04.016
UR - https://hal.science/hal-05771478v1
AB - Objectives Ceftazidime–avibactam (CZA) and cefiderocol are recently commercialized molecules active against highly drug-resistant bacteria, including carbapenem-resistant members of the Enterobacteriaceae. Mutants resistant to CZA have been described, notably in Klebsiella pneumoniae carbapenemase (KPC) producers. Considering the structural similarities between ceftazidime and cefiderocol, we hypothesized that resistance to CZA in KPC-producing members of the Enterobacterales may lead to cross-resistance to cefiderocol. Methods CZA-resistant mutants from three clinical isolates of the Enterobacterales carrying either bla KPC-2 or bla KPC-3 were selected in vitro . Mutants with increased MIC to CZA compared to the ancestral allele were cloned in a pBR322 plasmid and expressed in Escherichia coli TOP10. We evaluated the impact of these mutations on cefiderocol MICs and minimal bactericidal concentrations (MBCs), and we assessed the impact of bacterial inoculum size on cefiderocol MICs. Results We used 37 KPC mutants with increased CZA MICs. Of these, six have been described previously in clinical isolates. Compared to the wild-type alleles, increases in the cefiderocol MICs of 4- to 32-fold were observed for 75.6% of tested mutants (28/37), MICs reaching up to 4 mg/L in E. coli TOP10 for KPC-31 (D179Y–H274Y mutations). MBCs and MICs of cefiderocol were similar, confirming the bactericidal activity of this drug. Finally, when using higher inocula (10 7 CFU/mL), a large increase in cefiderocol MIC was observed, and all isolates were categorized as resistant. Conclusion We observed that most of the CZA-resistant KPC variants have a possible impact on cefiderocol by increasing the cefiderocol MICs. In addition, cefiderocol is greatly impacted by the inoculum effect, suggesting that precautions should be taken when treating infections with a suspected high inoculum.
SN - 1198-743X
SN - 1469-0691
ER -