Phenotypic, biochemical and genetic analysis of KPC-41, a KPC-3 variant conferring resistance to ceftazidime-avibactam and exhibiting reduced carbapenemase activity

Linda Mueller; Amandine Masseron; Guy Prod'Hom; Tatiana Galperine; Gilbert Greub; Laurent Poirel; Patrice Nordmann

doi:10.1128/AAC.01111-19

Phenotypic, biochemical and genetic analysis of KPC-41, a KPC-3 variant conferring resistance to ceftazidime-avibactam and exhibiting reduced carbapenemase activity

Antimicrob Agents Chemother. 2019 Sep 9;63(12):e01111-19. doi: 10.1128/AAC.01111-19. Epub 2019 Sep 16.

Authors

Linda Mueller^{1

2

3}, Amandine Masseron¹, Guy Prod'Hom³, Tatiana Galperine⁴, Gilbert Greub³, Laurent Poirel^{1

2

5}, Patrice Nordmann^{6

2

3

5}

Affiliations

¹ Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
² Swiss National Reference Center for Emerging Antibiotic Resistance (NARA), University of Fribourg, Fribourg, Switzerland.
³ Institut for Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
⁴ Infectiology Department, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
⁵ INSERM European Unit (IAME, France), University of Fribourg, Fribourg, Switzerland.
⁶ Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland [email protected].

Abstract

A novel KPC variant, KPC-41, was identified in a Klebsiella pneumoniae clinical isolate from Switzerland. This ß-lactamase possessed a three amino-acid insertion (Pro-Asn-Lys) located between amino acids 269 and 270 compared to the KPC-3 amino acid sequence. Cloning and expression of the bla _KPC-41 gene in Escherichia coli, followed by determination of MIC values and kinetic parameters, showed that KPC-41, compared to KPC-3, has an increased affinity to ceftazidime and a decreased sensitivity to avibactam, leading to resistance to ceftazidime-avibactam once produced in K. pneumoniae Furthermore, KPC-41 exhibited a drastic decrease of its carbapenemase activity. This report highlights that a diversity of KPC variants conferring resistance to ceftazidime-avibactam already circulate in Europe.