A Novel Variant of KPC-179 Conferring Ceftazidime-Avibactam Resistance in a Carbapenem-Resistant Klebsiella pneumoniae Isolate

Quanfeng Liao,1 Yu Feng,2 Jin Deng,1 Weili Zhang,1 Siying Wu,1 Ya Liu,1 Yi Xie,1 Mei Kang1 1Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Mei Kang, Email [email protected]: Ceftazidime-avibactam (CZA) is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant Klebsiella pneumoniae (CRKP) that produce Klebsiella pneumoniae carbapenemase (KPC). In this study, we report the first cases of CZA resistance to develop during treatment of CRKP infections and identify the resistance mechanism.Methods: APB/EDTA and NG-Test CARBA5 were used to detect the production of carbapenemase, whole-genome sequencing (WGS) and conjugation experiment were used to identify potential resistance mechanisms of CZA-susceptible (HX1032) and -resistant (HX1192) K. pneumoniae isolates.Results: HX1192 K. pneumoniae was not recognized by APB/EDTA and NG-Test CARBA5 phenotypic assays, WGS revealed it carrying a novel KPC variant, KPC-179, molecular analysis highlighted a G394A mutation, and an ATC insertion at 543 in the blaKPC-2 gene, resulting in an A133T substitution and insertion of the amino acid S at Ambler position 183 in the protein sequence. Remarkably, this mutation restored susceptibility of imipenem (MIC =  0.25 mg/L).Conclusion: Our study highlights the importance of monitoring susceptibility during CZA treatment and accurately detecting KPC variants.Keywords: CZA resistance, carbapenem-resistant, Klebsiella pneumoniae, KPC variant, phenotypic test