In vivo selection of ceftazidime-avibactam resistance in KPC-3 producing Klebsiella pneumoniae. Klebsiella pneumoniae CZA resistant

Ceftazidime-avibactam (CZA) is used to treat infections caused by carbapenem-resistant Enterobacteria (CRE), including KPC-producing Klebsiella pneumoniae (KPC-Kp). Resistance to CZA has been commonly related to point mutations in the blaKPC gene. We described the vivo emergence of CZA resistance in different isolates of KPC-Kp cultured from clinical samples of four patients treated with this combination. All isolates recovered before treatment were susceptible to CZA. Five KPC-kp isolates recovered after treatment with CZA were resistant to this drug. Whole Genome Sequencing analysis revealed that pretherapy isolates carried the wild-type blaKPC-3 gene. Two postherapy isolates had the previously described mutation D179Y. Additionally, we identified the novel substitution LN168-169H and the combination, in one isolate, of the two previously described mutations D179Y and T172A. All isolates belonged to ST512. blaKPC variants had restoration of carbapenem susceptibility which could imply a potential role for carbapenems. These isolates may escape surveillance programs since they can be reported just as ESBL producers. With the increased use of CZA, it is expected that resistance will keep emerging and plasmids carrying mutant genes may disseminate by horizontal gene transfer.