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In Vitro Mechanisms of Resistance Development to Imipenem-Relebactam in KPC-Producing Klebsiella pneumoniae.


ABSTRACT: Carbapenem-resistant Enterobacterales, such as KPC-producing Klebsiella pneumoniae, represent a major threat to public health. Novel drug combinations including imipenem-relebactam (IPM-REL) have recently been introduced and have been shown to exhibit excellent activity toward such strains. However, there has recently been reports of the in vivo emergence of IPM-REL resistance in KPC-producing K. pneumoniae. Here, we evaluated, in vitro, the nature of the mutations that lead to IPM-REL resistance in 5 KPC-producing K. pneumoniae strains, including 2 that produce KPC enzymes conferring ceftazidime-avibactam resistance. An in vitro multi-step selection assay was performed and corresponding mutants obtained. Mutations were identified in OmpK36 as well as 2 different mutant derivatives of KPC. Mutant strains exhibited decreased susceptibility to β-lactams, including the carbapenems, and meropenem-vaborbactam (MEM-VAB). Expression of blaKPC gene variants in an Escherichia coli recombinant strain resulted in a concomitant increased susceptibility to carbapenems and decreased susceptibility to CAZ-AVI, and enzymatic assays showed that the inhibitory activity of both AVI and REL was significantly lowered for both KPC mutants compared to parental enzymes. Complementation assays showed that OmpK36 plays a major role in IPM-REL resistance as well resistance to other ß-lactams and β-lactam/ß-lactamase inhibitor combinations. Overall, this study showed that (i) IPM-REL resistant strains can be obtained from CAZ-AVI-susceptible or -resistant KPC producers, (ii) selection of IPM-REL resistance has a collateral effect on MEM-VAB susceptibility - indicative of shared resistance mechanisms, (iii) and mutations in the KPC sequence may be obtained using IPM-REL selection leading to the possibility of vertical and horizontal transfer of this resistance trait.

SUBMITTER: Findlay J 

PROVIDER: S-EPMC9578389 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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<i>In Vitro</i> Mechanisms of Resistance Development to Imipenem-Relebactam in KPC-Producing Klebsiella pneumoniae.

Findlay Jacqueline J   Rens Céline C   Poirel Laurent L   Nordmann Patrice P  

Antimicrobial agents and chemotherapy 20220926 10


Carbapenem-resistant <i>Enterobacterales</i>, such as KPC-producing Klebsiella pneumoniae, represent a major threat to public health. Novel drug combinations including imipenem-relebactam (IPM-REL) have recently been introduced and have been shown to exhibit excellent activity toward such strains. However, there has recently been reports of the <i>in vivo</i> emergence of IPM-REL resistance in KPC-producing K. pneumoniae. Here, we evaluated, <i>in vitro,</i> the nature of the mutations that lead  ...[more]

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