In Vitro Selection of Meropenem Resistance among Ceftazidime-Avibactam-Resistant, Meropenem-Susceptible Klebsiella pneumoniae Isolates with Variant KPC-3 Carbapenemases

Abstract

Ceftazidime-avibactam resistance is mediated by bla KPC-3 mutations, which restore carbapenem susceptibility. We subjected Klebsiella pneumoniae isolates with different bla KPC-3 mutations (n ϭ 5) or wild-type bla KPC-3 (n ϭ 2) to serial passages with meropenem. The meropenem MIC against each isolate increased. Mutations in the ompK36 porin gene evolved in 5 isolates. Among isolates with D179Y substitutions in KPC-3, bla KPC-3 mutations reverted to wild type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam-resistant K. pneumoniae infections may select for carbapenem resistance.

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

“…We recently reported that KPC-3 mutations, in particular D179Y, can emerge and confer ceftazidime-avibactam resistance following treatment of carbapenemresistant K. pneumoniae infections (13,14,22). Imipenem MICs in the present study were significantly lower against K. pneumoniae with variant KPC-3 than against K. pneumoniae with wild-type KPCs.…”

“…However, the isolate was susceptible to imipenem-relebactam (MIC ϭ 0.5 g/ml), suggesting that this agent may be more reliably active than imipenem against infections caused by ceftazidime-avibactam-resistant Enterobacteriaceae. We recently demonstrated that meropenem resistance emerged in ceftazidime-avibactam-resistant K. pneumoniae isolates during in vitro passage at subinhibitory meropenem concentrations, often in association with reversion of mutant bla KPC-3 to wild-type bla KPC-3 (22). Therefore, studies are needed to determine the roles of imipenem-relebactam in treating infections caused by CRE that carry mutant KPC-3 enzymes and in suppressing carbapenem resistance among these isolates.…”

In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin American Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015

“…Upregulation of efflux transport systems or porin loss alone were not implicated in reduced susceptibility to ceftazidime-avibactam in a previous direct test of those mechanisms (27). Recently, isolated clinical cases in which ceftazidime-avibactam was prescribed to treat patients infected with KPC-producing K. pneumoniae have resulted in the emergence of resistance to ceftazidime-avibactam during treatment (23,(28)(29)(30)(31). In each case, resistance to ceftazidime-avibactam was reported to be the result of mutations within a plasmidborne bla KPC-3 , which was associated with a porin OmpK35 deficiency in one instance (23) and which coincidently restored carbapenem susceptibility in some isolates (28).…”

Emergence of Ceftazidime-Avibactam Resistance and Restoration of Carbapenem Susceptibility in Klebsiella pneumoniae Carbapenemase-Producing K pneumoniae: A Case Report and Review of Literature

“…However, meropenem resistance has emerged in ceftazidime-avibactam-resistant isolates from our patients during in vitro passage at subinhibitory meropenem concentrations [10]. In most passage experiments, resistance to ceftazidime-avibactam and other β-lactams was retained.…”