Clonal background, resistance gene profile, and porin gene mutations modulate in vitro susceptibility to imipenem-relebactam in diverse enterobacteriaceae

Abstract

Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) are limited. While Klebsiella pneumoniae strains harboring blaKPC account for most CRE, recent evidence points to increasing diversification of CRE. We determined whether the CRE species and antibiotic resistance genotype influence the response to relebactam (REL), a novel beta-lactamase inhibitor with class A/C activity, combined with imipenem-cilastatin (IMI). We carried out broth microdilution testing with IMI alone or in the presence of 4 g/ml REL against 154 clinical isolates collected at a New York City hospital with a high prevalence of organisms carrying blaKPC, including Enterobacter spp. (n 96), K. pneumoniae (n 44), Escherichia coli (n 1), Serratia marcescens (n 9), and Citrobacter spp. (n 4). Resistance gene profiles and the presence of major porin gene disruptions were ascertained by whole-genome sequencing. Addition of REL decreased the IMI MIC to the susceptible range (1 g/ml) against 88% of isolates. However, S. marcescens IMI-REL MICs were 4- to 8-fold higher than those for other organisms. Most blaKPC-positive isolates had IMI-REL MICs of 1 g/ml (88%), including isolates of Enterobacter cloacae ST171 (93%) and K. pneumoniae ST258 (82%). Nineteen isolates had IMI-REL MICs of 2 g/ml, among which 84% harbored blaKPC and one was blaNDM-1 positive. Isolates with IMI-REL MICs of 2 g/ml versus those with MICs of 1 g/ml were significantly more likely to demonstrate disruption of at least one porin gene (42% versus 19%; P 0.04), although most S. marcescens isolates (67%) had intact porin genes. In conclusion, while REL reduced IMI MICs in a majority of diverse CRE isolates, including high-risk clones, chromosomal factors had an impact on IMI-REL susceptibilities and may contribute to elevated MICs for S. marcescens.