Activity of imipenem/relebactam against carbapenem-resistant Escherichia coli isolates from the United States in relation to clonal background, resistance genes, co-resistance, and region

Imipenem/relebactam (I/R) is a recently developed carbapenem/beta-lactamase inhibitor combination agent that can overcome carbapenem resistance, which has now emerged in Escherichia coli, including sequence type 131 (ST131) and its fluoroquinolone-resistant H30R subclone, the leading cause of extra-intestinal E. coli infections globally. To clarify the likely utility of I/R for carbapenem-resistant (CR) E. coli infections in the U.S. we characterized 203 recent CR clinical E. coli isolates from across the U.S. (years 2002-2017) for phylogroup, clonal group (including ST131, H30R, and the CTX-M-15-associated H30Rx subset within H30R), relevant beta-lactamase genes, and broth microdilution MICs for I/R and 11 comparator agents. Overall, I/R was highly active (89% susceptible), more so than all comparators except tigecycline and colistin (both, 99% susceptible). I/R's activity varied significantly in relation to phylogroup, clonal background, resistance genotype, and region: it was greatest among phylogroup B2, ST131-H30R, H30Rx, Klebsiella pneumoniae carbapenemase (KPC)-positive, and northeast U.S. isolates, and lowest among phylogroup C, New Delhi metallo-beta-lactamase (NDM)-positive, and southeast U.S. isolates. Relebactam improved imipenem's activity against CR isolates within each phylogroup - especially groups A, B1, and B2 - and particularly against isolates containing KPC. I/R remained substantially active against isolates co-resistant to comparator agents, albeit somewhat less so than against the corresponding susceptible isolates. These findings suggest that I/R should be useful for treating most CR E. coli infections in the U.S., largely independent of co-resistance, although this likely will vary in relation to the local prevalence of specific E. coli lineages and carbapenem resistance mechanisms.