<i>In Vitro</i> Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program)

Abstract

Relebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including <i>Klebsiella pneumoniae</i> carbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the <i>in vitro</i> activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens (including <i>Klebsiella pneumoniae</i>, <i>n</i> = 689; <i>Acinetobacter baumannii</i>, <i>n</i> = 72; <i>Pseudomonas aeruginosa</i>, <i>n</i> = 845; and <i>Enterobacter</i> spp., <i>n</i> = 399) submitted by 21 clinical laboratories in the United States in 2015 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 μg/ml in combination with doubling dilutions of imipenem. Imipenem-relebactam MICs were interpreted using CLSI imipenem breakpoints. The respective rates of susceptibility to imipenem-relebactam and imipenem were 94.2% (796/845) and 70.3% (594/845) for <i>P. aeruginosa</i>, 99.0% (682/689) and 96.1% (662/689) for <i>K. pneumoniae</i>, and 100% (399/399) and 98.0% (391/399) for <i>Enterobacter</i> spp. Relebactam restored imipenem susceptibility to 80.5% (202/251), 74.1% (20/27), and 100% (8/8) of isolates of imipenem-nonsusceptible <i>P. aeruginosa</i>, <i>K. pneumoniae</i>, and <i>Enterobacter</i> spp. Relebactam did not increase the number of isolates of <i>Acinetobacter</i> spp. susceptible to imipenem, and the rates of resistance to all of the agents tested against this pathogen were >30%. Further development of imipenem-relebactam is warranted given the demonstrated ability of relebactam to restore the activity of imipenem against current clinical isolates of <i>Enterobacteriaceae</i> and <i>P. aeruginosa</i> that are nonsusceptible to carbapenems and its potential as a therapy for treating patients with antimicrobial-resistant Gram-negative infections.