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In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae

Author:
G.W. Langley, Lucas Tselepis, Gareth W. Langley, Ali F. Aboklaish, Emma Widlake, Dana E. Jackson, Timothy R. Walsh, Chris J. Schofield, Jürgen Brem, Jonathan M. Tyrrell
Source:
International journal of antimicrobial agents 2020 v.56 no.1 pp. 105925
ISSN:
0924-8579
Subject:
Enterobacteriaceae, anti-infective agents, beta-lactamase, beta-lactams, enzyme inhibitors, in vitro studies, integrated pest management, multiple drug resistance, recombinant proteins, screening, serine
Abstract:
To evaluate the potential clinical in vitro efficacy of novel β-lactam/β-lactamase-inhibitor combinations – including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) – against contemporary multidrug-resistant (MDR) Enterobacteriaceae.Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative β-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant β-lactamases covering representatives from all four Ambler classes of β-lactamases, were tested using a fluorescence-based assay.Using recombinant proteins, all four inhibitors were highly active against the tested class A serine β-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-β-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A β-lactamases (ESBLs) than the established inhibitors.The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of β-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies.
Agid:
6846872