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

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
International journal of antimicrobial agents 2020 v.56 no.1 pp. 105925
Enterobacteriaceae, anti-infective agents, beta-lactamase, beta-lactams, enzyme inhibitors, in vitro studies, integrated pest management, multiple drug resistance, recombinant proteins, screening, serine
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.