In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae.
Anti-Bacterial Agents
/ pharmacology
Azabicyclo Compounds
/ pharmacology
Carbapenem-Resistant Enterobacteriaceae
/ drug effects
Cefepime
/ pharmacology
Drug Combinations
Enterobacteriaceae Infections
/ drug therapy
Humans
Imipenem
/ pharmacology
Microbial Sensitivity Tests
Tazobactam
/ pharmacology
Triazoles
/ pharmacology
beta-Lactamase Inhibitors
/ pharmacology
beta-Lactamases
/ metabolism
AAI101 (enmetazobactam)
Avibactam
Carbapenemase
Extended spectrum β-lactamase
Relebactam
β-lactamase inhibitor
Journal
International journal of antimicrobial agents
ISSN: 1872-7913
Titre abrégé: Int J Antimicrob Agents
Pays: Netherlands
ID NLM: 9111860
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
13
06
2019
revised:
03
01
2020
accepted:
11
02
2020
pubmed:
23
2
2020
medline:
20
4
2021
entrez:
22
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32084512
pii: S0924-8579(20)30068-6
doi: 10.1016/j.ijantimicag.2020.105925
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Azabicyclo Compounds
0
Drug Combinations
0
Triazoles
0
beta-Lactamase Inhibitors
0
Imipenem
71OTZ9ZE0A
avibactam
7352665165
Cefepime
807PW4VQE3
enmetazobactam
80VUN7L00C
beta-Lactamases
EC 3.5.2.6
Tazobactam
SE10G96M8W
relebactam
Y1MYA2UHFL
Types de publication
Evaluation Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
105925Subventions
Organisme : Medical Research Council
ID : MC_PC_16092
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S013768/2
Pays : United Kingdom
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.