Activity of OP0595-β-lactam combination against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing β-lactama

Livermore, David M. ORCID: https://orcid.org/0000-0002-9856-3703, Mushtaq, Shazad, Warner, Marina and Woodford, Neil (2015) Activity of OP0595-β-lactam combination against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing β-lactama. Journal of Antimicrobial Chemotherapy, 70 (11). pp. 3032-3041. ISSN 0305-7453

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Abstract

Background: OP0595 is a diazabicyclooctane that (i) acts as a PBP2-ctive antibacterial, (ii) inhibits Class A and C β-lactamases and (iii), like mecillinam, gives β-lactamase-independent potentiation of β-lactams targeting other PBPs. We tested its behaviour against β-lactam-resistant Enterobacteriaceae and non-fermenters. Methods: Organisms were UK clinical isolates; MICs were determined by CLSI agar dilution for OP0595 alone or combined at 1–4 mg/L with aztreonam, biapenem, cefepime or piperacillin. Results: MICs of OP0595 for Escherichia coli, Enterobacter, Citrobacter and Klebsiella spp. were mostly 1–4 mg/L but values >4 mg/L were seen for minorities of isolates irrespective of other resistances, and for 50%–60% of those with ertapenem resistance involving porin loss plus ESBL or AmpC activity. OP0595 MICs for Serratia, Proteeae and non-fermenters mostly were >4 mg/L. When its MIC was ≤4 mg/L, OP0595's antibacterial activity dominated combination activity. For ‘OP0595-resistant’ (MIC >4 mg/L) isolates with Class A or C β-lactamases OP0595 achieved strong potentiation of substrate β-lactams, contingent on β-lactamase inhibition. β-Lactamase-independent potentiation was evident with aztreonam, cefepime and piperacillin—less so for biapenem—for many OP0595-resistant Enterobacteriaceae with Class B carbapenemases, which are not inhibited by OP0595. OP0595 acted solely as a β-lactamase inhibitor for non-fermenters. Conclusions: OP0595 inhibited Enterobacteriaceae, not non-fermenters; its combinations had broad activity versus Enterobacteriaceae, largely contingent on OP0595's antibacterial activity but also on inhibition of Class A and C β-lactamases and on the β-lactam-enhancer effect, which allowed activity against many OP0595-resistant metallo-β-lactamase-producing Enterobacteriaceae. For non-fermenters OP0595 acted only as a β-lactamase inhibitor.

Item Type:	Article
Uncontrolled Keywords:	-lactamase inhibitors,-lactamases,diazabicyclooctanes,op0595,avibactam
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023)
Depositing User:	Pure Connector
Date Deposited:	05 Jan 2016 13:00
Last Modified:	21 Oct 2022 02:37
URI:	https://ueaeprints.uea.ac.uk/id/eprint/56011
DOI:	10.1093/jac/dkv239

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