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The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers

Authors :
Zhuoren Ling
Alistair James Macdonald Farley
Aditya Lankapalli
Yanfang Zhang
Shonnette Premchand-Branker
Kate Cook
Andrei Baran
Charlotte Gray-Hammerton
Claudia Orbegozo Rubio
Edgars Suna
Jordan Mathias
Jürgen Brem
Kirsty Sands
Maria Nieto-Rosado
Maria Mykolaivna Trush
Nadira Naznin Rakhi
Willames Martins
Yuqing Zhou
Christopher Joseph Schofield
Timothy Walsh
Source :
Engineering, Vol 38, Iss , Pp 124-132 (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and Klebsiella pneumoniae carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii). The FoR to MEM plus InC58 ranged from 2.22 × 10−7 to 1.13 × 10−6. The resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.

Details

Language :
English
ISSN :
20958099
Volume :
38
Issue :
124-132
Database :
Directory of Open Access Journals
Journal :
Engineering
Publication Type :
Academic Journal
Accession number :
edsdoj.7e07e91858ca42e3a0aa3e27ecdb3e70
Document Type :
article
Full Text :
https://doi.org/10.1016/j.eng.2024.02.010