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

Engineering ›› 2024, Vol. 38 ›› Issue (7) : 142 -151. DOI: 10.1016/j.eng.2024.02.010

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Received	Accepted	Published
2023-08-05	2024-02-17	2024-07-01
Issue Date	Revised Date
2024-06-14	2024-01-15

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Abstract

This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-βlactamase (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-βlactamase (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.

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Keywords

Carbapenemase / Metallo/serine-β-lactamase inhibitor / Avibactam / Meropenem / Antimicrobial resistance

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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, , , , , , , , , , , , , , , , , , , , . The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers. Engineering, 2024, 38(7): 142-151 DOI:10.1016/j.eng.2024.02.010