In Vivo Efficacy of Meropenem with a Novel Non-β-Lactam-β-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model

Antimicrobial Agents and Chemotherapy
Marguerite L MonogueDavid P Nicolau

Abstract

Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with in vitro activity against class A and class C β-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem or nacubactam alone against 10 Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had meropenem-nacubactam MICs between 1 and 8 μg/ml. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving a ≥3 log reduction from the 48-h control in all isolates tested, including isolates pre...Continue Reading

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Citations

Jan 11, 2019·Expert Opinion on Drug Metabolism & Toxicology·Ilias KaraiskosHelen Giamarellou
Feb 1, 2019·Clinical Microbiology Reviews·Wenjing WuZhiyong Zong
Jun 12, 2019·Antimicrobial Agents and Chemotherapy·Melissa D BarnesRobert A Bonomo
Jul 26, 2019·Expert Review of Anti-infective Therapy·Marguerite L Monogue, David P Nicolau
Aug 23, 2019·Antibiotics·Beatriz Suay-García, María Teresa Pérez-Gracia
Mar 3, 2020·Chemical & Pharmaceutical Bulletin·Yasunari Otsuka
May 20, 2020·Antimicrobial Agents and Chemotherapy·Christian M GillDavid P Nicolau
Apr 17, 2019·Frontiers in Microbiology·Mansura S MulaniKarishma R Pardesi
Mar 7, 2019·Nature Reviews. Microbiology·Karen Bush, Patricia A Bradford
Nov 13, 2020·Clinical Microbiology Reviews·Dafna YahavLeonard Leibovici
Apr 4, 2021·Microorganisms·Corneliu Ovidiu VrancianuMariana Carmen Chifiriuc
Apr 9, 2021·Annals of the New York Academy of Sciences·Luke N YaegerLori L Burrows
May 26, 2021·Expert Review of Anti-infective Therapy·Ilias KaraiskosHelen Giamarellou
Oct 31, 2019·Journal of Medicinal Chemistry·Concepción González-BelloEsther Colchón
Jan 19, 2022·Expert Opinion on Investigational Drugs·Rachael CusackIgnacio Martín-Loeches

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