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.
Antimicrob Agents Chemother. 2018 Jul 16;:
Authors: Monogue ML, Giovagnoli S, Bissantz C, Zampaloni C, Nicolau DP
Urinary tract infections (UTIs) are a tremendous burden to the healthcare system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multi-drug 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. Herein, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem and nacubactam alone against 10 K. pneumoniae, E. coli, and E. cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM producing enzymes. Selected isolates had meropenem-nacubactam MICs between 1-8 μg/mL. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving ≥ 3 log reduction from 48h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed anti-bacterial properties, achieving > 1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam resistant isolates, meropenem-nacubactam demonstrated antibacterial kill upwards of 6 log10 CFU from 48h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in man against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed.
PMID: 30012751 [PubMed - as supplied by publisher]