Meropenem-nacubactam activity against AmpC-overproducing and KPC-expressing Pseudomonas aeruginosa in a neutropenic murine lung infection model.

Abstract:

:Nacubactam is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor under development for the treatment of serious Gram-negative infections. This study assessed the efficacy of human-simulated epithelial lining fluid (ELF) exposure of nacubactam in combination with meropenem against AmpC-overproducing (n=4) and Klebsiella pneumoniae carbapenemase (KPC)-expressing (n=3) Pseudomonas aeruginosa isolates in the neutropenic murine lung infection model. Meropenem, nacubactam and meropenem-nacubactam (1:1 concentration ratio) minimum inhibitory concentrations (MICs) were determined in triplicate using broth microdilution. Regimens that provided ELF profiles mimicking those observed in humans given nacubactam 2 g q8h (1.5-h infusion) alone and in combination with a subtherapeutic ELF exposure of meropenem were administered 2 h after inoculation. Efficacy was assessed as the change in log10 colony-forming units (CFU)/lung at 24 h compared with 24-h meropenem monotherapy. Meropenem, nacubactam and meropenem-nacubactam MICs were 8->64, 128->256 and 2-16 mg/L, respectively. Meropenem and nacubactam monotherapy groups demonstrated bacterial growth over 24 h for each isolate. Against AmpC-overproducing and KPC-expressing P. aeruginosa isolates, meropenem-nacubactam resulted in -2.73±0.93 and -4.35±1.90 log10CFU/lung reduction, respectively, relative to meropenem monotherapy. Meropenem-nacubactam showed promising in-vivo activity against meropenem-resistant P. aeruginosa, indicative of a potential role for the treatment of infections caused by these challenging pathogens.

authors

Asempa TE,Motos A,Abdelraouf K,Bissantz C,Zampaloni C,Nicolau DP

doi

10.1016/j.ijantimicag.2019.10.019

subject

Has Abstract

pub_date

2020-02-01 00:00:00

pages

105838

issue

2

eissn

0924-8579

issn

1872-7913

pii

S0924-8579(19)30299-7

journal_volume

55

pub_type

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