Efficacy of Human-Simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine β-Lactamase-Producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model

Abstract

Nacubactam is a novel, broad-spectrum, β-lactamase inhibitor that is currently under development as combination therapy with meropenem. This study evaluated the efficacy of human-simulated epithelial lining fluid (ELF) exposures of meropenem, nacubactam, and the combination of meropenem and nacubactam against class A serine carbapenemase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model. Twelve clinical meropenem-resistant Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates, all harboring KPC or IMI-type β-lactamases, were utilized in the study. Meropenem, nacubactam, and meropenem-nacubactam (1:1) combination MICs were determined in triplicate via broth microdilution. At 2 h after intranasal inoculation, neutropenic mice were dosed with regimens that provided ELF profiles mimicking those observed in humans given meropenem at 2 g every 8 h and/or nacubactam at 2 g every 8 h (1.5-h infusions), alone or in combination. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0-h controls. Meropenem, nacubactam, and meropenem-nacubactam MICs were 8 to >64 μg/ml, 2 to >256 μg/ml, and 0.5 to 4 μg/ml, respectively. The average bacterial density at 0 h across all isolates was 6.31 ± 0.26 log₁₀ CFU/lung. Relative to the 0-h control, the mean values of bacterial growth at 24 h in the untreated control, meropenem human-simulated regimen treatment, and nacubactam human-simulated regimen treatment groups were 2.91 ± 0.27, 2.68 ± 0.42, and 1.73 ± 0.75 log₁₀ CFU/lung, respectively. The meropenem-nacubactam combination human-simulated regimen resulted in reductions of -1.50 ± 0.59 log₁₀ CFU/lung. Meropenem-nacubactam human-simulated ELF exposure produced enhanced efficacy against all class A serine carbapenemase-producing Enterobacteriaceae isolates tested in the neutropenic murine lung infection model.

Keywords: Gram negative; OP0595; RG6080; carbapenemase; lung epithelial lining fluid; nacubactam; β-lactam; β-lactamase inhibitor.

FIG 1

Observed meropenem (top) and nacubactam (bottom) ELF concentrations in the neutropenic lung infection model, compared with human ELF profiles of meropenem (2 g every 8 h, as 1.5-h infusion) and nacubactam (2 g every 8 h, as 1.5-h infusion). Data are presented as mean ± standard deviation.

FIG 2

Changes in bacterial growth (mean ± SD) at 24 h, relative to 0-h controls, with meropenem, nacubactam, and meropenem-nacubactam against Enterobacteriaceae strains harboring class A serine carbapenemases.