Efficacy of Human-simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine {beta}-lactamase-producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model [Experimental Therapeutics]

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 meropenem-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 the combination meropenem-nacubactam (1:1) MICs were determined in triplicate via broth microdilution. At 2hr after intranasal inoculation, neutropenic mice were dosed with regimens that provided ELF profiles mimicking those observed in humans given meropenem 2g q8hr and nacubactam 2g q8hr (1.5hr infusions) alone or in combination. Efficacy was assessed as the change in log₁₀CFU/lung at 24hr compared with 0hr controls. Meropenem, nacubactam, and meropenem-nacubactam MICs were 8 – >64, 2 - >256 and 0.5 – 4 μg/mL, respectively. The average log₁₀CFU/lung at 0hr across all isolates was 6.31 ± 0.26. Relative to 0hr control, the mean bacterial growth at 24hr in the untreated control mice, meropenem human-simulated regimen (HSR), and nacubactam HSR treatment groups were 2.91 ± 0.27, 2.68 ± 0.42, and 1.73 ± 0.75 log₁₀CFU/lung, respectively. Meropenem-nacubactam combination HSR resulted in -1.50 ± 0.59 log₁₀CFU/lung reduction. 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.

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