Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing

Abstract

Background: Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains. Methods: Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh. Results: Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT>MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT>MIC=0%. Across different threshold plasma funobactam concentrations (CTs), %fT>CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT>CT=1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT>CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT>CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT>CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae. Conclusions: Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT>CT)/MIC appeared to best describe in vivo activity.