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