675. Efficacy of Human-Simulated Bronchopulmonary Exposures of Cefepime and Zidebactam (WCK 5222) Against Multidrug-Resistant (MDR) Pseudomonas aeruginosa (PSA) in a Neutropenic Murine Pneumonia Model

Abstract

BackgroundWCK 5222 combines cefepime (FEP) with zidebactam (ZID), a bicycloacyl hydrazide β-lactam enhancer which binds PBP2 in PSA and inhibits class A and C β-lactamases. The in vivo efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR PSA, a recalcitrant pneumonia-causing pathogen with few treatment options, was investigated in a neutropenic murine pneumonia model.MethodsThirteen clinical isolates of MDR PSA with FEP MIC ≥64 mg/L were studied in neutropenic CD-1 mice. FEP, ZID, and WCK 5222 MICs were measured by broth microdilution in triplicate. For in vivo experiments, lungs were intranasally inoculated with 107–108 CFU/mL bacterial suspensions. Human-simulated regimens (HSR) of FEP and ZID alone and in combination which achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g FEP/1 g ZID as a 1 hour infusion at steady state were developed. For each regimen, groups of 6 mice were dosed subcutaneously 2 hours after inoculation for 24 hours, then sacrificed. Vehicle-dosed control mice were sacrificed at the start (0 hour) and end (24 hours) of the dosing period. Lungs were aseptically harvested and bacterial CFU/lungs were determined.ResultsFEP MIC was >64 mg/L for all isolates, while ZID and WCK 5222 MICs ranged from 4–512 and 4–32 mg/L, respectively. Mean bacterial growth for all isolates at 0 hour was 6.68 log10 CFU/lungs. Mean changes ± SD in bacterial density at 24 hours compared with 0 hour controls for 12 isolates with WCK5222 MIC ≤16 mg/L were 2.08 ± 1.09, 1.09 ± 0.98, −0.92 ± 1.45, and −2.13 ± 0.75, for control, FEP, ZID, and WCK5222, respectively. Against these isolates, ZID yielded >1 log10 CFU/lungs reduction in 7/12, while activity was enhanced with WCK5222, producing >1 log10 CFU/lungs reduction in 11/12 and >2 log10 CFU/lungs reduction in 9/12. All isolates showed growth or stasis on FEP.ConclusionHuman-simulated bronchopulmonary exposures of WCK5222 is effective against MDR PSA at MIC up to 16 mg/L in a neutropenic murine model. These data support the clinical development of WCK5222 for the treatment of pseudomonal lung infections, but further studies of PSA with high WCK5222 MIC are necessary to delineate the susceptibility breakpoint.Disclosures All authors: No reported disclosures.