Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model

Objectives: WCK 5222 combines cefepime with zidebactam, alpha, B-lactam enhancer that binds PBP2 and inhibits doss A and C beta-lactamases. The efficacy of human-simulated bronchopuLmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model. Methods: Nineteen MDR isoLates of P. aeruginosa (cefepime MICs >= 64 mg/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512 mg/L and from 4 to 32 mg/L, respectiveLy. Dosing regimens of cefepime and zidebactam done and in combination that achieved epitheLiaL Lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g of cefepime/1 g of zidebactam every 8 h (1 h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasaLLy inoculated with 10(7) -10(8) cfu/mL bacteriaL suspensions. Mice were dosed subcutaneously 2 h after inoculation for 24 h, then Lungs were harvested. Results: In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean +/- SD changes in bacteriaL density at 24 h compared with 0 h controls (6.72 +/- 0.50 Log(10) cfu/Lungs) for 13 isoLates with WCK 5222 MICs <= 16 mg/L were 1.17 +/- 1.00, -0.99 +/- 1.45 and -2.21 +/- 0.79 Log(10) cfu/lungs for cefepime, zidebactam and WCK 5222, respectiveLy. Against these isoLates, zidebactam yielded >1 Log(10) cfu/Lungs reductions in 8/13, while activity was enhanced with WCK 5222, producing >2 Log(10) cfu/Lungs reductions in 10/13 and >1 Log(10)cfu/Lungs reductions in 12/13. Among isoLates with WCK 5222 MICs of 32 mg/L, five out of six showed a bacteriostatic response. Conclusions: Human-simulated bronchopuLmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC <= 16 mg/L in a murine pneumonia modeL. These data support the clinical development of WCK 5222 for pseudomonaL Lung infections.