Comparative in vivo activity of human-simulated plasma and epithelial lining fluid exposures of WCK 5222 (cefepime/zidebactam) against KPC- and OXA-48-like-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model

Objectives: This was a comparative assessment of WCK 5222 (cefepime/zidebactam 2/1 g as a 1 h infusion every 8 h) efficacy using human-simulated plasma and ELF exposures against serine-carbapenemase-producing Klebsiella pneumonlae in the neutropenic murine pneumonia model. Methods: Ten clinical isolates were utilized: eight were serine-carbapenemase-producing (KPC, n = 4; OXA-48-like, n = 4) Enterobacterales with WCK 5222 MICs (1:1) ranging from 1 to 4 mg/L; and two were previously studied MDR isolates serving as quality controls. Lungs of mice were inoculated with 50 mu L of 10(7) cfu/mL. Treatment mice received human-simulated regimens of cefepime, zidebactam or WCK 5222 derived from plasma or epithelial Lining fluid (ELF) profiles obtained from healthy subjects. Lung bacterial densities resulting from the humanized exposures in plasma and ELF were compared. Results: Initial Lung bacterial densities ranged from 6.06 to 6.87 Log(10) cfu/Lungs, with a mean bacterial burden increase to 9.06 +/- 0.42 after 24 h. Human-simulated plasma and ELF exposures of cefepime and zidebactam monotherapy had no activity. Human-simulated WCK 5222 plasma exposures resulted in a >1 Log(10) cfu/Lungs reduction in bacterial burden for all isolates. Humanized WCK 5222 ELF exposures achieved a >1 Log(10) cfu/Lungs reduction for all isolates. While statistically significant differences in bacterial burden reduction were observed between the plasma and ELF exposures for WCK 5222 in 5/8 isolates, all treatments achieved the translational kill target of a >1 Log(10) cfu reduction. Conclusions: Clinically achievable WCK 5222 plasma and ELF exposures produced in vivo killing of carbapenem-resistant Enterobacterales in the neutropenic murine pneumonia model that is predictive of efficacy in humans.

Automated summary

This study aimed to assess the efficacy of WCK 5222 against serine-carbapenemase-producing Klebsiella pneumoniae in a neutropenic murine pneumonia model using human-simulated plasma and ELF exposures. The results showed that WCK 5222 achieved a significant reduction in bacterial burden in both plasma and ELF exposures, demonstrating its potential efficacy in treating carbapenem-resistant Enterobacterales.