WCK 5222 (cefepime-zidebactam) pharmacodynamic target analysis against metallo-β-lactamase-producing Enterobacteriaceae in the neutropenic mouse pneumonia model

Abstract

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein 2 (PBP2) binding as well as inhibition of Ambler class A and C enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic parameter target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) strains secondary to metallo-β-lactamase (MBL) production. Plasma and epithelial lining fluid (ELF) pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg of body weight) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered protein binding is <10%. The two drugs exhibited similar PK exposures, including terminal elimination half-life (cefepime,̴0.4 h; zidebactam, 0.3 to 0.5 h). The penetration into ELF was concentration dependent for both drugs, reaching 50% and 70% for cefepime and zidebactam, respectively. Dose ranging studies were performed in lung-infected mice with one of eight MBL-producing clinical strains. WCK 5222 was administered in regimens of every 4 h (q4h) and q8h to adjust exposures from 0% to 100% T>MIC. The results were modeled to evaluate the relationship between the cefepime T>MIC (when zidebactam was coadministered) and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 = 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.