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 (PBP) 2 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 target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is <10%. Both drugs exhibited similar PK exposures including terminal elimination half-life (cefepime ∼0.4 h, zidebactam 0.3-0.5 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 Q4- and Q8-hourly regimens to vary exposures from 0-100% T>MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, 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.
Copyright © 2019 American Society for Microbiology.