Towards optimizing cefepime/tazobactam (WCK 4282) exposure to achieve efficacy against piperacillin/tazobactam-resistant ESBL infections: dose recommendations for various renal functions, including intermittent haemodialysis, in healthy individuals

• Published in: Journal of antimicrobial chemotherapy 2024-05, Vol.79 (5), p.1093-1100
• Main Authors: Muller, Anouk E, De Winter, Brenda C M, Koch, Birgit C P
• Format: Article
• Language: English
• Subjects: Adult; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; beta-Lactamases; Cefepime - administration & dosage; Cefepime - pharmacokinetics; Cephalosporins - administration & dosage; Cephalosporins - pharmacokinetics; Cephalosporins - therapeutic use; Female; Healthy Volunteers; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid - administration & dosage; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacokinetics; Piperacillin - administration & dosage; Piperacillin - pharmacokinetics; Piperacillin - pharmacology; Piperacillin, Tazobactam Drug Combination - administration & dosage; Piperacillin, Tazobactam Drug Combination - pharmacokinetics; Renal Dialysis; Tazobactam - administration & dosage; Tazobactam - therapeutic use; Young Adult
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkae076

WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination. We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required. The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L.