Optimization of cefepime dosage regimens for Pseudomonas aeruginosa infections in Japanese patients based on a pharmacokinetic/ pharmacodynamic analysis considering efficacy and safety: Is a 6 g daily dose and continuous infusion necessary?

Abstract

In Japan, the approved maximum daily dose of cefepime (4 g) is lower than international standards (6 g), potentially compromising efficacy against Pseudomonas aeruginosa (P. aeruginosa) infections. Using Monte Carlo simulations with a population pharmacokinetic model for Japanese patients, we determined optimal dosing regimens across renal function levels. The target was 60% fT > MIC (percentage of time free drug concentration exceeds minimum inhibitory concentration), with ≥ 90% probability of target attainment for minimum inhibitory concentration (MIC) up to 8 mg/L. Lower doses sufficed for impaired renal function, while higher doses with prolonged infusion (2 g q8 (3 h)) were needed for creatinine clearance (CCr) 101-130 mL/min. For augmented renal clearance (CCr > 130 mL/ min), continuous infusion (2 g loading dose followed by 4 g continuous infusion) achieved optimal attainment below neurotoxicity thresholds. Current approved dosing in Japan may be insufficient; adjustments including prolonged or continuous infusions are crucial for optimizing therapy.

Keywords: Monte Carlo simulations; cefepime; pharmacokinetics/pharmacodynamics; sepsis.