Infect Chemother.  2023 Mar;55(1):29-41. 10.3947/ic.2022.0087.

Population Pharmacokinetics and Monte Carlo Simulation of Cefepime in Critically Ill Patients with Hospital-Acquired/ Ventilator-Associated Pneumonia

• Seo H
• Kim YK
• Park S
• Kim Hi
• Lee DH

• KMID: 2541529
• DOI: http://doi.org/10.3947/ic.2022.0087

Abstract

Background
This study aimed to investigate the population pharmacokinetics (PK) profile and determine the optimal dosage regimen of cefepime in critically ill adult patients with hospital-acquired pneumonia (HAP) or ventilatorassociated pneumonia (VAP).
Materials and Methods
Population-PK models for cefepime were developed using a nonlinear mixed-effect modeling approach. The percentage of time within 24 h in which the free concentration exceeded the minimum inhibitory concentration (MIC) at a steady state (50%fT _>MIC , 100%fT _>MIC , and 100%fT _>4×MIC ) for various combinations of dosage regimens and renal function was explored using Monte Carlo simulation.
Results
Twenty-one patients were prospectively enrolled in this study. Cefepime PK was best described using a twocompartment model in which creatinine clearance (CL _CR ) through Cockcroft-Gault (CG) was a significant covariate for the total clearance of cefepime. The simulation results to determine the optimal cefepime dosing regimen for 50%fT _>MIC as treatment target with C _min <20 mg/L as safety target showed that a dosage regimen of 2 g through intravenous (IV) infusion every 12 h administered over 4 h was optimal at an MIC of 4 mg/L, rather than the currently recommended dosage regimen of 2 g administered through IV infusion every 8 h, in patients with normal renal function (CL _CR = 90 - 130 mL/min). For a treatment target of 100%fT _>MIC with C _min <35 mg/L as a safety target, a dosage regimen of 0.75 g administered through continuous infusion over 24 h would be sufficient at an MIC equal to or less than 8 mg/L in patients with renal dysfunction (CLv = 10 - 30 mL/min).
Conclusion
Our results suggest that clinicians should consider renal function and potential neurotoxicity when deciding the dosing regimen of cefepime in critically ill patients with HAP or VAP. Therapeutic drug monitoring (TDM) to adjust cefepime trough levels may be useful to improve clinical outcomes and reduce cefepime neurotoxicity.

Keyword

Cefepime; Population pharmacokinetics; Hospital-acquired pneumonia; Ventilator-associated pneumonia; Monte Carlo simulation