Effects of uric acid, creatinine clearance, and infusion duration on the population pharmacokinetics of meropenem in critically ill patients

Abstract

Background Meropenem is a carbapenem antibiotic that has demonstrated excellent in vitro activity against gram-negative clinical Isolates and is commonly used in critically ill patients. This study aimed to describe the population pharmacokinetics (PPK) of meropenem and determine the optimal dosage in these patients. Method: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix. Results A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), volume of peripheral compartment (V2) were 6.15 L/h, 2.83 L/h, 17.40L, and 17.48L, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance of 60 ml/min or less and uric acid greater than 400 µmol/l could achieve the target >\(\)90% under the minimum inhibitory concentration (MIC) of 8 mg/L, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC༜4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4MIC, no significant statistical difference was observed in critically ill patients. Conclusions Critically ill patients with lower creatinine clearance and higher uric acid levels were likely to need a lower dosage of meropenem. Prolonged infusion time were not appear to be beneficial for those who need a higher therapeutic target (100% fT > MIC,100% fT > 4 MIC) or with MIC\(>\)4mg/L. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients. Trial registration: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.