Does prolonged infusion time really improve the efficacy of meropenem therapy? A prospective study 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 find the pharmacokinetic/ pharmacodynamic of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. 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 always 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.