Population pharmacokinetics and dosing simulations of meropenem in septic critically ill patients with complicated intra-abdominal infection or pneumonia

Abstract

Objectives: Meropenem pharmacokinetics (PK) may be altered in septic critically ill patients with complicated intra-abdominal infections (cIAI) and pneumonia. We aimed to evaluate the covariates affecting meropenem PK and the performance of different dosing regimens to optimize the PK/pharmacodynamic target.

Methods: Population PK analysis was performed using non-linear mixed-effects modeling. The final model was validated and used to simulate meropenem exposure to assess the probability of attaining the 100 %ƒT_>MIC target.

Results: Forty-six and 14 patients were respectively enrolled for PK analysis and external validation. A one-compartment linear model adequately described the data of 226 concentrations. The typical clearance (CL) and volume of distribution (Vd) were 9.69 L/h and 27.4 L, respectively. Septic shock from cIAI (cIASS) and actual body weight were significant covariates for meropenem Vd in addition to the influential covariates of creatinine clearance (CL_CR-CG) and augmented renal clearance for CL. External validation showed the robustness and accuracy of this model. Simulation results proposed continuous infusion (CI) dosing regimens of meropenem against pathogens with MICs ≥ 2 mg/L in patients with cIASS and CL_CR-CG ≥ 60 mL/min.

Conclusions: For the patients with cIASS and CL_CR-CG ≥ 60 mL/min, CI meropenem is proposed for treatment of less sensitive pathogens with MICs ≥ 2 mg/L.

Keywords: Complicated intra-abdominal infection; Creatinine clearance; Dosing; Meropenem; Population pharmacokinetics; Septic shock.