Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Carbapenems in Critically Ill Patients

Abstract

Several pathophysiological changes in critically ill patients with severe infection can dramatically alter pharmacokinetic patterns of carbapenems. The objectives of this study were to (i) characterize and estimate the population pharmacokinetic parameters (PPK) of carbapenems (ii) determine the optimal carbapenem dosage regimens (iii) evaluate the relationship between pharmacokinetic/pharmacodynamic index of carbapenems and treatment outcome. Adult critically ill patients with bacterial infections receiving standard dosing of meropenem or imipenem were eligible for inclusion. Five blood samples were collected from each patient during the first 24 to 48 hours after intensive care unit admission. The population pharmacokinetic models were developed using a nonlinear mixed-effects modeling approach, and the final PPK model was subsequently used for Monte Carlo simulations to propose the optimal dosage regimens. A total of 248 unbound meropenem concentrations from 52 patients and 103 unbound imipenem concentrations from 21 patients were available for analysis. A two-compartment model with linear elimination best described the data. The mean PPK parameters of meropenem were: clearance (CL) 4.27 L/h, central volume of distribution (VC) 9.85 L, peripheral volume of distribution (VP) 12.5 L, and inter-compartment clearance (Q) 15.4 L/h. The mean PPK parameters of imipenem were: CL 8.99 L/h, VC 15.2 L, VP 23.4 L, and Q 15.9 L/h. The glomerular filtration rate (GFR) was a significant covariate affecting carbapenem clearance. Dopamine used and serum albumin level were the significant factors influencing meropenem VC. For clinical outcome evaluations, the treatment success and survival rate in patients who achieved fT>MIC ≥ 75% target were higher than those who did not but statistically insignificant. The simulation results showed that the current standard dosing of meropenem and imipenem consistently achieved the 75%fT>MIC target against susceptible pathogens with MIC ≤ 2 mg/L in patients with GFR ≤ 90 mL/min. For patients with GFR 90 – 130 mL/min, the standard dose of imipenem provided sufficient coverage for susceptible pathogens, while a continuous infusion of at least 3 gm daily was required for meropenem. In conclusion, the current study contributes a better understanding of carbapenem pharmacokinetics in critically ill patients. The current standard dosing of carbapenems provides sufficient coverage for susceptible pathogens in almost all patients. However, for patients with a high GFR level or treating pathogens with high MICs, dose increment and/or administered as continuous infusion might be needed.