Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

• Published in: International journal of antimicrobial agents Vol. 54; no. 6; pp. 702 - 708
• Main Authors: Vu, Dinh H., Nguyen, Duy A., Delattre, Isabelle K., Ho, Trong T., Do, Hong G., Pham, Hong N., Dao, Xuan C., Tran, Nhan T., Nguyen, Gia B., Van Bambeke, Françoise, Tulkens, Paul M., Nguyen, Hoang A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2019
• Subjects: Adult; Aged; allometry; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; blood serum; Computer Simulation; Continuous infusion; creatinine; Critical Illness; Critically ill; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; drugs; Enterococcus - drug effects; Female; hospitals; Humans; Loading dose; Maintenance dose; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; monitoring; Monte Carlo Method; nephrotoxicity; patients; pharmacokinetics; renal clearance; Staphylococcus aureus - drug effects; Vancomycin; Vancomycin - administration & dosage; Vancomycin - pharmacokinetics; Vietnam; Vietnam; Maintenance dose; Loading dose; Vancomycin; Continuous infusion; Critically ill
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2019.09.018

•Optimal vancomycin dosing in critically ill patients is still uncertain.•Population pharmacokinetics and simulations were performed using 274 samples from 55 intensive care unit patients.•A 25 mg/kg loading dose (based on distribution volume of ca. 1 L/kg) was optimal.•A daily maintenance dose of 1–4.5 g will cover creatinine clearance varying from 10–240 mL/min.•High inter-individual variability of vancomycin population pharmacokinetics still makes therapeutic drug monitoring essential. Despite extensive clinical use, limited data are available on optimal loading and maintenance doses of vancomycin in critically ill patients. This study aimed to develop a rational approach for optimised dosage of vancomycin given in a continuous infusion in critically ill patients. Vancomycin pharmacokinetic (PK) data (total serum concentrations) were obtained from 55 intensive care unit (ICU) patients (Bach Mai Hospital, Hanoi, Vietnam) receiving a 20 mg/kg loading dose followed by continuous infusion stratified by creatinine clearance (CLCr). Population PK modelling and Monte Carlo simulations were performed using a nonlinear mixed-effects modelling (NONMEM) program for a target of 20–30 mg/L to optimise efficacy and minimise nephrotoxicity. A two-compartment model with first-order elimination best fitted the PK data with central and peripheral volumes of distribution of 1.01 and 2.39 L/kg, respectively (allometric scaling to a 70 kg standard subject). The population total clearance of 3.63 L/h was only explained by renal function in the covariate and final model. The simulations showed that a 25-mg/kg loading dose infused over 90 minutes was optimal to reach the target range. The optimal maintenance dose for low renal function (CLCr < 45 mL/min) was 1000–1500 mg/day. For augmented renal clearance (CLCr > 130 mL/min) the dose should be up to 3500 mg/day or even 4500 mg/day to achieve adequate exposure. These simulated maintenance doses were larger than previously proposed for non-ICU patients. Large loading and maintenance doses of vancomycin are generally needed in critically ill patients. Because of high interindividual variability in vancomycin PK, drug monitoring may still be necessary.