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

Int J Antimicrob Agents. 2019 Dec;54(6):702-708. doi: 10.1016/j.ijantimicag.2019.09.018. Epub 2019 Oct 7.


Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Continuous infusion; Critically ill; Loading dose; Maintenance dose; Vancomycin.

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacokinetics
  • Computer Simulation
  • Critical Illness*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Monitoring
  • Enterococcus / drug effects
  • Female
  • Humans
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Models, Biological*
  • Monte Carlo Method
  • Staphylococcus aureus / drug effects
  • Vancomycin / administration & dosage*
  • Vancomycin / pharmacokinetics*


  • Anti-Bacterial Agents
  • Vancomycin