1 Int J Antimicrob Agents. 2019 54:702-708 doi:
10.1016/j.ijantimicag.2019.09.018. 
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.

Vu DH(1), Nguyen DA(2), Delattre IK(3), Ho TT(2), Do HG(4), Pham HN(5), Dao
XC(6), Tran NT(4), Nguyen GB(6), Van Bambeke F(3), Tulkens PM(3), Nguyen HA(2).

Author information: 
(1)National Drug Information and Adverse Drug Reaction Monitoring Center, Hanoi
University of Pharmacy, Hanoi, Vietnam. Electronic address: vudinhhoa@gmail.com.
(2)National Drug Information and Adverse Drug Reaction Monitoring Center, Hanoi
University of Pharmacy, Hanoi, Vietnam.
(3)Louvain Drug Research Institute, Université catholique de Louvain, Brussels,
Belgium.
(4)Department of Pharmacy, Bach Mai Hospital, Hanoi, Vietnam.
(5)Department of Microbiology, Bạch Mai Hospital, Hanoi, Vietnam.
(6)Intensive Care Unit, Bạch Mai Hospital, Hanoi, Vietnam.

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.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ijantimicag.2019.09.018 
PMID: 31600554