Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite the frequent use of vancomycin in intensive care unit (ICU) patients, few studies aimed at characterizing vancomycin population pharmacokinetics have been performed in this critical population. • Population pharmacokinetics coupled with pharmacodynamic analysis, in order to optimize drug exposure and hence antibacterial effectiveness, has been little applied in these specific patients. WHAT THIS STUDY ADDS • Our population model characterized the pharmacokinetic profile of vancomycin in adult ICU patients, higher distribution volume values (V) being observed when the patient's serum creatinine (CrSe) was greater than 1 mg dl−1. • Age and creatinine clearance (CLcr) were identified as the main covariates explaining the pharmacokinetic variability in vancomycin CL. • Our pharmacokinetic/pharmacodynamic (PK/PD) simulation should aid clinicians to select initial vancomycin doses that will maximize the rate of response in the ICU setting, taking into account the patient's age and renal function as well as the susceptibility of Staphylococcus aureus. AIM To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure. METHODS Five hundred and sixty‐nine concentration–time data from 191 patients were analysed using a population pharmacokinetic approach (NONMEN™). External model evaluation was made in 46 additional patients. The 24 h area under the concentration–time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC ≥ 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation. RESULTS Vancomycin CL showed a significant dependence on patient age and renal function whereas CrSe > 1 mg dl−1 increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, CrSe= 1.4 mg dl−1, measured CLCr= 74.7 ml min−1, the estimated values were CL = 1.06 ml min−1 kg−1 and V= 2.04 l kg−1. The cumulative fraction of response for a standard vancomycin dose (2 g day−1) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics. CONCLUSIONS Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population.

Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years

“…In our population of very elderly hospitalized patients, creatinine clearance was found to be associated with the vancomycin elimination rate constant, and body weight was associated with the volume of the central compartment. Apart from this relationship between creatinine clearance and elimination rate constant, we did not find any other significant relationships between patient age and pharmacokinetic parameters, contrary to studies carried out in young children (22) or in adult intensive care unit patients (28). This could be explained by the existence of immature processes in young children, such as kidney function (22), and by a larger range of ages in the population studied by Revilla et al (28), in which patients were between 18 and 85 years.…”

A higher dose of vancomycin in continuous infusion is needed in critically ill patients

“…The present results show that, in critically ill patients with normal renal function, a daily dose of 3000 mg of vancomycin in continuous infusion (following a loading dose) is required to achieve a plateau concentration of 25 mg/L. Only recently, Revilla et al [13] found, based on a M a n u s c r i p t 7 population model using Monte Carlo simulations, that a dose of 3 g vancomycin was needed for an adequate response in patients with S. aureus infections.…”

Review of vancomycin-induced renal toxicity: an update

“…Estimation of such parameters will be derived from input of data on patient characteristics, MIC of the pathogen and a priori population PK indices. The latter have been developed for children and adults with ESKD, malignancy, critical illness and neutropenia Haeseker et al 2016;Camaione et al 2013;Abdel Hadi et al 2015;Revilla et al 2010].…”