Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years

Abstract

cSince the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (؎ standard deviations) of vancomycin volume of distribution and clearance were 36.3 ؎ 15.2 liter and 2.0 ؎ 0.9 liter/h, respectively. In the validation group, the bias and precision were ؊0.75 mg/liter and 8.76 mg/liter for population predictions and ؊0.39 mg/liter and 2.68 mg/ liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin. Vancomycin is a glycopeptide antibacterial that is widely used for the treatment of serious Gram-positive infections, notably those caused by methicillin-resistant Staphylococcus aureus (MRSA) (1). With the widespread appearance of resistant pathogens such as MRSA, the use of vancomycin has dramatically increased since the early 1980s. The activity of vancomycin is related to an inhibition of the biosynthesis of the bacterial cell wall. The molecule diffuses into the cell wall and binds to the disaccharide pentapeptides, preventing their polymerization and leading to discontinuation of the synthesis of peptidoglycan of the bacterial cell wall.The concentration-effect relationship of vancomycin has been characterized, and the pharmacokinetic (PK)-pharmacodynamic parameter that best describes the efficacy is the ratio of the area under the serum drug concentration-time curve to the MIC (AUC/MIC) (2, 3). Regarding toxicity, it has been shown that vancomycin nephrotoxicity is dose dependent and linked to vancomycin trough concentration (4). As vancomycin elimination is mainly renal, patients with renal impairment are at risk of overexposure and toxicity. As a consequence, a careful monitoring of vancomycin serum concentrations is recommended (5, 6) to optimize efficacy and prevent toxicity.Several methods can be used to individualize dosage ...

A population pharmacokinetic model of vancomycin for dose individualization based on serum cystatin C as a marker of renal function

“…An appropriate PPK model is of importance for achieving vancomycin targeted C ss . Traditionally, vancomycin dosage was determined based on the CLcr estimated by Scr, and most of the vancomycin PPK models were focused on the CLcr . However, many other studies had shown that cystatin C predicted vancomycin trough levels better than Scr in hospitalized patients, and a vancomycin dosing nomogram based on GFR estimated by cystatin C could improve goal trough achievement compared to Scr .…”

“…So far, the results of external evaluation reported by 19 vancomycin PPK models concerning adult patients showed that the MPE, MPE%, MAE, MAE% and RMSE ranged from −2.99 to 1.8 mg/l, −7.7% to 17.9%, 0.22 to 9.28 mg/l, 16.4% to 35.1% and 0.45 to 9.19 mg/l, respectively. Almost all these studies took Scr as renal biomarker excepted for the Japanese study .…”

Intravenous Vancomycin Dosing in the Elderly: A Focus on Clinical Issues and Practical Application

“…Elderly patients represent a heterogeneous population [50], thus making it difficult to accurately estimate their renal function. Studies have examined several equations in an attempt to elucidate an accurate estimate of renal function: the Cockcroft–Gault (CG) method, the Modification of Diet in Renal Disease (MDRD) method, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method.…”

Assessing Vancomycin Dosing Per Pharmacy in Elderly Patients Over the Age of 74 Years

“…Bourguignon and colleagues evaluated the pharmacokinetics of patients over the age of 80 years on vancomycin and found that there can be large inter-individual variability of vancomycin pharmacokinetic parameters. (8) Additional variabilities in protein binding and volume of distribution may also account for the differences in target trough attainment between groups. (23,24) Moreover, the use of serum creatinine as an estimate of renal function in elderly pa-tients may not be reliable.…”

“…Additionally, there remains a sufficient amount of variability in clearance and volume of distribution observed in elderly patients. (8) Elderly patients may also have decreased muscle mass, which can lead to decreases in serum creatinine and affect drug distribution. (9) It has also been described that serum creatinine production in elderly patients may be within normal limits, but renal function may be lower than expected.…”