Plasma and interstitial fluid population pharmacokinetics of vancomycin in critically ill patients with sepsis

Abstract

Vancomycin is a commonly prescribed antibiotic in the intensive care unit. However, there are limited data describing its distribution into the interstitial fluid (ISF) of tissues. The aim of this study was to describe the plasma and tissue ISF population pharmacokinetics of vancomycin in critically ill patients with sepsis. Serial vancomycin blood and ISF samples were collected at pre-specified time intervals in critically ill patients with sepsis. ISF sampling occurred using a subcutaneously inserted microdialysis catheter. Bioanalysis was undertaken using a validated spectrometric assay method. Population pharmacokinetic analysis was performed using Pmetrics^®. Seven patients were recruited and pharmacokinetic data were available for six of them. The median (interquartile range) age, weight, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score and measured creatinine clearance (CL_Cr) were 55 (44-67) years, 85 (81-102) kg, 20 (16-29), 5 (4-8) and 90 (83-98) mL/min, respectively. Vancomycin pharmacokinetics was best described by a three-compartment linear model. Measured CL_Cr (on vancomycin clearance) and weight (on volume of distribution of the central compartment) were the only patient covariates that improved the model fit. Coefficients of variation for the vancomycin rate constants into and out of the peripheral and tissue ISF compartments were also high, ranging from 47% to 134%. There is significant variability of vancomycin distribution into tissue ISF, which it was not possible to explain with patient characteristics.

Keywords: Antimicrobial; Dosing; Microdialysis; Pharmacodynamics; Septic shock.