Factors impacting unbound vancomycin concentrations in different patient populations.
The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [n = 33 samples], intensive care unit [ICU] [n = 51], orthopedics [n = 44], and pediatrics [age range, 6 months to 14 years; n = 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (P < 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], -1.3 to 0.7 mg/liter; R(2) = 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.
University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium matthijsoyaert@telenet.be.
Matthijs
M
Oyaert
KU Leuven-University of Leuven, Department of Clinical Pharmacology and Pharmacotherapy, Leuven, Belgium University Hospitals Leuven, Pharmacy Department, Leuven, Belgium.
Isabel
I
Spriet
KU Leuven-University of Leuven, Department of Development and Regeneration, Leuven, Belgium University Hospitals Leuven, Neonatal Intensive Care Unit, Leuven, Belgium.
Karel
K
Allegaert
KU Leuven-University of Leuven, Department of Development and Regeneration, Leuven, Belgium University Hospitals Leuven, Neonatal Intensive Care Unit, Leuven, Belgium.
Anne
A
Smits
KU Leuven-University of Leuven, Department of Development and Regeneration, Leuven, Belgium University Hospitals Leuven, Neonatal Intensive Care Unit, Leuven, Belgium.
Kim
K
Vanstraelen
University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium.
Nele
N
Peersman
University Hospitals Leuven, Department of General Internal Medicine, Medical Intensive Care Unit, Leuven, Belgium.
Joost
J
Wauters
University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium KU Leuven-University of Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
Jan
J
Verhaegen
University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium KU Leuven-University of Leuven, Department of Cardiovascular Sciences, Leuven, Belgium.
Pieter
P
Vermeersch
University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium KU Leuven-University of Leuven, Department of Cardiovascular Sciences, Leuven, Belgium.
Steven
S
Pauwels
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000378:metabolism; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism; D007075:Immunoglobulin M / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D053719:Tandem Mass Spectrometry; D014640:Vancomycin / Q000097:blood* / Q000378:metabolism*; D055815:Young Adult
D000418:Albumins; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D014640:Vancomycin; D001663:Bilirubin