Unbound fraction of vancomycin in intensive care unit patients

Abstract

Published data on the unbound fraction of vancomycin in patient samples exhibit high variability. In the present study, a robust ultrafiltration method was developed and applied to 102 clinical samples from 22 intensive care unit patients who were treated with continuous infusion of vancomycin. A validated HPLC method was used for determination of total and unbound concentrations. The mean unbound fraction was 67.2% (standard deviation 7.5%, range 47.2-92.1%) and independent of total concentration of vancomycin or of albumin. The unbound fraction was significantly correlated (r = +0.67, P = .0009) with the renally filtered fraction (drug clearance/creatinine clearance), providing functional evidence for the validity of the measurements. Ultrafiltration proved to be susceptible to variations in the experimental conditions such as pH, temperature and centrifugal force. The measured unbound fraction increased from 60% at pH 6 to 100% at pH 9, from 57% at 4°C to 80% at 37°C, and was 76% at 1,000 g compared with 45% at 10,000 g. Lack of standardization may therefore partly explain the variable results reported in the literature.

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

“…For MER, the determined value of 52% f %T >MIC was also in good agreement with the clinical breakpoint for microbiological response of 54% determined in patients with lower respiratory tract infections, in which S. aureus was the second‐most abundant pathogen 39. For VAN, the f AUC/MIC breakpoints from the clinical studies40, 41 tended to be fairly higher (125–400) than the calculated values (59–94) of the present work, which could originate from the partly impaired tissue distribution of VAN,42 whereas for MER and LZD, unbound plasma concentrations might be a fair predictor of tissue concentrations,43, 44, 45 if determined under appropriate analytic conditions 24, 46, 47. Yet, the overall “correct” prediction of the PK‐PD index indicates that the developed semimechanistic PK‐PD model might adequately reflect the clinical situation for the antibiotics LZD, MER, and VAN and, hence, might support the validity of the drawn conclusions from the present translational study.…”

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

“…However, the specific effect of temperature on the rifampin-protein complex was not mentioned there or in the literature. For other drugs, an increase in experimental ultrafiltration temperatures has been associated with an increase in the free fraction (39)(40)(41), but as far as we know this has not been reported for rifampin. Indeed, we found that measurement of free rifampin at 37°C resulted in a small increase in the rifampin-free fraction (mean change in free fraction, ϩ1.2%; median change, ϩ1.1%; range, Ϫ0.7 to ϩ3.5%, n ϭ 10 rifampin concentrations measured, P ϭ 0.029 [paired t test]) (unpublished data).…”

Factors Impacting Unbound Vancomycin Concentrations in Different Patient Populations

“…Compared to other studies, ours examined relatively large patient populations and evaluated additional factors that are potentially associated with unbound vancomycin concentrations and consequently vancomycin PPB, like IgA and total bilirubin concentrations or drugs with a PPB of Ͼ70% in a large cohort of patients from different wards (9,10,12,14). Moreover, we were able to measure unbound vancomycin concentrations by means of an LC-MS/MS method validated for total and unbound drug concentrations, in contrast to other studies, in which an immunoassay (fluorescence polarization immunoassay [FPIA] or particle-enhanced turbidimetric inhibition immunoassay [PETINIA]) or high-performance liquid chromatography (HPLC) with UV detection was used (9)(10)(11)(12)(13)(14).…”

“…A protein binding proportion of 50% is generally used to calculate unbound vancomycin concentrations. However, protein binding of vancomycin shows considerable variability across studies (ranging from almost 0 to 90%), which could lead to different clinical responses even with the same total drug concentration (9)(10)(11)(12)(13)(14). Unbound drug concentrations can vary among patients (hematology, intensive care, pediatric, etc.)…”

“…Previous studies examining the correlation between unbound and total vancomycin concentrations did not distinguish between different patient populations (9,12,14). One study investigated only intensive care patients (10). Berthoin et al measured unbound and total drug concentrations in three patient groups (i.e., hematology, intensive care, and orthopedic patients) (11).…”