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影响不同患者群体中万古霉素游离浓度的因素。

Factors impacting unbound vancomycin concentrations in different patient populations.

作者信息

Oyaert Matthijs, Spriet Isabel, Allegaert Karel, Smits Anne, Vanstraelen Kim, Peersman Nele, Wauters Joost, Verhaegen Jan, Vermeersch Pieter, Pauwels Steven

机构信息

University Hospitals Leuven, Department of Laboratory Medicine, Leuven, Belgium

KU Leuven-University of Leuven, Department of Clinical Pharmacology and Pharmacotherapy, Leuven, Belgium University Hospitals Leuven, Pharmacy Department, Leuven, Belgium.

出版信息

Antimicrob Agents Chemother. 2015 Nov;59(11):7073-9. doi: 10.1128/AAC.01185-15. Epub 2015 Sep 8.

Abstract

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.

摘要

游离药物假说指出,只有游离药物浓度具有活性且可用于清除,并且文献中已报道了关于万古霉素游离分数的高度可变结果。我们通过液相色谱串联质谱(LC-MS/MS)方法测定了四个不同患者组中的万古霉素游离分数,并确定了调节万古霉素结合的因素。我们进一步开发并验证了一个预测模型来估计游离万古霉素浓度。采用经过验证的LC-MS/MS方法,对四个不同医院病房的90例患者(血液科[n = 33个样本]、重症监护病房[ICU][n = 51]、骨科[n = 44]和儿科[年龄范围,6个月至14岁;n = 18])的万古霉素(游离和总)浓度进行了测量。进行多元线性混合模型分析以确定可预测万古霉素游离分数和浓度的患者变量。模型中纳入的变量包括患者年龄、病房、同时使用的高蛋白结合药物数量、肾功能(估计肾小球滤过率[由慢性肾脏病流行病学协作公式确定])、α1酸性糖蛋白、白蛋白、总胆红素、IgA、IgM、尿素和总万古霉素浓度。在儿科队列中,万古霉素游离分数的中位数为81.3%(范围,61.9%至95.9%),显著高于三个成人患者队列中发现的游离分数(血液科,60.6%[48.7%至90.6%];ICU,61.7%[47.0%至87.6%];骨科,56.4%[45.9%至78.0%])(P < 0.01)。游离万古霉素浓度的最强显著预测因子是总药物浓度,在儿科队列中由白蛋白补充,在成人队列中由白蛋白和IgA补充。我们用13例成年患者的数据对模型进行了验证。测量的和计算的游离万古霉素浓度之间的平均差异为0.3 mg/L(95%置信区间[CI],-1.3至0.7 mg/L;R² = 0.99[95%CI,0.95至0.99]),表明我们模型的预测性能良好。儿科和成年患者之间的游离万古霉素分数差异显著。我们开发了一个公式来估计成年患者中由总万古霉素、白蛋白和IgA浓度得出的游离分数。

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