β-内酰胺类抗生素游离血浆浓度的测定：重症监护病房患者的适用性研究。

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients.

机构信息

Departments of Infection Prevention and Infectious Diseases and.

Anaesthesiology.

出版信息

Ther Drug Monit. 2021 Apr 1;43(2):264-270. doi: 10.1097/FTD.0000000000000827.

DOI:10.1097/FTD.0000000000000827

PMID:33086362

Abstract

BACKGROUND

The antibacterial effect of antibiotics is linked to the free drug concentration. This study investigated the applicability of an ultrafiltration method to determine free plasma concentrations of beta-lactam antibiotics in ICU patients.

METHODS

Eligible patients included adult ICU patients treated with ceftazidime (CAZ), meropenem (MEM), piperacillin (PIP)/tazobactam (TAZ), or flucloxacillin (FXN) by continuous infusion. Up to 2 arterial blood samples were drawn at steady state. Patients could be included more than once if they received another antibiotic. Free drug concentrations were determined by high-performance liquid chromatography with ultraviolet detection after ultrafiltration, using a method that maintained physiological conditions (pH 7.4/37°C). Total drug concentrations were determined to calculate the unbound fraction. In a post-hoc analysis, free concentrations were compared with the target value of 4× the epidemiological cut-off value (ECOFF) for Pseudomonas aeruginosa as a worst-case scenario for empirical therapy with CAZ, MEM or PIP/tazobactam and against methicillin-sensitive Staphylococcus aureus for targeted therapy with FXN.

RESULTS

Fifty different antibiotic treatment periods in 38 patients were evaluated. The concentrations of the antibiotics showed a wide range because of the fixed dosing regimen in a mixed population with variable kidney function. The mean unbound fractions (fu) of CAZ, MEM, and PIP were 102.5%, 98.4%, and 95.7%, with interpatient variability of <6%. The mean fu of FXN was 11.6%, with interpatient variability of 39%. It was observed that 2 of 12 free concentrations of CAZ, 1 of 40 concentrations of MEM, and 11 of 23 concentrations of PIP were below the applied target concentration of 4 × ECOFF for P. aeruginosa. All concentrations of FXN (9 samples from 6 patients) were >8 × ECOFF for methicillin-sensitive Staphylococcus aureus.

CONCLUSIONS

For therapeutic drug monitoring purposes, measuring total or free concentrations of CAZ, MEM, or PIP is seemingly adequate. For highly protein-bound beta-lactams such as FXN, free concentrations should be favored in ICU patients with prevalent hypoalbuminemia.

摘要

背景

抗生素的抗菌效果与游离药物浓度有关。本研究探讨了超滤法测定 ICU 患者β-内酰胺类抗生素游离血浆浓度的适用性。

方法

入选患者为接受头孢他啶（CAZ）、美罗培南（MEM）、哌拉西林（PIP）/他唑巴坦（TAZ）或氟氯西林（FXN）持续输注治疗的成年 ICU 患者。在稳态时采集至多 2 份动脉血样。如果患者接受另一种抗生素，则可多次入选。采用维持生理条件（pH7.4/37°C）的高效液相色谱法-紫外检测法测定游离药物浓度，超滤后测定游离药物浓度，并计算未结合分数。在事后分析中，将游离浓度与 CAZ、MEM 或 PIP/他唑巴坦治疗铜绿假单胞菌的经验性治疗最坏情况（4×流行病学折点值（ECOFF））和 FXN 针对甲氧西林敏感金黄色葡萄球菌的目标治疗的目标值 4×ECOFF 进行比较。

结果

评估了 38 例患者 50 种不同的抗生素治疗期。由于在肾功能不同的混合人群中采用固定剂量方案，抗生素浓度差异较大。CAZ、MEM 和 PIP 的平均未结合分数（fu）分别为 102.5%、98.4%和 95.7%，个体间变异性<6%。FXN 的平均 fu 为 11.6%，个体间变异性为 39%。观察到 CAZ 的游离浓度中有 2 个（12 个中的 2 个）、MEM 的游离浓度中有 1 个（40 个中的 1 个）和 PIP 的游离浓度中有 11 个（23 个中的 11 个）低于铜绿假单胞菌应用的目标浓度 4×ECOFF。FXN 的所有浓度（来自 6 例患者的 9 个样本）均>8×ECOFF，适用于甲氧西林敏感金黄色葡萄球菌。