Departments of Infection Prevention and Infectious Diseases and.
Anaesthesiology.
Ther Drug Monit. 2021 Apr 1;43(2):264-270. doi: 10.1097/FTD.0000000000000827.
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.
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.
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.
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.
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。
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。
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。
对于治疗药物监测目的，测定 CAZ、MEM 或 PIP 的总浓度或游离浓度似乎足够。对于 FXN 等高度结合的β-内酰胺类抗生素，在普遍存在低白蛋白血症的 ICU 患者中，应优先考虑游离浓度。
