Pharmacokinetic/pharmacodynamic indices of anti‐infective drugs should be referenced to free drug concentrations. In the present study, clindamycin, flucloxacillin and tedizolid have been determined in human plasma by HPLC–UV. The drugs were separated isocratically within 3–6 min on a C18 column using mixtures of phosphate buffer–acetonitrile of pH 7.1–7.2. Sample treatment for the determination of total drug concentrations in plasma included extraction/back‐extraction (clindamycin) or protein precipitation (flucloxacillin, tedizolid). The free drug concentrations were determined after ultrafiltration. An ultrafiltration device with a membrane consisting of regenerated cellulose proved to be suitable for all drugs. Maintaining a physiological pH was crucial for clindamycin, whereas maintaining body temperature was essential for tedizolid. The methods were applied to the analysis of total and free drug concentrations in clinical samples and were sufficiently sensitive for pharmacokinetic studies and therapeutic drug monitoring.

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/ 378C). 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 methicillinsensitive 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.

No abstract

No abstract

No abstract