Adequate cefazolin therapy for critically ill patients: can we predict active concentrations from given protein-binding data?

Abstract

Abstract Objectives Therapeutic drug monitoring of β-lactam antibiotics has become an important tool for treatment of severe infections, especially for critically ill patients who often exhibit altered PK/PD. Therapeutic targets are based on MIC, which refers to the active concentration of the drug. Cefazolin, a β-lactam agent used for treating of MSSA bacteraemia, has a protein binding of approximately 80 %. Therefore, a reliable determination of the active, non-protein-bound concentration is required to ensure optimal therapeutic outcome. Methods From seven critically ill patients who received an initial dose of 2 g cefazolin, followed by a continuous 24 h infusion, a total of 24 serum samples were obtained. The non-protein-bound concentration was directly measured after ultrafiltration and compared to prediction based total concentrations and protein binding values from the literature. For the analysis, a rapid and reliable LC-MS3 based assay was established, offering maximum sensitivity and specificity. Results The measured non-protein-bound concentration varied over a wide range (7.6–118 mg/L), with 22 out of 24 samples exhibiting cefazolin levels above the therapeutic target values (8–16 mg/L). Additionally, the observed protein binding ranged from 29 to 78 % (median 66.8 %), which was significantly lower than that reported in the literature. When comparing the measurements to the predictive performance of total concentrations and protein binding values, poor results were obtained. Conclusions The results show a high variability in plasma protein binding of cefazolin in critically ill patients. Therefore, the “one-dose-fits-all” principle can no longer be considered up to date. For personalised cefazolin therapy based on therapeutic drug monitoring (TDM) it is recommended to determine the active, non-protein-bound drug concentration, as calculations from the total fraction yield poor results.