Mass Spectrometric Characterization of Flucloxacillin Binding to Serum Albumin in Hospitalized Patients With Hypoalbuminemia: An Observational Pilot Study

PURPOSE: To facilitate antibiotic dose optimization, novel insights into flucloxacillin pharmacokinetics and serum protein binding in critically ill patients are needed. Therefore, this study assessed the number of flucloxacillin molecules bound to a serum albumin molecule (stoichiometry) in hospitalized patients with hypoalbuminemia. METHODS: Adult hospitalized patients with serum hypoalbuminemia administered intravenous flucloxacillin were enrolled in this prospective, observational, single-center pilot study. Patients treated with piperacillin/tazobactam or amoxicillin/clavulanic acid served as controls. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry measurements were performed to calculate the stoichiometry of the antibiotic/albumin complexes. In addition, the associations between the stoichiometry and antibiotic treatment duration, serum albumin concentration, or time since flucloxacillin treatment cessation were assessed using association plots. RESULTS: Eleven patients treated with flucloxacillin and 4 control patients were enrolled. A total of 251 stoichiometric measurements were considered. Large intra- and interindividual differences were observed in the stoichiometry. These values ranged from 0 to 6 flucloxacillin molecules bound to albumin. In 8 patients (72%), an increase in the stoichiometry as the number of flucloxacillin treatment days increased was confirmed. In addition, the stoichiometry increased at low albumin concentrations, and a stoichiometry of ≥3 was observed for 2-8 days after flucloxacillin treatment cessation. CONCLUSIONS: Prolonged flucloxacillin treatment and low serum albumin concentrations were associated with a high stoichiometry of flucloxacillin/albumin complexes in hospitalized patients with serum hypoalbuminemia. This study illustrates that protein binding is not a constant, thereby contributing to current understanding of the pharmacokinetics, effectiveness, and toxicity of flucloxacillin.