Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

• Published in: Journal of clinical laboratory analysis Vol. 34; no. 3; pp. e23100 - n/a
• Main Authors: Raaij, Joost J., Mabelis, Noortje J. D., Shudofsky, Kimberly N., Meenks, Sjoerd D., Noble, Jos L. M. L., Janssen, Paddy K. C.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2020; John Wiley and Sons Inc
• Subjects: Aged; Antibiotics; Cefuroxime; Cefuroxime - blood; Chromatography; Chromatography, High Pressure Liquid; Cohort Studies; Critical Illness; Drug dosages; Epidermal growth factor receptors; Feasibility studies; Female; Humans; hypoalbuminemia; Hypoalbuminemia - blood; Hypoalbuminemia - complications; intensive care unit; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Middle Aged; Minimum inhibitory concentration; Patients; Pharmacodynamics; Pharmacokinetics; Proteins; Reference Standards; Renal failure; Renal Insufficiency - blood; Renal Insufficiency - complications; Reproducibility of Results; Sampling; Scientific imaging; Sepsis; Tandem Mass Spectrometry; Temperature; therapeutic drug monitoring; Ultrafiltration; unbound concentration; unbound concentration; intensive care unit; cefuroxime; hypoalbuminemia; therapeutic drug monitoring
• ISSN: 0887-8013; 1098-2825
• DOI: 10.1002/jcla.23100

Background Pharmacokinetic studies of cefuroxime by ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC‐MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. Methods Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC‐MS/MS. Sampling times were categorized as trough (180‐1 min prior to administration), peak (10‐30 min after administration), mid (30‐360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). Results Intra‐assay and inter‐assay precision was <3%. Recovery was 99.7%‐100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54‐77). Median albumin serum concentrations and eGFR were 19 g/L (range 11‐40 g/L) and 48 mL/min/1.73 m2 (range 7‐115 mL/min/1.73 m2), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42‐54.03 mg/L) and 71.49 mg/L (range 53.87‐73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%‐99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85‐32.39 mg/L) (trough) and 55.62 mg/L (range 10.03‐62.62 mg/L) (mid). Conclusion The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5‐100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.