Plasma protein binding of ceftriaxone in critically ill patients: can we predict unbound fractions?

• Published in: Journal of antimicrobial chemotherapy 2023-04, Vol.78 (4), p.1059-1065
• Main Authors: Ewoldt, Tim M J, Bahmany, Soma, Abdulla, Alan, Muller, Anouk E, Endeman, Henrik, Koch, Birgit C P
• Format: Article
• Language: English
• Subjects: Albumins - analysis; Albumins - metabolism; Anti-Bacterial Agents - therapeutic use; Blood Proteins - metabolism; Ceftriaxone - pharmacokinetics; Chromatography, Liquid; Critical Illness; Humans; Original Research; Prospective Studies; Protein Binding; Tandem Mass Spectrometry
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkad046

Abstract Background Standard antibiotic dosing is not suitable for critically ill patients, due to altered pharmacokinetics (PK) in these patients. Knowledge of protein binding is important for optimizing antibiotic exposure because only the unbound fraction is pharmacologically active. If unbound fractions can be predicted, minimal sampling techniques and less costly methods can be routinely used. Methods Data from the DOLPHIN trial, a prospective randomized clinical trial that included critically ill patients, were used. Total and unbound ceftriaxone concentrations were determined using a validated UPLC-MS/MS method. A non-linear saturable binding model was made using 75% of the trough concentrations and validated on the remaining data. Our model and previously published models were tested for their performance for subtherapeutic (10 mg/L) unbound concentrations. Results In total, 113 patients were sampled [Acute Physiology And Chronic Health Evaluation version 4 (APACHE IV) score 71 (IQR 55–87), albumin 28 g/L (IQR 24–32)]. This resulted in 439 samples (trough = 224, peak = 215). Unbound fractions were significantly different between samples taken at trough and peak times [10.9% (IQR 7.9–16.4) versus 19.7% (IQR 12.9–26.6), P