Unbound Ceftriaxone Concentrations in Plasma Measured Using Ultrafiltration Versus Equilibrium Dialysis

Background: Ceftriaxone is a first-line beta-lactam antibiotic used in diverse clinical settings. Owing to pharmacokinetic alterations, ceftriaxone therapeutic drug monitoring is currently recommended for patients in the intensive care unit. Ultrafiltration is typically used to measure unbound ceftriaxone concentrations, as it is less costly and time-consuming compared with equilibrium dialysis. However, the reference method, equilibrium dialysis, has not been compared with equilibrium dialysis for ceftriaxone to measure the unbound ceftriaxone concentrations. Therefore, unbound ceftriaxone fractions measured by ultrafiltration versus equilibrium dialysis were compared in patients in the intensive care unit. Methods: Total and unbound ceftriaxone plasma fractions were measured by ultrafiltration (9500 g at 37°C for 30 minutes) and equilibrium dialysis (12 kDa, 37°C for 4 hours) in 32 plasma samples from 28 patients who were critically ill collected during a previous prospective pharmacokinetic study. Passing–Bablok regression and Bland–Altman analyses were performed to evaluate the agreements between both methods. Results: The median (range) total ceftriaxone plasma concentration was 108.6 (5.2–233) mg/L. The median unbound concentration measured by equilibrium dialysis and ultrafiltration was 14.5 (0.7–52.9) and 23.3 (0.9–79.2) mg/L, respectively, showing a significant difference. Passing–Bablok regression analysis revealed significant proportional and systematic bias. This result was confirmed by Bland–Altman analysis, with a mean relative bias of 43.3% and wide agreement limits (−21% to 108%). Conclusions: Ultrafiltration substantially overestimates the unbound ceftriaxone fraction compared with equilibrium dialysis at 37°C. It is important to report methodological details and consider this information when interpreting unbound fractions of ceftriaxone and other drugs. These findings may impact the therapeutic drug monitoring of ceftriaxone.