RESUMO
PURPOSE: Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in > 90% of adult patients receiving once-daily dosing presenting to the emergency department (ED) with sepsis. METHODS: We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum therapeutic ceftriaxone exposure in > 90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min. CONCLUSIONS: Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in > 90% of patients presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.
