Aaron J Heffernan1,2, Rebecca A Curran3, Kerina J Denny4, Fekade B Sime5,6, Claire L Stanford7, Brett McWhinney8, Jacobus Ungerer8,9, Jason A Roberts5,6,10,11,12, Jeffrey Lipman6,11,12. 1. School of Medicine, Griffith University, Southport, Australia. aaron.heffernan@griffithuni.edu.au. 2. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, University of Queensland, Woolloongabba, Australia. aaron.heffernan@griffithuni.edu.au. 3. Department of Pharmacy, Gold Coast University Hospital, Southport, Australia. 4. Department of Intensive Care, Gold Coast University Hospital, Southport, Australia. 5. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, University of Queensland, Woolloongabba, Australia. 6. University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Australia. 7. Department of Emergency Medicine, Gold Coast University Hospital, Southport, Australia. 8. Department of Chemical Pathology, Pathology Queensland, Herston, Australia. 9. Faculty of Biomedical Science, University of Queensland, St Lucia, Australia. 10. Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Australia. 11. Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia. 12. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
Abstract
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.
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.