Population Pharmacokinetics of Total and Free Ceftriaxone in Critically Ill and Non-Critically Ill Hospitalised Adult Patients

Eko Setiawan; Alvaro Gonzalez; Saskia A Wölky; Menino Osbert Cotta; Xin Liu; Hernycane Sosilya; Diane Maresco-Pennisi; Emmanuel Novy; Jenny Ordonez; Dwi Lily Lukas; Steven C Wallis; Jiao Xie; Jason A Roberts; Mohd H Abdul-Aziz

doi:10.1016/j.ijantimicag.2026.107817

Population Pharmacokinetics of Total and Free Ceftriaxone in Critically Ill and Non-Critically Ill Hospitalised Adult Patients

Int J Antimicrob Agents. 2026 Apr 21;67(8):107817. doi: 10.1016/j.ijantimicag.2026.107817. Online ahead of print.

Authors

Affiliations

¹ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia; Department of Clinical Pharmacy, Faculty of Pharmacy, University of Surabaya, Surabaya, Indonesia; Center for Medicines Information and Pharmaceutical Care (CMIPC), Faculty of Pharmacy, University of Surabaya, Surabaya, Indonesia.
² University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia; Pharmacy Department, Madrid, Spain.
³ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia; Hospital Pharmacy, Heidelberg University Hospital, Heidelberg, Germany.
⁴ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia.
⁵ Dr Mohamad Soewandhie Public Hospital, Surabaya, Indonesia.
⁶ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia; Department of Anesthesiology, Critical Care and Peri-operative Medicine, University Hospital of Nancy, Nancy, France.
⁷ School of Medicine Ciputra University, Dr Mohamad Soewandhie Regional General Hospital Surabaya, Surabaya, Indonesia.
⁸ Department of Pharmacy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁹ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia; Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia; Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; Division of Anesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
¹⁰ University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia. Electronic address: h.abdulaziz@uq.edu.au.

PMID: 42025646
DOI: 10.1016/j.ijantimicag.2026.107817

Abstract

Objective: To characterise the population pharmacokinetics of total and free ceftriaxone in critically ill and non-critically ill Indonesian patients, define optimised dosing regimens against common hospital pathogens implicated in severe pneumonia and complicated urinary tract infections (UTI), and compare these findings with published data to support broader applicability.

Method: This study recruited critically ill and non-critically ill adults receiving intravenous ceftriaxone. Serial plasma samples were collected over one dosing interval. Total and free ceftriaxone concentrations were measured using a validated UHPLC-MS/MS method. Population pharmacokinetic analysis was performed using Monolix. Dosing simulations were performed to assess the probability of efficacy (100%fT>MIC for a given MIC) and toxicity risk (total trough concentration >100 mg/L) on days 1 and 3 of therapy. Fractional target attainment was evaluated using EUCAST MIC distributions for common pathogens implicated in severe pneumonia and complicated UTI.

Results: Fifty-three patients were recruited (median age, 57 years [IQR 39-65]; median eGFR_CKD-EPI 67 mL/min/1.73 m² [31.4-92.3]; 26 males; 42% ICU). A two-compartment model with complex protein binding best described the data with eGFR_CKD-EPI as the primary determinant of clearance. Once-daily intermittent infusion regimens (1 and 2 g every 24 h) failed to achieve optimal efficacy targets in patients with preserved or augmented renal function (eGFR_CKD-EPI ≥60 mL/min/1.73 m²).

Conclusion: A simplified renal function-stratified dosing strategy provided the best balance between safety and efficacy for empirical treatment; 1 g every 24 h for patients with eGFR_CKD-EPI ≤60 mL/min/1.73 m² and 1 g every 12 h for patients with eGFR_CKD-EPI >60 mL/min/1.73 m².

Keywords: Cephalosporins; Dosing; Pharmacokinetics; Severe pneumonia.