Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
Clinical Pharmacokinetics, vol. 60, pp. 1361–1372
Abstract
Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Critically ill children (aged 0–18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%). Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1–16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m 2 , the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m 2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).
Authors 10
-
Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Health Sciences
Affiliation as printed
Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
-
Parth J. Upadhyay Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
-
Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Division of General Pediatrics, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
-
Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
-
Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Division of General Pediatrics, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
-
Radboud University Nijmegen · Radboud University Medical Center · University Medical Center Utrecht · Amalia Kinderziekenhuis · Wilhelmina Children's Hospital
Affiliation as printed
Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
Section Pediatric Infectious Diseases, Pediatric Infectious Diseases and Immunology, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands
-
Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Pediatric Nephrology, Radboud Institute of Molecular Life Sciences, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands
-
Radboud University Nijmegen · Radboud Institute for Health Sciences
Affiliation as printed
Department of Pharmacy, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
-
Catherijne A. J. Knibbe Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Leiden University · St. Antonius Ziekenhuis
Affiliation as printed
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
-
Saskia N. de Wildt corresponding
Radboud University Nijmegen · Erasmus MC · Radboud University Medical Center · Erasmus MC - Sophia Children’s Hospital · Radboud Institute for Health Sciences
Affiliation as printed
Department of Intensive Care Medicine, Radboud Institute of Health Sciences, Radboudumc, Nijmegen, The Netherlands. Saskia.deWildt@radboudumc.nl
Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. Saskia.deWildt@radboudumc.nl
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands. Saskia.deWildt@radboudumc.nl
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Cited by 20 stored of 21
20 results
No patents citing this paper on Lens.org (checked 2026-10-11).