Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population
Stan J F Hartman1, Parth J Upadhyay2, Nienke N Hagedoorn3
1Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
Insights
Ceftriaxone dosing in critically ill children needs adjustment for optimal effectiveness. A twice-daily 50 mg/kg regimen improves target attainment for severe infections, especially with higher pathogen resistance.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Infectious Diseases
Background:
- Ceftriaxone is vital for severe pediatric infections.
- Pharmacokinetic data in critically ill children is limited.
- Optimal dosing strategies require further investigation.
Purpose of the Study:
- To determine ceftriaxone pharmacokinetics in critically ill children.
- To propose optimized ceftriaxone dosing guidelines.
- To achieve adequate therapeutic target attainment.
Main Methods:
- Population pharmacokinetic modeling and simulation.
- Analysis of total and unbound ceftriaxone concentrations.
- Non-linear mixed-effects modeling (NONMEM™).
Main Results:
- A two-compartment model described ceftriaxone pharmacokinetics.
- Bodyweight and eGFR influenced ceftriaxone clearance and distribution.
- Current once-daily dosing achieved 96.8% target attainment for MIC 0.5 mg/L, but only 60.8% for MIC 2 mg/L.
Conclusions:
- Current ceftriaxone regimens are adequate for susceptible pathogens.
- Consider 50 mg/kg twice-daily dosing for enhanced target attainment.
- Adjustments are recommended for higher MIC pathogens or impaired renal function.
Background And Objective:
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.
Methods:
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%).
Results:
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 m2, 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.
Conclusions:
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 m2 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.
Clinical Trial Registration:
POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).
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