Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study

Abstract

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).

Conflict of interest statement

Roger J. Brüggemann has no conflicts of interest that are directly relevant to the content of this article. Outside of this work, he has served as consultant to and has received unrestricted research grants from Astellas Pharma Inc., F2G, Amplyx, Gilead Sciences, Merck Sharpe and Dohme Corp., and Pfizer Inc. All payments were invoiced by the Radboud University Medical Centre. Saskia N. de Wildt has no conflicts of interest that are directly relevant to the content of this article. Outside of this work she has served as consultant to and had received unrestricted research grant or in kind support from UCB Pharma, Spingotec, and Pfizer Inc. Saskia N. de Wildt is the director of the Dutch Pediatric Formulary and its internationally licensed versions (Stichting Nederlands Kenniscentrum Pharmacotherapy voor Kinderen & Kinderformularium B.V.) All payments were invoiced by the Radboud University Medical Centre. Stan J.F. Hartman, Parth J. Upadhyay, Nienke N. Hagedoorn, Ron A.A. Mathôt, Henriëtte A. Moll, Michiel van der Flier, Michiel F. Schreuder, and Catherijne A. Knibbe have no conflicts of interest that are directly relevant to the content of this article.

© 2021. The Author(s).

Figures

Fig. 1

Goodness of fit of predicted total (gray) and unbound ceftriaxone (white) concentrations. Diagnostic plots for ceftriaxone: observed ceftriaxone concentrations vs population predictions and individual predictions and conditional weighted residuals vs time after the last dose and population predictions. Dots represent individual total (gray) and unbound (white) ceftriaxone concentrations. The red line represents the regression line, the blue line represents the correlation of our observations and predictions. CWRES conditional weighted residuals

Fig. 2

Impact of the final covariates weight and estimated glomerular filtration (eGFR) on ceftriaxone clearance. Dots represent the individual estimated clearance values, with colors and shapes representing different categories of median eGFRcreat during the study period (red squares <30 mL/min/1.73 m2, yellow dots 30–80 mL/min/1.73 m2, blue triangles 80–120 mL/min/1.73 m2, and green diamonds > 120 mL/min/1.73 m2. Solid lines represent the range of weight in each eGFR category observed in our dataset. Dotted lines represent extrapolated clearance for each category for a weight of 0–80 kg

Fig. 3

Probability of target attainment (PTA) for different ceftriaxone dosing regimens for patients with a median estimated glomerular filtration rate for different MICs. The PTA for patients with p50 estimated glomerular filtration rate (85.22 mL/min/1.73 m2) and albumin levels (27 g/L) for the four tested dosing regimens (red circles 100 mg/kg once daily; yellow squares 50 mg/kg once daily; blue diamonds 80 mg/kg once daily, and green triangles 50 mg/kg twice daily). The dashed horizontal line represents target PTA of 90%. Shaded areas represent MICs selected for the primary (0.5 mg/L, gray) and high (2.0 mg/L, blue) MIC target