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

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 chi...

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Autores principales: Hartman, Stan J. F., Upadhyay, Parth J., Hagedoorn, Nienke N., Mathôt, Ron A. A., Moll, Henriëtte A., van der Flier, Michiel, Schreuder, Michiel F., Brüggemann, Roger J., Knibbe, Catherijne A., de Wildt, Saskia N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505376/
https://www.ncbi.nlm.nih.gov/pubmed/34036552
http://dx.doi.org/10.1007/s40262-021-01035-9
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author Hartman, Stan J. F.
Upadhyay, Parth J.
Hagedoorn, Nienke N.
Mathôt, Ron A. A.
Moll, Henriëtte A.
van der Flier, Michiel
Schreuder, Michiel F.
Brüggemann, Roger J.
Knibbe, Catherijne A.
de Wildt, Saskia N.
author_facet Hartman, Stan J. F.
Upadhyay, Parth J.
Hagedoorn, Nienke N.
Mathôt, Ron A. A.
Moll, Henriëtte A.
van der Flier, Michiel
Schreuder, Michiel F.
Brüggemann, Roger J.
Knibbe, Catherijne A.
de Wildt, Saskia N.
author_sort Hartman, Stan J. F.
collection PubMed
description 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 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. 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 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. CLINICAL TRIAL REGISTRATION: POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01035-9.
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spelling pubmed-85053762021-10-19 Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study Hartman, Stan J. F. Upadhyay, Parth J. Hagedoorn, Nienke N. Mathôt, Ron A. A. Moll, Henriëtte A. van der Flier, Michiel Schreuder, Michiel F. Brüggemann, Roger J. Knibbe, Catherijne A. de Wildt, Saskia N. Clin Pharmacokinet Original Research Article 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 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. 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 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. CLINICAL TRIAL REGISTRATION: POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01035-9. Springer International Publishing 2021-05-26 2021 /pmc/articles/PMC8505376/ /pubmed/34036552 http://dx.doi.org/10.1007/s40262-021-01035-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Hartman, Stan J. F.
Upadhyay, Parth J.
Hagedoorn, Nienke N.
Mathôt, Ron A. A.
Moll, Henriëtte A.
van der Flier, Michiel
Schreuder, Michiel F.
Brüggemann, Roger J.
Knibbe, Catherijne A.
de Wildt, Saskia N.
Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title_full Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title_fullStr Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title_full_unstemmed Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title_short Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study
title_sort current ceftriaxone dose recommendations are adequate for most critically ill children: results of a population pharmacokinetic modeling and simulation study
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505376/
https://www.ncbi.nlm.nih.gov/pubmed/34036552
http://dx.doi.org/10.1007/s40262-021-01035-9
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