Agathe Béranger1,2, Mehdi Oualha3,4, Saïk Urien5,3, Mathieu Genuini4, Sylvain Renolleau4, Radia Aboura3,6, Déborah Hirt3,6, Claire Heilbronner4, Julie Toubiana7, Jean-Marc Tréluyer5,3,6, Sihem Benaboud3,6. 1. Unité de Recherche Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, Paris, France. agathe.beranger@gmail.com. 2. EA7323, Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Université Paris Descartes, Paris, France. agathe.beranger@gmail.com. 3. EA7323, Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Université Paris Descartes, Paris, France. 4. Service de Réanimation et Surveillance Continue Médico-Chirurgicales, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France. 5. Unité de Recherche Clinique, Hôpital Cochin-Necker, Université Paris Descartes, Sorbonne-Paris Cité, Paris, France. 6. Service de Pharmacologie Clinique, Hôpital Cochin, Université Paris Descartes, Sorbonne-Paris Cité, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France. 7. Service de Pédiatrie Générale, Equipe Mobile D'Infectiologie, Hôpital Necker-Enfants Malades, Université Paris Descartes, Sorbonne-Paris Cité, 149 rue de Sèvres, 75015, Paris, France.
Abstract
BACKGROUND: During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. OBJECTIVE: The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. METHODS:All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittentcefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L-1) throughout the dosing interval. RESULTS: We included 49 children with a median (range) postnatal age of 23.7 (0.2-229) months, and median body weight (range) of 10.9 (2.5-68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3-7.1) L·h-1, 3.2 (0.6-16.3) L·h-1, and 0.3 (0.2-0.41) L·kg-1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg-1·day-1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight. CONCLUSIONS: Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice. TRIAL REGISTRATION NUMBER: Registered at http://www.clinicaltrials.gov , NCT02539407.
RCT Entities:
BACKGROUND: During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. OBJECTIVE: The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. METHODS: All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L-1) throughout the dosing interval. RESULTS: We included 49 children with a median (range) postnatal age of 23.7 (0.2-229) months, and median body weight (range) of 10.9 (2.5-68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3-7.1) L·h-1, 3.2 (0.6-16.3) L·h-1, and 0.3 (0.2-0.41) L·kg-1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg-1·day-1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight. CONCLUSIONS: Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice. TRIAL REGISTRATION NUMBER: Registered at http://www.clinicaltrials.gov , NCT02539407.
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