Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus

E Salvador; M Oualha; E Bille; A Beranger; F Moulin; S Benaboud; S Boujaafar; I Gana; S Urien; Y Zheng; J Toubiana; C Briand; O Bustarret; G Geslain; S Renolleau; J-M Treluyer; D Hirt

doi:10.1016/j.cmi.2020.04.022

Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus

Clin Microbiol Infect. 2021 Mar;27(3):413-419. doi: 10.1016/j.cmi.2020.04.022. Epub 2020 Apr 29.

Authors

E Salvador¹, M Oualha², E Bille³, A Beranger², F Moulin³, S Benaboud⁴, S Boujaafar⁴, I Gana⁴, S Urien⁵, Y Zheng⁴, J Toubiana⁶, C Briand⁷, O Bustarret⁸, G Geslain⁸, S Renolleau⁹, J-M Treluyer¹⁰, D Hirt⁴

Affiliations

¹ Department of Paediatric Intensive Care Unit, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France; Pharmacology and Drug Evaluation in Children and Pregnant Women EA7323, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France. Electronic address: elodie.salvador@aphp.fr.
² Department of Paediatric Intensive Care Unit, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France; Pharmacology and Drug Evaluation in Children and Pregnant Women EA7323, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France.
³ Microbiological Laboratory, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France.
⁴ Pharmacology and Drug Evaluation in Children and Pregnant Women EA7323, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France; Department of Clinical Pharmacology, Cochin Hospital, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France.
⁵ Pharmacology and Drug Evaluation in Children and Pregnant Women EA7323, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France.
⁶ Department of General Paediatrics and Paediatric Infectious Diseases, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France.
⁷ Department of Paediatric Immunohaematology, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France.
⁸ Department of Surgical Paediatric Intensive Care Unit, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France.
⁹ Department of Paediatric Intensive Care Unit, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France.
¹⁰ Department of Paediatric Intensive Care Unit, Necker Enfants Malades Hospital, Paris Descartes University, Sorbonne-Paris Cité, 149 Rue de Sèvres, 75015, Paris, France; Pharmacology and Drug Evaluation in Children and Pregnant Women EA7323, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France; Department of Clinical Pharmacology, Cochin Hospital, Paris Descartes University, 27 Rue Du Faubourg Saint Jacques, 75014, Paris, France.

PMID: 32360445
DOI: 10.1016/j.cmi.2020.04.022

Abstract

Objectives: Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens.

Methods: We included all children (age < 18 years, body weight (BW) > 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT _{> 4 ×}_MIC.

Results: Thirty-nine patients with a median (range) age of 7 (0.1-17) years and a BW of 21 (2.8-79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR >200 mL/min/1.73m² were the best schemes to reach the PK target of 100% fT_{> 4 ×}_MIC.

Conclusions: In critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT _{> 4 ×}_MIC in children with normal and augmented renal function.

Keywords: Augmented renal clearance; Cephalosporin; MSSA; Paediatric intensive care unit; Pharmacokinetics; β-lactam.

MeSH terms

Adolescent
Anti-Bacterial Agents / blood
Anti-Bacterial Agents / pharmacokinetics
Anti-Bacterial Agents / therapeutic use*
Cefazolin / blood
Cefazolin / pharmacokinetics*
Cefazolin / therapeutic use*
Child
Child, Preschool
Critical Illness
Dose-Response Relationship, Drug
Female
Humans
Infant
Male
Microbial Sensitivity Tests
Staphylococcal Infections / drug therapy*
Staphylococcal Infections / microbiology*
Staphylococcus aureus / drug effects*

Substances

Anti-Bacterial Agents
Cefazolin