Cerebrospinal pharmacokinetic and pharmacodynamic analysis of efficacy of meropenem in paediatric patients with bacterial meningitis

Yuka Ohata, Yoshiko Tomita, Keisuke Sunakawa, George L. Drusano, Yusuke Tanigawara

Research output: Contribution to journalArticle

Abstract

Background: Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. Objectives: A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). Patients and methods: Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50%T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. Results: Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration–time curve and attainment of 50%T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50%T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3%T>MIC(CSF). Conclusions: A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.

Original languageEnglish (US)
Pages (from-to)292-300
Number of pages9
JournalInternational Journal of Antimicrobial Agents
Volume54
Issue number3
DOIs
StatePublished - Sep 1 2019

Fingerprint

meropenem
Bacterial Meningitides
Cerebrospinal Fluid
Pharmacokinetics
Pediatrics
Microbial Sensitivity Tests
Population
Central Nervous System Diseases
Streptococcus pneumoniae

Keywords

  • Bacterial meningitis
  • Cerebrospinal fluid
  • Meropenem
  • Paediatric patients
  • Time above MIC

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Cerebrospinal pharmacokinetic and pharmacodynamic analysis of efficacy of meropenem in paediatric patients with bacterial meningitis. / Ohata, Yuka; Tomita, Yoshiko; Sunakawa, Keisuke; Drusano, George L.; Tanigawara, Yusuke.

In: International Journal of Antimicrobial Agents, Vol. 54, No. 3, 01.09.2019, p. 292-300.

Research output: Contribution to journalArticle

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abstract = "Background: Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. Objectives: A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). Patients and methods: Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50{\%}T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. Results: Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration–time curve and attainment of 50{\%}T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50{\%}T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3{\%}T>MIC(CSF). Conclusions: A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.",
keywords = "Bacterial meningitis, Cerebrospinal fluid, Meropenem, Paediatric patients, Time above MIC",
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AU - Tomita, Yoshiko

AU - Sunakawa, Keisuke

AU - Drusano, George L.

AU - Tanigawara, Yusuke

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AB - Background: Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. Objectives: A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). Patients and methods: Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50%T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. Results: Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration–time curve and attainment of 50%T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50%T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3%T>MIC(CSF). Conclusions: A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.

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KW - Cerebrospinal fluid

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KW - Paediatric patients

KW - Time above MIC

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