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

Abstract

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. 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). 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. 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). A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.