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

Abstract Background Meropenem is widely used in 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 in order to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial meningitis). Patients and methods Paediatric patients’ data from three clinical studies were used to build a novel population-PK model with a cerebrospinal flow (CSF) compartment, assuming a 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 MIC distributions and a newly developed population-PK model including CSF concentrations. The effects of dose increase and/or prolongation of infusion duration on target attainment were investigated. Results Clinical data from 154 patients aged 30.6 ± 34.4 months, with a body weight of 12.4 ± 7.6 kg (mean ± S.D.), 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 infusion duration 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 with whom satisfactory clinical cure was achieved showed at least 75.3%T >MIC (CSF). Conclusions A high dose of meropenem (40 mg/kg q8h) is necessary for achieving clinical efficacy in paediatric patients with bacterial meningitis.