High-Dose Ceftriaxone for Bacterial Meningitis and Optimization of Administration Scheme Based on Nomogram

Abstract

High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not recommended. Ceftriaxone pharmacokinetics (PK) was investigated by a population approach in patients enrolled in a French multicenter prospective cohort study who received high-dose ceftriaxone for CNS infection as recommended by French guidelines (75 to 100 mg/kg of body weight/day without an upper limit). Only those with suspected bacterial meningitis were included in the PK analysis. A population model was developed using Pmetrics. Based on this model, a dosing nomogram was developed, using the estimated glomerular filtration rate (eGFR) and total body weight as covariates to determine the optimal dosage allowing achievement of targeted plasma trough concentrations. Efficacy and toxicity endpoints were based on previous reports, as follows: total plasma ceftriaxone concentrations of ≥20 mg/liter in >90% of patients for efficacy and ≤100 mg/liter in >90% of patients for toxicity. Based on 153 included patients, a two-compartment model including eGFR and total body weight as covariates was developed. The median value of the unbound fraction was 7.57%, and the median value of the cerebral spinal fluid (CSF)/plasma ratio was 14.39%. A nomogram was developed according to a twice-daily regimen. High-dose ceftriaxone administration schemes, used to treat meningitis, should be adapted to the eGFR and weight, especially to avoid underdosing using current guidelines. (This study has been registered at ClinicalTrials.gov under identifier NCT01745679.).

Keywords: antibiotics; modeling; nomogram; pharmacokinetics; simulation.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Graphical representations allowing the validation of the population pharmacokinetic model. (A and B) Observed concentrations plotted against population (A) or individual (B) predicted concentrations (milligrams per liter) (R2 = 0.684 and 0.947, respectively). (C) Weighted residuals plotted against individual predicted concentrations (milligrams per liter). (D) Weighted residuals plotted against time postadministration (hours).

FIG 2

Visual predictive checks of ceftriaxone concentrations against estimated glomerular filtration rate (eGFR) values by the CKD-EPI. Open circles represent all observed ceftriaxone concentrations included in modelization. Solid lines represent the 5th, 50th, and 95th percentiles for observed concentrations. Dashed lines represent the 5th, 50th, and 95th percentiles for simulated concentrations. Vertical lines at the top of the plots are bin separators.

FIG 3

Nomogram of the daily dose of ceftriaxone per kilogram of total weight to be administered to achieve a trough concentration target of 20 mg/liter (full line) and to not exceed 100 mg/liter (broken line) with a probability of 0.9, accounting for renal function estimated by the CKD-EPI formula (eGFR) using a twice-daily regimen. Dotted lines represent the 95% confidence interval.