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

Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00634-19. doi: 10.1128/AAC.00634-19. Print 2019 Sep.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / therapeutic use
  • Body Weight
  • Ceftriaxone / administration & dosage*
  • Ceftriaxone / pharmacokinetics*
  • Ceftriaxone / therapeutic use
  • Cohort Studies
  • Cross Infection / drug therapy
  • Drug Administration Schedule
  • Female
  • Glomerular Filtration Rate
  • Humans
  • Male
  • Meningitis, Bacterial / drug therapy*
  • Middle Aged
  • Monte Carlo Method
  • Nomograms*
  • Prospective Studies
  • Treatment Outcome


  • Anti-Bacterial Agents
  • Ceftriaxone

Associated data

  • ClinicalTrials.gov/NCT01745679