Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children

Clin Pharmacol Ther. 2015 Dec;98(6):622-9. doi: 10.1002/cpt.202. Epub 2015 Oct 22.


Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adolescent
  • Adult
  • Age Factors
  • Antitubercular Agents / administration & dosage*
  • Antitubercular Agents / blood
  • Antitubercular Agents / cerebrospinal fluid
  • Antitubercular Agents / pharmacokinetics
  • Body Weight
  • Child
  • Child, Preschool
  • Clinical Trials, Phase II as Topic
  • Computer Simulation
  • Drug Dosage Calculations*
  • Humans
  • Infant
  • Levofloxacin / administration & dosage*
  • Levofloxacin / blood
  • Levofloxacin / cerebrospinal fluid
  • Levofloxacin / pharmacokinetics
  • Models, Biological*
  • Mycobacterium tuberculosis / drug effects*
  • Randomized Controlled Trials as Topic
  • Rifampin / administration & dosage*
  • Rifampin / blood
  • Rifampin / cerebrospinal fluid
  • Rifampin / pharmacokinetics
  • Tuberculosis, Meningeal / diagnosis
  • Tuberculosis, Meningeal / drug therapy*
  • Tuberculosis, Meningeal / microbiology


  • Antitubercular Agents
  • Levofloxacin
  • Rifampin