title: Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model.
abstract: BACKGROUND
  The dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose.
  
  
  OBJECTIVE
  Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic parameters and pharmacokinetic/pharmacodynamic indices.
  
  
  METHODS
  A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. The maximum tolerated dosage, pharmacokinetic parameters, and pharmacokinetic/pharmacodynamic index were determined. Therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed.
  
  
  RESULTS
  Maximum tolerated dosage of rifampin in the murine TB was 160 mg/kg/d. Pharmacokinetic measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a C(max) of 16.2 and 157.3 mg/L, an AUC(0-24h) of 132 and 1,782 h·mg/L, and AUC(0-24h)/minimum inhibitory concentration ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-week single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection.
  
  
  CONCLUSIONS
  Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/d enabled a significant reduction in therapy duration without adverse effects.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. j.desteenwinkel@erasmusmc.nl
authors.forename: Jurriaan E M
authors.initials: JE
authors.lastname: de Steenwinkel
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Gerjo J
authors.initials: GJ
authors.lastname: de Knegt
authors.forename: Marian T
authors.initials: MT
authors.lastname: ten Kate
authors.forename: Marga
authors.initials: M
authors.lastname: Teulen
authors.forename: Henri A
authors.initials: HA
authors.lastname: Verbrugh
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin