Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model
Publication year
2013Source
American Journal of Respiratory and Critical Care Medicine, 187, 10, (2013), pp. 1127-1134ISSN
Publication type
Article / Letter to editor

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Organization
Clinical Pharmacy
Pulmonary Diseases
Medical Microbiology
Journal title
American Journal of Respiratory and Critical Care Medicine
Volume
vol. 187
Issue
iss. 10
Page start
p. 1127
Page end
p. 1134
Subject
N4i 3: Poverty-related infectious diseases; N4i 3: Poverty-related infectious diseases NCEBP 13: Infectious diseases and international health; N4i 3: Poverty-related infectious diseases NCMLS 1: Infection and autoimmunity; N4i 3: Poverty-related infectious diseases NCMLS 1: Infection and autoimmunityAbstract
Rationale: 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. Objectives: 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. Measurements and Main 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 Cmax of 16.2 and 157.3 mg/L, an AUC0-24h of 132 and 1,782 h.mg/L, and AUC0-24h/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.
This item appears in the following Collection(s)
- Academic publications [204860]
- Faculty of Medical Sciences [81031]
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