Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model.
Am J Respir Crit Care Med
; 187(10): 1127-34, 2013 May 15.
Article
em En
| MEDLINE
| ID: mdl-23525933
ABSTRACT
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 MAINRESULTS:
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.
Texto completo:
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Base de dados:
MEDLINE
Métodos Terapêuticos e Terapias MTCI:
Plantas_medicinales
Assunto principal:
Rifampina
/
Tuberculose
/
Antibióticos Antituberculose
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Am J Respir Crit Care Med
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Holanda