Combination Therapy With Rifapentine May Shorten TB Treatment

Use of the antibiotic rifapentine was found to significantly shorten duration of treatment for tuberculosis (TB) in an animal study led by Eric L. Nuermberger, MD, assistant professor, Center for Tuberculosis Research at Johns Hopkins University School of Medicine, Baltimore. The study, published online December 17 in PLoS Medicine, was funded by the National Institute of Allergy and Infectious Diseases.

Nuermberger and colleagues used 7 different courses of treatment containing rifapentine, moxifloxacin, and pyrazinamide, as well as the standard daily, short-course, high-dose antibiotic regimen containing rifampin, isoniazid, and pyrazinamide, to treat mice with active TB. For each regimen, they measured bactericidal activity by counting how many bacterial colonies could be grown from the mice's lungs at specific intervals (2, 3, 4, and 6 months) during treatment and sterilizing activity by assessing the number of mice with any live bacteria in their lungs (a culture-positive relapse) after treatment completion.

Rifapentine, approved by the FDA in 1998, was developed as a once-weekly tablet. However, the drug "was never really considered effective in low doses when compared to the gold standard, daily, high-dose regimens with rifampin," explained Nuermberger. Rifampin received FDA approval in 1968.

The researchers found that after 2 months of treatment, cultures of lung specimens from mice receiving the rifapentine- and moxifloxacin-containing regimens were negative for Mycobacterium tuberculosis, a point not reached with the standard regimen until after 4 months of treatment. Three months of treatment with daily or thrice-weekly rifapentine and moxifloxacin-containing regimens prevented any culture-positive relapses, whereas the standard regimen had to be continued for 6 months to achieve cure.

Testing of additional drug combinations showed that rifapentine was the most important medication in the new regimen, and that by replacing rifampin with rifapentine and retaining isoniazid, the duration of therapy was shortened to 3 months. Throughout treatment, the blood concentration of rifapentine remained 3 times higher than that of rifampin.

The results of this study are so promising that 2 clinical trials to assess high-dose and daily combinations with rifapentine are set to begin in mid-2008. Richard E. Chaisson, MD, director, Center for Tuberculosis Research at Johns Hopkins University School of Medicine, will conduct one of the studies; researchers led by Susan Dorman, MD, assistant professor, Johns Hopkins University School of Medicine, and scientists from the CDC will study persons with TB in 40 cities in 6 countries.