Abstract
BackgroundAvailability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.Methods and FindingsUsing a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.ConclusionsRifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.
Highlights
The development of simplified treatment regimens is a major priority of the Global Plan to Stop TB [1]
Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less
High-Dose Aerosol Infection with M. tuberculosis In the first chemotherapeutic study, mice were aerosol infected with M. tuberculosis H37Rv in four separate runs
Summary
The development of simplified treatment regimens is a major priority of the Global Plan to Stop TB [1]. TMC-207 has been highly regarded as a candidate for shortening therapy [4], but is currently being developed as a drug for multidrug-resistant TB rather than for drugsusceptible disease, at least in part due to a drug–drug interaction with rifampin. The bacteria remain dormant within the body and can cause disease years later if host immunity declines. Combinations of drugs are needed to prevent the bacteria from developing resistance to the treatment, and because of the complex biology of M. tuberculosis. Effective treatments contain a ‘‘bactericidal’’ drug such as isoniazid to kill the actively multiplying bacteria, a drug to kill the less actively multiplying bugs (for example, pyrazinamide), and a sterilizing drug (the most potent of which is rifampin) to kill the near-dormant bacteria and prevent the disease from recurring
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