Date Published: December 18, 2007
Publisher: Public Library of Science
Author(s): Ian M Rosenthal, Ming Zhang, Kathy N Williams, Charles A Peloquin, Sandeep Tyagi, Andrew A Vernon, William R Bishai, Richard E Chaisson, Jacques H Grosset, Eric L Nuermberger, Eric Rubin
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.
Partial Text: The development of simplified treatment regimens is a major priority of the Global Plan to Stop TB . Novel regimens that are substantially shorter than the current 6-mo regimen are expected to simplify tuberculosis (TB) treatment, facilitate global implementation of directly observed therapy, improve treatment completion rates, and limit the emergence of multidrug-resistant TB.
We set out to determine whether two currently registered drugs, rifapentine and moxifloxacin, could be used more effectively to improve the treatment of TB. Our results demonstrate that the combination of increasing rifamycin drug exposure by replacing rifampin with rifapentine and replacing isoniazid with moxifloxacin in the standard 6-mo daily treatment regimen may radically shorten the duration of therapy necessary to cure patients of TB. Treatment with P7.5MZ and P10MZ 5 d/wk (5/7) eliminated M. tuberculosis bacilli at a rate more than twice as fast as treatment with R10HZ (5/7). During the first month of treatment, the rates of kill were 1.17 and 1.31 log10 CFU/week for P7.5MZ and P10MZ (5/7), respectively, versus 0.54 log10 CFU/week for the standard control regimen (p < 0.01). All mice treated with PMZ (5/7) had negative lung cultures after 2 mo of treatment, while more than 4 mo was required to render all lung cultures negative in mice treated with RHZ (5/7). Finally, the proportion of mice relapsing after treatment with PMZ (5/7) regimens was 19 out of 40 (47.5%) and one out of 40 (2.5%) after 2 and 3 mo of treatment, respectively, compared to 18 out of 20 (90%) and 0 out of 20 (0%) after RHZ (5/7) for 4 and 6 mo, respectively. Relapse was not assessed after 5 mo of treatment with RHZ (5/7) in this study, but comparisons with other recent experiments in our model on the bases of the 4- and 6-mo relapse rates suggest that the 5-mo relapse rate would have been between 17% and 60% [18,24]. Therefore, daily (5/7) treatment with the PMZ-based regimens may permit the treatment duration to be reduced by at least 50%, from 6 mo to 3 mo, without sacrificing efficacy. Source: http://doi.org/10.1371/journal.pmed.0040344