A Once-Weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis
Date
2008-11-23
Authors
Veziris, Nicolas
Ibrahim, Murad
Lounis, Nacer
Chauffour, Aurelie
Truffot-Pernot, Chantal
Andries, Koen
Jarlier, Vincent
Journal Title
Journal ISSN
Volume Title
Publisher
The American Thoracic Society
Abstract
Rationale: R207910 (TMC207 or J) is a member of the diarylquinolines,
a new family of antituberculous drugs with high bactericidal
activity when given daily in the murine model of tuberculosis.
R207910 exhibits a long half-life and thus is a good candidate for
once-weekly therapy of tuberculosis.
Objectives: To study the activity of once-weekly R207910 monotherapy
and combinations of R207910 with other antituberculous agents
(isoniazid, rifapentine, moxifloxacin, and pyrazinamide).
Methods: The established infection model of murine tuberculosis was
used. Colony counts were determined in the lungs.
Measurements and Main Results: Eight weeksofmonotherapy reduced
the bacillary load by 3 to 4 log10 for rifapentine and by 5 to 6 log10 for
R207910 (P , 0.05). The addition of rifapentine and isoniazid or
moxifloxacin did not improve the bactericidal activity of R207910
monotherapy. In contrast, the triple combination of R207910 plus
rifapentine plus pyrazinamide given once weekly for 2 months (i.e.,
a total of only eight administrations), was significantly (P , 0.05)
more active than R207910 monotherapy or other R207910 combinations,
and led to lung culture negativity in 9 of 10 mice, whereas all
lungs were culture positive in the groups treated with other drug
combinations. Moreover, R207910 plus rifapentine plus pyrazinamide
given once weekly was more active than the current standard
regimen of rifampin plus isoniazid plus pyrazinamide given five
times per week.
Conclusions: The unprecedented activity of the triple combination of
R207910 plus rifapentine plus pyrazinamide suggests that it may be
feasible to develop a fully intermittent once-weekly regimen.
Description
Keywords
tuberculosis , animal models , directly observed therapy , R207910 , diarylquinolines