Published ahead of print on October 23, 2008, doi:10.1164/rccm.200711-1736OC
© 2009 American Thoracic Society doi: 10.1164/rccm.200711-1736OC
A Once-Weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis1 Laboratoire de Bactériologie-Hygiène, Université Pierre et Marie Curie, Université Paris 6, Paris; 2 Laboratoire de Bactériologie-Hygiène, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris; 3 Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Paris, France; and 4 Department of Antimicrobial Research, Tibotec BVBA, Johnson & Johnson, Beerse, Belgium Correspondence and requests for reprints should be addressed to Nicolas Veziris, M.D., Laboratoire de Bactériologie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75634 Paris Cedex 13, France. E-mail: nveziris{at}gmail.com 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 weeks of monotherapy 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.
Key Words: tuberculosis • animal models • directly observed therapy • R207910 • diarylquinolines
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