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Sterilizing Activity of R207910 (TMC207)-containing Regimens in the Murine Model of Tuberculosis

¹ 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; ⁴ Department of Microbiology & Immunology, Faculty of Medicine, Abu Dies, Jerusalem; and ⁵ Department of Antimicrobial Research, Tibotec BVBA, Beerse, Belgium

Correspondence and requests for reprints should be addressed to Nicolas Veziris, M.D., Ph.D., Laboratoire de Bactériologie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'hôpital, 75634 Paris Cedex 13, France. E-mail: nicolas.veziris{at}upmc.fr

Rationale: The diarylquinoline R207910 (TMC207) has potent bactericidal activity in a murine model of tuberculosis (TB), but its sterilizing activity has not been determined.

Objectives: To evaluate the sterilizing activity of R207910-containing combinations in the murine model of TB.

Methods: Swiss mice were intravenously inoculated with 6 log₁₀ of Mycobacterium tuberculosis strain H37Rv, treated with R207910-containing regimens, and followed for 3 months to determine relapse rates (modified Cornell model).

Measurements and Main Results: Quantitative lung and spleen colony-forming unit counts and bacteriological relapse rates 3 months after the end of therapy were compared for the following regimens: 2, 3, or 4 months of R207910 (J) and pyrazinamide (Z) combined with rifampin (R) or isoniazid (H) or both and 3 or 4 months of a moxifloxacin (M)-containing regimen and 6 months of the standard WHO regimen RHZ. All J-treated mice were culture negative after 4 months of therapy. The relapse rate in the group treated with 4 months of JHRZ was similar to that of mice treated for 6 months with the RHZ regimen (6 vs. 17%; P = 0.54) and lower than that of RMZ (6 vs. 42%; P = 0,03), a moxifloxacin-containing regimen that was the most active in mice on once-daily basis.

Conclusions: Four months of treatment with some J-containing regimens was as effective as the 6-month standard regimen and more effective than 4 months of treatment with M-containing regimens. Supplementation of standard regimen (RHZ) with J or substitution of J for H may shorten the treatment duration needed to cure TB in patients.

Key Words: Mycobacterium tuberculosis • diarylquinoline • R207910 • TMC207 • experimental chemotherapy • sterilizing activity

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The efficacy of the current treatment of tuberculosis is limited by its complexity (four drugs) and its length (6 months). What This Study Adds to the Field TMC207-containing combinations can potentially shorten the duration of tuberculosis treatment from 6 to 4 months.