Published ahead of print on October 23, 2008, doi:10.1164/rccm.200711-1736OC Am. J. Respir. Crit. Care Med., Volume 179, Number 1, January 2009, 75-79 A more recent version of this article appeared on January 1, 2009
Submitted on November 26, 2007 A Once-weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine TuberculosisNicolas Veziris1*,1 laboratoire de Bacteriologie-Hygiene, UPMC Universite Paris, Paris, France; laboratoire de Bacteriologie-Hygiene, AP-HP, Hopital Pitie-Salpetriere, Paris, France; Centre National de Reference des Mycobacteries et de la Resistance des Mycobacteries aux Antituberculeux, Paris, France, 2 Department of Antimicrobial Research, Tibotec BVBA, Johnson and Johnson, Beerse, Belgium * To whom correspondence should be addressed. E-mail: veziris{at}chups.jussieu.fr.
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. Methods: The activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, pyrazinamide) were studied in the established infection model of murine tuberculosis. Colony counts were determined in the lungs of the treated mice. 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 R207910+rifapentine+pyrazinamide given once-a-week during 2 months (i.e. a total of only 8 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, while all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910+rifapentine+pyrazinamide given once-weekly was more active than the current standard regimen rifampin+isoniazid+pyrazinamide given 5 times-a-week. Conclusions: The unprecedented activity of the triple combination R207910+rifapentine+pyrazinamide suggests that it may be feasible to develop a fully intermittent once-a-week regimen. Key words: tuberculosis • animal models • directly observed therapy • R207910 • diarylquinolines
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