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Antimicrob. Agents Chemother. doi:10.1128/AAC.00898-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Synergistic activity of R207910 combined with pyrazinamide in murine tuberculosis

Laboratoire de Bactériologie, Faculté de Médecine Pitié-Salpêtrière, Université Pierre et Marie Curie Paris 6 and Centre National de Référence de la Résistance des Mycobactéries aux Antituberculeux, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France.; Antimicrobial Research, Tibotec Pharmaceuticals Ltd, Johnson and Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium

^* To whom correspondence should be addressed. Email: veziris{at}chups.jussieu.fr.

	Abstract

In previous studies, the diarylquinoline R207910 (TMC207) was demonstrated to have high bactericidal activity when combined with first or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activity of single, double and triple drug associations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.3 log10 CFU).

Two months of treatment with the combinations R207910+PZA, R207910+PZA+INH, R207910+PZA+RIF or R207910+PZA+MXF, resulted in culture negative lung homogenates in 70 to 100% of the mice, while mice treated with INH+RIF+PZA (the reference regimen) or RIF+MXF+PZA remained culture positive. Combinations including R207910 but not PZA (e.g. R207910+INH+RIF, R207910+MXF+RIF) were less active than R207910+PZA containing regimens INH+RIF+PZA.

These results reveal a synergistic interaction between R207910 and pyrazinamide. Triple combinations containing these 2 drugs and INH, RIF or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including relapses.

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