Synergistic Activity of R207910 Combined with Pyrazinamide against Murine Tuberculosis
- 1 March 2007
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 51 (3), 1011-1015
- https://doi.org/10.1128/aac.00898-06
Abstract
In previous studies, the diarylquinoline R207910 (also known as 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 activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log 10 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 and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two 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 periods of relapse.Keywords
This publication has 19 references indexed in Scilit:
- Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential To Shorten Treatment DurationAntimicrobial Agents and Chemotherapy, 2006
- Severe or Fatal Liver Injury in 50 Patients in the United States Taking Rifampin and Pyrazinamide for Latent Tuberculosis InfectionClinical Infectious Diseases, 2006
- National Survey to Measure Rates of Liver Injury, Hospitalization, and Death Associated with Rifampin and Pyrazinamide for Latent Tuberculosis InfectionClinical Infectious Diseases, 2005
- Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of TuberculosisAntimicrobial Agents and Chemotherapy, 2005
- New Small-Molecule Synthetic AntimycobacterialsAntimicrobial Agents and Chemotherapy, 2005
- A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosisScience, 2005
- Fluoroquinolone-Containing Third-Line Regimen against Mycobacterium tuberculosis In VivoAntimicrobial Agents and Chemotherapy, 2003
- Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acidJournal of Antimicrobial Chemotherapy, 2003
- Antagonism between isoniazid and the combination pyrazinamide-rifampin against tuberculosis infection in miceAntimicrobial Agents and Chemotherapy, 1992
- Activities of pefloxacin and ofloxacin against mycobacteria: in vitro and mouse experimentsTubercle, 1991