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Title
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Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis
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Author
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Abstract
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| To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone. |
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Language
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English
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Source (journal)
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Antimicrobial agents and chemotherapy. - Washington, D.C., 1972, currens
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Publication
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Washington, D.C.
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American Society for Microbiology
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2011
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ISSN
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0066-4804
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DOI
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10.1128/AAC.05293-11
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Volume/pages
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55
:12
(2011)
, p. 5485-5492
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ISI
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000296920600010
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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