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Title
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Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis
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Author
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Abstract
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| Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing 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, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further. |
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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.
:
American Society for Microbiology
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2012
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ISSN
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0066-4804
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DOI
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10.1128/AAC.00384-12
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Volume/pages
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56
:6
(2012)
, p. 3114-3120
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ISI
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000304432800045
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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