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The diarylquinoline TMC207 for multidrug-resistant tuberculosis

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dc.contributor.author Diacon, A. H.
dc.contributor.author Pym, A.
dc.contributor.author Grobusch, M.
dc.contributor.author Patientia, R.
dc.contributor.author Rustomjee, R.
dc.contributor.author Page-Shipp, L.
dc.contributor.author Pistorius, C.
dc.contributor.author Krause, R.
dc.contributor.author Bogoshi, M.
dc.contributor.author Churchyard, G.
dc.contributor.author Venter, A.
dc.contributor.author Allen, J.
dc.contributor.author Palomino, J. C.
dc.contributor.author De Marez, T.
dc.contributor.author van Heeswijk, R. P. G.
dc.contributor.author Lounis, N.
dc.contributor.author Meyvisch, P.
dc.contributor.author Verbeeck, J.
dc.contributor.author Parys, W.
dc.contributor.author de Beule, K.
dc.contributor.author Andries, K.
dc.contributor.author McNeeley, D. F.
dc.date.accessioned 2009-07-07T09:52:10Z
dc.date.available 2009-07-07T09:52:10Z
dc.date.issued 2009
dc.identifier.issn 0028-4793
dc.identifier.doi http://dx.doi.org/10.1056/NEJMoa0808427
dc.identifier.other ITG-M13A
dc.identifier.other MICRO
dc.identifier.other U-MYCOB
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other UPD15
dc.identifier.other ABSTRACT
dc.identifier.other FTA
dc.identifier.uri http://hdl.handle.net/10390/2710
dc.description.abstract BACKGROUND: The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis. METHODS: In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative. RESULTS: The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04). CONCLUSIONS: The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.) en
dc.language English en
dc.subject Drug development en
dc.subject Bacterial diseases en
dc.subject Tuberculosis en
dc.subject Multidrug resistance en
dc.subject Second-line drugs en
dc.subject Diarylquinoline TMC207 en
dc.subject Efficacy en
dc.subject Clinical trials en
dc.title The diarylquinoline TMC207 for multidrug-resistant tuberculosis en
dc.type Article en
dc.citation.issue 23 en
dc.citation.jtitle New England Journal of Medicine en
dc.citation.volume 360 en
dc.citation.pages 2397-2405 en
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/19494215
dc.citation.jabbreviation N Engl J Med en


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