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The diarylquinoline TMC207 for multidrug-resistant tuberculosis.
N Engl J Med 2009; 360(23):2397-405NEJM

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.)

Authors+Show Affiliations

Centre for Clinical Tuberculosis Research, the Department of Science and Technology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, all in South Africa.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

19494215

Citation

Diacon, Andreas H., et al. "The Diarylquinoline TMC207 for Multidrug-resistant Tuberculosis." The New England Journal of Medicine, vol. 360, no. 23, 2009, pp. 2397-405.
Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009;360(23):2397-405.
Diacon, A. H., Pym, A., Grobusch, M., Patientia, R., Rustomjee, R., Page-Shipp, L., ... Mc Neeley, D. F. (2009). The diarylquinoline TMC207 for multidrug-resistant tuberculosis. The New England Journal of Medicine, 360(23), pp. 2397-405. doi:10.1056/NEJMoa0808427.
Diacon AH, et al. The Diarylquinoline TMC207 for Multidrug-resistant Tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405. PubMed PMID: 19494215.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The diarylquinoline TMC207 for multidrug-resistant tuberculosis. AU - Diacon,Andreas H, AU - Pym,Alexander, AU - Grobusch,Martin, AU - Patientia,Ramonde, AU - Rustomjee,Roxana, AU - Page-Shipp,Liesl, AU - Pistorius,Christoffel, AU - Krause,Rene, AU - Bogoshi,Mampedi, AU - Churchyard,Gavin, AU - Venter,Amour, AU - Allen,Jenny, AU - Palomino,Juan Carlos, AU - De Marez,Tine, AU - van Heeswijk,Rolf P G, AU - Lounis,Nacer, AU - Meyvisch,Paul, AU - Verbeeck,Johan, AU - Parys,Wim, AU - de Beule,Karel, AU - Andries,Koen, AU - Mc Neeley,David F, PY - 2009/6/5/entrez PY - 2009/6/6/pubmed PY - 2009/6/13/medline SP - 2397 EP - 405 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 360 IS - 23 N2 - 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.) SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/19494215/The_diarylquinoline_TMC207_for_multidrug_resistant_tuberculosis_ L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa0808427?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -