The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis Export

@article{citeulike:4744646, 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 log10 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 .) 10.1056/NEJMoa0808427}, author = {Diacon, Andreas H. and Pym, Alexander and Grobusch, Martin and Patientia, Ramonde and Rustomjee, Roxana and Page-Shipp, Liesl and Pistorius, Christoffel and Krause, Rene and Bogoshi, Mampedi and Churchyard, Gavin and Venter, Amour and Allen, Jenny and Palomino, Juan C. and De Marez, Tine and van Heeswijk, Rolf P. and Lounis, Nacer and Meyvisch, Paul and Verbeeck, Johan and Parys, Wim and de Beule, Karel and Andries, Koen and Neeley, David F.}, citeulike-article-id = {4744646}, citeulike-linkout-0 = {http://dx.doi.org/10.1056/NEJMoa0808427}, citeulike-linkout-1 = {http://content.nejm.org/cgi/content/abstract/360/23/2397}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19494215}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19494215}, day = {4}, doi = {10.1056/NEJMoa0808427}, journal = {N Engl J Med}, keywords = {tb}, month = {June}, number = {23}, pages = {2397--2405}, posted-at = {2009-06-04 14:23:01}, priority = {2}, title = {The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis}, url = {http://dx.doi.org/10.1056/NEJMoa0808427}, volume = {360}, year = {2009} }

TY - JOUR ID - citeulike:4744646 L3 - citeulike-article-id:4744646 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 log10 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 .) 10.1056/NEJMoa0808427 IS - 23 JF - N Engl J Med EP - 2405 TI - The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis VL - 360 SP - 2397 KW - tb AU - Diacon, Andreas 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 AU - De Marez, Tine AU - van Heeswijk, Rolf AU - Lounis, Nacer AU - Meyvisch, Paul AU - Verbeeck, Johan AU - Parys, Wim AU - de Beule, Karel AU - Andries, Koen AU - Neeley, David PY - 2009/06/04/ UR - http://dx.doi.org/10.1056/NEJMoa0808427 ER -