BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
BACKGROUND:Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
Authors: Andreas H Diacon; Rodney Dawson; Florian von Groote-Bidlingmaier; Gregory Symons; Amour Venter; Peter R Donald; Christo van Niekerk; Daniel Everitt; Helen Winter; Piet Becker; Carl M Mendel; Melvin K Spigelman Journal: Lancet Date: 2012-07-23 Impact factor: 79.321
Authors: N R Gandhi; J R Andrews; J C M Brust; R Montreuil; D Weissman; M Heo; A P Moll; G H Friedland; N S Shah Journal: Int J Tuberc Lung Dis Date: 2012-01 Impact factor: 2.373
Authors: Sandeep Tyagi; E Nuermberger; T Yoshimatsu; K Williams; I Rosenthal; N Lounis; W Bishai; J Grosset Journal: Antimicrob Agents Chemother Date: 2005-06 Impact factor: 5.191
Authors: Andrew J Nunn; Patrick P J Phillips; Sarah K Meredith; Chen-Yuan Chiang; Francesca Conradie; Doljinsuren Dalai; Armand van Deun; Phan-Thuong Dat; Ngoc Lan; Iqbal Master; Tesfamarium Mebrahtu; Daniel Meressa; Ronelle Moodliar; Nosipho Ngubane; Karen Sanders; Stephen Bertel Squire; Gabriela Torrea; Bazarragchaa Tsogt; I D Rusen Journal: N Engl J Med Date: 2019-03-13 Impact factor: 91.245
Authors: Amina Jindani; Thomas S Harrison; Andrew J Nunn; Patrick P J Phillips; Gavin J Churchyard; Salome Charalambous; Mark Hatherill; Hennie Geldenhuys; Helen M McIlleron; Simbarashe P Zvada; Stanley Mungofa; Nasir A Shah; Simukai Zizhou; Lloyd Magweta; James Shepherd; Sambayawo Nyirenda; Janneke H van Dijk; Heather E Clouting; David Coleman; Anna L E Bateson; Timothy D McHugh; Philip D Butcher; Denny A Mitchison Journal: N Engl J Med Date: 2014-10-23 Impact factor: 91.245
Authors: Andreas H Diacon; Veronique R De Jager; Rodney Dawson; Kim Narunsky; Naadira Vanker; Divan A Burger; Daniel Everitt; Frances Pappas; Jerry Nedelman; Carl M Mendel Journal: Antimicrob Agents Chemother Date: 2020-06-23 Impact factor: 5.191
Authors: Kristina M Bigelow; Rokeya Tasneen; Yong S Chang; Kelly E Dooley; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2020-09-21 Impact factor: 5.191
Authors: Wael A Alghamdi; Mohammad H Al-Shaer; Guohua An; Abdullah Alsultan; Maia Kipiani; Ketevan Barbakadze; Lali Mikiashvili; David Ashkin; David E Griffith; J Peter Cegielski; Russell R Kempker; Charles A Peloquin Journal: Antimicrob Agents Chemother Date: 2020-09-21 Impact factor: 5.191