Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial
Chandrasekaran Padmapriyadarsini, Vikas Oswal, Chetankumar D Jain, M. Mariappan, Neeta Singla, Santosh Kumar, Bella Devaleenal Daniel, Jigna Dave, Parul Vadgama, Balaji Ramraj, Surya Kant, Anuj Bhatnagar, Sivakumar Shanmugam, Dhamodharan Paul, Jeyadeepa Bharathi, Manasi Palav, Neha V Shah, Rameshkumar Santhanakrishnan, Ravindra Kumar Dewan, Nadim Shekh, Prabhakaran Rathinam, Arvind B Sisara, Shubhangi Dhakulkar Mankar, Jyoti Bajpai, Upasana Mittal, Sandeep Chauhan, Ravinder Kumar, Mallik Parmar, Sanjay K Mattoo, Jyoti Jaju, modified BPaL (mBPaL) Study Team, Chandrasekaran Padmapriyadarsini, Bella Devaleenal Daniel, Balaji Ramraj, Sivakumar Shanmugam, M. Mariappan, Jeyadeepa Bharathi, Shanmugapriya Kumaravadivelu, Ghazala M. H. Shamail, Shakila Shankar, Antonysamy Mary, Mangalambal Ganesan, Sreenisha Sreedhar, G Subhashini, A Shilna, Ravindra Kumar Dewan, Neeta Singla, Rupak Singla, Manpreet Bhalla, Saroj Meena, Mukesh Kumar Singh, Renu Kanwar, Gopal Singh Bisht, Parul Vadgama, Pranav Patel, Vani Jain, Grinish Tamaku Wala, Biswarup Biswajit Chatterjee, Dipti Rana, Gamit Aishwarya Dipakbhai, Chetan Kumar Jain, Rashi I. Mehta, Neha V Shah, Manasvi Nanavare, Tejasvi Parade, Amol Ghadage, Anuj Bhatnagar, Rishikesh Nath Mukherjee, Upasana Mittal, Shivani Rawat, Alok Rawat, Krishan Kumar, Surya Kant, Amita Jain, Jyoti Bajpai, Rohit Pandey, Sushma Yadav, Jigna Dave, Aravind Sisara, Amanankur, Mamta Padaya, Vikas Oswal, Shubhangi Dhakulkar Mankar, Manasi Palav, Vrushali Shete, Santosh Kambli, Santosh Kumar, Alok Awasthi, Nadim Shekh, Vijay Kumar, Praveen Kumar, Prabhakaran Rathinam, Dhamodharan Paul, Dhivya Baskaran, Ramesh Kumar, Sandeep Chauhan, Mallik Parmar, Jyoti Jaju, Umesh Alavadi, Ravinder Kumar
Abstract
BACKGROUND: Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. METHOD: Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. RESULTS: Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. CONCLUSIONS: In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry of India (CTRI/2021/03/032189).