Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial
Author:
Padmapriyadarsini Chandrasekaran1ORCID, Oswal Vikas S2, Jain Chetankumar D3, Mariappan Muthu Vijayalakshmi1, Singla Neeta4, Kumar Santosh5, Daniel Bella Devaleenal1, Dave Jigna D6, Vadgama Parul7, Ramraj Balaji1, Kant Surya8, Bhatnagar Anuj K9, Shanmugam Sivakumar1, Paul Dhamodharan10, Bharathi Jeyadeepa1, Palav Manasi2, Shah Neha V3, Santhanakrishnan Rameshkumar1, Dewan Ravindra K4, Shekh Nadim5, Rathinam Prabhakaran10, Sisara Arvind B6, Mankar Shubhangi Dhakulkar2, Bajpai Jyoti8, Mittal Upasana9, Chauhan Sandeep11, Kumar Ravinder11, Parmar Mallik12, Mattoo Sanjay K11, Jaju Jyoti13, , Padmapriyadarsini C, Daniel Bella Devaleenal, Ramraj Balaji, Shanmugam Sivakumar, Mariappan Muthu Vijayalakshmi, Bharathi Jeyadeepa, Kumaravadivelu Shanmugapriya, Shamail Ghazala, Shankar Shakila, Mary A Stella, Ganesan Mangalambal, Sreedhar Sreenisha, Subhashini G, Shilna A, Dewan Ravindra K, Singla Neeta, Singla Rupak, Bhalla Manpreet, Meena Saroj, Singh Mukesh Kumar, Kanwar Renu, Bisht Gopal Singh, Vadgama Parul, Patel Pranav, Jain Vani, Wala Grinish Tamaku, Chatterjee Biswarup, Rana Dipti, Dipakbhai Gamit Aishwarya, Jain Chetan Kumar, Mehta Rashi, Shah Neha V, Nanavare Manasvi, Parade Tejasvi, Ghadage Amol, Bhatnagar Anuj K, Mukherjee Rishikesh Nath, Mittal Upasana, Rawat Shivani, Rawat Alok, Kumar Krishan, Kant Surya, Jain Amita, Bajpai Jyoti, Pandey Rohit Kumar, Yadav Sushma, Dave Jigna D, Sisara Aravind, Amanankur , Padaya Mamta, Oswal Vikas, Mankar Shubhangi Dhakulkar, Palav Manasi, Shete Vrushali, Kambli Santosh, Kumar Santosh, Awasthi A K, Shekh Nadim, Kumar Vijay, Kumar Praveen, Rathinam Prabhakaran, Paul Dhamodharan, Baskaran Dhivya, Kumar Ramesh, Chauhan Sandeep, Parmar Mallik, Jaju Jyoti, Alavadi Umesh, Kumar Ravinder, Mattoo Sanjay K
Affiliation:
1. Department of Clinical Research, ICMR–National Institute for Research in Tuberculosis , Chennai , India 2. DRTB Site, Pandit Malviya Shatabdi Centenary Hospital , Mumbai , India 3. DRTB DOTS Plus Site, Sarvodaya Charitable Trust Hospital , Mumbai , India 4. Department of Epidemiology and Public Health, National Institute for Tuberculosis and Respiratory Diseases , New Delhi , India 5. Department of Pulmonary Medicine, Sarojini Naidu Medical College , Agra , India 6. Department of Respiratory Medicine, Government Medical College , Bhavnagar , India 7. Department of Respiratory Medicine, Government Medical College , Surat , India 8. Department of Respiratory Medicine, King George's Medical University , Lucknow , India 9. Department of Chest and TB Rajan Babu Institute of Pulmonary Medicine and Tuberculosis , Delhi , India 10. Department of Respiratory Medicine, Government Rajaji Hospital , Madurai , India 11. National Tuberculosis Elimination Programme, Central TB Division , New Delhi , India 12. Drug-resistant TB, World Health Organization, India Office, New Delhi, India 13. iDFFEAT TB Project, International Union Against Tuberculosis and Lung Disease , New Delhi , India
Abstract
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)
Funder
United States Agency for International Development
Publisher
Oxford University Press (OUP)
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