Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial
Authors: Padmapriyadarsini Chandrasekaran , Oswal Vikas S , Jain Chetankumar D , Mariappan Muthu Vijayalakshmi , Singla Neeta , Kumar Santosh , Daniel Bella Devaleenal , Dave Jigna D , Vadgama Parul , Ramraj Balaji , Kant Surya , Bhatnagar Anuj K , Shanmugam Sivakumar , Paul Dhamodharan , Bharathi Jeyadeepa , Palav Manasi , Shah Neha V , Santhanakrishnan Rameshkumar , Dewan Ravindra K , Shekh Nadim , Rathinam Prabhakaran , Sisara Arvind B , Mankar Shubhangi Dhakulkar , Bajpai Jyoti , Mittal Upasana , Chauhan Sandeep , Kumar Ravinder , Parmar Mallik , Mattoo Sanjay K , Jaju Jyoti ,   modified BPaL (mBPaL) Study Team, 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 
Published: August 2024

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 &lt;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)