Bedaquiline, Delamanid, Linezolid, and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis
Authors: Padmapriyadarsini Chandrasekaran , Vohra Vikram , Bhatnagar Anuj , Solanki Rajesh , Sridhar Rathinam , Anande Lalitkumar , Muthuvijaylakshmi M , Rana Meera Bhatia , Jeyadeepa Bharathi , Taneja Gaurav , Balaji S , Shah Prashant , Saravanan N , Chavan Vijay , Kumar Hemanth , Ponnuraja Chinnayin , Livchits Viktoriya , Bahl Monica , Alavadi Umesh , Sachdeva K S , Swaminathan Soumya ,   for the BEAT India Team, Padmapriyadarsini C , Jeyadeepa B , Lakshana  , Akbar Nabila , Arulraj Edwin , Karthikeyan  , Muthukumar  , Tamizharasan  , Balaji S , Shivakumar S , Muthuvijayalakshmi M , Gayathri  , Ponnuraja C , Kumar Hemanth , Saravanan N , Sridhar R , Kumar R , Ramesh  , Vohra Vikram , Rana Meera Bhatia , Singla Neeta , Myneedu V P , Lawrence Ananiya , Kushwaha Dipti , Shivam Deepak Kheraliya , Sarin Rohit , Bhatnagar Anuj K , Taneja Gaurav , Rawat Alok , Haniff M , Rahul  , Rai Padma , Saini Savita , Mathur Krishan Kumar , Solanki Rajesh N , Patel Pranav G , Prajapati Vaidehi , Parmar Bhavesh , Wadkar Kajal , Shah Prashant L , Parmar Snehal , Vyas Palak , Mistri Krupa , Anade Lalitkumar , Chavan Vijay , Bhui Namrata Kaur , Tipre Pranita , Shah Daksha , Patwa Surendra K , Nhavakar Anis , Brito Audrey , Keny Kiran , Karanjkar Vijaykumar , Pal Kuntal , Godam Komal , Huje Madri , Ghadge Sanjana , Udmalle Madhuri , Posture Vivek Vijay , Bansode Jaipal , Bhal Monica , Ranjan  , Pillai Divya , Semwal Supriya , Livchits Shirali Labroo Viktoriya , Alavadi Umesh , Swamikan Reuben , Nasubo Dorothy Nanzala , Parmar Mallik , Sahu Suvanad , Mukadi YaDiul , Swaminathan Soumya 
Published: June 2022

Abstract

Background
Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with bedaquiline and delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+).

Methods
We prospectively determined the effectiveness and safety of combining 2 new drugs with 2 repurposed drugs—bedaquiline, delamanid, linezolid, and clofazimine—for 24–36 weeks in adults with pulmonary MDR-TBFQ+ and/or MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as 2 consecutive negative cultures taken 4 weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during the treatment period.

Results
Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: 4 deaths, 7 treatment changes, 2 bacteriological failures, and 1 withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation &gt;500 ms. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority.

Conclusions
After 24–36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

Clinical Trials Registration
ClinicalTrials Registry of India (CTRI/2019/01/017310).