Bedaquiline – Shot in the Arm for Shorter Drug-resistant Tuberculosis Regimens

Management of drug-resistant tuberculosis (DRTB) got revolutionized with the approval of bedaquiline in 2012. In 2019, the World Health Organization (WHO) published consolidated drug-resistant TB treatment guidelines that included key changes like adding BEDAQUILINE as a key drug in Group A. In 2020, WHO revised the consolidated guidelines, introducing short-course 9–12 months all oral Bdq containing regimens with specific inclusion and exclusion criteria.[1] All oral Bdq-based shorter regimens significantly improved sputum culture conversions and treatment success while reducing mortality and treatment failures.[2] Data from 12 studies involving 1902 DRTB patients across 11 countries indicate that shorter Bdq-based oral regimens yielded a high treatment success rate (TSR) of 83%. The pooled rates for treatment failure, mortality, and lost to follow-up are relatively low at 4%, 5%, and 4%, respectively. No significant differences between multidrug-resistant/rifampicin-resistant TB patients and preextensively drug-resistant TB patients, similarly between HIV positive and negative patients proves the effectiveness of Bdq-containing regimens as standard of care.[2] The higher rate of successful treatment and lower mortality rate observed with Bdq can be attributed to its unique mechanism of action, achieved by obstructing the ion binding sites in the C subunit of the Fo domain of adenosine triphosphate (ATP) Synthase, disrupting energy metabolism pathways.[3–5] With this mechanism, Bdq effectively combats all forms of Mycobacterium tuberculosis, including dormant, active, nonreplicating, replicating extracellular and intracellular mycobacteria.[6] Pretomanid, a novel oral bicyclic nitroimidazooxazole derivative, when combined with Bdq, is found to be associated with improved TSR and lower mortality in patients with DRTB.[7] Pretomanid exerts its effects through bactericidal and sterilising mechanisms.[8] Sorfequiline (TBAJ 876), a next-generation diaryl quinoline, has the potential to improve TB treatment in combination with Sorefequiline, Pretomanid and Linezolid (SPaL).[9] TB Alliance conducted the NC-009 trial (a pan phase 2 clinical trial) in 22 sites in South Africa, the Philippines, Georgia, the United Republic of Tanzania, and Uganda. Overall, Sorfequiline has greater activity than bedaquiline. The 100 mg SPaL regimen had greater activity than bedaquiline, indicating the potential to shorten treatment of active DSTB. Thus, newer derivatives of bedaquiline (Sorfequiline) and linezolid (Sutezolid) in combination with pretomanid are offering hope to reduce the duration of DSTB as well as DRTB regimens. Such shorter regimens will help in the elimination of TB by offering better TSR and minimal loss to follow-up.