A recent letter to the New England Journal of Medicine highlights a case where bedaquiline resistance developed in a patient with MDR-TB who failed initial treatment and eventually died.
Overall, eight Mycobacterium tuberculosis isolates were assessed by whole-genome sequencing and phenotypic bedaquiline resistance testing. All five isolates taken after bedaquiline was started (during month nine) were phenotypically resistant to bedaquiline, with the emergence of new mutations associated with resistance even after bedaquiline was ceased. This was in the presence of a potentially effective regimen and good adherence. This shows the particular risk of resistance amplification after cessation of treatment with a drug that has a long half-life (5.5 months for bedaquiline).
However, we do not know how frequently this might occur and although it raises a red flag, careful and considerate use of bedaquiline in the presence of adequate companion drugs is not discouraged. Bedaquiline is now recommended as first line treatment for all people with MDR-TB and has been shown to reduce mortality vs standardised regimens. One clinical question this letter raises is the management of MDR-TB failures and duration of treatment for bedaquiline.
Previous cases of bedaquiline resistance have been reported in 2015 (Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis. N Engl J Med 2015; 373(20): 1986–1988. Doi 10.1056/NEJMc1505196) and 2017 (Rapid emergence of Mycobacterium tuberculosis bedaquiline resistance: lessons to avoid repeating past errors. Eur Respir J 2017;49:1601719; doi: 10.1183/13993003.01719-2016).
Bedaquiline resistance mutations have also been detected in patients not previously exposed to the drug: Martinez E, Hennessy D, Jelfs P, Crighton T, Chen SC, Sintchenko V. Mutations associated with in vitro resistance to bedaquiline in Mycobacterium tuberculosis isolates in Australia. Tuberculosis 2018; 111: 31-34
The 2019 WHO MDR-TB treatment guidelines1 recommend bedaquiline as part of an individualised longer regimen for all people with MDR-TB containing at least four effective agents. A cohort analysis from South Africa demonstrated that bedaquiline-containing regimens had a large reduction in mortality compared with standard regimens without bedaquiline2.
Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment. De Vos M, Ley SD, Cox H et al. N Engl J Med 2019; 380:2178-2180. doi: 10.1056/NEJMc1815121
References
2. Schnippel K, Ndjeka N, Maartens G et al. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. The Lancet Respiratory 2018; Jul 7:1–8.