The Kinetics of Bedaquiline Diffusion in Tuberculous Cavities Open a Window for the Emergence of Resistance

Cavitary tuberculosis is difficult to cure and constitutes a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug-resistant tuberculosis, but emergence of resistance threatens the sustainability of its success. We designed site-of-disease pharmacokinetic studies to spatially resolve the penetration of bedaquiline, and 2 next-generation diarylquinolines, TBAJ876 and TBAJ587, in cavities.

Rabbits with established cavitary tuberculosis received the study drugs. A laser-capture microdissections scheme was developed to measure drug concentrations as a function of distance from blood supply in caseum. To simulate drug coverage in patient cavities, the data were modeled, and parameter estimates were linked to clinical plasma pharmacokinetic models.

Pharmacokinetic-pharmacodynamic simulations in caseum revealed that bedaquiline reaches steady state and efficacious concentrations in deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ876 and TBAJ587, achieve bactericidal concentrations in caseum layers more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline.

The slow kinetics of diffusion of bedaquiline into and out of caseum creates spatiotemporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ587 and TBAJ876 predict reduced opportunities for resistance development.