Bedaquiline does not enhance a clofazimine-azithromycin-ethambutol regimen against Mycobacterium avium in the hollow-fiber system

Abstract

Bedaquiline has been proposed as a second-line drug to treat pulmonary disease caused by Mycobacterium avium complex. Based on in vitro synergy and interactions, a logical regimen would combine bedaquiline and clofazimine as additions to an ethambutol-azithromycin backbone. Here, we evaluate the added benefit of bedaquiline in a regimen of azithromycin, ethambutol, and clofazimine. THP-1 cells infected with M. avium ATCC 700898 were seeded in a hollow-fiber model and exposed to a regimen of azithromycin, ethambutol, and clofazimine with or without bedaquiline for 3 weeks. Epithelial lining fluid pharmacokinetic profiles of azithromycin and ethambutol were simulated, while an average steady-state concentration was sought for clofazimine and bedaquiline. Pharmacokinetics and pharmacodynamics were monitored throughout the experiment. Both regimens led to sustained bacterial killing (both intracellular and extracellular) throughout the experiment. No difference in kill rate was observed between the two therapies. The extracellular kill rate for the 3-drug regimen was 0.65 (95% CI 0.63–0.67) and for the 4-drug regimen 0.65 (95% CI 0.64–0.67). The intracellular kill rate was 0.48 (95% CI 0.46–0.50) for the 3-drug regimen and 0.48 (95% CI 0.46–0.50) for the 4-drug regimen. Macrolide-tolerant subpopulations were observed with both treatment regimens at day 21. Bedaquiline does not add killing activity to a clofazimine-ethambutol-azithromycin regimen and did not improve suppression of the emergence of macrolide resistance, which makes its role as a second-line agent doubtful.