Bedaquiline does not enhance clofazimine treatment efficacy with an azithromycin-ethambutol backbone against Mycobacterium avium in a hollow fibre system

To evaluate the additional pharmacodynamic effect of bedaquiline in a regimen of azithromycin, ethambutol and clofazimine. Mycobacterium avium complex bacteria are the most frequent causative agents of nontuberculous mycobacterial pulmonary disease worldwide. Treatment based on azithromycin, ethambutol and clofazimine has been proposed to overcome the limited efficacy of currently recommended therapy. Novel combinatorial therapies can improve therapeutic outcomes, such as utilising the synergy between clofazimine and bedaquiline. In an in vitro hollow fibre experiment, epithelial lining fluid pharmacokinetic profiles of a regimen consisting of azithromycin, ethambutol and clofazimine with or without bedaquiline were simulated. Pharmacokinetics were confirmed on day 0 and 21. Intracellular M. avium ATCC 700898 was treated for 21 days. Samples were taken on days 0, 3, 7, 14 and 21 to determine cellular densities. Bacterial samples (intracellular and extracellular fractions) were inoculated onto drug-free 7H10 agar plates and plates containing azithromycin (8xMIC). Both therapies were able to maintain 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%C.I. 0.63–0.67) and for the 4-drug regimen 0.65 (95%C.I. 0.64–0.67). The intracellular kill rate for the 3-drug regimen was 0.48 (95%C.I. 0.46–0.50) and for the 4-drug regimen 0.48 (95%C.I. 0.46-0.50). Macrolide-resistant subpopulations were observed with both treatment regimens. Bedaquiline did not add to the pharmacodynamic effect to the 3-drug regimen and was unable to suppress the emergence of macrolide resistance.