Inhaled clofazimine adminsitration increases antimycobacterial effect compared to oral administration in a hollow-fibre system

To compare the antimycobacterial effect of inhaled versus oral clofazimine administration with an azithromycin-ethambutol backbone. Mycobacterium avium complex causes non-tuberculous pulmonary disease. Clofazimine can replace rifampicine in combination with an azithromycin-ethambutol backbone. Inhalation of clofazimine instead of oral administration can increase the antibiotic concentration at the site of infection while minimising systemic exposure and thus drug-induced toxicity. Pharmacokinetic exposures of azithromycin, ethambutol and either inhaled or oral clofazimine administration were simulated in an in vitro hollow-fibre system. Intracellular and extracellular samples of Mycobacterium avium ATCC 700898 were collected and bacterial densities were enumerated at day 0, 3, 7, 14 and 21. The development of macrolide resistance was assessed on the above-mentioned days by inoculation of agar plates containing azithromycin (8-fold minimum inhibitory concentration). Pharmacokinetic exposures were confirmed on day 0 and 21. Inhalation administration of clofazimine statistically increased the antimycobacterial effect of the treatment for both intracellular and extracellular fractions. The inhaled treatment showed an intracellular kill rate of 1.37 (95%C.I. 1.36–1.39), while the oral formulation showed a kill rate of 1.33 (95%C.I. 1.30-1.35). For the extracellular fraction, inhaled administration showed a kill rate of 1.24 (95%C.I. 1.22–1.26) and the oral formulation a kill rate of 1.19 (95%C.I. 1.18–1.20). The inhaled clofazimine formulation reduced the development of macrolide resistance and increased the offset. Inhalation of clofazimine with an azithromycin-ethambutol backbone increases treatment efficacy and decreases the development of macrolide resistance compared to oral administration in a hollow-fibre system.