# Enhanced antimycobacterial efficacy of simulated inhaled clofazimine versus oral clofazimine in combination with azithromycin and ethambutol in a hollow-fiber system

## TL;DR

Inhaling clofazimine instead of taking it orally improves its effectiveness against Mycobacterium avium and reduces antibiotic resistance.

## Contribution

Demonstrates that inhaled clofazimine enhances antimycobacterial efficacy and delays resistance compared to oral administration.

## Key findings

- Inhaled clofazimine showed higher kill rates for both intracellular and extracellular M. avium bacteria compared to oral administration.
- Inhalation reduced and delayed the emergence of macrolide resistance in the treatment regimen.
- Pharmacokinetic simulations confirmed the effectiveness of inhaled clofazimine in a hollow-fiber system.

## Abstract

Treatment outcomes in Mycobacterium avium complex pulmonary disease may be improved by adding clofazimine, instead of rifampicin, to the azithromycin-ethambutol backbone. Inhalation of clofazimine instead of oral administration has been suggested to increase the antibiotic concentration at the site of infection and to improve its efficacy, while minimizing systemic exposure and adverse effects. We evaluated the efficacy of inhaled clofazimine compared to oral clofazimine with an azithromycin-ethambutol backbone against M. avium.

We simulated pharmacokinetic exposures to azithromycin, ethambutol and either inhalational or oral clofazimine administration in an in vitro hollow-fiber system during 3 weeks. Intracellular and extracellular Mycobacterium avium ATCC 700898 bacteria were exposed to these antibiotic regimens and bacterial densities were enumerated at day 0, 3, 7, 14 and 21. The development of macrolide resistance was assessed by inoculation of agar plates containing azithromycin. Pharmacokinetic exposures were confirmed on day 0 and 21.

Inhalational administration of clofazimine significantly increased the antimycobacterial effect of the regimen against both intracellular and extracellular bacteria. The inhaled treatment showed an intracellular kill rate of 0.62 (95%C.I. 0.61–0.64) per day, while the oral administration showed a kill rate of 0.55 (95%C.I. 0.54–0.56) per day. For the extracellular fraction, inhaled administration showed a kill rate of 0.56 (95%C.I. 0.55–0.58) per day and the oral administration a kill rate of 0.50 (95%C.I. 0.50–0.51) per day. Inhaled clofazimine exposures reduced and delayed the emergence of macrolide resistance.

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-fiber system. This calls for a clinical trial of inhaled clofazimine.