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Rifampicin substituted by clofazimine in the recommended therapy of Mycobacterium avium pulmonary disease: a hollow-fibre model study

S Salillas(1) J Raaijmakers(2) J van Ingen(2)

1:Universidad de Zaragoza; 2:Radboud University Medical Center

The treatment of M. avium pulmonary disease consists of a long-term multidrug regimen (macrolide, ethambutol and rifampicin) that shows limited efficacy. Here, we assess the efficacy of clofazimine as a rifampicin substitute within the recommended treatment of M. avium pulmonary disease in an intracellular hollow-fibre infection model (HFIM). THP-1 cells were infected with M. avium ATCC 700898 and exposed to either a regimen of azithromycin, ethambutol rifampicin or azithromycin, ethambutol clofazimine for 21 days. Lung pharmacokinetic profiles (Cmax, Tmax, T1/2) of azithromycin, ethambutol and rifampicin were simulated. For clofazimine, a Cavg was targeted. PK profiles were generated on the first day on day 16. Bacterial densities (azithromycin sensitive and resistant fraction) were determined at days 0, 3, 7, 14, and 21. On day 0 the Cmax of azithromycin, ethambutol and rifampicin were lower than targeted whereas the clofazimine Cmax was higher than targeted. Not all results are obtained up to day 21 yet. Until day 14 both rifampicin- and clofazimine-containing arms were able to maintain stasis. In the first week, rifampicin systems developed azithromycin resistance on day 3, whereas clofazimine ones did not show emergence of resistance. The substitution of rifampicin by clofazimine showed similar efficacy in terms of bacterial densities in the HFIM until day 14, although in the clofazimine arm there was no resistance observed at least until day 7. Therefore, substituting rifampicin with clofazimine might be a good alternative for the treatment of M. avium pulmonary disease.

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