Clofazimine as a substitute for rifampicin improves efficacy of Mycobacterium avium pulmonary disease treatment in the hollow-fiber model

Abstract

Mycobacterium avium complex pulmonary disease is treated with an azithromycin, ethambutol, and rifampicin regimen, with limited efficacy. The role of rifampicin is controversial due to inactivity, adverse effects, and drug interactions. Here, we evaluated the efficacy of clofazimine as a substitute for rifampicin in an intracellular hollow-fiber infection model. THP-1 cells, which are monocytes isolated from peripheral blood from an acute monocytic leukemia patient, were infected with M. avium ATCC 700898 and exposed to a regimen of azithromycin and ethambutol with either rifampicin or clofazimine. Intrapulmonary pharmacokinetic profiles of azithromycin, ethambutol, and rifampicin were simulated. For clofazimine, a steady-state average concentration was targeted. Drug concentrations and bacterial densities were monitored over 21 days. Exposures to azithromycin and ethambutol were 20%-40% lower than targeted but within clinically observed ranges. Clofazimine exposures were 1.7 times higher than targeted. Until day 7, both regimens were able to maintain stasis. Thereafter, regrowth was observed for the rifampicin-containing regimen, while the clofazimine-containing regimen yielded a 2 Log₁₀ colony forming unit (CFU) per mL decrease in bacterial load. The clofazimine regimen also successfully suppressed the emergence of macrolide tolerance. In summary, substitution of rifampicin with clofazimine in the hollow-fiber model improved the antimycobacterial activity of the regimen. Clofazimine-containing regimens merit investigation in clinical trials.

Keywords: PK/PD; clofazimine; hollow-fiber infection model; nontuberculous mycobacteria; pharmacodynamics; pharmacokinetics.

Fig 1

Hollow-fiber pharmacodynamic effects (solid lines) and emergence of macrolide tolerance (dashed lines) of the growth control, rifampicin therapy, and clofazimine therapy in the hollow-fiber experiment. I, intracellular fraction; E, extracellular fraction. Detection limit and stasis correspond to 1.5 Log₁₀ CFU/mL and 5.7 Log₁₀ CFU/mL, respectively.

Fig 2

Steady-state pharmacokinetic graph of the rifampicin-containing therapy (A) and the clofazimine-containing therapy (B) on day 16. Dots represent mean drug concentrations values, which are connected by lines, whereas bars correspond to standard deviations.