P2119 Clofazimine can replace ethambutol but not rifabutin in regimens against intracellular Mycobacterium avium in a hollow fibre model Mike Marvin Ruth*1, Tawanda Gumbo2, Sanne Zweijpfenning3, Paula Bendet2, Wouter Hoefsloot3, Pooi Lee2, Saskia Kuipers1, Heiman Wertheim1, Jakko Van Ingen1, Devyani Deshpande2

1 Medical Microbiology, Radboudumc, Nijmegen, Netherlands, 2 Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States, 3 Department of Pulmonary Disease, Radboudumc, Nijmegen, Netherlands Background Mycobacterium avium complex (MAC) bacteria cause severe opportunistic pulmonary diseases. The recommended treatment regimen is a combination of a rifamycin, ethambutol and a macrolide, of which only the macrolide shows in vitro activity. The rifamycin and ethambutol prevent macrolide resistance formation in MAC, in vitro and in vivo. Clofazimine might replace either the rifamycin or ethambutol, preventing macrolide resistance while adding bactericidal activity to the regimen. Here, we investigated replacement of either ethambutol or rifabutin by clofazimine using the intracellular MAC hollow-fiber. Materials/methods THP-1 cells were infected with MAC (MOI 1:1), washed and brought into a hollow fiber system (HFS-MAC). HFS- MAC was exposed once-daily to either a rifabutin-ethambutol-azithromycin (REM), a clofazimine-ethambutol- azithromycin (CEM), a rifabutin-clofazimine-azithromycin (RCM), or a rifabutin-ethambutol–clofazimine- azithromycin regimen(RECM). An untreated control was added. All drug exposures were based on published pharmacokinetics studies. At pre-determined time points, HFS-MAC was sampled for quantitative culture. Azithromycin and ethambutol resistance was monitored by inoculating agar plates supplemented with these drugs at 3 times the MIC. Results The rifabutin-free CEM regimen could not lower the bacterial burden below stasis. All other regimens achieved >3 log10 cfu/mL kill by day 28 (Figure). The recommended REM regimen had the lowest bacterial load at day 28 with 1.5 log10 cfu/mL. Adding clofazimine to the REM regimen (i.e. RECM) did not add activity. For azithromycin, we only observed low resistance occurrence, never observing more than 10% resistant population. All regimens were able to suppress macrolide resistance evenly. There was no correlation between duration of exposure, regimen and ethambutol resistance. Conclusions Clofazimine can’t replace rifabutin in an ethambutol-azithromycin-based regimen, as is evidenced by failure of lowering the bacterial burden below stasis. Clofazimine can replace ethambutol, without a loss in activity or prevention of macrolide resistance. Figure 1: Intracellular hollow-fiber system derived time-kill kinetics of HFS-MAC.

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