Clofazimine for the treatment of Mycobacterium kansasii [PublishAheadOfPrint]

Mycobacterium kansasii pulmonary infection is global problem. Standard combination therapy consists of isoniazid 300 mg/day, rifampin 600 mg/day, and ethambutol 15 mg/kg/day for 18 months. Co-incubation of M. kansasii with different clofazimine concentrations over 7 days in test-tubes resulted in maximal kill (E_max) of 2.03 log₁₀ CFU/mL below day 0. The concentration associated with E_max was 110 times the minimum inhibitory concentration. Next, the effect of human-like concentration-time profiles of clofazimine human-equivalent doses ranging between 0 to 200 mg daily for 21 days were examined in the intracellular-infection hollow fiber model of M. kansasii (HFS-Mkn). On day 14, when clofazimine microbial effect was maximal, the E_max was 2.57 log₁₀ CFU/mL while dose associated with E_max was 100 mg/day. However, no dose killed M. kansasii to below day 0. Thus, the antimicrobial effect of clofazimine monotherapy in the HFS-Mkn was modest. Human equivalent concentration-time profiles of standard combination therapy and doses were used as comparator in the HFS-Mkn. On day 14, standard therapy had killed 2.32 log₁₀ CFU/mL below day 0. The effect of standard therapy was consistent with a bi-exponential decline with kill rate constants of 1.85 per day (half-life=0.37 days) and 0.06 per day (half-life=12.76 days), r²>0.99. This means that standard therapy would take 9.3-12 months to completely eliminate M. kansasii in the model, which is consistent with clinical observations. This observation for standard therapy means that the modest to poor effect of clofazimine on M. kansasii identified here is likely to be the same in the clinic.

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