Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis

Abstract

The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts. Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ∼100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid. The human-equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ∼6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg. Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined.