Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis

Abstract

The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human-equivalent dose of thioridazine was determined to be 25 mg/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug-resistant M. tuberculosis.

FIG 1

Serum and lung homogenate concentration profile following repeated dosing of 25 mg/kg thioridazine in mice (3 to 4 per time point). The data are medians ± standard deviations. Statistically significant differences were noted between serum and lung concentrations (*, P < 0.01; **, P < 0.001; ***, P < 0.0001). BLQ, below the limit of quantitation.

FIG 2

Antitubercular activity of thioridazine in infected mice. Animals were infected via aerosol with ∼10² (A and B) and ∼10⁴ (C) CFU of M. tuberculosis H37Rv and were either left untreated or treated with drugs daily (5 days/week, once daily) beginning 4 or 2 weeks after infection, respectively. R, rifampin at 10 mg/kg; H, isoniazid at 10 mg/kg; T, thioridazine; HED, human-equivalent dose (25 mg/kg). **, P < 0.001 between untreated and INH groups; *, P < 0.05 between INH and INH+TRZ groups.