Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis

Noton K. Dutta, Michael L. Pinn, Ming Zhao, Michelle A. Rudek, Petros C. Karakousis

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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

Original languageEnglish (US)
Pages (from-to)1327-1330
Number of pages4
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Chemotherapy
  • Guinea pigs
  • Isoniazid
  • Mycobacterium tuberculosis
  • Phenothiazine
  • Toxicity

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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