ArticleAntimicrobial agents and chemotherapy2016
Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
- Novel regimens for treatment ofbioRxiv : the preprint server for biology · 2026Article
- Rifamycin-, macrolide-, and ethambutol-free combinations to treatThe international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2026Article
- Pharmacodynamic evidence for tedizolid use inIJTLD open · 2026Article
- Tigecycline pharmacodynamics in the hollow fiber system ofbioRxiv : the preprint server for biology · 2025Article
- Targeting Autophagy as a Strategy for Developing New Host-Directed Therapeutics Against Nontuberculous Mycobacteria.Pathogens (Basel, Switzerland) · 2025Review
- Phenothiazines enhance antibacterial activity of macrophage by inducing ROS and autophagy.Frontiers in immunology · 2025Article
- Tigecycline pharmacodynamics in the hollow fiber system ofFrontiers in pharmacology · 2025Article
- Ertapenem's therapeutic potential for Mycobacterium avium lung disease in the hollow fibre model.International journal of antimicrobial agents · 2024Article
- Ceftriaxone Efficacy for Mycobacterium avium Complex Lung Disease in the Hollow Fiber and Translation to Sustained Sputum Culture Conversion in Patients.The Journal of infectious diseases · 2024Article
- Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning.Frontiers in pharmacology · 2024Review
- Potency of the novel PolC DNA polymerase inhibitor CRS0540 in a disseminated Listeria monocytogenes intracellular hollow-fibre model.The Journal of antimicrobial chemotherapy · 2022Article
- Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.The Journal of antimicrobial chemotherapy · 2022Article
- Autophagy as a Target for Drug Development Of Skin Infection Caused by Mycobacteria.Frontiers in immunology · 2021Review
- Comparison of Rifamycins for Efficacy AgainstFrontiers in pharmacology · 2021Article
- Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research.Pathogens (Basel, Switzerland) · 2020Review
- Thioridazine Is an Efflux Pump Inhibitor in Mycobacterium avium Complex but of Limited Clinical Relevance.Antimicrobial agents and chemotherapy · 2020Article
- Efflux Pump Inhibitors Against Nontuberculous Mycobacteria.International journal of molecular sciences · 2020Review
- Effect of efflux pump inhibitors on the susceptibility of Mycobacterium avium complex to clarithromycin.The Journal of antibiotics · 2020Article
- Looking beyond Typical Treatments for Atypical Mycobacteria.Antibiotics (Basel, Switzerland) · 2020Review
- The New Frontier of Host-Directed Therapies forFrontiers in immunology · 2020Review
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine thioridazine kills mycobacteria by inhibiting the electron transport chain. In several experiments with bacterial populations of up to 10(12) CFU/ml, we failed to isolate any bacteria resistant to 3 times the MIC of thioridazine, suggesting the absence of resistant mutants at bacterial burdens severalfold higher than those encountered in patients. In the hollow-fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 h and an intracellular half-life of 19.7 h. Thioridazine concentrations were >28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 ± 0.75 log10 CFU/ml on day 7 (r(2) = 0.96) and 7.19 ± 0.31 log10 CFU/ml on day 14 (r(2) = 0.99), the highest seen with any drug in the system. Dose fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by the peak concentation-to-MIC ratio, with a 50% effective concentration (EC50) of 2.78 ± 0.44 for microbial killing. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when the concentration of fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine.
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