Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases

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 1012 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 (r2 = 0.96) and 7.19 ± 0.31 log10 CFU/ml on day 14 (r2 = 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.

Mycobacterial Response to Organic Solvents and Possible Implications on Cross-Resistance With Antimicrobial Agents

“…Thioridazine was also suggested for the treatment of Mycobacterium avium complex (MAC) infections. The number of chronic infections caused by MAC are surpassing tuberculosis in the United States ( Deshpande et al, 2016 ). The proton pump inhibitor omeprazole is effective in several eukaryotic and prokaryotic cells ( da Silva et al, 2011 ) and it also presents antibacterial effects against several bacterial strains including Helicobacter pylori ( Jonkers et al, 1996 ).…”

Efflux Pump Inhibitors against Nontuberculous Mycobacteria

“…A following study on M. avium and M. intracellulare clinical strains from AIDS patients showed that resistance to clarithromycin was significantly reduced in the presence of TZ, CPZ, and VP, and the same EPIs were effective in decreasing the efflux of EtBr from mycobacterial cells; moreover, increased retention of [ 14 C]-erythromycin in the presence of these EPIs further demonstrated that active efflux contributes to MAC resistance to macrolides [42]. A further study evaluated TZ as chemotherapy for MAC diseases by investigating its pharmacokinetics/pharmacodynamics against a reference strain of M. avium [59].…”

Clofazimine for the Treatment of Mycobacterium kansasii

“…Clofazimine dose-response in the HFS-Mkn. The hollow-fiber system model has been used to establish the PK/PD relationships of drugs used to treat M. tuberculosis, MAC, and M. abscessus infections, as well as for M. kansasii (13,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). In the HFS-Mkn dose-response studies, the human monocytederived THP-1 monocytes were infected with M. kansasii to get a multiplicity of infection of 10 bacteria per THP-1 cell (10:1).…”