{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T09:50:13Z","timestamp":1775382613981,"version":"3.50.1"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T00:00:00Z","timestamp":1469145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI079497"],"award-info":[{"award-number":["R01AI079497"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["DP2 OD001886"],"award-info":[{"award-number":["DP2 OD001886"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium avium-intracellulare<\/jats:named-content>\n            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\n            <jats:sup>12<\/jats:sup>\n            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 &gt;28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 \u00b1 0.75 log\n            <jats:sub>10<\/jats:sub>\n            CFU\/ml on day 7 (\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            = 0.96) and 7.19 \u00b1 0.31 log\n            <jats:sub>10<\/jats:sub>\n            CFU\/ml on day 14 (\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            = 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 (EC\n            <jats:sub>50<\/jats:sub>\n            ) of 2.78 \u00b1 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 EC\n            <jats:sub>50<\/jats:sub>\n            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.\n          <\/jats:p>","DOI":"10.1128\/aac.02985-15","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T16:26:28Z","timestamp":1464107188000},"page":"4652-4658","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases"],"prefix":"10.1128","volume":"60","author":[{"given":"Devyani","family":"Deshpande","sequence":"first","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashikant","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandirai","family":"Musuka","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tawanda","family":"Gumbo","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA"},{"name":"Department of Medicine, University of Cape Town, Observatory, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200604-571ST"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.156.2.atsstatement"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2011.10.001"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/314865"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/170.3.573"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl500"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.3.800-804.2001"},{"key":"e_1_3_2_9_2","first-page":"733","article-title":"The in vitro activity of phenothiazines against Mycobacterium avium: potential of thioridazine for therapy of the co-infected AIDS patient","volume":"19","author":"Viveiros M","year":"2005","unstructured":"Viveiros M, Martins M, Couto I, Kristiansen JE, Molnar J, Amaral L. 2005. 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