title: Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis.
abstract: The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro activities against antibiotic-sensitive and -resistant Mycobacterium tuberculosis. These compounds have not been used as anti-M. tuberculosis agents because their in vitro activities take place at concentrations which are beyond those that are clinically achievable. In addition, chronic administration of CPZ produces frequent severe side effects. Because CPZ has been shown to enhance the killing of intracellular M. tuberculosis at concentrations in the medium that are clinically relevant, we have investigated whether TZ, a phenothiazine whose negative side effects are less frequent and serious than those associated with CPZ, kills M. tuberculosis organisms that have been phagocytosed by human macrophages, which have nominal killing activities against these bacteria. Both CPZ and TZ killed intracellular antibiotic-sensitive and -resistant M. tuberculosis organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant M. tuberculosis isolates. Nevertheless, we must await the outcomes of clinical trials to determine whether TZ itself may be safely and effectively used as an antituberculosis agent.
authors.affiliation: Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-008 Lisbon, Portugal.
authors.forename: Diane
authors.initials: D
authors.lastname: Ordway
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.forename: Clara
authors.initials: C
authors.lastname: Leandro
authors.forename: Rosário
authors.initials: R
authors.lastname: Bettencourt
authors.forename: Josefina
authors.initials: J
authors.lastname: Almeida
authors.forename: Marta
authors.initials: M
authors.lastname: Martins
authors.forename: Jette E
authors.initials: JE
authors.lastname: Kristiansen
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
mesh_terms: D017302:Annexins / Q000378:metabolism; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D003470:Culture Media; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D017302:Annexins; D014150:Antipsychotic Agents; D003470:Culture Media; D013881:Thioridazine