This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ordway, D.
Right arrow Articles by Amaral, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ordway, D.
Right arrow Articles by Amaral, L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, March 2003, p. 917-922, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.917-922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

Diane Ordway,1 Miguel Viveiros,1 Clara Leandro,1 Rosário Bettencourt,1 Josefina Almeida,1 Marta Martins,1 Jette E. Kristiansen,2 Joseph Molnar,3 and Leonard Amaral1*

Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-008 Lisbon, Portugal,1 Department of Clinical Microbiology, Sonderborg Sygehus, 6400 Sonderborg, Denmark,2 Institute of Medical Microbiology, Albert-Szent Gyorgyi School of Medicine, 6720 Szeged, Hungary3

Received 12 August 2002/ Returned for modification 29 October 2002/ Accepted 12 December 2002

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.

* Corresponding author. Mailing address: Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua Da Junqueira 96, 1349-008, Lisbon, Portugal. Phone: 351 21 365 2653. Fax: 351 21 363 2105. E-mail: lamaral{at}ihmt.unl.pt.

Antimicrobial Agents and Chemotherapy, March 2003, p. 917-922, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.917-922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • MISHRA, U.S., CHAKRABORTY, P., DASGUPTA, A., DASTIDAR, S.G., MARTINS, M., AMARAL, L. (2009). Potent Bactericidal Action of a Flavonoid Fraction Isolated from the Stem Bark of Butea frondosa. In Vivo 23: 29-32 [Abstract] [Full Text]  
  • Sohaskey, C. D. (2008). Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration. J. Bacteriol. 190: 2981-2986 [Abstract] [Full Text]  
  • Gumbo, T., Louie, A., Liu, W., Brown, D., Ambrose, P. G., Bhavnani, S. M., Drusano, G. L. (2007). Isoniazid Bactericidal Activity and Resistance Emergence: Integrating Pharmacodynamics and Pharmacogenomics To Predict Efficacy in Different Ethnic Populations. Antimicrob. Agents Chemother. 51: 2329-2336 [Abstract] [Full Text]  
  • Amaral, L., Martins, M., Viveiros, M. (2007). Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J Antimicrob Chemother 59: 1237-1246 [Abstract] [Full Text]  
  • Kristiansen, J. E., Hendricks, O., Delvin, T., Butterworth, T. S., Aagaard, L., Christensen, J. B., Flores, V. C., Keyzer, H. (2007). Reversal of resistance in microorganisms by help of non-antibiotics. J Antimicrob Chemother 59: 1271-1279 [Abstract] [Full Text]  
  • Yano, T., Li, L.-S., Weinstein, E., Teh, J.-S., Rubin, H. (2006). Steady-state Kinetics and Inhibitory Action of Antitubercular Phenothiazines on Mycobacterium tuberculosis Type-II NADH-Menaquinone Oxidoreductase (NDH-2). J. Biol. Chem. 281: 11456-11463 [Abstract] [Full Text]  
  • Park, J. S., Tamayo, M. H., Gonzalez-Juarrero, M., Orme, I. M., Ordway, D. J. (2006). Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. J. Leukoc. Biol. 79: 80-86 [Abstract] [Full Text]  
  • Xie, Z., Siddiqi, N., Rubin, E. J. (2005). Differential Antibiotic Susceptibilities of Starved Mycobacterium tuberculosis Isolates. Antimicrob. Agents Chemother. 49: 4778-4780 [Abstract] [Full Text]  
  • Di Perri, G., Bonora, S. (2004). Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?. J Antimicrob Chemother 54: 593-602 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»