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The TB laboratory of the future: macrophage-based selection of XDR-TB therapeutics

    Marta Martins

    Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal and, UPMM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal.

    ,
    Miguel Viveiros

    Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal.

    &
    Leonard Amaral

    † Author for correspondence

    Unit of Mycobacteriology, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal and UPMM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira, 96, 1349-008 Lisboa, Portugal.

    Published Online:https://doi.org/10.2217/17460913.3.2.135

    Therapy of multidrug-resistant (MDR)-TB is highly problematic; that of extensively drug-resistant (XDR)-TB even more so. Both infections result in high mortality, especially if the patient is coinfected with HIV or presents with AIDS. Selection of therapy for these infections is limited and, for most situations, it is performed ‘blind’. However, there is a solution for the selection of effective therapy and this is presented herein. Ideal therapy of the patient infected with MDR-TB or XDR-TB can be determined a priori by the mycobacteriology laboratory. This would involve the isolation of the patient’s macrophages, the phagocytosis of the mycobacterial isolate and the presentation of the antitubercular agent to the macrophage–bacterium complex. This system is reviewed in its entirety and its potential and feasibility are supported by hard experimental demonstrations.

    Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

    Bibliography

    • World Health Organization Report 2007 – Global tuberculosis control surveillance, planning, financing. World Health Organization. Geneva, Switzerland (2007).
    • Report of the meeting of the WHO Global Task Force on XDR-TB. World Health Organization. Geneva, Switzerland, 9–10 October (2006).
    • Centers for Disease Control and Prevention (CDC): Extensively drug-resistant tuberculosis-United States, 1993–2006. MMWR Morb. Mortal. Wkly Rep.56(11),250–253 (2007).
    • Shah NS, Wright A, Bai GH et al.: Worldwide emergence of extensively drug-resistant tuberculosis. Emerg. Infect. Dis.13(3),380–387 (2007).
    • Goldman RC, Plumley KV, Laughon BE: The evolution of extensively drug resistant tuberculosis (XDR-TB): history, status and issues for global control. Infect. Disord. Drug Targets7(2),73–91 (2007).
    • Spigelman MK: New tuberculosis therapeutics: a growing pipeline. J. Infect. Dis.196(Suppl. 1),S28–S34 (2007).
    • Amaral L, Viveiros M, Kristiansen JE: ‘Non-antibiotics’: alternative therapy for the management of MDRTB and MRSA in economically disadvantaged countries. Curr. Drug Targets7(7),887–891 (2006).
    • Amaral L, Martins M, Viveiros M: Phenothiazines as anti-multi-drug resistant tubercular agents. Infect. Disord. Drug Targets7(3),257–265 (2007).•• Provides cogent in vitro, ex vivo and in vivo evidence that supports the use of a variety of commonly available phenothiazines for the therapy of multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB.
    • Amaral L, Martins M, Viveiros M: Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J. Antimicrob. Chemother.59(6),1237–1246 (2007).•• Covers the specific characteristics of MDR-TB and identifies a variety of agents that have potential for managing MDR-TB.
    • 10  Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW: The emergence of drug-resistant tuberculosis in New York City. N. Engl. J. Med.328(8),521–526 (1993).
    • 11  Parsons LM, Somoskövi A, Urbanczik R, Salfinger M: Laboratory diagnostic aspects of drug resistant tuberculosis. Front. Biosci.9,2086–2105 (2004).
    • 12  Hale YM, Pfyffer GE, Salfinger M: Laboratory diagnosis of mycobacterial infections: new tools and lessons learned. Clin. Infect. Dis.33(6),834–846 (2001).
    • 13  Antunes ML, Aleixo-Dias J, Antunes AF, Pereira MF, Raymundo E, Rodrigues MF: Anti-tuberculosis drug resistance in Portugal. Int. J. Tuberc. Lung. Dis.4(3),223–231 (2000).
    • 14  Viveiros M, Leandro C, Rodrigues L et al.: Direct application of the INNO-LiPA Rif.TB line-probe assay for rapid identification of Mycobacterium tuberculosis complex strains and detection of rifampin resistance in 360 smear-positive respiratory specimens from an area of high incidence of multidrug-resistant tuberculosis. J. Clin. Microbiol.43(9),4880–4884 (2005).•• The INNO-LiPA Rif.TB assay for the identification of Mycobacterium tuberculosis complex strains and the detection of rifampin resistance was evaluated in specimens from an area of high incidence of MDR-TB.
    • 15  Sam IC, Drobniewski F, More P, Kemp M, Brown T: Mycobacterium tuberculosis and rifampin resistance, United Kingdom. Emerg. Infect. Dis.12(5),752–759 (2006).
    • 16  Direcção Geral de Saúde: Programa Nacional De Luta Contra A Tuberculose (PNT). Ponto da Situação Epidemiológica e de Desempenho Ano 2006, 1–12. DGS, Lisboa, Portugal (2007).
    • 17  Amaral L, Viveiros M, Molnar J: Antimicrobial activity of phenothiazines. In vivo18(6),725–732 (2004).
    • 18  Saunders BM, Britton WJ: Life and death in the granuloma: immunopathology of tuberculosis. Immunol. Cell Biol.85(2),103–111 (2007).
    • 19  Ordway D, Viveiros M, Leandro C et al.: Chlorpromazine has intracellular killing activity against phagocytosed Staphylococcus aureus at clinical concentrations. J. Infect. Chemother.8(3),227–231 (2002).
    • 20  Ordway D, Viveiros M, Leandro C et al.: Clinical concentrations of thioridazine kill intracellular multi-drug resistant Mycobacterium tuberculosis. Antimicrob. Agents Chemother.47(3),917–922 (2003).• This study evaluated whether thioridazine (TZ) kills M. tuberculosis that has been phagocytosed by human macrophages.
    • 21  Ordway D, Viveiros M, Leandro C, Arroz MJ, Amaral L: Intracellular activity of clinical concentrations of phenothiazines including thioridazine against phagocytosed Staphylococcus aureus. Int. J. Antimicrob. Agents.20(1),34–43 (2002).• This study was focused on the enhancement of the killing activity of macrophages infected with Staphylococcus aureus. The concentrations of the phenothiazines used in this macrophage assay were clinically acceptable.
    • 22  Daniel WA, Wojcikowski J: The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions. Toxicol. Appl. Pharmacol.158(2),115–124 (1999).
    • 23  Martins M, Bleiss W, Marko A et al.: Clinical concentrations of thioridazine enhance the killing of intracellular methicillin-resistant Staphylococcus aureus: an in vivo, ex vivo and electron microscopy study. In vivo18(6),787–794 (2004).•• Study includes the in vitro and ex vivo effect of TZ on methicillin-resistant S. aureus. Microscopy studies were also conducted in order to evaluate the ultrastructural changes that TZ induces in bacterial cells.
    • 24  Martins M, Viveiros M, Kristiansen JE, Molnar J, Amaral L: The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis. In vivo21,771–776 (2007).•• This study evaluates the effectiveness of TZ of different doses on Balb/C mice that had been infected with a massive dose of M. tuberculosis.
    • 25  Martins M, Ordway D, Kristiansen M et al.: Inhibition of the Carpobrotus edulis methanol extract on the growth of phagocytosed multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus. Fitoterapia76(1),96–99 (2005).
    • 26  Ordway D, Hohmann J, Viveiros M et al.: Carpobrotus edulis methanol extract inhibits the MDR efflux pumps, enhances killing of phagocytosed S. aureus and promotes immune modulation. Phytother. Res.17(5),512–519 (2003).
    • 27  Martins M, Schelz Z, Martins A et al.: In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis.Int. J. Antimicrob. Agents.29(3),338–340 (2007).• New derivatives of TZ were synthesized and their in vitro and ex vivo activity against M. tuberculosis was evaluated.
    • 28  Guidelines for the programmatic management of drug-resistant tuberculosis. World Health Organization. Geneva, Switzerland (2006).
    • 29  Pai M, Kalantri S, Dheda K: New tools and emerging technologies for the diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance. Expert. Rev. Mol. Diagn.6(3),423–432 (2006).
    • 30  Palomino JC: Newer diagnostics for tuberculosis and multi-drug resistant tuberculosis. Curr. Opin. Pulm. Med.12(3),172–178 (2006).
    • 31  Migliori GB, Loddenkemper R, Blasi F, Raviglione MC: 125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is ‘science’ enough to tackle the epidemic? Eur. Respir. J.29(3),423–427 (2007).
    • 32  Hamilton CD, Sterling TR, Blumberg HM et al.: Extensively drug-resistant tuberculosis: are we learning from history or repeating it? Clin. Infect. Dis.45,338–342 (2007).
    • 33  Martins M, Viveiros M, Amaral L: Enhanced killing of intracellular pathogenic bacteria by phenothiazines and the role of K+ efflux pumps of the bacterium and the killing macrophage. Anti- Infective Agents In Medicinal Chemistry7,63–72 (2008).
    • 34  Lemaire S, Van Bambeke F, Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM: Role of acidic pH in the susceptibility of intraphagocytic methicillin-resistant Staphylococcus aureus strains to meropenem and cloxacillin. Antimicrob. Agents Chemother.51(5),1627–1632 (2007).
    • 35  Baudoux P, Bles N, Lemaire S, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F: Combined effect of pH and concentration on the activities of gentamicin and oxacillin against Staphylococcus aureus in pharmacodynamic models of extracellular and intracellular infections. J. Antimicrob. Chemother.59(2),246–253 (2007).
    • 36  Barcia-Macay M, Lemaire S, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F: Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. J. Antimicrob. Chemother.58(6),1177–1184 (2006).
    • 37  Matteelli A, Migliori GB, Cirillo D, Centis R, Girard E, Raviglion M: Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control. Expert. Rev. Anti Infect. Ther.5(5),857–871 (2007).
    • 38  Yew WW, Leung CC: Management of multidrug-resistant tuberculosis: Update 2007. Respirology.13(1),21–46 (2008).
    • 39  Sungkanuparph S, Eampokalap B, Chottanapund S, Thongyen S, Manosuthi W: Impact of drug-resistant tuberculosis on the survival of HIV-infected patients. Int. J. Tuberc. Lung Dis.11(3),325–330 (2007).
    • 40  Ormerod LP: Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. British Med. Bull.73–74,17–24 (2005).