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Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to Humanity Natalia Grob April 28, 2005.

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Presentation on theme: "Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to Humanity Natalia Grob April 28, 2005."— Presentation transcript:

1 Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to Humanity Natalia Grob April 28, 2005

2 Outline M. tuberculosis  History  Pathogenicity  Infection MDR-TB  1 st and 2 nd line drugs  Public Health  Treatment  Future

3 Worldwide Concern 20 million people will die in the next decade Most common cause of death due to single infectious agent Disease of poverty

4 History Eradication: 2010 Re-emergence & resurgence  Immigration  HIV epidemic  Deteriorating health infrastructure  Inadequate institutional control  MDR-TB

5 Basic Biology Gram positive Slow growing No basic virulence factors (exotoxins, capsules, etc.) Facultative intracellular parasite of macrophages

6 Genome H37Rv 4,411,529 base pairs 4,000 genes Aerobic and anaerobic enzymes Cole et al. (1998)

7 Pathogenicity Slow generation time High lipid concentration in cell wall  Impermeability and resistance to antimicrobials  Resistance to killing by acidic/alkaline compounds  Resistance to osmotic lysis via complement deposition and attack by lysozyme Phagosome maturation arrest

8 Blocking Phagolysosome Fusion No phagolysosome formation  persistence of tubercule bacillus Key players:  Ca 2+  LAM  EEA1  Syntaxin 6

9 Calcium Cascade Ca 2+ CaMKII LAM *LAM EEA1 hVPS34 Phagosome maturation

10 Maturation cascade EEA1 & Syntaxin 6 Lysosome hydrolases Acidification Maturation ATPase Acidification Maturation

11 Transmission One droplet = 3 bacilli Talking five minutes = 3000 droplets = 9000 bacilli!

12 Infection T-lymphocytes  more macrophages Spherical granulomas  tubercles

13 Necrosis: Soft White Cheese

14 Outline M. tuberculosis  History  Pathogenicity  Infection MDR-TB  1 st and 2 nd line drugs  Public Health  Treatment  Future

15 Drug Resistance Types:  Acquired resistance  Transmitted resistance/Primary resistance  Amplified resistance MDR-TB: isoniazid + rifampicin  Statistics  Diagnosis: mycobacterial culture and in vitro sensitivity testing.

16 First-line Drugs Sharma & Mohan (2004)

17 First-line Drugs: Rifampin MDR-TB marker Affects transcription of RNA Cheruvu et al. (2001)  rpoB gene  RRDR  New mutations continually arise

18 First-line Drugs: Mutations Cheruvu et al. (2001)

19 Second-line Drugs Increased treatment difficulties  Expensive,unavailable  More side effects  Difficult Ab penetration  Longer treatment Controversy  Standard treatments  Everything it takes

20 Second-line Drugs: SQ109 EMB analog; enhanced efficacy Penetrates macrophage phagosome High concentration in target organs Jia et al. (2004)

21 Second First-Line Drugs: Hope? 40 years! Standard regime Promise of R Andries et al. (2005)

22 DOTS WHO guidelines  Political commitment  Detection of TB  Standardized short- course chemotherapy (SCC)  Uninterrupted supply drugs  Recording and reporting system

23 Emergence of MDR-TB Errors in treatment  monotherapy Errors in diagnosis  Pre-existing MDR Noncompliance  Drug addiction, mental illness  Low socioeconomic status, age, race, education level

24 History Little action from WHO NYC outbreak  global attention Dr. Paul Farmer  “Mountains Beyond Mountains”

25 The Irony Model of MDR-TB emergence Poor control of TB leads to MDR-TB  Less infectious than wild-type Successful TB program  hot zones

26 Treatment: Where? Pablos-Mendez et al. (2002)

27 Treatment: How? First-line drugs whenever possible Injectable agent Second-line drugs

28 Treatment: Who? Children = important special cases  Difficulty in obtaining sample  Cost constraints  Importance of medical history  Importance of early diagnosis

29 What Now? Control is priority Locally severe problem Three-part response:  SCC implementation  Surveillance and testing  Second-line drugs?

30 What Now? DOTS and DOTS-Plus  Promotion of adherence  Monitor adverse effects  Enablers and enhancers

31 Concluding Remarks Big issue, many opinions, many (often opposing) theories New drugs needed Medicine and public health Read “Mountains Beyond Mountains”

32 Thanks a bunch! Peer reviewers Amy Malhowski and Caitlin Reed Professor Christine White-Ziegler Emerging Infectious Diseases Class

33 References Andries, K., Verhasselt, P., Guillemont, J., Gohlmann, H.W.H., Neefs, J.M., Winkler, H., Gestel, J.V., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N., and V. Jarlier (2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307: Blower, S.M. and T. Chou (2004). Modeling the emergence of the ‘hot zones’: tuberculosis and the amplification dynamics of drug resistance. Nature Medicine 10: Cheruvu, M., Selvakumar, N., Narayanan, S., and P.R. Narayanan (2001). Mutations in the rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates from India. Journal of Clinical Microbiology 39: Cohen, M.L. (2000). Changing pattern of infectious disease. Nature 406: Cole, S.T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S.V., Eiglmeier, K., Gas, S., Barry, C.E. III, Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holyroyd, S., Hornsby, T., Jagels, K., Kroghs, A., Mclean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J., Quail, M.A., Rajandream, M.A., Rogers, J., Rutter, S., Seeger, K., Skelton, J., Squares, R., Sulston, J.E., Taylor, K., Whitehead, S., and B.G. Barrell (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:

34 References De Clercq, E., Flower, R., Fujita, Y., Hefti, F., Brown, J.H., Thomsen, M.K., Kubinyi, H., Langer, R., Licino, J., Lipinski, C., Sawyer, T., and J. Woodcock (2005). Tackling tuberculosis. Nature 4: 103. Dye, C., Williams, B.G., Espinal, M.A., and M.C. Raviglione. (2002). Erasing the world’s slow strain: strategies to beat multidrug-resistant tuberculosis. Science 295: Finlay, B.B. and S. Falkow (1997). Common themes in microbial pathogenicity revisited. Microbiology and Molecular Biology Reviews 37: Fisher M. (2002). Diagnosis of MDR-TB: a developing world problem on a developed world budget. Expert Rev Mol Diagn 2: Jia, L., Tomaszewski, J.E., Hanrahan, C., Coward, L., Noker, P., Gorman, G., Nikonenko, B., and M. Protopopova (2005). Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. British Journal of Pharmacology 144: Kidder, Tracy. Mountains Beyond Mountains. Random House Publications: New York, Kim, J.Y., Mukherjee, J.S., Rich, M.L., Mate, K., Bayona, J., and M.C. Becerra (2003). From multidrug-resistant tuberculosis to DOTS expansion and beyond: making the most of a paradigm shift. Tuberculosis 83:

35 References Mani, C., Selvakumar, N., Narayanan, S., and P.R. Narayanan (2001). Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis clinical isolates from India. Journal of Clinical Microbiology 39: Pablos-Mendez, A., Gowda, D.K., and T.R Frieden (2002). Controlling multidrug- resistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 80: Mukherjee, J.S., Rich, M.L., Socci, A.R., Josephy, J.K., Viru, F.A., Shin, S.S., Furin, J.J., Becerra, M.C., Barry, D.J., Kim, J.Y., Bayona, J., Farmer, P., Smith Fawzi, M.C., and K.J. Seung (2004). Programmes and principles in treatment of multidrug-resistant tuberculosis. The Lancet 363: Schaaf, H.S., Shean, K., and P.R. Donald (2003). Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome. Archives of Disease in Childhood 88: Sharma, S.K., and A. Mohran (2004). Multidrug-resistant tuberculosis. Indian Journal of Medical Research 120:

36 References Valway, S.E., Sanchez, M.P.C., Shinnick, T.F., Orme, I., Agerton, T., Hoy, D., Jones, S., Westmoreland, H., and I.M.Onorato (1998). An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. New England Journal of Medicine 338: Van Rie, A., Warren, W., Mshanga, I., Jordaan, A.M., van der Spuy, G.D., Richardson, M., Simpson, J., Gie, R.P., Enarson, D.A., Beyers, N., van Helden, P.D., and T.C. Victor (2001). Analysis of a limited number of gene codons can predict drug resistance of Mycobacterium tuberculosis in a high-incidence community. Journal of Clinical Microbiology 39: Vergne, I., Chua, J., and V. Deretic (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/Calmodulin-PI3K hVPS34 Cascade. Journal of Experimental Medicine 198:


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