Скачать презентацию Multidrug-resistant Mycobacterium tuberculosis The Next Threat to Humanity Скачать презентацию Multidrug-resistant Mycobacterium tuberculosis The Next Threat to Humanity

11205ef7446aab2bbb1104b00d0a0512.ppt

  • Количество слайдов: 36

Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to Humanity Natalia Grob April 28, 2005 http: Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to Humanity Natalia Grob April 28, 2005 http: //www. i-volume. com/stoptb/details. asp? id=660

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

Worldwide Concern 20 million people will die in the next decade l Most common Worldwide Concern 20 million people will die in the next decade l Most common cause of death due to single infectious agent l Disease of poverty l http: //stoptb. lpipserver. com/library_new. asp

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

Basic Biology Gram positive l Slow growing l No basic virulence factors (exotoxins, capsules, Basic Biology Gram positive l Slow growing l No basic virulence factors (exotoxins, capsules, etc. ) l Facultative intracellular parasite of macrophages l http: //www-medlib. med. utah. edu/Web. Path/INFEHTML/INFEC 033. html

Genome H 37 Rv l 4, 411, 529 base pairs l 4, 000 genes Genome H 37 Rv l 4, 411, 529 base pairs l 4, 000 genes l Aerobic and anaerobic enzymes l Cole et al. (1998)

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

Blocking Phagolysosome Fusion No phagolysosome formation persistence of tubercule bacillus l Key players: l Blocking Phagolysosome Fusion No phagolysosome formation persistence of tubercule bacillus l Key players: l ¡ ¡ Ca 2+ LAM EEA 1 Syntaxin 6

Calcium Cascade Ca 2+ Ca. MKII LAM *LAM EEA 1 h. VPS 34 Phagosome Calcium Cascade Ca 2+ Ca. MKII LAM *LAM EEA 1 h. VPS 34 Phagosome maturation

Maturation cascade EEA 1 & Syntaxin 6 Lysosome hydrolases Acidification Maturation ATPase Acidification Maturation Maturation cascade EEA 1 & Syntaxin 6 Lysosome hydrolases Acidification Maturation ATPase Acidification Maturation

Transmission One droplet = 3 bacilli l Talking five minutes = 3000 droplets = Transmission One droplet = 3 bacilli l Talking five minutes = 3000 droplets = 9000 bacilli! l http: //catalog. cmsp. com/datav 3/it 060009. htm

Infection T-lymphocytes more macrophages l Spherical granulomas tubercles l http: //www-medlib. med. utah. edu/Web. Infection T-lymphocytes more macrophages l Spherical granulomas tubercles l http: //www-medlib. med. utah. edu/Web. Path/TUTORIAL/MTB 008. html

Necrosis: Soft White Cheese http: //www-medlib. med. utah. edu/Web. Path/TUTORIAL/MTB 002. html Necrosis: Soft White Cheese http: //www-medlib. med. utah. edu/Web. Path/TUTORIAL/MTB 002. html

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

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

First-line Drugs Sharma & Mohan (2004) First-line Drugs Sharma & Mohan (2004)

First-line Drugs: Rifampin l MDR-TB marker l Affects transcription of RNA l Cheruvu et First-line Drugs: Rifampin l MDR-TB marker l Affects transcription of RNA l Cheruvu et al. (2001) ¡ ¡ ¡ rpo. B gene RRDR New mutations continually arise

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

Second-line Drugs l Increased treatment difficulties ¡ ¡ l Expensive, unavailable More side effects Second-line Drugs l Increased treatment difficulties ¡ ¡ l Expensive, unavailable More side effects Difficult Ab penetration Longer treatment Controversy ¡ ¡ Standard treatments Everything it takes http: //www. tbcta. org/Pages/home. php

Second-line Drugs: SQ 109 EMB analog; enhanced efficacy l Penetrates macrophage phagosome l High Second-line Drugs: SQ 109 EMB analog; enhanced efficacy l Penetrates macrophage phagosome l High concentration in target organs l Jia et al. (2004)

Second First-Line Drugs: Hope? 40 years! l Standard regime l Promise of R 207910 Second First-Line Drugs: Hope? 40 years! l Standard regime l Promise of R 207910 l Andries et al. (2005)

DOTS l WHO guidelines ¡ ¡ ¡ Political commitment Detection of TB Standardized shortcourse DOTS l WHO guidelines ¡ ¡ ¡ Political commitment Detection of TB Standardized shortcourse chemotherapy (SCC) Uninterrupted supply drugs Recording and reporting system http: //www. tbcta. org/Pages/home. php

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

History Little action from WHO l NYC outbreak global attention l Dr. Paul Farmer History Little action from WHO l NYC outbreak global attention l Dr. Paul Farmer l ¡ “Mountains Beyond Mountains” http: //www. brighamandwomens. org/socialmedicine/farmerbio. asp

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

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

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

Treatment: Who? l Children = important special cases ¡ ¡ Difficulty in obtaining sample Treatment: Who? l Children = important special cases ¡ ¡ Difficulty in obtaining sample Cost constraints Importance of medical history Importance of early diagnosis http: //stoptb. lpipserver. com/library_new. asp

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

What Now? l DOTS and DOTS-Plus ¡ ¡ ¡ Promotion of adherence Monitor adverse What Now? l DOTS and DOTS-Plus ¡ ¡ ¡ Promotion of adherence Monitor adverse effects Enablers and enhancers

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

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

References l l l Andries, K. , Verhasselt, P. , Guillemont, J. , Gohlmann, References l l l 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: 223 -227. 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: 1111 -1116. Cheruvu, M. , Selvakumar, N. , Narayanan, S. , and P. R. Narayanan (2001). Mutations in the rpo. B Gene of Multidrug-Resistant Mycobacterium tuberculosis Clinical Isolates from India. Journal of Clinical Microbiology 39: 2987 -2990. Cohen, M. L. (2000). Changing pattern of infectious disease. Nature 406: 762 -767. 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: 537 -544.

References l l l l De Clercq, E. , Flower, R. , Fujita, Y. References l l l l 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: 2042 -2046. Finlay, B. B. and S. Falkow (1997). Common themes in microbial pathogenicity revisited. Microbiology and Molecular Biology Reviews 37: 136 -169. Fisher M. (2002). Diagnosis of MDR-TB: a developing world problem on a developed world budget. Expert Rev Mol Diagn 2: 151 -159. Jia, L. , Tomaszewski, J. E. , Hanrahan, C. , Coward, L. , Noker, P. , Gorman, G. , Nikonenko, B. , and M. Protopopova (2005). Pharmacodynamics and pharmacokinetics of SQ 109, a new diamine-based antitubercular drug. British Journal of Pharmacology 144: 80 -87. Kidder, Tracy. Mountains Beyond Mountains. Random House Publications: New York, 2003. 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: 59 -65.

References l l l Mani, C. , Selvakumar, N. , Narayanan, S. , and References l l l Mani, C. , Selvakumar, N. , Narayanan, S. , and P. R. Narayanan (2001). Mutations in the rpo. B gene of multidrug-resistant Mycobacterium tuberculosis clinical isolates from India. Journal of Clinical Microbiology 39: 2987 -2990. Pablos-Mendez, A. , Gowda, D. K. , and T. R Frieden (2002). Controlling multidrugresistant tuberculosis and access to expensive drugs: a rational framework. Bull World Health Organ 80: 489 -495. 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: 474 -481. 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: 1106 -1111. Sharma, S. K. , and A. Mohran (2004). Multidrug-resistant tuberculosis. Indian Journal of Medical Research 120: 354 -376.

References l l l Valway, S. E. , Sanchez, M. P. C. , Shinnick, References l l l 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: 633 -639. 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: 636 -641. Vergne, I. , Chua, J. , and V. Deretic (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca 2+/Calmodulin-PI 3 K h. VPS 34 Cascade. Journal of Experimental Medicine 198: 653 -659.