Post on 02-Apr-2015
transcript
Multidrug-resistant Mycobacterium tuberculosis: The Next Threat to
Humanity
http://www.i-volume.com/stoptb/details.asp?id=660
Natalia Grob
April 28, 2005
Outline
M. tuberculosis History Pathogenicity Infection
MDR-TB 1st and 2nd line drugs Public Health Treatment Future
Worldwide Concern
20 million people will die in the next decade
Most common cause of death due to single infectious agent
Disease of poverty
http://stoptb.lpipserver.com/library_new.asp
History
Eradication: 2010 Re-emergence & resurgence
Immigration HIV epidemic Deteriorating health infrastructure Inadequate institutional control MDR-TB
Basic Biology
Gram positive Slow growing No basic virulence
factors (exotoxins, capsules, etc.)
Facultative intracellular parasite of macrophages
http://www-medlib.med.utah.edu/WebPath/INFEHTML/INFEC033.html
Genome
H37Rv 4,411,529 base pairs 4,000 genes Aerobic and
anaerobic enzymes
Cole et al. (1998)
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
Blocking Phagolysosome Fusion
No phagolysosome formation persistence of tubercule bacillus
Key players: Ca2+
LAM EEA1 Syntaxin 6
Calcium Cascade
Ca2+
CaMKII
LAM
*LAM
EEA1
hVPS34
Phagosome maturation
Maturation cascade
EEA1 & Syntaxin 6
Lysosome hydrolases ATPase
Acidification
Maturation
Acidification
Maturation
Transmission
One droplet = 3 bacilli Talking five minutes =
3000 droplets = 9000 bacilli!
http://catalog.cmsp.com/datav3/it060009.htm
Infection
T-lymphocytes more macrophages Spherical granulomas tubercles
http://www-medlib.med.utah.edu/WebPath/TUTORIAL/MTB/MTB008.html
http://www-medlib.med.utah.edu/WebPath/TUTORIAL/MTB/MTB002.html
Necrosis: Soft White Cheese
Outline
M. tuberculosis History Pathogenicity Infection
MDR-TB 1st and 2nd line drugs Public Health Treatment Future
Drug Resistance
Types: 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: Rifampin
MDR-TB markerAffects transcription of RNACheruvu et al. (2001)
rpoB gene RRDR New mutations continually arise
First-line Drugs: Mutations
Cheruvu et al. (2001)
Second-line Drugs
Increased treatment difficulties 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: SQ109
EMB analog; enhanced efficacy
Penetrates macrophage phagosome
High concentration in target organs
Jia et al. (2004)
Second First-Line Drugs: Hope?
40 years! Standard regime Promise of R207910
Andries et al. (2005)
DOTS
WHO guidelines Political commitment Detection of TB Standardized short-
course chemotherapy (SCC)
Uninterrupted supply drugs
Recording and reporting system
http://www.tbcta.org/Pages/home.php
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
History
Little action from WHO
NYC outbreak global attention
Dr. Paul Farmer “Mountains Beyond
Mountains”
http://www.brighamandwomens.org/socialmedicine/farmerbio.asp
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
Treatment: Where?
Pablos-Mendez et al. (2002)
Treatment: How?
First-line drugs whenever possible Injectable agent Second-line drugs
Treatment: Who?
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 Locally severe problem Three-part response:
SCC implementation Surveillance and testing Second-line drugs?
What Now?
DOTS and DOTS-Plus Promotion of adherence Monitor adverse effects Enablers and enhancers
Concluding Remarks
Big issue, many opinions, many (often opposing) theories
New drugs needed Medicine and public
health Read “Mountains
Beyond Mountains”
Thanks a bunch!
Peer reviewers Amy Malhowski and Caitlin Reed
Professor Christine White-Ziegler
Emerging Infectious Diseases Class
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: 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 rpoB Gene of Multidrug-Resistant Mycobacterium tuberculosis
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References
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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 SQ109, a new diamine-based antitubercular drug. British Journal of Pharmacology 144: 80-87.
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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: 2987-2990.
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Sharma, S.K., and A. Mohran (2004). Multidrug-resistant tuberculosis. Indian Journal of Medical Research 120: 354-376.
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
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Vergne, I., Chua, J., and V. Deretic (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/Calmodulin-PI3K hVPS34 Cascade.
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