multidrug-resistant mycobacterium tuberculosis: the next threat to humanity natalia grob april 28,...

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

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

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 SQ109, 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

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.

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: 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

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 Ca2+/Calmodulin-PI3K hVPS34 Cascade.

Journal of Experimental Medicine 198: 653-659.