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Mycobacterium

Tuberculosis

a microbiologist perspective...

  • Acid-Fast
  • Bacilli
  • Non-Motile
  • Obligate Aerobe
  • Slow Growing

Mycolic Acid

  • A waxy lipid present in the cell wall that renders M.tuberculosis resistent to staining

Major Virulence

Factors

Exported Repetitive

Proteins

  • Prevent phagosome from joining with lysosome
  • Bacterium therefore not exposed to degradative components
  • Toxic components released into lung tissue causing damage

Lipoarbinomannan

  • Carbohydrate surface antigen allows M.tuberculosis to reside in lung macrophages
  • Prevents secretion of anti-inflammatory cytokines
  • Destroys oxygen free radicals produced by macrophages

Where does it

come from?

Mycobacterium Species

  • The genus Mycoplasma was originally derived from cattle and was called M. Bovis. It was later discovered that the disease could be transmitted to humans via the milk from infected cows.
  • M. Tuberculosis is the human pathogen from this Genus.

Talk

Laugh

Cough

The bacili are inhaled into the alveoli of the lungs where they take up residence in the Macrophages and begin to multiply.

Disease Progression

  • Bacterium inhaled into lungs and reside in lung macrophages
  • Some inflammation occurs and macrophages compile called an "exudative lesion"
  • End up with a pile of live and dead bacteria, phagocytes surrounded by macrophages called a "granuloma"
  • Granuloma then surrounded by fibrin which calcifies creating a tubercule
  • Tubercule can burst causing reactivation of TB later

Specimen Collection

Depends on the manifestation of the symptoms....

Pulmonary

  • Sputum: spot-morning-spot method
  • Bronchioalveolar lavages and brushings

Extrapulmonary

  • CSF
  • Urine
  • Lymph
  • Joint fluid

Laboratory

Diagnosis

Microscopic

  • Acid fast staining with Zeihl-Neelson stain
  • Fluorescent microscopy using Auramine

Culture

  • Lowenstein-Jensen or Middlebrook media (egg-based)
  • Tan/buff colonies
  • Heaped up
  • Slow growth (2-6 weeks)

Biochemically

Differentiated from other non-tuberculous Mycobacterium

  • Nitrate positive
  • Catalase positive
  • Niacin producer

Other Tests

  • PCR/LCR
  • Interferon gamma
  • Activated specific T-cells

Treatment and

Prevention

Treatment is based on three principles:

  • Multiple drugs must be used
  • The drugs must be taken regularly
  • Drug therapy must continue for a sufficient period

Isoniazid

  • Most widley used anti-TB agent
  • Critical in early therapy
  • Bactericidal
  • Rapidly reduces sputum viable count
  • Active against organisms growing aerobically
  • Mechanism of action:
  • targets fatty acid pathways involved in the formation of the mycobacterial capsule

Rifampin

Eliminates TB that are slow metabolizers

Sterilizes sputum of TB not removed by INH

  • Bactericidal
  • Mechanism of action
  • Bacterial RNA synthesis inhibitor

Pyrazinamide

  • Effective only at low pH
  • Active against slowly metabolizing or dormant bacilli in macrophages
  • Mechanism of action:
  • Remains unknown
  • Possible inhibitor of trans-translation

Ethambutol

  • Bacteriostatic
  • can be -cidal if given in high doses
  • Easily administered
  • Low frequency of adverse reactions
  • Mechanism of action:
  • peptidoglycan synthesis inhibitor

Emergence of

Resistance

Major Issue!

  • 1990: Multidrug-resistant TB
  • Resistant to at least INH and RIF
  • 2006: Extensively drug resistant TB
  • Resistant to INH, RIF, all fluoroquinolones, and at least one second line anti-TB drug
  • 2009-Present: Totally drug-resistant TB
  • Resistant to all the first and second line drugs currently available.

Mechanism of Resistance

How is this bacteria managing to outsmart us?

  • M. Tuberculosis is usually acquired early in life and enters a long latency period
  • Little interaction between the individual strains occurs
  • This eliminates the acquisition of resisitance by mobile genetic elements:
  • transposons, integrons and plasmids
  • The resistant phenotype can only be acquired through chromosomal mutation

References

1. Kaiser, G. E. The Prokaryotic Cell: Bacteria – The Cell Wall, [homepage on the internet]. C2011 [updated 2011 April; cited 2012 March 20.] http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/afcw.html

2. Knechel, N. CE Article: Tuberculosis: Pathophysiology, Clinical Features, and DiagnosisCrit Care Nurse. April 2009 29:34-43; doi:10.4037/ccn2009968

3. Toriyama S, Yano I, Masui M, Kusunose E, Kusunose M, Akimori N. Regulation of cell wall mycolic acid biosynthesis in acid-fast bacteria: I. Temperature-Induced changes in mycolic acid molecular species and related compounds in Mycobacterium phlei J Biochem (1980) 88(1): 211-221

4. Nair A. The times of India. Animals big source of TB infection: expert [homepage on the internet]. c2011 [updated 2011 Dec 27; cited 2012 Mar 12]. Available from: http://articles.timesofindia.indiatimes.com/2011-12-27/nagpur/30561236_1_tb-patients-animals-disease

5. Tuberculosis: Learn the signs and symptoms of TB disease [homepage on the internet]. c2010 [updated 2010 Jul 14; cited 2012 Mar 10]. Available from: http://www.cdc.gov/Features/TBsymptoms/

6. Tuberculosis [homepage on the internet]. c2012 [updated 2012 Mar; cited 2012 Mar 5]. Available from: http://www.who.int/mediacentre/factsheets/fs104/en/

7. Mahon C, Lehman D, Manuselis G. Textbook of diagnostic microbiology. 4th ed. W. B. Saunders Company; 2011.

8. Martinko J. Brock biology of microorganisms. 11th ed. Pearson Prentice Hall; 2006.

9. Center for Disease Control. Module 3: Diagnostic laboratory methods for tuberculosis. Atlanta. Available from: wwwn.cdc.gov/dls/ILA/.../Kenya1103/Ch2/Module3methods.rtf.

10. Ogbaini-Emovon E. Current trends in the laboratory diagnosis of tuberculosis. Benin J. Postgrad. Med.[serial of internet]. 2009 Dec;11:79-90.

11. Duerden BI. Standards of laboratory diagnosis of tuberculosis [unpublished lecture notes] Department of Health. Available from: https://s3-eu-west-1.amazonaws.com/bsmt/asm21/Brian_Duerden.ppt.

12. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. American Journal of Respiratory Care and Critical Medicine. 1994; 149: 1359-1374.

13. Center for Disease Control and Prevention: Treatment for TB Disease [homepage on the Internet]. 2011 [updated 2011 December 9; cited 2012 March 19]. Available from: http://www.cdc.gov/tb/topic/treatment/tbdisease.htm.

14. Janin YL. Antituberculosis Drugs: Ten years of research. Bioorganic and Medicinal Chemistry. 2007; 15: 2479-2513.

15. Gillespie SH. Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective. Antimicrobial Agents and Chemotherapy. 2002; 46(2): 267-274.

16. Kalinda AS, Aldrich CC. Pyrazinamide: A Frontline Drug Used for Tuberculosis. Molecular Mechanism of Action Resolved After 50 Years? ChemMedChem. 2012; 7(3).

17. Center for Disease Control and Prevention: Drug-Resistant TB [homepage on the Internet]. 2011 [updated 2012 January 17; cited 2012 March 19]. Available from: http://www.cdc.gov/tb/topic/drtb/default.htm.

18. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally Drug-Resistant Tuberculosis in India. Clinical Infectious Diseases. 2011; 54(4): 579-581.

19. Nature: Totally Drug-Resistant TB Emerges in India [homepage on the Internet]. 2012 [updated 2012 January 13; cited 2012 March 20]. Available from: http://www.nature.com/news/totally-drug-resistant-tb-emerges-in-india-1.9797

Initial Treatment Phase

Continuation of Treatment

Therapeutic Agent:

  • Isoniazid
  • Rifampin

Time Course:

  • Taken daily over the course of 18 weeks

Therapeutic Agent:

  • Isoniazid
  • Rifampin
  • Pyrazinamide
  • Ethambutol

Time Course:

  • Taken daily over the course of 8 weeks

http://pathmicro.med.sc.edu/infectious%20disease/mycobacterial%20diseases.htm

http://www.finddiagnostics.org/programs/tb/find_activities/led_microscopy.html

What is

M. tuberculosis?

Agarwal et al. Annals of Clinical Microbiology and Antimicrobials 2005 4:18   doi:10.1186/1476-0711-4-18

Description of the Organism....

http://textbookofbacteriology.net/tuberculosis.html - Kenneth Todar PhD

http://www.icrc.org/eng/resources/documents/photo-gallery/tuberculosis-photos-2011-03-17.htm

http://www.google.ca/imgres?q=TB+resistant+strains&um=1&hl=en&sa=N&rlz=1R2ADFA_enCA455&biw=1215&bih=730&tbm=isch&tbnid=ea5WDD5BuFCosM:&imgrefurl=http://www.maltastar.com/dart/20120319-malta-among-countries-with-low-tb&docid=RWEdC8hocebg5M&imgurl=http://www.maltastar.com/userfiles/tn/t_460x0_tuberculosis.jpg&w=460&h=272&ei=vZ13T_LzE62-0QHcgaWlDQ&zoom=1&iact=hc&vpx=567&vpy=86&dur=32&hovh=173&hovw=292&tx=184&ty=117&sig=107943214122160261010&page=4&tbnh=127&tbnw=214&start=68&ndsp=20&ved=1t:429,r:7,s:68

Why is it different?

How is it Spread?

Cover your mouth when you cough....

M. Tuberculosis is spread from one person to another via respiratory aerosols. These are produced whenever we...

http://homepage.usask.ca/~trn186/pth205/path.html

http://www.hss.gov.yk.ca/tb.php

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