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Mycobacteria
Dr. Sri Mulyaningsih
Important Human Pathogens
yco ac er um u ercu os s
Mycobacterium leprae (uncommon)
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Lipid Rich Cell Wall of MycobacteriumMycolic acids
CMN Group: Unusual cell wall lipids (mycolic acids,etc.)
(Purified Protein Derivative)
Mycobacterium tuberculosisM.tuberculosis complex includes several species:1. Mycobacterium tuberculosis2. Mycobacterium bovis unpasteurized milk; recent
rash of cases in US3. Mycobacterium bovis BCG
. canetti = rare causes of tuberculosis in Africa
5. Mycobacterium microti = pathogen for rodents
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Organism characteristics
1. Aerobic, non motile, non spore forming bacillus2. High cell wall content of high molecular weight
lipids mycolic acid3. SLOW GROWTH RATE
a. generation time of 20 hours vs E.coli eneration time o 20 minutes
b. 38 weeks before growth on solid media;c. implications for length of treatment for complete
sterilization compared with most bacterial pathogens
Pathogenesis of Tuberculosis Inhalation of small (15 m) droplet nuclei
con a n ng . u ercu os s expe e y coughing, sneezing, or talking of another individual with cavitary tuberculosis
Primary infection by M . tuberculosis of non immune alveolar macro ha es with unrestrained proliferation within the infected macrophages
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Lungs are the portal of entry except M. bovis in unpasteurized
dairy products from other countriesInhalation of droplet nuclei (bacillus 5 microns): from infectious
, PPD
a. cough: most efficient at 3000 infectious droplet nuclei per cough
b. talking: similar quantity over 5 minutesc. sneezing more efficient than coughing; singing intermediate
between talking and coughing.d. Bacillus remains alive and infectious in air for long period;
ventilation key in preventing transmission; isolation of patient and mandated number of air exchanges in hospital rooms
Pathogenesis of Tuberculosis Dissemination of infected macrophages
roug e ra n ng ymp a cs n o e circulation
Development within 38 weeks of a CD4+ T cell dependent cell mediated immune res onse with ranuloma formation and macrophage activation at sites of infection
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Pathogenesis of Tuberculosis Active infection usually transformed into
atent n ect on except ons: n ants, With decrement in Tcell dependent cell
mediated immunity (years later) infection reactivated with development of tuberculosis HIV infection diabetes mellitus renal
disease, cancer, advanced age)
Pathogenesis of Tuberculosis Reactivation of M . tuberculosis infection with
par a mmun y pro uces g ssue concentrations of mycobacterial antigens that provoke an intense mononuclear cell response (type 4 hyper sensitivity reaction)
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Pathogenesis of Tuberculosis Dense mononuclear cell infiltrates damage
t ssue ue to re ease o act ve oxygen ra ca s and lysosomal neutral proteases
Tissue damage occurs as caseation necrosis that progresses to liquefaction necrosis in the absence of tuberculosis dru treatment
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Clinical Features of Tuberculosis Apical cavitary lesions in upper lobes of lung
y ray m o t e c est Positive tuberculin skin test with PPD
(purified protein derivative)
Chest X Ray of Patient with Active Pulmonary Tuberculosis
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Tuberculosis and the Disadvantaged
Homeless persons Intravenous drug abusers Prison inmates (Russia and other previous
states of the Soviet Union) Recent immigrants to the United States (Asia,
a n mer ca
HIV1 infection/AIDS
Epidemiology World wide: WHO Maps: Estimated incidence vs. case
notifications1. M. tuberculosis infects one third worlds population
causes 8 million new cases active disease annually2. Causes 2 million deaths= 2nd only to HIV as cause of
death from infectious agent world wide among adults3. HIV/TB relationship has exacerbated problem with TB
ncreas ng n areas w t g nc ence spec a y sub Saharan Africa4. Absolute numbers of cases of TB highest in Asia
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Epidemiology
Downward trend in incidence even before advent of
Annual decrease in mortality and morbidity of 4%6% in developed countries
between 1900 and WW2: Better living conditions less conducive to airborne
spread.
Advent of
antibiotics
late
1940s
(Streptomycin)
and
INH
in 1952: Tuberculosis is curable
Diagnostic procedures: SPUTUM: staining, cultures and molecular
diagnostics
1. Acid fast stain :
ZiehlNeelsen stain=fixed smear covered with carbol fuchsin, heated, rinsed, decolorized with acid alcohol; Kinyoun stain is similar but
ea ng unnecessarySMEAR POSITIVITY MEANS AT LEAST 10,000
ORGANISMS/mL SPUTUM
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Diagnostic procedures
2. Culture :a. o me a= owenste n ensen egg aseb. Middlebrook 7H11 (agar based): can detect
colony morphology, mixed infections; can detect 10 100 organisms/mL; 38 weeks incubation to detect organisms
CULTURE NECESSARY TO DETERMINE DRUG SUSCEPTIBILITIES
Lowenstein Jensen Egg Base Medium Coagulated whole eggs Potato flour Glycerol Defined salts Malachite Green (0.025 g/100 mL)
(Petragnani 0.052 g/100 mL)(ATS 0.020 g/100 mL)
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Middlebrook Agar Base 7H10 Medium Defined salts am ns an o ac ors Oleic acid Albumin Catalase
Dextrose Malachite Green (0.0025g/100 mL)
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Diagnostic procedures3. Nucleic acid amplification
can detect M. tuberculosis com lex in resh s utum: developed world technologytoo costly for resource poor countries
4. DNA fingerprinting : Molecular epidemiologic tool: RFLP (Restriction fragment length polymorphism); also developed world technologyRestriction endonuclease produces DNA fragments; separate fragments by electrophoresis; probe to repetitive DNA sequence=Insertion sequence (IS)6110 numerous copies of IS6110 present in M.tuberculosischromosome at highly variable locations
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Treatment
1. Always use at least 2 drugs; usua y eg n w t or pen ng sens t v t es
2. Prolonged length necessary: 69 months if organism pan sensitive
3. Directly Observed Therapy for all patients. , , ,
educationb. Daily treatment for first 2 months;
TreatmentDrugs: ALL GIVEN ONCE DAILY TOGETHER: NEVER DIVIDE
DOSES1. Isoniazid=INH; bactericidal against dividing organisms2. Rifampin=RMP=bactericidal; Enables short course
treatmentdrug drug interactions: RMP is potent inducer of hepatic microsomal enzymes: cytochrome p450
3. Pyrazinamide=PZA; Enables shortening of regimen from 9
4. Ethambutol=EMB: Used in drug resistance and situations where INH or RMP cannot be used (INH hepatotoxicity; RMP drug drug interactions)
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Prevention: BCGMost widely used and most controversial vaccine in the
worldA. What is it?
M. bovis strain attenuated through serial passageB. Does it work?
1. Largest study: India= no protection from TB infection2. Other studies: England= protection from TB infection3. Prevalence of non tuberculous mycobacteria in given region may
4. Background prevalence of tuberculosis determines utility
C. Who
uses
it?Newborns vaccinated in all high prevalence areas of world
shown on first map
Mycobacterium leprae
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Mycobacterium leprae Infections
Mycobacterium leprae Infections (cont.)
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Tuberculoid vs. Lepromatous Leprosy Clinical Manifestations and Immunogenicity
Lepromatous vs. Tuberculoid Leprosy
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Lepromatous Leprosy (Early/Late Stages)
Lepromatous Leprosy Pre and Post Treatment