Download - Mycobacterium species Acid fast bacilli - cell walls contain unusual glycolipids (e.g.mycolic acids)
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Mycobacterium species
Acid fast bacilli - cell walls contain unusual glycolipids (e.g.mycolic acids)
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Mycobacterium species
Acid fast bacilli - cell walls contain unusual glycolipids (e.g.mycolic acids)
Intracellular organisms (some are facultative others are obligate)
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Diseases caused by Mycobacterium species
M. tuberculosis - tuberculosis
M. leprae - leprosy
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Diseases caused by Mycobacterium species
M. avium - lung and skin infections in immunocompromised hosts
- lymphadenopathy in children
- catheter-related infections
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Mycobacterium tuberculosis
Closely related to M. bovis (a cattle parasite/pathogen?)
M. tuberculosis believed to have evolved from M. bovis after domestication of cattle (8,000-4,000 BC)
Archeologists have shown that tuberculosis of the bones seems to have preceded the disease of the lungs
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Tuberculosis (TB)
Most common cause of death due to bacterial infection worldwide
2 billion infected worldwide / 8-9 million new cases per year
Aggressive measures decreased infections in developed countries
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Tuberculosis (TB)
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TB
Once known as consumption
Afflicted individuals considered beautiful and erotic
Thought that TB sparked genius
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TB
Spread by aerosols
Symptoms include : fever
coughing (often with blood)
weight loss
malaise (loss of energy)
progressive lung damage
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Systemic TB
Can infect any area of the body including:
Bones and joints
Internal organs
Brain
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Progression of TB
M. tuberculosis can survive within unactivated macrophages
Activated macrophages can kill the bacteria
Individual’s immunological response determines the outcome of exposure
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Progression of TB
T-cells involved in controlling infection
Gamma interferon (IFN-) activates macrophages
Cytotoxic T-cells (Tc -cells) kill infected macrophages
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Progression of TB
Healthy individual exposed to low dose
activated macrophages stop infection
Individuals unable to mount a rapid response
bacteria multiply in lung macrophages
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Progression of TB
Individuals unable to mount a rapid response
bacteria multiply in lung macrophages
phagocytes attracted to site of infection
infection may be walled-off/ forms tubercle
Tubercles may calcify and become visible in chest X-rays (Ghon complex)
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Ghon complex
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Progression of TB
Continuous growth of bacteria causes interior of tubercle to liquefy
Rupture of tubercle allows bacteria to escape
Leads to infection of others (aerosols) or other parts of the body
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Progression of TB
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Progression of TB
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Progression of TB
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Progression of TB
Bacteria in tubercles may survive for decades (latency)
Suppression of immune system may allow bacteria to break out of lesions and multiply (reactivation)
Old age, cancer, immunosuppressive drugs and HIV infection can lead to reactivation
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Virulence factors
Invasion of and survival within phagocytes
Interference with T-cell activation
Eliciting inflammatory response
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Diagnosis of TB
Acid-fast staining of sputum samples
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Diagnosis of TB
TB skin test - injection of M. tuberculosis proteins (tuberculin)
- positive test leads to red area at injection site
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Treatment of TB
Streptomycin - first antibiotic used against M. tuberculosis
- did not always cure patients
- slowly dividing cells became resistant
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Treatment of TB
Rifampin - used to treat TB and prophylactically for bacterial meningitis
- resistant mutants arise readily
- used in combination with other drugs
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M. tuberculosis specific drugs
Isoniazid - isonicotinic acid hydrazide or INH
- must be converted into the active form by a bacterial enzyme (catalase-peroxidase)
- inhibits the formation of mycolic acid
- resistance occurs by inactivation of catalase- peroxidase or by mutation of enzyme in mycolic acid synthesis pathway
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M. tuberculosis specific drugs
Pyrazinamide - bacterial enzyme (PZase) converts it to pyrazinoic acid (active form)
- target of the drug is unknown
- uptake increases under acidic conditions (vacuoles of phagocytes)
- targets bacteria inside phagocytic cells
- lowered activity of PZase results in resistance
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DOTS - directly observed therapy short course
System in which patients were monitored by health care workers to ensure they took their medications
Cocktail of different drugs are required to ensure resistant strains do not arise
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Development of resistant M. tuberculosis
DOTS system dismantled in the 1970s
Rise in prison population
Rise in the homeless living in crowded shelters
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Development of resistant M. tuberculosis
Physicians no longer trained to diagnose and treat TB
Organisms exist in different compartments and exhibit different metabolic activities one or more drug may not be effective
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Multidrug resistant tuberculosis (MDR-TB)
Defined as the presence of M. tuberculosis resistant to at least isoniazid and rifampicin
Treatment involves use of “second line” drugs
Some of these were first line antituberculosis drugs when they were first introduced (e.g. Streptomycin and p-Aminosalicylic acid (PAS))
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Multidrug resistant tuberculosis (MDR-TB)
Good diagnostics is critical in controlling MDR-TB
DOTS Plus strategy - includes monthly monitoring of patients for presence of resistant strains and changing drug regimen as resistance status changes