Transcript Tuberculosis

Mycobacterium species
Acid fast bacilli - cell walls contain unusual glycolipids
(e.g.mycolic acids)
Mycobacterium species
Acid fast bacilli - cell walls contain unusual glycolipids
(e.g.mycolic acids)
Intracellular organisms (some are facultative others are obligate)
Diseases caused by Mycobacterium species
M. tuberculosis - tuberculosis
M. leprae - leprosy
Diseases caused by Mycobacterium species
M. avium - lung and skin infections in immunocompromised
hosts
- lymphadenopathy in children
- catheter-related infections
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
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
Tuberculosis (TB)
TB
Once known as consumption
Afflicted individuals considered
beautiful and erotic
Thought that TB sparked genius
TB
Spread by aerosols
Symptoms include : fever
coughing (often with blood)
weight loss
malaise (loss of energy)
 progressive lung damage
Systemic TB
Can infect any area of the body including:
Bones and joints
Internal organs
Brain
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
Progression of TB
T-cells involved in controlling infection
Gamma interferon (IFN-) activates macrophages
Cytotoxic T-cells (Tc -cells) kill infected macrophages
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
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)
Ghon complex
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
Progression of TB
Progression of TB
Progression of TB
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
Virulence factors
Invasion of and survival within phagocytes
Interference with T-cell activation
Eliciting inflammatory response
Diagnosis of TB
Acid-fast staining of sputum samples
Diagnosis of TB
TB skin test - injection of M. tuberculosis proteins (tuberculin)
- positive test leads to red area at injection site
Treatment of TB
Streptomycin - first antibiotic used against M. tuberculosis
- did not always cure patients
- slowly dividing cells became resistant
Treatment of TB
Rifampin - used to treat TB and prophylactically for bacterial
meningitis
- resistant mutants arise readily
- used in combination with other drugs
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 catalaseperoxidase or by mutation of enzyme in mycolic acid
synthesis pathway
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
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
Development of resistant M. tuberculosis
DOTS system dismantled in the 1970s
Rise in prison population
Rise in the homeless living in crowded shelters
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
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))
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