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 catalase- peroxidase 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