TUBERCULOSIS :

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• TUBERCULOSIS
• BACKGROUND, CAUSES TREATMENTS
• By Hardik Modi

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What is TB?

• TB is an infectious airborne disease the germs
  (Mycobacterium tuberculosis) are transferred from
  person to person.
• Spreads via air, exchanging same air with a TB
  patient gives rise to a latent TB infection
• It is believed to have spread from Cows
  (Mycobacterium bovis) to Humans (Mycobacterium
  tuberculosis)

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Initial Body defense

• Initially Macrophages try to attack the bacteria.
• Phagocytosis, chemotaxis, etc.
• If bacteria not killed, latent TB infection
  develops
• Gives rise to active form, as the immune system
  weakens

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• Bodies defense system walls the clumps of
  bacteria into the lumps of scar tissues, the
  tubercles.
• The mixture of dead and latent bacteria and the
  macrophages in the tubercle is called caseous.

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s_caseous_granuloma_(2)_TBLB.jpg
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Harmful effects of Mycobacteria tuberculosis

• The bacteria slowly eats away the healthy lung
  tissue
• Ulcer-like cavities full of pus, form in the
  sponge-like portion of the lungs
• Coughs increase
• A one inch cavity may contain 1million of these
  remorseless bacteria
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• Abscesses and deformities of the shoulders, hips,
  legs or spine
• Cause harm to the kidneys
• Infection of the GI tract, cause devastating
  diarrhea

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Spread of the disease

• For centuries the symptoms of the disease were
  known, not the spread
• Weight loss, weakness and prolonged sickness
• It was thought to be a hereditary disease
• Robert Koch suggested that it spreads via air.
• He had observed the similarities between
  Mycobacteria bovis and Mycobacteria tuberculosis
• The sputum could be obtained and it became easy
  to diagnose the disease

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Previously Practiced Treatments

• Pneumothorax treatment (air in the chest)
• First invented by Giorgio Baglivi
• Collapsing the lungs some how cured TB
• Thoracoplasty ribs on one side were taken off,
  to collapse the lung
• Ping pong balls, heavy thick oil were inserted to
  keep lungs collapsed

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Introduction of Vaccine

• Calmette and Geurin invented BCG vaccine after
  231 transfers
• 14 million people received this vaccine between
  1948 and 1951
• Problems with this vaccine TB bacteria
  naturally mutated
• BCG strains may vary from one batch to another
  and one lab to another.
• No methods were present for assessing the potency
• Did not know what strain of vaccine was being
  used or what its characteristics were.

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Discovery of Rifampin

• Dr. Sensi and his collegue Parenti discovered
  Rifampin in the early 1960s
• Found Nocardia mediterranei as antibiotic
  agianst mycobacteria family
• RIF inhibits gene transcription, by interacting
  with the beta subunit of the RNA polymerase
  enzyme.
• Bactericidal against dividing mycobacteria
• Some activity against non-dividing bacilli

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Rifampicin

• It could be given via IV
• In blood, it is bound to plamsa protein
• Distributes into body tissues and fluids,
  including cerebrospinal fluid and breast milk.
• Side effects
• Diverse alteration in the GI tract, skin, kidney
  and nervous system.
• Red-orange coloration of the body fluids.

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Isoniazid (INH)

• It is a pro-drug
• It becomes active in the cell by the activation
  of catalse-peroxidase (KatG) enzyme
• INH acts by inhibiting the biosynthesis of
  mycolic acids, important components of
  mycobacterial cell wall.

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• INH is metabolized in the liver
• It is acetylated into various metabolites
• INH concentrations are lower in rapid acetylators
  than slow acetylators
• Slow acetylators have higher risk of developing
  adverse effects
• About 10-20 may develop transient increase in
  liver enzymes and sometimes develop hepatic
  damage.

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Pyrazinamide (PZA)

• It is also a pro-drug, it needs to be converted
  into pyrazinoic acid by pyrazinamidases.
• It is active against persisting and non- dividing
  bacilli
• Even against those located intracellularly
• The use of PZA into treatment regimens for TB has
  reduced the duration of such regimens to six
  months

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Adverse effects

• Patients may develop liver alterations, such as
  transient increase in enzymes, hepatomegaly,
  splenomegaly and jaundice.
• Hyperuricemia, leading to attack of gout

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Ethambutol (EMB)

• EMB is a bacteriostatic drug, only active against
  dividing mycobacteria
• It affects the biosynthesis of the cell wall
• Increases susceptibility of M. tuberculosis to
  other drugs

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Adverse effects

• EMB causes reduction in visual acuity
• Green-red color blindness
• Constriction of the central or peripheral
  scomata

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Streptomycin

• It was the first drug used in the treatment of TB
  
• It is an aminoglycoside
• Administered by intramuscular injection

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Periods in which these drugs are used

• INH, RIF, PZA, EMB and SM are the first line
  drugs
• usually isoniazid, rifampicin, pyrazinamide and
  ethambutol or streptomycin are used for first two
  months
• From the next 4-7 months usually INH and RIF are
  used
• Second line drugs are aminoglycosides kanamycin
  and amikacin, the polypeptide capreomycin, PAS,
  cycloserine, the thioamides ethionamide and
  prothionamide

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TB in recent years

• XDR- TB, extremely drug resistant and MDR-TB have
  recently developed
• Second line drugs are said to be used for the
  treatment
• But the drugs are expensive, and toxic and have
  more side effects
• It has mainly risen in regions of Asia and South
  Africa

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Further research

• Drug target interactions
• Drug drug interactions
• How the first line drugs interact with other
  drugs and inhibit their effectiveness
• Second-line drugs
• Treatments for the side effects
• Dosage of each of the drugs
• Other forms of treatments being implemented to
  cure the XDR and MDR forms of TB