Antimicrobial Agents

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Antimicrobial Agents
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Mycobacterium tuberculosis

• TB is hard to kill with antibiotics
• Slow growth
• Fortified cell wall
• Intracellular growth
• Very good at developing resistance to single
  agents

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Treatment of TB Old School

• Surgical collapse of infected lung
• Vitamin D heliotherapy (can you say melanoma
• Bed rest and fresh air

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Modern Treatment of TB A Rigorous Course of
Multiple Antibiotics

• First line drugs
• Isoniazid
• Rifampin
• Ethambutol
• Streptomycin
• Pyrazinomide
• Second line drugs
• Moxi-or gatifloxacin
• Ethionamide
• Aminosalicylic acid
• Cycloserine
• Amikacin and kanamycin
• Capreomycin
• linezolid

6 months of taking a handful of pills!
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Multi-Drug Resistant TB
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Isoniazid (INH)

• Synthetic hydrazide of isonicotinic acid
• Requires catalase-peroxidase for activation
• Bacteriocidal for growing cells, static for
  resting cells
• Prevents synthesis of mycolic acids

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Isoniazid (INH)

• Oral or parental
• Water soluble, penetrates into caseous material
  of granuloma
• Acetylated and secreted into urine
• Toxicity
• Rash and fever
• Jaundice (rare)
• Peripheral neuritis (rare)

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Rifamycins

• Natural and semi-derived from filamentous soil
  bacteria
• Complex macrocyclic antibiotics
• Members of the class
• Rifabutin (for HIV)
• Rifapentine
• Rifampin rifampicin (for everyone else)

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Rifamycins

• Broad spectrum, bactericidal
• Inhibit DNA-dependent RNA polymerase
• Resistance generated by altering target

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Rifamycins

• Administered orally
• Absorbed in GI tract
• Asprin will interfere with its absorbance
• Wide distribution
• Can discolor body waste, saliva, tears orange-red
• Acetylated and then excreted into bile and
  ultimately pooped out

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Uses of Select Rifamycins

• Rifampicin
• Treatment of TB
• Prophylaxis against meningocccus
• Staph infections
• Rifabutin and rifapentine
• TB therapy for HIV patients
• MAC infections

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Toxicity/Contraindications of Rifamycins

• Rifampicin
• Flu-like illness
• Decreases half life of many drugs by inducing
  CYPs
• HIV protease inhibitors and non-nucleoside RT
  inhibitors
• Corticosteroids
• Oral contraceptives
• Rifambutin
• Induces CYPs but not to the same degree as
  rifampicin
• Polymalgia, pseudojaundice, anterior uveitis

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Ethambutol

• Inhibits arabinosyl transferases involved in cell
  wall synthesis
• Given orally and excreted mostly unchanged in the
  urine
• Dose dependent diminished visual acuity,
  red-green color blindness

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Pyrazinamide

• Synthetic pyrazine analog of nicotinamide
• Bactericidal at weak pH, where TB can be found in
  MF
• Inhibits fatty acid synthase I gene

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Pyrazinamide

• Oral administration
• Excellent penetration
• Hydrolyzed and hydroxylated before being excreted
  by kidneys
• Hepatotoxicity (uncommon)
• Hyperuricermia gout (rare)

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Mechanisms
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The End! Finally