Mycobacterium TB

• acid fast rods

• obligate aerobes

• slow growing

• virulent strains grow in serpentine pattern (trehalose-dimycolate)

Transmission TB

• breathing
• P2P spread via airborne aerosols
• infectious dose--1 to 3 bacilli on 2 micron

primary TB

• intracellular growth in mos
• IL-12 production
• gamma interferon production by T & NK cells
• activated TH1
• type IV response (DTH)

Primary TB

• granulomas may be seen via chest x-ray as lobar

• progressive primary TB--middle lobe infiltrate plus adenopathy & AFB -

• granulomas may be healed by calcification

• PPD skin test + (type IV sensitivity)

TB: latency

• Majority of TB latent

• use glyoxalate to make carbs from fatty acids

• no symptoms

• chest radiograph normal

Reactivation of TB

• lack TH1 reactivation occurs--> inc bacterial growth

• defeated phagocytes cause damage to lung tissue & endothelium

work on the mycolic acid synthesis

• isoniazid

• pyrazinamide

work on arabinogalactan

ethambutol

works on peptidoglycan

d-cycloserine

work in the cytoplasm

• streptomycin

• rifampin & rifabutin

Isoniazid Mechanism

• bactercidal against dividing microorganisms

• nicotinamide analogue that forms dysfunctional NAD+, inhibiting fatty acid synthetase-2 & mycolic acid synthesis

Isoniazid resistance

• mutation of inhA enzyme target (chromosomal)
• no cross resistance w/pyrazinamide bc they have different targets
  • can be used together

Isoniazid Toxicity

• generation of metabolic oxidants due to competitive inhibition of NAD causes liver damage
• conjugation w/pyridoxal--> excretion of schiff's base--> B6 depletion--> CNS toxicity & peripheral neruopathy

pyrazinamide

• bactericidal
• MOA:  nicotinamide analogue that forms dysfunctional NAD+ preventing fatty acid synthesis (FAS I)
• toxicity: hepatotoxicity--monitor liver enzymes

ethambutol

• bacteriostatic
• synergistic
• MOA:  inhibits assembly of arabinogalactan saccharide modules that form scaffold for mycolic acid barrier
• Toxicity: toxic to myelin--optic neuritis--MS signs

2nd line drugs for TB

• ethionamide
• macrolide
• fluoroquinolones
• aminoglycosides: all protein synthesis inhibitors & injectable drugs

TB Initial therapy

• INH+RIF+PZA+EMB+vit B6 (once daily)
• 6 months
• Latent TB 1yr ISONIAZID