What are the challenges of Antimycobacterial therapy?
- Difficult to kill: Vulnerable to -cidal drugs only when metabolically active. Small populations are semi-dormant
- Slow growth: Hampers identification/susceptibility
- Length therapy: Compliance and toxicity are problems
- Intracellular forms: difficulty with penetrance
- Chronic disease: Well-established before patient is symptomatic
Why is multi-drug therapy standard of practice for treatment of TB?
The spontaneous mutation rate creates high levels of resistance to single drug therapy.
- What is Arabinogalactan?
- What is the role of mycolic acids in mycobacteria?
- A substance unique to mycobacteria that binds the cell wall to the outer membrane
- A major component of the outer membrane.
What are the first line drugs used to treat TB?
- Isoniazid
- Rifampin
- Ethambutol
- Pyrazinamide
- Streptomycin
- What is the mechanism for Isoniazid?
- How is Isoniazid activated?
- What does it target?
- What type of activity does it have against TB? -cidal or -static?
- Inhibits synthesis of mycolic acids
- Activated by the catalase-peroxidase (KatG protein)
- targets the enoyl-acyl carrier protein reductase (InhA protein)
- It is a -cidal agent
What are the two major reasons for resistance to Isoniazid?
- Mutations in KatG:prevents drug activation
- Mutations in InhA:prevents activated drug from binding target
What are the recommendations for Isoniazid use?
- All patients infected with isoniazid-sensitive strains should receive it.
- Always given in combination with other drugs for active TB
How does a N-acetyltransferase-2 polymorphism affect the TB patient?
Slow acetylators will have impaired drug metabolism and subsequently clearance.
What are the adverse effects of Isoniazid?
- Neurotoxicity, especially peripheral neuritis: improved with B6 administration
- Hepatotoxicity (10-20%): highly correlated with patients age >35 years.
- What is the mechanism of action for Rifampin? Is it -cidal or -static?
- Inhibits DNA-dependent RNA polymerase, thereby suppressing RNA synthesis
- It is bactericidal
What are the adverse effects of Rifampin?
- Hepatotoxicity: sever in alcoholics and elderly
- ** Increased metabolism of other drugs**: potent inducer of multiple CYPs.
- Orange-red colored secretions: Urine, feces, saliva, sputum, tears, sweat.
What is the mechanism of action for Ethambutol?
Is it -cidal or -static?
- Interferes with arabinosyl transferase with blocks cell wall synthesis: prevents arabinoglycan polymerization.
- It is tuberculostatic: it weakens cell barrier enhancing combination drug entry.
What is a major adverse effect of Ethambutol?
What is less of a concern with Ethambutol?
- Optic neuritis (5-15%)
- It is NOT hepatotoxic
- What is the mechanism for Pyrazinamide?
- Is it -cidal or -static?
- Blocks mycolic acid synthesis by inhibiting fatty acid synthase 1
- It is bactericidal
When is Pyrazinamide particularly useful?
In CNS involvement with TB.
What is the major adverse effect of Pyrazinamide?
Hepatotoxicity: <15%, particularly concerning when combined with rifampin.
