Antimycobacterials

Question 1

What are the challenges of Antimycobacterial therapy?

Answer 1

1. Difficult to kill: Vulnerable to -cidal drugs only when metabolically active. Small populations are semi-dormant
2. Slow growth: Hampers identification/susceptibility
3. Length therapy: Compliance and toxicity are problems
4. Intracellular forms: difficulty with penetrance
5. Chronic disease: Well-established before patient is symptomatic

Question 2

Why is multi-drug therapy standard of practice for treatment of TB?

Answer 2

The spontaneous mutation rate creates high levels of resistance to single drug therapy.

Question 3

1. What is Arabinogalactan?
2. What is the role of mycolic acids in mycobacteria?

Answer 3

1. A substance unique to mycobacteria that binds the cell wall to the outer membrane
2. A major component of the outer membrane.

Question 4

What are the first line drugs used to treat TB?

Answer 4

1. Isoniazid
2. Rifampin
3. Ethambutol
4. Pyrazinamide
5. Streptomycin

Question 5

1. What is the mechanism for Isoniazid?
2. How is Isoniazid activated?
3. What does it target?
4. What type of activity does it have against TB? -cidal or -static?

Answer 5

1. Inhibits synthesis of mycolic acids
2. Activated by the catalase-peroxidase (KatG protein)
3. targets the enoyl-acyl carrier protein reductase (InhA protein)
4. It is a -cidal agent

Question 6

What are the two major reasons for resistance to Isoniazid?

Answer 6

1. Mutations in KatG:prevents drug activation
2. Mutations in InhA:prevents activated drug from binding target

Question 7

What are the recommendations for Isoniazid use?

Answer 7

1. All patients infected with isoniazid-sensitive strains should receive it.
2. Always given in combination with other drugs for active TB

Question 8

How does a N-acetyltransferase-2 polymorphism affect the TB patient?

Answer 8

Slow acetylators will have impaired drug metabolism and subsequently clearance.

Question 9

What are the adverse effects of Isoniazid?

Answer 9

1. Neurotoxicity, especially peripheral neuritis: improved with B₆ administration
2. Hepatotoxicity (10-20%): highly correlated with patients age >35 years.

Question 10

1. What is the mechanism of action for Rifampin? Is it -cidal or -static?

Answer 10

1. Inhibits DNA-dependent RNA polymerase, thereby suppressing RNA synthesis
2. It is bactericidal

Question 11

What are the adverse effects of Rifampin?

Answer 11

1. Hepatotoxicity: sever in alcoholics and elderly
2. ** Increased metabolism of other drugs**: potent inducer of multiple CYPs.
3. Orange-red colored secretions: Urine, feces, saliva, sputum, tears, sweat.

Question 12

What is the mechanism of action for Ethambutol?

Is it -cidal or -static?

Answer 12

1. Interferes with arabinosyl transferase with blocks cell wall synthesis: prevents arabinoglycan polymerization.
2. It is tuberculostatic: it weakens cell barrier enhancing combination drug entry.

Question 13

What is a major adverse effect of Ethambutol?

What is less of a concern with Ethambutol?

Answer 13

1. Optic neuritis (5-15%)
2. It is NOT hepatotoxic

Question 14

1. What is the mechanism for Pyrazinamide?
2. Is it -cidal or -static?

Answer 14

1. Blocks mycolic acid synthesis by inhibiting fatty acid synthase 1
2. It is bactericidal

Question 15

When is Pyrazinamide particularly useful?

Answer 15

In CNS involvement with TB.

Question 16

What is the major adverse effect of Pyrazinamide?

Answer 16

Hepatotoxicity: <15%, particularly concerning when combined with rifampin.