Anti-Mycobacterial Therapy

Question 1

What is the general idea in drug therapy of TB?

Answer 1

Multiple drugs are used

Question 2

Isoniazid HCl MOA

Answer 2

• Isoniazid is a “prodrug” that is activated by catalase peroxidase, which is regulated by the TB katG gene
• Targets the TB inhA gene product – enoyl- reductase – and therefore inhibits synthesis of mycolic acid in the TB cell wall

Question 3

Isoniazid HCl Resistance Mechanisms

Answer 3

• Mutations in katG gene result in inactivation of catalase-peroxidase
• Mutation in regulatory region of inhA gene, which is involved in mycolic acid synthesis

Question 4

Isoniazid HCl Metabolism

Answer 4

INH acetylation in liver by N-acetyltransferase - rate is dependent upon genetics

Question 5

Does INH cross the BBB?

Answer 5

Yes - CSF levels 20% plasma levels but may equal

plasma levels with meningeal inflammation

Question 6

Isoniazid HCl SE

Answer 6

• Hepatotoxicity
• Neurotoxicity
• Hypersensitivity Reactions

Question 7

How is a diagnosis of TB made?

Answer 7

• PPD skin test is shown to be positive
• The Hx will then be reviewed for any signs of risk factors
• Presence of risk factors will prompt a CXR
• Abnormal CXR will lead to AFB of the sputum for mycobacteria
• Positive AFB will the lead to the NAAT test for TB

Question 8

What are the drug interactions of INH?

Answer 8

• INH + rifampin increases occurrence of hepatitis

Question 9

Rifampin MOA

Answer 9

Inhibits DNA-dependent RNA polymerase encoded by the rpoB gene

Question 10

Rifampin Resistance Mechanisms

Answer 10

Mutations in the rpoB gene will grant resistance

Question 11

Does rifampin cross the BBB into the CNS?

Answer 11

Yes it penetrates well

Question 12

Rifampin SE

Answer 12

• Hepatotoxicity increased with other hepatotoxic drugs like INH
• Red discoloration of body fluids – urine, tears, soft contacts
• Acute renal failure, interstitial nephritis

Question 13

What are the drug interactions of rifampin?

Answer 13

Induces hepatic microsomal enzymes - interacts with hundreds of drugs

Question 14

What is the clinical use of ethambutol?

Answer 14

A “helper” drug that inhibits resistance to other drugs

Question 15

Ethambutol MOA

Answer 15

Inhibits synthesis mycobacterial arabinosyl transferase encoded by embB which affects wall synthesis

Question 16

Does ethambutol cross the BBB into the CNS?

Answer 16

No - very poorly even with inflammation

Question 17

Ethambutol SE

Answer 17

• Optic neuritis

- Peripheral neuropathy

Question 18

What is the clinical use of pyrazinamide?

Answer 18

First line TB drug – for the 1st two months of therapy - increases the cure rate and reduces the likelihood of relapse

Question 19

Pyrazinamide MOA

Answer 19

A “prodrug” activated by TB pyrazinamidase, encoded by pncA

Question 20

Does pyrazinamide cross the BBB into the CNS?

Answer 20

Distribution is good, including in the CSF in tuberculous meningitis

Question 21

Pyrazinamide SE

Answer 21

• Hepatitis, worse in patients with preexisting liver disease
• Skin rash and gastrointestinal intolerance
• Increased serum uric acid levels, but acute gout is uncommon

Question 22

What is the clinical use of streptomycin in TB?

Answer 22

Second line TB drug

Question 23

Streptomycin MOA

Answer 23

Inhibits protein synthesis by binding to ribosome

Question 24

Streptomycin SE

Answer 24

• Ototoxicity

- Nephrotoxicity

Question 25

What is primary TB resistance?

Answer 25

Infection by a source case with drug-resistant TB - acquired with the infection

Question 26

What is secondary TB resistance?

Answer 26

From ineffective therapy causing resistance to develop during treatment

Question 27

Why is multi drug therapy used in cases of TB?

Answer 27

Risk of evolution of resistance to two drugs is the product of the risk of the development of resistance to each drug - FAR lower

Question 28

What is multi-drug resistant TB?

Answer 28

Resistance to both INH and rifampin - more common in those with HIV

Question 29

What is extensively drug resistant TB?

Answer 29

• Resistance to INH and Rifampin
• Resistance to a fluoroquinolone antibiotic
• Resistance to one of three injectable antibiotics (amikacin, kanamycin, capreomycin)

Question 30

What is the problem with therapy in MDR-TB?

Answer 30

Requires therapy for at least 18-24 months because rifampin resistance eliminates the short course therapy

Question 31

What is the 6 month TB treatment regimen?

Answer 31

• 4-drug regimen (“RIPE” therapy = Rifampin-INH-PZA-Ethambutol)
• Initial phase: RIPE
• Continuation phase: RI (Note: Emb not needed if pan-suceptible)

Question 32

How is intermittent treatment of TB administered (2-3 times a week)?

Answer 32

Directly Observed Therapy

Question 33

Why is rifampin resistance so important clinically?

Answer 33

Loss of rifampin from the regimen means loss of the option for short-course (6 month) TB therapy

Question 34

What are some of the treatments for latent TB infection?

Answer 34

• INH monotherapy for 9 months is highly effective

- Rifampin – 4 month, daily therapy

Question 35

What are the drugs that are unique to NTM treatment?

Answer 35

• Clarithromycin

- Azithromycin

Question 36

What drugs are used for both TB and NTM?

Answer 36

• Rifampin
• Ethambutol
• FQs
• AGs

Question 37

Is the treatment of leprosy different than that of TB?

Answer 37

Yes. Leprosy treatment is different treatment from TB treatment.

Question 38

Paucibacillary Leprosy Treatment

Answer 38

Rifampin + dapsone daily for 12 months

Question 39

Multibacillary Leprosy Treatment

Answer 39

Rifampin + dapsone + clofazimine daily for 24 months