Anti-mycobacterial Therapies

Question 1

What is MDR TB?

Answer 1

Multi-drug resistant TB. These strains are resistant to two different first line drugs (like isoniazid and rifampin).

This form has increased mortality, more drug side effects and much more expensive to treat.

Question 2

What is XDR TB?

Answer 2

Extremely drug resistant TB.

Recently emerged, and is resistant to at least 3 different first line drugs. This strain is typically 50% fatal, more expensive, and take longer to treat.

Question 3

TB And HIV: twin epidemics?

Answer 3

TB can remain in the latent form, but when you have HIV its more likely to become active again faster.

Question 4

Brief characteristics of mycobacteria

Answer 4

1. Stain acid fast with aryl methane dyes (like carbon fuchsin)
2. Aerobic
3. Mycolic acid in cell wall
4. Genome has 59-65% GC content

Question 5

Cell wall of mycobacterium (4 layers from the inside out)

Answer 5

1. Cytoplasmic membrane
2. Peptidogylcan layer
3. Arabinogalactan layer
4. Mycolic acid layer

Question 6

What complicates treatment of TB? 4 things.

Answer 6

1. Infection is chronic (long term tx)
2. Bacteria often intracellular
3. Bacteria develop resistance to single drugs
4. Often dormant w/ slow growth rate

Question 7

First line drugs:

Answer 7

RIPE

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

Question 8

Isoniazid. How does it work?

Answer 8

1. It inhibits mycotic acid synthesis.
2. Active against extra and intracellular mycobacteria.
3. Bactericial
4. High specificity
5. Pro-drug that must be converted to active form by KatG enzyme

Question 9

Describe the pharmacokinetics of isoniazid.

Answer 9

Absorbed from the GIT and diffuses into all body fluids and tissue (Even CNS).

Similar intra and extracellular concentrations

Question 10

How is isoniazid inactivated?

Answer 10

Acetylation

There is genetic variation in how fast or slow a person acetylates this drug, affecting its therapeutic and toxic effects

Question 11

What are the side effect of isoniazid?

Answer 11

1. Neurotoxicity
2. Hepatotoxicity: caused by acylated metabolites
3. Allergic rxns

Question 12

What drug can be given to counteract the neurotoxic side effects of isoniazid?

Answer 12

Pyridoxine (vitamin B6)

Question 13

What drug-drug interaction should you look out for with isoniazid?

Answer 13

Isoniazid and phenytoin (epileptic drug)

Question 14

Rifapmpin mechanism?

Answer 14

1. Inhibits DNA dependent RNA polymerase (no effect on host enzyme). This makes it more broad spectrum than other TB drugs
2. Bactericidal
3. Can kill intra and extracellular mycobacteria

Question 15

Describe the pharmacokinetics

Answer 15

1. Absorbed via GIT
2. Excreted into bile and undergoes enterohepatic recirculation.
3. Excreted into bodily builds, causing orange-red colorant of urine, feces, saliva

rifamPIN makes your pee PUMPKIN colored

Question 16

Side effects of rifampin

Answer 16

Well tolerated but:

1. Jaundice, rash, thrombocytopenia, nephritis
2. If you give it less often (

Question 17

Drug interactions with rifampin

Answer 17

Potent inducer of CYP450 enzymes (can reduce half life of anticoagulants, OCPs, chloramphenicol, methadone, PIs etc)

Question 18

Rifapentine. Same as rifampin?

Answer 18

Pretty much. The “long-acting rifampin” (2x week dosage=patient compliance). Same side effects and drug interactions as rifampin

Question 19

Ethambutol mechanism of action?

Answer 19

1. Inhibits arabinogalactan synthesis (remember, 2nd from the outside layer, right under mycotic acid)
2. Bacteriostatic for mycobacteria
3. Specific for mycobacteria

Question 20

Pharmacokinetics of ethambutol?

Answer 20

Absorbed in GIT, excreted in urein

Question 21

Side effects of ethambutol (2).

Answer 21

1. Optic neuritis: loss of ability to differentiate red from green.
2. Decrease urate secretion–>gout

Question 22

Mechanism of action of pyrazinamide?

Answer 22

1. Inhibits fatty acid synthetase1 (FAS1) or mycobacterium TB.
2. Can enter cells
3. Prodrug

Question 23

Pharmacokinetics of pyrazinamide?

Answer 23

Absorbed in GIT, excreted in urine mainly

Question 24

Side effects of pyrazinamide?

Answer 24

1. Hepatotoxicity
2. Nongouty polyarthralgia
3. GI sx
4. Gout arthritis

Question 25

What a common (and stupid) reason for drug resistance in TB? What do we do about it?

Answer 25

People start taking their meds and then stop, leading to an increase in resistance. This is where DOT (direct observed therapy) comes in (having pt come in or someone go out to pt to make sure they take their drugs)

Question 26

Describe the typical TB treatment regiment?

Answer 26

RIPE therapy for 2 months while susceptibility to drugs is tested If susceptible: continue RI for either 4 or 7 months

Question 27

Latent TB: when should you treat?

Answer 27

1. They have HIV | 2. kids

Question 28

Treatment for Latent TB?

Answer 28

1. Isoniazid and Rifapentine (3 month, 1x/wk) (most recent regiment) 2. Isoniazid for 9 months (daily, or 2x/wk DOT)

Question 29

What are some second line drugs for TB?

Answer 29

1. Steptomycin 2. Ethionamide 3. PAS 4. Cycloserine 5. Careomycin 6. Fluoroquinolones *Use when you get drug resistance to first line drugs (Tx for 9-18 months, with way worse side effects :( )

Question 30

Mycobacterium avim complex is a common infection in AIDS patients. What is the treatment?

Answer 30

1. Clarithromycin or Azithromycin + ethambutol (ACE) | 2. Use AC for prophylaxis in HIV pts

Question 31

Leprosy is caused by Mycobacterium leprae. What sx does it cause?

Answer 31

Causes peripheral nerve damage, skin and mucous membranes affected too. Difficult to transmit to others.

Question 32

What animal can transmit leprosy to us?

Answer 32

Armadillos

Question 33

Treatment for leprosy

Answer 33

``` Paucibacillary leprosy (skin smear negative): dapsone and rifampin Multibacillary leprosy (skin smear pos): dapsone, rifampin, clofazimine ```

Question 34

How does dapsone work?

Answer 34

Inhibits folate synthesis and competes with PABA for active site of dihydropteroate synthetase

Question 35

Side effects of dapsone?

Answer 35

1. Hemolysis | 2. Hemolytic anemia

Question 36

Clofazimine mechanism of action?

Answer 36

Unknown

Question 37

Side effects of clofazimine?

Answer 37

1. GI sx | 2. Red discoloration of skin