Antimycobacterials

Question 1

Latent TB infection

Answer 1

TB bacilli live dormant inside the lung, but do not cause destruction of organs

No signs/symptoms of disease

NOT infections

Question 2

TB disease

Answer 2

TB bacilli progressively invade and damage a part(s) of the body

Signs and symptoms of disease appear

Can be infectious

Question 3

TB symptoms

Answer 3

*(Night) cough for > 3 weeks
*Profuse night sweats
*Weight loss
Extreme tiredness
Fever
No appetite

Question 4

Is tuberculosis:
A. Gram positive
B. Gram negative
C. Acid fast
D. None of the above

Answer 4

Acid fast based on cell wall components

Question 5

TB replication time

Answer 5

Slow - 15-20 hours

Because of that, they can sense, change, adapt during replication cycle so drug resistance is a problem

Question 6

TB is a facultative intracellular parasite, usually of the _________.

Answer 6

Macrophages.

Not just limited to lungs, can affect really any part of the body where macrophages are present.

Question 7

What two components of the mycobacterium cell well are unique?

Answer 7

Mycolic Acid and Arabinogalactan

TB drugs target these components

These components are what make them “acid fast” bacteria

Question 8

First line drugs for TB

Answer 8

*Isoniazid
*Rifampin
*Pyrazinamide
*Ethambutol
(Streptomycin and Rifabutin) are back ups to these first four

ALWAYS use in combo - never monotherapy

Remember the patient is “RIPE” for treatment

Question 9

What makes something a “second line” drug

Answer 9

Not as effective and more toxic

CAN be used in cases of resistance, but won’t work as well as the front line and may kill the pt

Question 10

What does MDR mean?

Answer 10

Multi drug resistant TB - resistant to both Isoniazid and Rifampin

Question 11

What does XDR mean?

Answer 11

Extreme Drug Resistance - resistant to Isoniazid, Rifampin and some some second line drugs (ie fluroquinolone)

Question 12

For a healthy individual with active TB the treatment regime is…

Answer 12

All four front line for TWO months (Isoniazid, Rifampin, Pyrazinamide, and Ethambutol), followed by FOUR months of Isoniazid and Rifampin alone (to reduce resistance)

Question 13

For Latent TB (contracted, harbor bacteria, but not symptomatic) can be treated with…

Answer 13

Either Isoniazid OR Rifampin monotherapy

Question 14

MOA for Isoniazid

Answer 14

Inhibits biosynthesis of mycolic acid (mycobacterium cell wall)

Prodrug that requires enzyme KatG within bacillus to activate the drug

Question 15

Possible site of resistance to Isoniazid

Answer 15

Mutation of KatG (because KatG is required to active Isoniazid, which is a prodrug)

Question 16

Isoniazid prophylaxis

Answer 16

For post-exposure to TB

Weigh benefits of prophylaxis v risks of INH-associated hepatic, esp in patients >35 years

Question 17

Is Isoniazid bacteriostatic or bactericidal?

Answer 17

Static, unless combined with Rifampin

Doesn’t really matter - you’ll treatment regardless

Question 18

Metabolism of Isoniazid

Answer 18

By acetylation —> inactivated the drug

Metabolic rate of INH is depended on genetic makeup. There are Rapid and Slow metabolizers. About 1/2 of whites and blacks in the US are “slow”. Many eskimos, native Americans, and Asians are “rapid” acetylators.

Slow acetylators —> more likely to develop peripheral neuritis
Rapid acetylators —> more likely to develop hepatitis
Doesn’t change the dosage though

Primarily excreted through urine

Question 19

Main toxicities for Isoniazid

Answer 19

• **Hepatitis - monitor LFTs MONTHLY, look for jaundice. More common with fast acetylators
• *Peripheral neuritis (esp with slow acetylators) - antagonized by Pyridoxine B6)
• Hemolysis in patients with G6PD (not a contraindication but caution)
• Lupus-like Syndrome (it’s the I in the “HIP” drugs: hydralazine, INH, procainamide)

Question 20

MOA for Rifampin

Answer 20

Inhibits DNA dependent RNA polymerase (rpoB subunit) —> inhibits transcripts

**rpoB mutations confer resistance

Question 21

Rifampin primarily used for TB but also effective against…

Answer 21

Leprosy

Most G+ cocci and some G- microbes, chlamydia and pox viruses

Question 22

Rifampin toxicities

Answer 22

Generally fairly well tolerated (no hepatotoxicity)

Potent INDUCER of CYP3A4 - lots of drug interactions (NOT Recommended for HIV pt)

Orange color to urine, sweat, tears, contacts

Decrease effectiveness of birth control b/c induces liver metabolism of progestin

Question 23

MOA for Ethambutol

Answer 23

Inhibits arabinosyl transferases (embCAB) involved in the synthesis of arabinogalactan (AG) - bacteriostatic

Question 24

Which frontline TB drug can penetrate the CNS?

Answer 24

Ethambutol

Question 25

Ethambutol toxicities

Answer 25

Decrease in visual acuity and loss of GREEN-RED perception (usually reversible with discontinuation)
• Not recommended in children <13; Monitor for vision changes

Also beware in renal insufficiency - give smaller doses

Question 26

MOA for Pyrazinamide

Answer 26

Prodrug - mechanism unknown
Active at acidic pH - optimal for Mtb within macrophages (which have low pH)
Greatest activity against dormant organisms
Oral, well absorbed, good penetration

Question 27

Pyrazinamide use

Answer 27

Must be used in combo with INH and rifampin for 2 months
Critical first line drug - responsible for reducing therapy to current standard of 6 months

If hepatic dysfunction, remove PZA before INH (both contribute synergistically, but remove PZA first)

Question 28

Streptomycin

Answer 28

Aminoglycoside, inhibitor of 30s ribosomes
Bactericidal, Parenteral
Dose-related oto- and nephrotoxicity

Not used often but helpful for MDR/XDR

Question 29

Rifabutin

Answer 29

Same family as rifampin but LESS POTENT INDUCER of p450s - so helpful if you’re worried about drug interactions (esp HIV-TB coinfections)

Same orange colored secretions as with rifampin

Question 30

Mycobacterium avium complex (MAC)

Answer 30

M. avium and M. intracellulare

Common environmental pathogen; infection following inhalation (similar to pulmonary TB) or swallowing bacteria (GI distress, diarrhea)

Intrinsically resistant to anti-TB/antimicrobials

Treatment with 2 or 3 antimicrobials for 12 MONTHS

Co-infection with HIV is prevalent

Question 31

Treatment for Mycobacterium avium complex (MAC)

Answer 31

1. Include either clarithromycin or azithromycin
2. Include ethambutol
3. Add third oral drug (Rifabutin, rifampin, ciprofloxacin)

Inclusion of I.V. Amikacin in certain cases (if resistance to clarithromycin)

Question 32

Mycobacterium leprae

Answer 32

Leprosy

Multi drug therapy necessary - treatment with only one antileprosy drug will always result in development of resistance (NEVER monotherapy)

Question 33

Treating PB leprosy (1-5 patches)

Answer 33

Rifampin and dapsone for 6 months

Question 34

Treating MB leprosy (>5 patches)

Answer 34

Rifampin and Dapsone for 6-12 months

Question 35

Dapsone

Answer 35

Most widely use and least expensive anti-leprosy drug

MOA - similar to sulfonamides (think PABA antagonist) but other sulfas aren’t effective

Oral administration with rapid absorption and slow excretion

Question 36

Dapsone toxicities

Answer 36

Common - nausea, vomiting, HA etc

***Nasal obstructive (severe): improves in 3-6 months (need pt ed)

Question 37

Thalidomide use in leprosy

Answer 37

NOT for treating the mycobacterium, but for treating the leprosy related ENL (erythema nodosum leprosum)

Orphan drug status b/c of teratogenicity - very heavily regulated