TB Drugs

Question 1

What factors make TB so difficult to treat?

Answer 1

• Impermiable cell wall (mycolic acid)
• Intrinsic Resistance re efflux pumps
• Inaccessible when latent because it is intracellular
• Slow growing so antimetabolites, anti DNA, anti RNA dont work as well
• Latent vs Active infection

Question 2

What four medicaitons

comprise the standard treatment for TB?

Answer 2

Think RIPE

Rifampin

Isoniazid

Pyrazinamide

Ethambutal

Question 3

What is the sequence and duration of standard treatment for latent and active TB?

Answer 3

Latent: INH x 9 months or RIF x 4 months

Active: Rifampin, Isoniazid, Pyrazinamide

(plus Ethambutal if suspect INH resistance)

X 2 months

Then RIF and INH x 4 mo if not INH resistant

Question 4

Why are the RIPE drugs given initially for 2 months?

Answer 4

To culture INH and RIF for resistance

To destroy any TB that is resistant to INH or RIF

Question 5

What are MDR-TB and XDR-TB and how are they treated?

Answer 5

MDR = multi-drug resistant: resistant to INH and RIF

Tx: 4-6 drugs x 18 mos based on evidence of susceptibility

XDR = extensive drug resistant: resistant to 4+ medications

Tx: $500K!!

Question 6

What is the MoA and Resistance of Isoniazid?

Answer 6

MoA: bacteriocidal; inhibits mycolic acid synthesis; able to penetrate inside macrophages to get to the TB

Resistance: deletion/mutation of KatG that activates it

Overexpression of its target: InhA

Question 7

How is isoniazid metabolized and how does this affect dosing?

Answer 7

Metabolized in the host from Isoniazid (INH) to N-acetyle INH by NAT2.

Fast acetylators (Inuit, Japanese)

Slow acetylators (Euro- and African-Americans, Egyptians): buildup of INH leads to toxic metabolites leading to hepatotoxicity and peripheral neuropathy and SLE

Question 8

How can Isoniazid lead to peripheral neuropathy?

Answer 8

It outcompetes for B6/pyridoxine

(especially in slow acetylators).

Tx: give supplemental B6

Question 9

What are the drug drug interactions re Isoniazid

Answer 9

HUGE!

Induces CYP for some medications (acetaminophen)

Inhibits CYPs for many others (warfarin, diazepam, phenytoin)

Question 10

What is the MoA and primary resistance re Pyrazinamide?

Answer 10

MoA: analog of Nicotinamide inhibits Fatty Acid Synthase I and thereby inhibits cell membrane synthesis.

Prodrug that is inactive at neutral pH but converted to by mycobacteria pncA (acidic) into active.

Resistance: pncA mutations

Question 11

What are the key adverse effects of Pyrazinamide?

Answer 11

Hepatotoxicity

Hyperuricemia leading to gout sx

Arthralgia

Question 12

What is the MoA of Ethambutal?

Answer 12

MoA: inhibits mycobacteria arabinosyl transferase from polymerizing cell wall leading to holes in cell wall

Question 13

What are the key adverse effects of Ethambutal?

Answer 13

Optic neuritis (1%, rare): decreased vision and red/green color blindness. Warn them about this!

Also: fever, rash.

Question 14

What is the MoA and primary resistance re Rifampin?

Answer 14

MoA: penetrates macrophages, binds to bacterial DNA dependent RNA polymerase (rpoB) but not eukaryote version.

Thus is inhibits RNA synthesis.

Resistance: mutation of rpoB

Question 15

What is an odd side effect of Rifampin?

Answer 15

It can turn tears and urine reddish orange and can permanently stain contact lenses and permanent lenses.

Warn your patient!

Also: N, V, fever, rash, and liver disease (re alcoholics)

Question 16

What are the drug drug interactions re Rifampin and what comorbidity does this affect?

Answer 16

It induces hepatic CYPs causing therapeutic failure of HIV protease inhibitors, methodone, warfarin, OCPs.

This makes it hard to treat the 500,000 patients

who have both TB and HIV

Treat with Rifabutin instead.

Question 17

Bedaquiline is reserved for a special group of patients.

Who are they?

Answer 17

Patients with MDR-TB (multi-drug resistant)

They take Bedaquiline with three or more additional meds. x 24 weeks ($30K)!!

Question 18

What medication cannot be taken with Bedaquiline?

Answer 18

Rifampin because it is metabolized by CYP3A4.

Question 19

What are the principal adverse effects of Bedaquiline?

Answer 19

Increased liver enzymes

Question 20

What is the MoA and Resistance for Bedaquiline?

Answer 20

MoA: unique: inhibits ATP synthesis in mycobacterial so it does not have enough energy to survive.

Resistance: atpE of ATP synthase

Question 21

Bedaquiline has a Box Warning. Why?

Answer 21

Can cause deadly QT prolongation.

Patients should get regular EKGs.

Question 22

What is the MoA of streptomycin?

Answer 22

Targets 30S ribosomal unit to inhibit protein synthesis

Question 23

Under what circumstances to you prescribe streptomycin for TB and why?

Answer 23

Severe active TB

It cannot enter the cells re latent TB

It is ototoxic and hepatotoxic and C/I re pregnancy

Question 24

What TB drug is okay re pregnancy?

Answer 24

Bedaquiline.

Question 25

What is the MoA of flouroquinolones like levofloxacin?

Answer 25

Inhibit DNA synthesis and supercoiling by targeting topoisomerase.

Question 26

What drugs regimen is used to treat M. avium complex (MAC)?

Answer 26

A macrolide (clarithromycin or azithromycin)

+

Ethambutol

+

A rifamycin (rifabutin or rifampin)

Question 27

What drug regiment is used to treat M. leprae?

(aka Leprosy or Hansen’s Disease)

Answer 27

Rifampin

+

Dapsone (anti-folate)

+

Clofazimine

Question 28

What is the primary risk factor for isoniazid- associated hepatitis?

Answer 28

Old age

Question 29

Why do you give B6 when taking isoniazid?

Answer 29

It causes isoniazid induced depletion of B6/pyridoxine

Question 30

What is the mechanism of the drug drug interaction between protease inhibitors and rifampin?

Answer 30

Rifampin induces CYP 3A4 enzyme making PIs less effective

Question 31

What affect does ethnic background have on the use of isoniazid?

Answer 31

Whites and blacks tend to be slow acetylators leading to drug toxicity.