TB therapeutics

Question 1

What are the 3 main principles of TB treatment?

Answer 1

1) multi drug therapy
2) focus on increasing adherence
3) adequate duration of therapy

Question 2

What is the first line drug for active pulmonary TB?

Answer 2

isoniazid HCl (INH)

but not used as a single drug - used in combination

Question 3

What is the MOA of INH?

Answer 3

prodrug activated by catalase peroxidase (the TB katG gene) then targets the inhA gene product

it is CIDAL for replicating orgs and STATIC for resting orgs

Question 4

Name two mechanisms for INH resistance?

Answer 4

1) mutations in katG gene (cannot activate INH)

2) mutations in inhA gene (cannot impair cell wall synthesis)

Question 5

How is INH metabolized?

Answer 5

acetylated in liver (degree of acetylation varies with one’s genetics)

non acetylated drug is excreted in urine

Question 6

true or false: INH distributes to the CNS

Answer 6

TRUE

Question 7

What are 3 toxicities of INH?

Answer 7

1) hepatotoxicity (especially bad with rifampin)
2) neurotoxicity
3) hypersensitivity rxns

Question 8

What can rifampin NOT be used alone?

Answer 8

rapid development of resistance

Question 9

What are the main mechanisms of resistance for rifampin?

Answer 9

rpoB mutations

rpoB encodes RNA polymerase

Question 10

What are 3 common toxicities of rifampin?

Answer 10

1) red discoloration of body fluids
2) influenza syndrome
3) thrombocytopenia

Question 11

What is a huge pitfall of rifampin?

Answer 11

drug interactions!! accelerates clearance and reduces effective conc of many drugs

Question 12

What is the MOA of ethambutol?

Answer 12

inhibits TB arabinosyl transferase encoded by embB gene (affects cell wall synthesis)

Question 13

What are the 2 big toxicities?

Answer 13

1) optic neuritis

2) peripheral neuropathy

Question 14

What TB drug has known optic toxicity?

Answer 14

ethambutol

Question 15

What is the P in RIPE TB therapy?

Answer 15

pyrazinamide (PZA)

Question 16

When do you use PZA?

Answer 16

the first two months of therapy

Question 17

What is the MOA of PZA?

Answer 17

it is a prodrug activated by TB pyrazinamidase encoded by pncA

(resistance comes in the form of pncA mutations)

Question 18

Which TB drug is only used in the initial stages of TB?

Answer 18

PZA

Question 19

What is a big toxicity of PZA?

Answer 19

hepatitis

Question 20

What is the second line TB drug?

Answer 20

streptomycin

Question 21

What are the two types of TB resistance?

Answer 21

primary (acquired at infection by getting a drug resistant bug)

secondary (developed during therapy due to ineffective therapy design or adherence)

Question 22

What is the rationale for treatment with multiple drugs for TB

Answer 22

decrease the odds of evolution of resistance

Question 23

How do you calculate the risk f evolution of resistance to two drugs?

Answer 23

the product of the risk of development of resistance to each drug

Question 24

Define multi drug resistant TB

Answer 24

resistance to BOTH INH and rifampin

Question 25

Why is rifampin resistance so concerning?

Answer 25

eliminates the option of short course (6 month) therapy and instead requires 18-24 month therapy

Question 26

Define extensively drug resistant TB

Answer 26

resistance to ALL of the following

• INH and rifampin
• fluoroquinolones
• one of three injectable antibiotics

Question 27

The initial phase of TB treatment is ______ while the continuation phase is ___

Answer 27

RIPE

RI

Question 28

True or False: intermittent therapy (2-3x week) is ONLY with daily observance

Answer 28

True

6 month therapy can be successful on if adherence is high, sputum cultures convert by 2 months and there is no major cavitary lung problems