TB therapeutics Flashcards
What are the 3 main principles of TB treatment?
1) multi drug therapy
2) focus on increasing adherence
3) adequate duration of therapy
What is the first line drug for active pulmonary TB?
isoniazid HCl (INH)
but not used as a single drug - used in combination
What is the MOA of INH?
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
Name two mechanisms for INH resistance?
1) mutations in katG gene (cannot activate INH)
2) mutations in inhA gene (cannot impair cell wall synthesis)
How is INH metabolized?
acetylated in liver (degree of acetylation varies with one’s genetics)
non acetylated drug is excreted in urine
true or false: INH distributes to the CNS
TRUE
What are 3 toxicities of INH?
1) hepatotoxicity (especially bad with rifampin)
2) neurotoxicity
3) hypersensitivity rxns
What can rifampin NOT be used alone?
rapid development of resistance
What are the main mechanisms of resistance for rifampin?
rpoB mutations
rpoB encodes RNA polymerase
What are 3 common toxicities of rifampin?
1) red discoloration of body fluids
2) influenza syndrome
3) thrombocytopenia
What is a huge pitfall of rifampin?
drug interactions!! accelerates clearance and reduces effective conc of many drugs
What is the MOA of ethambutol?
inhibits TB arabinosyl transferase encoded by embB gene (affects cell wall synthesis)
What are the 2 big toxicities?
1) optic neuritis
2) peripheral neuropathy
What TB drug has known optic toxicity?
ethambutol
What is the P in RIPE TB therapy?
pyrazinamide (PZA)
When do you use PZA?
the first two months of therapy
What is the MOA of PZA?
it is a prodrug activated by TB pyrazinamidase encoded by pncA
(resistance comes in the form of pncA mutations)
Which TB drug is only used in the initial stages of TB?
PZA
What is a big toxicity of PZA?
hepatitis
What is the second line TB drug?
streptomycin
What are the two types of TB resistance?
primary (acquired at infection by getting a drug resistant bug)
secondary (developed during therapy due to ineffective therapy design or adherence)
What is the rationale for treatment with multiple drugs for TB
decrease the odds of evolution of resistance
How do you calculate the risk f evolution of resistance to two drugs?
the product of the risk of development of resistance to each drug
Define multi drug resistant TB
resistance to BOTH INH and rifampin
Why is rifampin resistance so concerning?
eliminates the option of short course (6 month) therapy and instead requires 18-24 month therapy
Define extensively drug resistant TB
resistance to ALL of the following
- INH and rifampin
- fluoroquinolones
- one of three injectable antibiotics
The initial phase of TB treatment is ______ while the continuation phase is ___
RIPE
RI
True or False: intermittent therapy (2-3x week) is ONLY with daily observance
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
