anti-TB, Linger, CIS/DSA Flashcards
most likely anti-TB first line to cause hepatotoxicity
pyrazinamide
MOA isoniazid INH
mycolic acid synthesis
most active drug for Tx TB
isoniazid
mech R isoniazid
mutations causing overexpression inhA
mutation deletion of katG gene (katG metabolizes drug and makes it acitve)
promoter mutations causing overexpression ahpC
mutations in kasA(kasA carrienr protein synthesis)
combination of drugs rec for active TB?
isoniazid, rifampin, pyrazinamide, ethambutol
when do you use streptomycin for Tx of TB
severe forms
because of adverse effects and only IV
MOA ethambutol
inhibit mycobacterial arabinosyl transferases which are endoed by the embCAB operon(essential in mycobacterial cell wall)
primary purpose of ethambutol in empirical Tx TB
if you were R to isoniazid, pyrazinamide or rifampin
mech of R for ethambutol
mutations causing overexpression emb gene
mutations with embB gene
adverse rxn ethambutol
retrobulbar neuritis, loss visual acuity and red-green color blindness
why is ehtambutol relatively contraindicated in young patients
visual acuity and red-green color discrimination
adverse effects of isoniazid
INH induced hepatitis (increased aminotransferases)
clinical hepatitis (depends on age and risk factors)
peripheral neuropathy (B6 deficiency because INH promotes excretion)
CNS toxicity
fever skin rashes, iatrogenic SLE
INH is contraindicated in what
people who develop INH induced hepatitis or have had any serious reaction to isoniazid
at what point do you need to stop isoniazid based on aminotrasnferase levels
5x maximal level
3x still okay–> monitor very closely
MOA rifampin
binds to beta subunit of bacterial DNA dependent RNA polymerase and inhibits RNA synthesis
bactericidal mycobacteria
active in vitro against gram + and - cocci, some enteric bacteria, mycobacteria and chlamydia
R to rifampin occurs how
point mutations in rpoB gene that encodes B subunit of RNA polymerase
no cross-resistance to other classes of antimicrobials but cross resistance to other rifamycin derivatives (rifabutin and rifapentine)
mech R pyrazinamide
impaired uptake
mutations on pncA that impair biotransformation
no cross R to other anti-TB agents
clinical uses pyrazinamide
first line agen in conjucntion with INH and rigampin in short term regimens
wither targets intra or extra cell organisms
adverse effects pyrazinamide
Hepatotoxicity (most of first line agents)
GI upset
hyperuricemia
most common cause of drug rash among first line agents
MOA pyrazinamide
taken up by macrophages where converted to pyrazinoic acid which is transported via efflux pump and may renter
exact MOA unknown
disrupts mycobacterial cell membrane synthesis and transport functions
What enzymes are involved with biotransformation of INH
N acetyltransferase NAT2
CYP450s
NAT2 again
which TBdrug is potent reducer of CYP450s
rifampin
clinical uses of isoniazid
approved for Tx active TB and latent TB
typically dosed daily sometimes 2x weekly with second anti TB agent
as monoTx, duration 9 mo
clinical uses rifampin
mycobacterial infections can be given alone for latent TB meningococcal asymptomatic carrier prophylaxis in contact of children with H influenza type b staph carriage serious staph infections
what can you take prophylactically after contact with child wiht H influenza type b
rifampin
adverse rxns rifampin
strong p450 inducer (extreme caution in HIB taking protease reverse transcriptase inhibitors)
harmless red urine, feces, saliva, sweat, CSF, tears, contact lenses
rashes, GI distrubances, thrombocytopenia, nephritis
hepatotoxicity can occur but less common
can cause flue like syndrome
what drugs have reduced effects if taken concurrently with rifampin
digoxin, propanolol, ketoconazole, metoprolol, verapamil, methadone, corticosteroids, oral contraceptives
what can occur if administer rifampin less tahn 2x/week
flue like syndrome: fever, chills, myalgias, anemia and thrombocytopenia
MOA streptomycin
irreversible inhibitor protein synthesis but exact mech for bactericidal activity is not known
binds S12 ribosome of 30s subunit
poorly penetrates cells (extracell tubercle bacilli)
R to streptomycin occurs how
mutations in rpsl gene encoding S12 or the rrs gene encoding 16S rRNA which alter ribosomal binding site
Which mycobacteria are susceptible to streptomycin
tuberculosis, MAC, kansasii