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
clinical uses streptomycin
used when injectable drug is needed (life threatening TB) or severe R
IM or IB dosing dialy for adults for several weeks follwed by few times a week for months
adverse effects streptomycin
ototoxicity- vertigo and hearing loss **most common
nephrotoxicity (dose related)
streptomycin relative contraindications
pregnancy from potential cause of deafness in newborn
first line TB Tx
ethambutol isoniazid pyrazinamide rifampin streptomycin
least potent P450 inducer
rifabutin
second line TB drugs
amikacin aminosalicylic acid capremycin cycloserine ethionamide FQ knamycin linezolid rifabutin rifapentine
Tx fo leprosy
clofazimine and dapsone
Tx for INH resistant TB
dialy rifampin alone for 4 mo (6mo in children)
what 2 factors increase risk of Tx failure
cavitary disease at presentation and a + sputum culture taken at 2 mo
if TB patient has both risk factors how long should the coninutation phase of Tx be
7 mo
how long is Tx for TB osteomyelitis
6-9 mo
how long is TB meningitis Tx for
9-12 mo
what additional drug is added for TB pericarditis
corticosteroid for 1-2 mo
what is beneficial about the addition of pyrazinamide to INH-rifampin Tx
reduces duration time of Tx to 6 mo without loss of efficacy
When is rifabutin substituted for rifampin
intolerance or unacceptable drug interactions
IF patient is R to INH what is Tx
rifampin, pyrazinamide and ethambutol for 6 mo
patient R to INH and cannot take pyrazinamide what is Tx
rifampin and ehtabutol for 12 mo
Tx for R to rifamycins
12 mo with INH, ethambutol and FQ
pyrazinamide initial 2 mo
MDR TB and XDR TB are treated how
daily DOT therapy
Tx for MDR TB
all active first line agents and FQ and one injectable drug
how long is Tx for MDR TB
18-24 mo
tx regimen for LTBI
daily isoniazid for 9 mo
patient jsut Dx with TB and not on ART, but CD<50
plan?
immediately begin ART with antiTB drugs
even though inc the risk of immune reconstitution inflammatory syndrome
how does TB change Tx of an TNF inhibitor
stop TNF inhibitor in active TB or latent
patient DX with LTBI but is pregnant, what do you do
wait to Tx till 2-3 mo post delivery because risk hepatotoxicity
when do you not delay Tx of LTBI in pregnant women
if HIV+ or recent infection TB
Initial Tx for recent TB infection in pregnant woman
INH, rifampin, ehtambutol for 2 mo
INH and rifampin for 7 mo
Agents to avoid for TB Tx in pregnancy
streptomycin: congenital deaness
Kanamycin, amikacin and capreomycin– assumed to share toxicity of streptomycin
when do we use second line agents in TB
in case of R
in case of failure of clinical response to Therapy
in case of serious Tx-limiting advserse drug reactions
What second line drugs are similar to INH
ethionamide
which second line TB drug inhibits cell wall synthesis?
adverse effects?
cycloserine
can cause peripheral neuropathy and CNS dysfunction
Which second line TB drug can cause crytalluria and GI upset and HS reactions that are severe
aminosalicyclid acid (PAS) folate synthesis antagonist
Which second line TB drugs are similar to streptomycin?
MOA?
kanamycin and amikacin
AG antibiotics
protein synthesis inhibitors
what is amikacin used for
the most resistant strains and aytpical mycobacteria
rrs mutations is assoc with which TB drug
capreomycin
R to FQ in TB occurs how
point mutations in gyrase A subunit
DM patients should use caution with what second line TB drug
FQ, because can impair glucose control
severe side effects with linezolid
bone marrow suppression and irreversible peripheral and optic neuropathy
What strains if rifabutin used to Tx
M tb, MAC, M fortuitum
which rifamycin is preferered in HIV patients
rifabutin
When is rifapentine indicated
rifampin-susceptible TB during continuation phase only
What drug combination is used in Tx leprosy
dapsone rifampin and clofazimine
what adverse effects are common with dapson
hemolysis and methemoglobinemia
MOA dapson
inhibit folate synthesis
What is used to prevent and Tx pneumocystitis jiroveci pneumonia
dapsone
when is clofazimine indicated
sulfone-R leprosy or when patienets intolerant to sulfones
adverse effects clofazimne
skin discoloration ranging from red-brown to black
GI intolerance occasionally
