anti-TB, Linger, CIS/DSA Flashcards by Amanda Beach

most likely anti-TB first line to cause hepatotoxicity

pyrazinamide

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MOA isoniazid INH

mycolic acid synthesis

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most active drug for Tx TB

isoniazid

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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)

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combination of drugs rec for active TB?

isoniazid, rifampin, pyrazinamide, ethambutol

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when do you use streptomycin for Tx of TB

severe forms

because of adverse effects and only IV

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MOA ethambutol

inhibit mycobacterial arabinosyl transferases which are endoed by the embCAB operon(essential in mycobacterial cell wall)

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primary purpose of ethambutol in empirical Tx TB

if you were R to isoniazid, pyrazinamide or rifampin

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mech of R for ethambutol

mutations causing overexpression emb gene

mutations with embB gene

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adverse rxn ethambutol

retrobulbar neuritis, loss visual acuity and red-green color blindness

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why is ehtambutol relatively contraindicated in young patients

visual acuity and red-green color discrimination

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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

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INH is contraindicated in what

people who develop INH induced hepatitis or have had any serious reaction to isoniazid

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at what point do you need to stop isoniazid based on aminotrasnferase levels

5x maximal level

3x still okay–> monitor very closely

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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

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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)

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mech R pyrazinamide

impaired uptake
mutations on pncA that impair biotransformation
no cross R to other anti-TB agents

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clinical uses pyrazinamide

first line agen in conjucntion with INH and rigampin in short term regimens
wither targets intra or extra cell organisms

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adverse effects pyrazinamide

Hepatotoxicity (most of first line agents)
GI upset
hyperuricemia
most common cause of drug rash among first line agents

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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

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What enzymes are involved with biotransformation of INH

N acetyltransferase NAT2
CYP450s
NAT2 again

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which TBdrug is potent reducer of CYP450s

rifampin

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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

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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

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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