Ch.47 Antimycobacterial Drugs

Front 1

drugs used in TB

Back 1

isoniazid (INH), rifampin, ethambutol, pyrazinamide, streptomycin

Front 2

isoniazid is a structural congener of what?

Back 2

pyridoxine (B6)

Front 3

mechanism of action of isoniazid?

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inhibition of mycolic acids, characteristic components of mycobacterial cell walls

Front 4

what occurs if isoniazid is used alone?

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rapid resistance

Front 5

mutations of what genes results in resistance to isoniazid?

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deletion of katG gene for catalase-peroxidase involved in bioactivation of INH

Front 6

deletion of katG gene results in what?

Back 6

codes for catalase-peroxidase involved in bioactivation of INH so become resistant if don't have it

Front 7

deletion of inhA gene results in what?

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resistance to INH b/c deletion of gene that encodes the "target enzyme", an acyl carrier protein reductase

Front 8

INH is active against which bacteria?

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bactericidal for actively growing tubercle bacilli, less effective against dormant organisms

Front 9

liver metabolism of INH?

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via acetylation and under genetic control

Front 10

how does INH work?

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absorbed orally and penetrates cells to act on intracellular mycobacteria

Front 11

half life of INH in "fast acetylators" and "slow acetylators"

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fast- 60-90 minutes
slow- 3-4 hours

Front 12

which population contains highest fast acetylators?

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Asians origin including Native American

Front 13

clinical use of INH?

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single most important drug used in TB and is component of most drug combination regimens

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toxicity of INH?

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neurotoxic effects: peripheral neuritis, restlessness, muscle twitching, insomnia
Hemolysis if patient has glucose-6-phosphate deficiency
hepatotoxicity

Front 15

what can be used to treat neurotoxic effects of INH?

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pyridoxine (B6)

Front 16

rifampin is a derivative what drug?

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rifamycin

Front 17

rifampin is used for treatment of what?

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bactericidal against M. tuburculosis

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MOA of rifampin?

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inhibits DNA-dependent RNA polymerase encoded by rpo gene

Front 19

metabolism of rifampin?

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undergoes enterohepatic cyclin and partially metabolized by the liver. produces orange colored metabolites

Front 20

when can rifampin be used as a sole drug?

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in latent TB when INH-intolerant patient or in close contacts of patients with INH-resistant strains

Front 21

rifampin and vancomycin in combination is used for treatment of what?

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infections due to resistant staph (MRSA) or pneumococci (PRSP)

Front 22

what drug causes light chain proteinuria and can impair antibody responses

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rifampin

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side effects of rifampin?

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skin rashes, thrombocytopenia, nephritis, liver dysfunction

Front 24

if given less than twice weekly, what effects may rifampin cause?

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flulike syndrome and anemia

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effect of rifampin on liver?

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strongly induces liver drug metabolizing enzymes and enhances elimination rate of many drugs

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what drug is used over rifampin that has less drug interactions and equally effective as antimycobacterial agent?

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rifabutin

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when is rifabutin preferred over rifampin?

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for treatment of tuberculosis or other mycobacterial infections in AIDS patients

Front 28

MOA of ethambucol?

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inhibits arabinosyl transferases (encoded by embCAB operon)

Front 29

what is arabinosyl transferases involved in?

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the synthesis of arabinogalactan, a component of mycobacterial cell walls

Front 30

how does resistance occur to ethambutol?

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mutations in emb gene if drug is used alone

Front 31

clinical use of ehtambutol?

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tuberculosis, in combination with other drugs

Front 32

which drug causes dose-dependent visual disturbances?

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ethambutol

Front 33

adverse effects of ethambutol?

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dose-dependent visual disturbances including red-green color blindness, optic neuritis, possible retinal damage

Front 34

MOA of pyrazinamide?

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bacteriostatic, requires metabolic conversion via pyrazinamides (encoded by pncA gene) present in M. tuberculosis

Front 35

how does resistance to pyrazinamide occur?

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mutations in gene that encodes enzymes involved in bioactivation of pyrazinamide, and by increased efflux

Front 36

which drug has minimal cross resistance with other antimycobacterial drugs?

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pyrazinamide

Front 37

40% of patients using this drug develop nongouty polyarthralgia

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pyrazinamide

Front 38

which drug should be avoided during pregnancy?

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pyrazinamide

Front 39

toxicity of pyrazinamide?

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nongouty polyarthragia, hyperuricemia, myalgia, GI irritation, maculopapular rash, hepatic dysfunction, porphyria, photosensitivity reactions

Front 40

when is streptomycin used?

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treatment of life threatening TB, including meningitis, miliary dissemination, and severe organ TB

Front 41

drug used for treatment of TB suspected to be caused by streptomycin-resistant or multi-drug resistant mycobacterial strains

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amikacin

Front 42

which two fluoroquinolones are used as second line therapy for treatment of M. tuberculosis resistant to first line therapy?

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ciprofloxacin and ofloxacin

Front 43

which drug is a congener of INH?

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ethionamide

Front 44

toxicities of ethionamide?

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severe GI irritation and adverse neurologic effects at doses needed to achieve effective plasma levels

Front 45

drug rarely used due to ototoxicity and renal dysfunction?

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capreomycin

Front 46

drug with limited use b/c peripheral neuropathy and CNS dysfunction?

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cycloserine

Front 47

standard drug regimen for TB

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initial 3 drug regimen of INH, rifampin, and pyrazinamide. discontinue pyrazinamide after 2 months (if HIV negative) and use 2 drug regimen for following 4 months

Front 48

alternative regimen for TB

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INH, rifampin for 9 months, or INH + ethambutol for 18 months

Front 49

when treating TB, if resistance to INH >4%, what drugs should be included in the regimen?

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ethambutol or streptomycin

Front 50

TB resistant only to INH should be treated with what drugs?

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treated for 6 months with rifampin + pyrazinamide, ethambutol or streptomycin

Front 51

treatment of MAC infections?

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combination of drugs, consisting of azithromycin or clarithromycin with ethambutol and rifabutin

Front 52

which drugs are used for prophylaxis for MAC in patients with CD4 count < 50/microL

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clarithromycin or azithromycin with or without rifabutin

Front 53

drug regimen for leprosy?

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combinations of dapsone with rifampin (or rifabutin) plus or minus clofazimine

Front 54

which drug is a phenazine dye that may interact with DNA, causes GI irritation and skin discoloration ranging from red-brown to nearly black?

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clofazimine

Front 55

what is clofazimine?

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it is a phenazine used in combination for treatment of leprosy

Front 56

what is the most active drug against M leprae?

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dapsone, a sulfone

Front 57

MOA of sulfones?

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involve inhibition of folic acid synthesis

Front 58

dapsone should be used in combination with which other drugs?

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rifampin or clofazimine or both b/c of increasing resistance

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adverse effects of dapsone?

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GI irritation, fever, skin rash, methemoglobinemia, hemolysis if glucose-6-dehydrogenase deficient

Front 60

which drug is a respiratory form of dapsone?

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acedapsone

Front 61

acedapsone is used for treatment of what?

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leprosy, and alternative drug for pneumocysitis jiroveci pneumonia in AIDS patients