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FM2 > TB Drugs > Flashcards

TB Drugs Flashcards

1
Q

Give some reasons that mycobacteria are intrinsically resistant to many antibiotics

A
  1. slow growing organisms, not hit by antibiotics that act only against growing cells
  2. Mycolic acid residues in wall renders in impermeable to many agents
  3. intracellular pathogens- inaccessible to drugs that do not penetrate macrophages
  4. rapidly develop resistance mutations
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2
Q

Isoniazid is a ___ that is converted to an isonicotinoyl radical by ____, a mycobacterial heme-containing catalase-peroxidase enzyme.

A

prodrug

KatG

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3
Q

Isonicotinoyl radicals formed by KatG react with ___ and ___ to form adducts.

A

NAD and NADP

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4
Q

Describe the action of the isonicotinoyl-NAD adduct

A

inhibits enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA), decreasing the synthesis of mycolic acid and leading to cell death

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5
Q

Describe the action of the isonicotinoyl-NADP adduct

A

inhibits DHFR to reduce nucleic acid synthesis

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6
Q

Genetic variations in acetylation rate are relevant in the parmacokinetics of _____

A

isoniazid

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7
Q

List two major adverse effects of isoniazid and how to manage them

A

Elevated LFTs/ hepatitis- monitor LFTs and avoid alcohol and acetaminophen
Neuropathy- administer vitamin B6 to prevent

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8
Q

Rifampin is a broad spectrum antibiotic that can be used to treat:

A

TB, gram positive and gram negative bacteria and micobacteria
DOC for leprosy, DOC for prophylaxis of H. influenzae meningitis and meningococcal disease

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9
Q

Rifampin is bactericidal- it binds to the Beta subunit of ___________ and inhibits _____ synthesis of ________

A

RNA polymerase, proteins

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10
Q

Rifampin resistance arises from point mutations in rpoB, the gene encoding for_________

A

Beta subunit of RNA polymerase

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11
Q

List side effects of rifampin

A

GI: DVD, cramps, hepatitis
CYP induction- drug interactions
flu like symptoms
Red-orange discoloration of bodily fluids

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12
Q

Precautions for rifampin use include hepatic disease and if CrCL is less than 10 mL/min, dose should be reduced by _____

A

50%

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13
Q

Ethambutol is a first line TB agent with a complex mechanism of action:

A

blocks arabinosyl transferase III involved in cell wall biosynthesis; appears to inhibit RNA synthesis, resulting in impaired protein synthesis; may interfere with mycolic acid biosynthesis

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14
Q

Ethambutol is only effective against bacilli that are actively dividing, so it is _______

A

bacteriostatic

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15
Q

Metabolism of ethambutol is via _________

A

sequential oxidation of alcohols resulting in dicarboxylic acid metabolite

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16
Q

The most common adverse effect of ethambutol is _________

A

optic neuritis resulting in decreased visual acuity and red-green color blindness

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17
Q

List precautions for ethambutol

A

optic neuritis
monitor visual function
adjust dosage for renal impairment
gout- can interfere with uric acid excretion

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18
Q

Pyrazinamide requires metabolic activation (hydrolysis) to ________ by tuberculin _______ enzyme

A

pyrazinoic acid

pyrazinamidase enzyme

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19
Q

Describe the proposed mechanisms of action of pyrazinamide

A

1) inhibition of eukaryotic-like fatty acid synthetase I of M. tuberculosis
2) reduction of intracellular pH
3) disruption of membrane transport

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20
Q

Pyrazinamide is ______ at low concentrations and _______ at high concentrations

A

bacteriostatic at low

bactericidal at high

21
Q

List adverse reactions to pyrazinamide

A

Hetaptotoxicity
Hyperuricemia
Rash, photosensitivity
Arthralgia

22
Q

List precautions for pyrazinamide

A

hepatic disease, gout, interferes with urine ketone determination

23
Q

List some second line TB therapeutic agents

A

Ethionamide
Aminoglycoside antibiotics- bind to 30S, inhibit protein synthesis
Fluoroquinolone antibiotics- inhibit topoisomerase

24
Q

List some aminoglycoside antibiotics

A

amikacin, gentamicin, kanamycin, neomycin, tobramycin, streptomycin; all are amino sugars

25
Q

Describe the spectrum of activity of aminoglycoside antibiotics

A

Mostly gram negative, aerobic bacilli including E coli, Klebsiella, Enterobacter, Proteus, Pseudomonas

26
Q

Describe the mechanism of action of aminoglycosides

A

Bactericidal- inhibit protein synthesis by binding 30S

27
Q

Describe the mechanism of resistance to aminoglycosides

A

Resistance via inactivating enzymes, increased expression of efflux pumps, mutations in 30S subunit components 16S mRNA and ribosomal protein S12

28
Q

True or false: aminoglycosides are great for at-home therapy because they are well absorbed in PO form

A

FALSE- must be given parenterally, IV at clinic

29
Q

The major elimination route of aminoglycosides is __________; excretion is directly proportional to ______________ and adjustments in dosing should be made accordingly

A

glomerular filtration; creatinine clearance

30
Q

List some toxicities of aminoglycosides

A 
Ototoxicity
Nephrotoxicity
Curare-like neuromuscular blockade
Allergic skin reaction/ contact dermatitis
Pregnancy Risk D
31
Q

__________ is a fluoroquinolone antibacterial agent for second line TB therapy in relapse, treatment failure, or resistance to first line agents

A

Moxifloxacin

32
Q

Describe the mechanism of action of moxifloxacin

A

Interferes with bacterial DNA function by stabilizing topoisomerase II- and topoisomerase IV-DNA cleavage complexes, inhibiting DNA duplication, transcription, repair, and recombination

33
Q

How does moxifloxacin resistance arise?

A

Mutations in topoisomerase and by multi-drug efflux pumps (P glycoprotein)

34
Q

List side effects of moxifloxacin

A

NVD, abdominal discomfort
Joint swelling, tendinitis, tendon rupture
QT prolongation, mild
Worsening of myasthenia gravis due to neuromuscular blockade

35
Q

List precautions for moxifloxacin

A

Myasthenia gravis

Long QT syndrome or on IA or III anti-arrythmai drugs

36
Q

Moxifloxacin shortens the time to __________________

A

sputum culture conversion

37
Q

A newly approved TB drug, _________, works by binding to mycobacterial ________________ to inhibit production of ____

A

bedaquiline
ATP synthase
ATP

38
Q

List adverse reactions to bedaquiline

A

GI
MSK
Headache
QT prolongation- get baseline and serial EKGs

39
Q

Why is it important to use multidrug regimens to treat TB?

A

decreased likelihood of resistance
with monotherapy: Isoniazid and rifampin both have a rate of ~ 1 resistance mutation in every 10^6 bacilli. Since lesions often contain more than 10^8 bacilli, TX of active tuberculosis with one drug results in the rapid emergence of resistance

40
Q

Drugs used for TB are often synergistic and can shorten:

A

treatment period
infectious period
spread of disease

41
Q

In biphasic regimens, at what point does the switch from initial phase to continuation phase occur?

A

culture conversion (disappearance of bacilli from sputum)

42
Q

List some populations that should be prioritized for directly observed therapy

A 
Pulmonary tuberculosis with positive sputum smears
Treatment failure, relapse
Drug resistance
HIV infection
Prior treatment for either active or latent tuberculosis infection
Current or prior substance abuse
Psychiatric illnesses, memory impairment
Previous nonadherence to therapy
Children and adolescents
43
Q

Describe the standard TB regimen for active disease

A
  1. Daily-to-thrice weekly INH + RIF + PZA + EMB for 8 weeks
    - If organisms are susceptible (areas of < 4% isoniazid resistance), can DC EMB
    - If isoniazid resistance is > 4%, add EMB or streptomycin
44
Q

Describe the continuation phase for active TB treatment

A

daily to once weekly INH + RIF for 18 weeks

45
Q

Describe prophylactic therapy for latent TB

A

Isoniazid monotherapy for 6-9 months

46
Q

Why are once weekly INH + RIF continuation phase regimens contraindicated in people who are HIV+?

A

unacceptably high rate of relapse, frequently with organisms with acquired resistance to rifamycins

47
Q

What drug is used for treatment of leprosy?

A

Dapsone

48
Q

What is the mechanism of action of dapsone?

A

Inhibition of dihydropteroate synthase, decreased folic acid, decreased DNA synthesis

49
Q

What is a major adverse effect of dapsone treatment?

A

Hemolysis, anemia, leukopenia

FM2 (11 decks)

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