TB Drugs

Question 1

Give some reasons that mycobacteria are intrinsically resistant to many antibiotics

Answer 1

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

Question 2

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

Answer 2

prodrug

KatG

Question 3

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

Answer 3

NAD and NADP

Question 4

Describe the action of the isonicotinoyl-NAD adduct

Answer 4

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

Question 5

Describe the action of the isonicotinoyl-NADP adduct

Answer 5

inhibits DHFR to reduce nucleic acid synthesis

Question 6

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

Answer 6

isoniazid

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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

Question 9

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

Answer 9

RNA polymerase, proteins

Question 10

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

Answer 10

Beta subunit of RNA polymerase

Question 11

List side effects of rifampin

Answer 11

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

Question 12

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

Answer 12

50%

Question 13

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

Answer 13

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

Question 14

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

Answer 14

bacteriostatic

Question 15

Metabolism of ethambutol is via _________

Answer 15

sequential oxidation of alcohols resulting in dicarboxylic acid metabolite

Question 16

The most common adverse effect of ethambutol is _________

Answer 16

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

Question 17

List precautions for ethambutol

Answer 17

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

Question 18

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

Answer 18

pyrazinoic acid

pyrazinamidase enzyme

Question 19

Describe the proposed mechanisms of action of pyrazinamide

Answer 19

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

Question 20

Pyrazinamide is ______ at low concentrations and _______ at high concentrations

Answer 20

bacteriostatic at low

bactericidal at high

Question 21

List adverse reactions to pyrazinamide

Answer 21

Hetaptotoxicity
Hyperuricemia
Rash, photosensitivity
Arthralgia

Question 22

List precautions for pyrazinamide

Answer 22

hepatic disease, gout, interferes with urine ketone determination

Question 23

List some second line TB therapeutic agents

Answer 23

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

Question 24

List some aminoglycoside antibiotics

Answer 24

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

Question 25

Describe the spectrum of activity of aminoglycoside antibiotics

Answer 25

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

Question 26

Describe the mechanism of action of aminoglycosides

Answer 26

Bactericidal- inhibit protein synthesis by binding 30S

Question 27

Describe the mechanism of resistance to aminoglycosides

Answer 27

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

Question 28

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

Answer 28

FALSE- must be given parenterally, IV at clinic

Question 29

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

Answer 29

glomerular filtration; creatinine clearance

Question 30

List some toxicities of aminoglycosides

Answer 30

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

Question 31

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

Answer 31

Moxifloxacin

Question 32

Describe the mechanism of action of moxifloxacin

Answer 32

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

Question 33

How does moxifloxacin resistance arise?

Answer 33

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

Question 34

List side effects of moxifloxacin

Answer 34

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

Question 35

List precautions for moxifloxacin

Answer 35

Myasthenia gravis | Long QT syndrome or on IA or III anti-arrythmai drugs

Question 36

Moxifloxacin shortens the time to __________________

Answer 36

sputum culture conversion

Question 37

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

Answer 37

bedaquiline ATP synthase ATP

Question 38

List adverse reactions to bedaquiline

Answer 38

GI MSK Headache QT prolongation- get baseline and serial EKGs

Question 39

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

Answer 39

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

Question 40

Drugs used for TB are often synergistic and can shorten:

Answer 40

treatment period infectious period spread of disease

Question 41

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

Answer 41

culture conversion (disappearance of bacilli from sputum)

Question 42

List some populations that should be prioritized for directly observed therapy

Answer 42

``` 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 ```

Question 43

Describe the standard TB regimen for active disease

Answer 43

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

Question 44

Describe the continuation phase for active TB treatment

Answer 44

daily to once weekly INH + RIF for 18 weeks

Question 45

Describe prophylactic therapy for latent TB

Answer 45

Isoniazid monotherapy for 6-9 months

Question 46

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

Answer 46

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

Question 47

What drug is used for treatment of leprosy?

Answer 47

Dapsone

Question 48

What is the mechanism of action of dapsone?

Answer 48

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

Question 49

What is a major adverse effect of dapsone treatment?

Answer 49

Hemolysis, anemia, leukopenia