anti-mycobacterial therapies

Question 1

how are mycobacteria different from bacteria?

Answer 1

in cell wall structure :
• enclosed by inner cytoplasmic membrane and a murein cell wall layer
• the outer membrane is thick, asymmetric and highly impermeable due to the presence of mycolic acids
• cell wall of 3 linked macromolecules: 70-90C branched FAs (the mycolic acids) forming the outer lipid layer; linked to carbohydrate middle arabinogalactan; which is linked to the peptidoglycan inner layer.

Question 2

why is mycobacterial treatment hard?

Answer 2

• infections tend to be chronic ( long treatment)
• bacteria are often intracellular
• bacteria tend to develop resistance to any one drug (must use combination therapy)

Question 3

first line agents used in combination for TB treatment

Answer 3

isoniazid (INH)
rifampin
ethambutol
pyrazinamide
(IREP)

Question 4

isoniazid

Answer 4

part of IREP to treat TB

o Mechanism: Inhibits mycolic acid synthesis
o bacteriostatic for resting and bactericidal for dividing organisms
o extra- and intracellular levels are similar, therefore it is effective against intracellular mycobacteria
o enters CNS

Question 5

INH resistance

Answer 5

INH has to be activated by catalase peroxidase enzyme encoded by the KatG gene. A mutation in this gene can easily lead to resistance.

Question 6

rifampin

Answer 6

part of IREP to treat TB
o	Mechanism: inhibits the bacterial DNA dependent RNA polymerase 
o	Bactericidal 
o	kills intracellular bacteria as well.
o	turns body fluids orange-red color 

Other uses: prophylaxis of h. infleunzae meningitis and staph infections (endocarditis, osteo-myelitis, nasopharyngeal)
o Induces CYP450 enzymes

Question 7

why is rifampin significant with HIV patients?

Answer 7

o Drug Interactions: Induces many hepatic CYP450 enzymes  reduces the half-life of many drugs
 Particularly important with HIV patients, as concentration of protease inhibitors is significantly affected by rifampin

Question 8

dosing of rifampin

Answer 8

flu like symptoms when given less than 2x/wk so administer more often!

Question 9

ethambutol

Answer 9

part of ‘irep to treat TB
o Mechanism: Inhibits the synthesis of arabinogalactan. Bacteriostatic.
o Side effects: optic neuritis resulting in decreased visual acuity and loss of differentiating red/green;

Question 10

which drug of irep causes optic neuritis/loss of visual acuit?

Answer 10

ethambutol

Question 11

pyrazinamide

Answer 11

o Mechanism: Inhibits mycobacterial FA synthase I gene involved in mycolic acid biosynthesis
o Activated by pyrazinamidase
o Side effects: Hepatotoxicity. Contra indicated in patients with severe liver disease or gout.

Question 12

mutation that will cause resistance to pyrazinamide?

Answer 12

mutation in pyrazinamidase

Question 13

MDR-TB

Answer 13

TB that is resistant to isoniazid and rifampin

Question 14

XDR-TB

Answer 14

TB that is resistant to atleast 2 first line drugs and at least 3 second line drus

Question 15

second line agents for resistant TB

Answer 15

FACES
fluoroquinolones
aminosalycilic acid (PAS)
cycloserine
ethionamide
streptomycin

Question 16

fluoroquinolones that are 2nd line for TB

Answer 16

levofloacin
moxifloxacin
ofloxacin

–antibiotics

Question 17

streptomycin

Answer 17

2nd line for TB, combine w other drugs

aminoglycoside; does NOT enter cells and kill intracellularly

side effect- ototoxicity and nephrotoxicity

Question 18

ethionamide

Answer 18

similar to INH, inhibits mycolic acid synthesis

poorly tolerated due to GI issues, metallic taste, and vision/smell issues

Question 19

aminosalycilic acid

Answer 19

PAS
2nd line for TB; similar to sulfonamide; bacteriostatic

high levels are reached in the urine –> keep urine alkaline to prevent crystalluria

Question 20

what drug can reach high [] in urine?

how to prevent bad consequence?

Answer 20

PAS (aminosalycilic acid) - 2nd line for TB

keep urine alkaline to prevent crystalluria

Question 21

cycloserine

Answer 21

2nd Line drug for TB

o Mechanism: Irreversible inhibitor of alanine racemase and D-Ala-D-Ala synthetase which are involved in bacterial cell wall synthesis.

Also a partial agonist at NMDA receptors, leading to significant CNS side-effects.

CNS dysfunctions =(somnolence, headache, tremor, etc.) and psychotic reactions (suicidal tendencies, paranoid reactions, etc.).

Question 22

cycloserine side effects

Answer 22

a 2nd line for TB

CNS dysfunctions =(somnolence, headache, tremor, etc.) and psychotic reactions (suicidal tendencies, paranoid reactions, etc.).

Question 23

standard chemo treatment for TB lasts ______________;

_____ for ____months followed by ________ for ____months

Answer 23

6 months

IREP for 2 months
followed by
combo of rifampin and INH for 4 months

Question 24

using more drugs shortens treatment of TB length

true or false

Answer 24

true

Question 25

in TB treatment, HIV patients sometimes have issues with which IREP drug?

replacement?

Answer 25

rifampin

rifabutin is the replacement

Question 26

treatment of TB in kids

Answer 26

Kids not given ethambutol due to side effects – so INH/ RIF/ PZA for 2 months followed by INH/RIF for 4 months.

Question 27

a single agent is never added to a failed regimen

true or false

Answer 27

true

Question 28

how to treat MAC (mycobacterium avium complex)

Answer 28

standard anti-microbials have little efficiency over M. avium complex

Clarithromycin or azithromycin (macrolide antibiotics) with ethambutol

Question 29

hansens disease

Answer 29

• a chronic, infectious disease caused by Mycobacterium leprae.

M. Leprae is intracellular - lives in the cytoplasm of the macrophage.
• Require multi-drug treatment

2 types

Question 30

o Paucibacillary (PB) leprosy

Answer 30

characterized by 5 or less lesions with absence of organisms on smear.

includes the tuberculoid and borderline lepromatous categories

Question 31

treatment of PB leprosy

Answer 31

Dapsone + Rifampin

Question 32

o Multibacillary (MB) leprosy

Answer 32

6 + lesions with visualization of bacilli on smear.

Lepromatous, borderline lepromatous, and midborderline are included in the multibacillary category

Question 33

treatment of MB leprosy

Answer 33

Dapsone + Rifampin + Clofazimine

Question 34

dapsone

Answer 34

to treat hansens disease

Mechanism: Same as sulfonamides (inhibits folate synthesis), bacteriostatic

Side effects: Hemolysis, methemoglobinemia, and erythema nodosum leprosum

Question 35

clofazimine

Answer 35

slow acting, accumulates in tissues (half life 2 months)

o side effects: GI intolerance; red discoloration of the skin (it is a phenazine dye).

Question 36

what drug causes red coloring of the skin?

Answer 36

clofazimine (for hansens disease)