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Therapeutics P3 Spring > Exam 5 Lecture 5 > Flashcards

Exam 5 Lecture 5 Flashcards

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1
Q

What does acid fast bacteria (AFB) mean?

A

Mycobacterium tuberculosis is acid fast.

Is neither gram positive nor gram negative. After staining with a dye (ziehl-neelsen stain) cannot be decolorized by acid wash

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2
Q

WHat type of bacteria is mycobacterium tuberculosis

A

Obligate aerobes

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3
Q

What is most common tx of active Tb infection? Alternative tx

A

RIPE- Combination of rifampin, isoniazid (INH), pyrazinamide, and ethambutol

Alternative- Rifapentine, INH, pyrazinamide and moxifloxacin

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4
Q

Why do we treat TB using combination of drugs

A

Different drugs are needed to combat dividing and dormant forms

Tb rapidly develops resistance to individual drugs

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5
Q

Describe the composition of the mycobacterial cell wall, how it differs from the cell walls
of Gram-negative and Gram-positive bacteria, and how it influences mycobacterial
susceptibility to antibiotics

A

mycobacterium lipid rich cell wall contains mycolic acids and is impermeable to many drugs

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6
Q

What is isoniazid activated by? static/cidal? What is it specific for

A

Pro drug that is activated by M. tb KatG protein

bactericidal

Specific for M. tb

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7
Q

Isoniazid MOA

A

It is activated by KatG

Forms adducts with NAD+ and NADP+

Inhibits enzymes that use NAD+ and NADP+

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8
Q

When isoniazid adducts with NAD and NADP, what enzymes do they inhibit

A

NAD adduct inhibits INhA and KasA

NADP adduct inhibits
- DHFR

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9
Q

What are InHA and KasA used for

A

mycolic acid synthesis

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10
Q

What is InhA a component of? WHat does it do?

A

FAS II (fatty acid synthase II)
It catalyzes the NADH dependent reduction of fatty acids bound to acyl carrier protein (synthesis of mycolic acid)

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11
Q

Summarize MOA of isoniazid? How does resistance to isoniazid occur

A

Isoniazid activated by KatG, forms adducts with NAD/P, which inhibit InhA, which blocks mycolic acid synthesis. Leads to a defective cell wall.

Resistance can emerge if we overexpress InhA (low level resistance)
Mutation of KatG (high level resiistance)

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12
Q

How is isoniazid metabolized?

A

acetylation by liver N-acetyltransferase (NAT2)

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13
Q

WHat is the major concern of toxicity for isoniazid

A

Hepatitis

Peripheral neuropathy is also common

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14
Q

how is peripheral neuropathy caused by isoniazid reversed?

A

Pyridoxine

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15
Q

How does pyridoxine reverse isoniazid peripheral neuropathy

A

Isoniazid resembles pyridoxine, so isoniazid competitively inhibits pyridoxine phosphokinase.

(pyridoxine phosphokinase converts pyridoxine to pyridoxal phosphate (active form)

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16
Q

What is the MOA of pyrazinamide? (what is it actuvated by? PH?? What is it converted to?) What does it treat?

A

It is a prodrug that requires conversion to pyrazinoic acid by pncA. It is inactive at neutral PH and is activated by low PH (<5.5).

It is a sterilizing agent against residual intracellular bacteria (non replicating perisistent bacteria (NRPB)

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17
Q

What does panD do?

A

Involved in making coenzyme A

pyrazinamide inhibits panD

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18
Q

How is panD inhibited?

A

pyrazinoic acid (POA) binds o panD, precursor pyrazinamide does not

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19
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25
How does resistance to pyrazinamide happen
Pyrazinoic acid does not bind to mutant panD
25
toxicity of pyrazinamide (most common and most dangerous)
Joint pain (arthralgia) is most common side effect Hepatitis is most dangerous side effects
25
How does pyrazinamide treatment work
Pyrazinamide reduces accumulation of coA precursors after panD step Increases level of free fatty acid
25
How does resistance to pyrazinamide occur
Generated easily, but suppressed when used in combo Primarlly due to mutations in pncA
25
What is the cause of toxicity of pyrazinamide
Hydroxylated POA
25
Is ethambutol bacteriostatic or cidal? MOA?
Bacteriostatic MOA- inhibits mycobacterial arabinosyl transferase
26
What is arabinosyl transferase involved in? WHat inhibits it? WHat does this inhibition lead to?
It is involved in polymerization of arabinogalactan Ethambutol is the inhibitor Results in build up of arabinan
26
What parts of mycobacteroium do isoniazid and ethambutol inhibit
Ethambutol inhibits arabinogalactan Isoniazid inhibits mycolic acid
27
What is ethambutol synergistic with
rifampin
28
How does resistance occur in ethambutol
is due to over expression of mutations in arabinosyl transferase. Not used alone bc of resistance
29
What is the most important toxicity in ethambutol
Optic neuritis. Can be irreversible if tx not dx
30
What is the most effective drug in RIPE? Why?
Rifampin. Can kill M tb inaccessible to many other drugs (highly sterilizing and rapidly renders pts non infectious) active against growing and stationary (non dividing cells) with low metabolic activity
31
Is rifampin cidal or static? WHen is it the most effective
Bactericidal Most effective when cell division is occuing
32
Rifampin MOA
binds to RNA polymerase deep within the DNA/RNA channel (blocks path of elongating RNA (Not chain terminator)
33
rifampin adverse effects
Colors urine, tears and sweat orange (can permanently stain contact lenses)
34
Use of fluoroquinolones in TB
Can be used instead of ethambutol
35
MOA of fluoroquinolones (moxifloxacin)? Cidal or static?
Traps gyrase on DNA as ternary complex and prevents resolution of supercoiled DNA. Disrupts DNA replication Bactericidal
36
preferred fluoroquinolone for tb
Mox- better PK (better penetration from plasma to tissue)
37
WHat TB drugs have hepatitis toxicity? Eye damage? Orange discoloration of urine? How often to monitor for adverse effects
Hepatitis- isoniazid, pyrazinamide, rifampin Eye damage- Ethambutol Orange discoloration- Rifampin Monitor patients monthly
38
What do we use to treat extensively drug resistant tb and treatment intolerant or non responsive multi drug resistant tb
BPaL Bedaquiline Pretomanid Linezolid
39
linezolid MOA
inhibits protein synthesis
40
Bedaquiline MOA? Cidal or static? ROA?
Oral bactericidal drug MOA- inhibits ATP synthase
41
How does resistance occur in bedaquiline
Mutations in atpE
42
pretomanid MOA
prodrug activated by m.tb deazaflavin dependent nitroreductase (Ddn)
43
How does pretomanid differ in aerobic and anaerobic conditions
Aerobic- forms reactive intermediate metabolite that inhibits mycolic acid production Anaerobic (non replicating, persistent bacilli) - generates reactive nitrogen species such as NO -Direct poisoning of the respiratory complex (ATP depletion) - increases killing by innate immune system
44
When are second line agents for TB considered
-Resistance to first line agent - Failure of clinical response to 1st line agent - intolerance to 1st line agent
45
name second line agents against TB
Streptomycin Ethionamide Para aminosalicylic acid Cycloserine Capreomycin
46
What TB drug is especially useful in cerebral meningitis due to strong penetration into the CSF
PZA
47
What TB drug is avoided in kids
EThambutol
48
Addition of what drug reduces mortality of TB meningitis
Dexamethasone
49
Describe the hepatitis isoniazid, pyrazinamide and rifampin cause
Isoniazid causes a slower and less acute hepatotos that progressively gets worse, but PZA and RIF cause a more acute and fulminant hepatotoxicity
50
What are different tests for TB? describe them (check slide)
1. PPD- delayed skin test (within days) 2. IGRA (Quantiferon)- Interferon test that is fast working (within hours) Culture- slow test sputum smear- we do 3 different tests to discharge patients
51
which LTBI medication would we typically avoid or be cautious of in pts living with HIV? How soon do we see this interaction?
rifampin (IMPORTANT) and other rifamycin derivatives Takes a couple of days to a few weeks.
52
What are the 5 different TB types
Drug susceptible TB Monoresistant TB Polyresistant TB MDR TB extensively drug resistant TB (XDR)
53
describe each different type of TB (exam)
Drug susceptible TB- TB strains that are sensitive to the standard 1st line agents Monoresistant- TB strains that are sensitive to just one anti-TB drug Polyresistant- TB strains that are resistant to more than one anti TB drug but not INH and RIF MDR TB- TB strains that are resistant to RIF and INH Extensively drug resistant TB- TB strains that are resistant to RIF and INH + At least one injectable agent (amikacin, kanamycin or capreomycin) + any of the fluoroquinolones
54
how is resistance in TB different than other bacteria (exam)
TB has a spontaneous rate of mutation. (They do not transmit mutation to each other the way other bacteria do) Every 10^-8 will be resistant to rifampin spontaneously. If we have a large enough load, we can calculate this rate
55
For drug susceptible TB, what are the intensive phase and continous phase? How did guidelines change?
The first two months are the intensive phase where we take 4 drugs (rifapentine+ Isoniazid+ Moxifloxacin+ pyrazinamide) and rifapentine + Isoniazid + Moxifloxacin for 4 2 months (4 month total) Guideline used to be rifampin + Isoniazid+ethambutol and pyrazinamide as intensive 2 month and rifampin + isoniazid as contionious phase for 4 months (6 month total)
56

Therapeutics P3 Spring (33 decks)

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