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Respiratory II > Pharmacology- Chen Fluoroquinolones > Flashcards

Pharmacology- Chen Fluoroquinolones Flashcards

1
Q

What are the 3 strategies employed by antibacterial agents?

A
  1. Fight cell wall synthesis (Humans don’t have cell walls)
  2. Fight nucleic acid synthesis (Humans use the 60S/40S sub-units, while bacterial use 50S/30S)
  3. Fight protein synthesis (Humans use slightly different enzymes than bacteria)
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2
Q

What are antibiotics?

A

NATURAL SUBSTANCES synthesized by an organism which can inhibit the growth of another organism

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3
Q

What are antibacterials?

A

Substances synthesized in a LAB that can inhibit the growth of another organism

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4
Q

How was quinolone discovered?

A

As a by-product of the anti-malarial agent chloroquine

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5
Q

What is the generation 0 fluoroquinolone?

A

Nalidixic acid

-This was the byproduct of chloroquine

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6
Q

What was the first antibacterial?

A

The quinolone ring

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7
Q

What did they do to the quinolone ring to get flouroquinolones?

A

Added a fluorine atom at position C6

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8
Q

What did this addition of the fluorine atom do?

A
  • Increased DNA gyrase inhibitory activity
  • Facilitated penetration into the bacterial cell
  • Provided activity against staphylococci
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9
Q

MOA of fluoroquinolones?

A

Block bacterial DNA synthesis by inhibiting DNA gyrase and Topoisomerase IV

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10
Q

Is the blocking of topoisomeriase II (DNA Gyrase) more specific for gram - or gram + bacteria?

A

Gram NEGATIVE

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11
Q

What does blocking of DNA gyrase do?

A

Prevents relaxation of positively supercoiled DNA

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12
Q

Is blocking Topoisomerase IV more specific for gram + or gram - bacteria?

A

Gram POSITIVE

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13
Q

What does blocking of Topoisomerase IV do?

A

Interferes with separation of replicated chromosomal DNA into respective daughter cells during cell division

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14
Q

If you increase the dose of fluoroquinolone enough, can you target both enzymes for gram + and gram - bacteria?

A

YES
-Gram + and gram - have both enzymes and while structural differences determine the selectivity of which enzyme is affected, at high enough doses, fluoroquinolones will block both

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15
Q

Are fluoroquinolones bactericidal or bacteristatic?

A

Bactericidal

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16
Q

What are the 3 mechanisms of resistance for Fluoroquinolones?

A
  1. Mutation that alters drug target
  2. Mutation that reduces drug accumulation
  3. Plasmid-Mediated resistance
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17
Q

What are the genes that can be mutated to block fluoroquinolone binding to DNA Gyrase?

A

GyrA and GyrB which encode GyrA and GyrB proteins

-These make up the subunits for DNA Gyrase

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18
Q

What are the genes that can be mutated to block fluoroquinolone binding Topoisomerase IV?

A

ParC and ParE which encode ParC and ParE protein

-These make up the subunits for Topoisomerase IV

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19
Q

In gram + bacteria what do fluoroquinolones have to cross to get inside?

A

The cell wall and cytoplasmic membrane

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20
Q

In gram - bacteria what do fluoroquinolones have to cross to get inside?

A

Cell wall, cytoplasmic membrane, and the extra outer membrane

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21
Q

What can bacteria mutate to increase fluoroquinolones being pumped out of their cells?

A

Efflux pumps

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22
Q

What can bacteria mutate to decrease fluroquinolones from entering their cells

A

Porins

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23
Q

Describe the transfer of plasmids between bacterial cells

A
  1. Resistant bacteria comes in close proximity with sensitive bacteria
  2. Plasmid carrying resistance gene is transferred to sensitive bacteria
  3. Sensitive bacteria incorporate resistance gene and becomes resistant
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24
Q

What is the resistance gene that can be transferred via plasmid to protect DNA gyrase and topoisomerase IV against fluoroquinolone inhibition?

A

Plasmid-mediated quinolone resistance gene (gnr)

-This makes a shield for the bacteria

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25
Q

What is another plasmid-transferred gene that can inhibit fluoroquinolone activity?

A

A variant of aminoglycoside acetyltransferase

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26
Q

How does aminoglycoside acetyltransferase work to block fluoroquinolone activity?

A

It allows bacteria to transfer an acetyl group to floroquinolone so it can’t bind and thus inhibits it

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27
Q

Is plasmid-mediated resistance low level or high level?

A

Typically low level, but it can facilitate point mutations that confer high level resistnace

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28
Q

If you increase the dose of the drug, can you inhibit the bacteria?

A

Typically

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29
Q

What can happen if you increase the drug dose?

A

You can increase bacterial developing resistance due to gene mutations

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30
Q

What do fluoroquinolones end in?

A

-floxacin

31
Q

What is the first generation fluoroquinolone that isn’t used anymore?

A

Nofloxacin

32
Q

What drug is an enantiomer of ofloaxacin that has better activity and can be used for gram + and gram - organisms?

A

Levofloxacin

33
Q

What type of bacteria is ciprofloxacin most active against?

A

Gram negatives

-Has moderate activity against gram +, but used more for gram -

34
Q

Why can’t you use cipro against S. Pneumoniae?

A

It has a right MIC against this and you would need really high concentrations (gram +)

35
Q

What are the 3 respiratory fluoroquinolones?

A

Levofloxacin, Moxifloxacin, and Gemifloxacin

36
Q

Why are they respiratory fluoroquinolones?

A

Have low MIC against S. Pneumoniae (can be used against gram + with good activity

37
Q

What other type of bacteria is Moxifloxacin good for?

A

Anaerobes

38
Q

Can you use moxifloxacin against gram -?

A

Hasn’t been established yet

39
Q

Do fluoroquinolones have good oral bioavailability?

A

YES (70-95%)

40
Q

What can impair oral absorption in floroquinolones?

A

Divalent or trivalent cations
ANTACIDS
-Form insoluble chelation complexes with cations

41
Q

Where is moxifloxacin metabolized/eliminated?

A

LIVER

42
Q

Do you need to dose adjust moxifloxacin in patients with renal insufficiency?

A

NO

43
Q

Is moxifloxacin contraindicated in patients with hepatic failure?

A

RELATIVELY

44
Q

What fluoroquinolones are good for use in UTI?

A

Cipro, Levo, Gemi

-They are eliminated/metabolized in kidneys

45
Q

Which fluoroquinolones do you have to dose adjust for people with renal insufficiency?

A

Cipro, Levo, Gemi

46
Q

Which fluroquinolone is given orally only?

A

Gemi

All others are oral or IV

47
Q

What respiratory conditions can fluoroquinolones be used for?

A
  • Community aquired respiratory tract infections
  • Nosocomial pneumonia
  • Inhalation anthrax
48
Q

What non-respiratory infections can fluoroquinolones be used for?

A
  1. GU infections
  2. Chronic bacterial prostatitis
  3. Skin Infections
  4. Intra-abdominal infections
49
Q

Which drugs are used for acute bacterial sinusitis?

A

Cipro, Levo, Moxi

50
Q

Which drugs are used for CAP?

A

Levo, Moxi, Gemi

51
Q

Which drug cannot be used for CAP?

A

CIPRO… doesn’thave good activity against S. Pneumoniae

52
Q

Which 2 respiratory conditions are Cipro and Levo good for?

A

Nosocomial pneumonia and inhalation anthrax

53
Q

Which 2 non-respiratory conditions are Cipro and Levo good for?

A

Genito-urinary tract infections and chronic bacterial prostatitis

Remember, moxi is metabolized by liver so it won’t work and gemi is still pending FDA approval

54
Q

What 2 drugs can be used for skin infections?

A

Levo and Moxi

55
Q

Which drug can be used for intra-abdominal infections?

A

Cipro

56
Q

What CV AE do fluoroquinolones cause and what is the mechanism?

A

QT interval prolongation

-Not clear, but has something to do with K channels

57
Q

What dermatological AE do fluoroquinolones case and what is the mechansim

A

Photosensitivity and Stevens-Johnson Syndrome

-Due to degradation of the fluoroquinolone ring which makes the skin sensitive to UV light

58
Q

What GI AE do fluoroquinolones cause?

A

N/V/D

59
Q

What MSK AE do fluoroquinolones cause?

A

Tendonitis, rupture of tendon, and arthropathy

60
Q

What are the risk factors for tendon rupture?

A

Being old (already have cartilage damage), renal insufficiency (won’t be clearing drugs from system well), and using steroids (damage cartilage)

61
Q

Why do we avoid these drugs in patients under 18?

A

Because of arthropathy… we don’t want to damage their growing cartilage

62
Q

What neurological AE do fluoroquinolones cause?

A

Dizzyness, headache, and peripheral neuropathy

63
Q

How long can the peripheral neuropathy last and how does it present?

A

Can last months-years (long-term incapacitation) and the onset is QUICK

64
Q

Are these safe for your preggo patients?

A

NOPE…caused fetal toxicity in animals so we haven’t tried em on humans yet

65
Q

Can these drugs be given to nursing mothers?

A

NOPE… they are excreted in breast milk

66
Q

What is the prevalence of tendonitis and tendon rupture in patients receiving fluoroquinolones?

A

1/6000

67
Q

Which fluoroquinolone seems to have a higher incidence of tendonitis and tendon rupture?

A

Cipro… although this AE is assocaited with all of them

68
Q

What is the second most common type of AE reported in floroquinolone?

A

Neurologic effects

69
Q

How are fluoroquinolones neurotoxic?

A

The produce dose-related CNS excitation

70
Q

What receptors do fluoroqunolones inhibit to produce neurotoxicity?

A

GABA, NMDA, or adenosine

71
Q

Which fluoroquinolone is non-respiratory and why?

A

Cipro, because it lacks activity against S. Pneumoniae

72
Q

What are the 3 respiratory fluoroquinolones?

A

Levo, Moxi, Gemi

73
Q

What classes of bacteria can levo be used against?

A

Gram - and gram +

74
Q

What can gemi be used for and how is it given?

A

UTI/Oral

Respiratory II (8 decks)

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