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1. CP - Core Microbiology > (5) Introduction to antifungal agents > Flashcards

(5) Introduction to antifungal agents Flashcards

1
Q

What are fungi classified as for practical purposes?

A
  • moulds/filamentous fungi
    or
  • yeasts
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2
Q

What does dimorphic mean?

A

The fungi exists in both forms (mould and yeast)

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3
Q

Give some examples of dimorphic fungi

A
  • the causes of “endemic mycoses”
  • candida albicans
  • malasezzia spp.
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4
Q

What are the different anti fungal targets?

A
  • cell wall
  • cell membrane
  • mitochondria
  • golgi
  • ribosomes (protein synthesis)
  • nucleus (DNA synthesis, mitosis)
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5
Q

What does the cell wall of fungi consist of?

A

B-1,3-glucan

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6
Q

What does the cell membrane of fungi consist of?

A

Ergosterol

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7
Q

Give a characteristic of ergosterol

A
  • found mainly in fungal cell membranes

- forms clusters within the phospholipid bilayer

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8
Q

What role does ergosterol play?

A

Regulation of membrane permeability

Required for normal growth and function of the fungal cell wall, hence fungal viability

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9
Q

What are the 3 molecules in ergosterol biosynthesis?

A
  • squalene
  • lanosterol
  • ergosterol
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10
Q

What enzymes are required in ergosterol biosynthesis?

A

Squalene

SQUALENE EPOXIDASE

Lanosterol

LANOSTEROL 14a DEMETHYLASE

Ergosterol

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11
Q

B-1,3-glucans is a large polymer of what?

A

UDP-glucose

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12
Q

What makes up 50-60% of the dry weight of the fungal cell wall?

A

B-1,3-glucans

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13
Q

What is B-1,3-glucans synthesised by?

A

B-1,3-glucan synthase

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14
Q

B-1,3-glucans forms what?

A

A fibrous network on the inner surface of the cell wall

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15
Q

What are the classes of anti fungal agents?

A
  • polyenes
  • allylamines
  • azoles
  • echinocandins
  • others
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16
Q

What is the mode of action of polyenes?

A
  • association with ergosterol
  • formation of pore-like molecular aggregates (aqueous vs. non-aqueous pores)
  • loss of membrane integrity and leakage of K+
  • cell death
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17
Q

Give examples of polyenes

A
  • Amphotericin B

- Nystatin

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18
Q

Polyenes cause loss of fungal membrane integrity and leakage of which ion? (which leads to cell death)

A

K+

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19
Q

Polyenes associate with which molecule?

A

Ergosterol (fungal cell membrane component)

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20
Q

What is the spectrum of activity of Amphotericin B?

A

Most fungi of medical importance

Aspergillus spp., Candida spp., Cryptococcus spp.

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21
Q

What are the adverse effects of Amphotericin B?

A
  • allergic reactions

- nephrotoxicity (pores are formed in ergosterol-frer membranes)

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22
Q

What is special about lipid-associated AmB?

A

Minimise delivery of AmB to kidney cells

Reduces nephrotoxicity

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23
Q

In lipid-associated AmB, delivery to kidney cells is minimised. Where is delivery targeted?

A

Targeted to fungal cells and/or reticulo-endothelial system (liver, spleen, lymph nodes)

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24
Q

By how much does lipid-associated AmB reduce nephrotoxicity?

A

23% vs. 3% in one study with L-AmB

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25
Q

What are the different formulations of lipid-associated AmB?

A
  • liposomal AmB (L-AmB)
  • AmB lipid complex (ABLC)
  • AmB colloidal dispersion (ABCD)
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26
Q

Describe the important clinical points concerning use of Amphotericin B

A
  • not absorbed orally
  • administered parenterally
  • serious/systemic infectious
  • not used, if possible, in patients with existing nephrotoxicity
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27
Q

Describe the important clinical points concerning use of Nystatin

A
  • not absorbed orally
  • too toxic for systemic use
  • superficial infections
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28
Q

Give some examples of fungal infections which Amphotericin B might be prescribed for?

A

Serious/sytemic infections

  • aspergillosis
  • candidiasis
  • cryptococcosis
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29
Q

Give some examples of fungal infections which Nystatin might be prescribed for

A

Superficial infections

  • oral candidiasis
  • vaginal candidiasis
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30
Q

Which polyene would be used for systemic infection?

A

Amphotericin B

Nystatin is too toxic for systemic use

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31
Q

What is the mode of action of allylamines?

A

Inhibit ergosterol synthesis (target = squalene epoxidase)

32
Q

Give an example of an allylamine

A

Terbinafine

33
Q

What is the spectrum of activity of allylamines (terbinafine)?

A

Broad spectrum of activity in vitro

34
Q

What are the adverse effects of allylamine?

A

Liver toxicity (jaundice, hepatitis - rarely fatal)

35
Q

What are the clinical uses of allylamines?

A

Dermatophyte infections (superficial fungal infections)

  • topical use
  • systemic (oral) use
36
Q

For what infections would you use allylamines topically?

A
  • athlete’s foot (tinea pedis)
  • tinea corporis
  • tinea cruris
37
Q

For what infections would you use allylamines systemically?

A
  • scalp ringworm (tinea capitis)

- onychomycosis

38
Q

What is onychomycosis?

A

Fungal infection of the nail - it is the most common disease of the nails

Also known as tinea unguium

39
Q

What are dermatophytes?

A

Dermatophytes are fungi that require keratin for growth - these fungi can cause superficial infections of the skin, hair, and nails

40
Q

What are azoles?

A

Synthetic compounds containing a 5-membered azole ring

41
Q

What characterises an imidazole?

A

Two nitrogen atoms

42
Q

What characterises a triazole?

A

Three nitrogen atoms

43
Q

What is the mode of action of azoles?

A

Inhibit ergosterol synthesis (target = lanosterol 14a-demethylase)

  • build up of non-ergosterol 14a-sterols in cell membrane
44
Q

What is the spectrum of activity of azoles?

A
  • complex, varies between drugs
  • essentially broad spectrum (yeasts and filamentous fungi)
  • exceptions (fuconazole/aspergillus spp.)
45
Q

Which, out of imidazoles and triazoles, is toxic?

A

Imidazoles = toxic

Triazoles = less toxic

46
Q

Which, out of imidazoles and triazoles, is used systemically?

A

Imidazoles = rarely used systemically - ketoconazole

Triazoles = systemic use is common

47
Q

Give some examples of imidazoles

A
  • clotrimazole
  • miconazole
  • ketoconazole
48
Q

Give some examples of triazoles

A
  • fluconazole
  • itraconazole
  • voriconazole
  • posaconazole
  • isavuconazole
49
Q

What are the adverse effects of azoles?

A
  • hepatotoxicity
    (mild liver enzyme abnormalities eg. 7% with fluconazole, life-threatening hepatitis eg. 1/10,000 patients with ketoconazole)
50
Q

What are the drug interactions of azoles?

A

Inhibition of cytochrome P450 enzymes

= increases concentration of all drugs metabolised by Cy P450 enzymes

51
Q

What is the anti fungal spectrum of fluconazole? (a triazole)

52
Q

What is the anti fungal spectrum of itraconazole/voriconazole? (triazoles)

A
  • yeasts

- aspergillus spp.

53
Q

What is the anti fungal spectrum of posaconazole/isauvconazole? (triazoles)

A
  • yeasts
  • aspergillus spp.
  • mucoraceous moulds
54
Q

What are the clinical uses of imidazoles?

A

Superficial infections (topical administration)

  • candidiasis
  • dermatophyte infections
55
Q

What are the clinical uses of triazoles?

A

Systemic infections (oral/parenteral administration)

  • aspergillosis
  • candidiasis
56
Q

Triazoles are used for aspergillosis, for treatment and for what else?

A

Used in treatment and occasionally as prophylaxis

57
Q

Give an imidazole and a triazole used to treat candidiasis

A

imidazole = clotrimazole (canesten)

triazole = fluconazole

58
Q

What is the mode of action of echinocandins?

A

Inhibition of B-1,3-glucan synthesis

Construction of severely abnormal cell wall

59
Q

Give some examples of echinocandins

A
  • anidulafungin
  • caspofungin
  • micafungin
60
Q

What is the spectrum of activity of echinocandins?

A
  • aspergillus spp. and candida spp.

- misses certain moulds and cryptococcus spp.

61
Q

What are the adverse effects of echinocandins?

A

Minimal

eg. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug

62
Q

What are the clinical uses of echinocandins?

A

Systemic infections

  • parenteral formulations only
63
Q

What is 5-flurocytosine (5-FC)?

A

Synthetic analogue of cytosine (pyrimidine nucleoside)

64
Q

What was 5-FC originally developed as?

A

Developed as an anti-cancer drug

Has no anti-cancer activity, but was found incidentally to have anti fungal activity

65
Q

What is the mode of action of 5-fluorocytosine?

A
  • enters cell (requiring fungal cytosine permease)
  • coverted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate
  • inhibits RNA/protein synthesis and DNA synthesis
66
Q

What allows 5-fluorocytosine to have selective toxicity?

A

Entry of 5-FC into the cell requires fungal cytosine permease

67
Q

What 2 products is 5-fluorocytosine converted to?

A

5-fluorouracil
and
5-fluorodeoxyuridine monophosphate

68
Q

What does 5-fluorocytosine ultimately do to kill the fungus?

A

Inhibits RNA/protein synthesis and DNA synthesis

69
Q

What is the spectrum of activity of 5-fluorocytosine?

A

Yeasts only

  • candida and cryptococcus spp.
70
Q

What are the adverse effects of 5-flurorocytosine?

A

Bone marrow suppression

  • selective toxicity is incomplete
  • 5-fluorouracil (5FU) is an anti-cancer drug
71
Q

What is the clinical use of 5-fluorocytosine?

A

Cryptococcal meningitis (in combination with AmB)

72
Q

What is the mode of action of griseofulvin?

A

Inhibition of fungal mitosis

73
Q

What is the spectrum of activity of griseofulvin?

A

Dermatophytes

74
Q

What are the adverse effects of griseofulvin?

75
Q

What are the clinical uses of griseofulvin?

A
  • dermatophyte infections in children requiring systemic treatment (eg. kerion, onychomycosis)
76
Q

What are the reasons for therapeutic drug monitoring?

A
  • to minimise toxicity (level should remain below a threshold value)
  • to maximise efficacy (level should exceed a threshold value)
77
Q

Give 3 anti fungal drugs that require TDM (therapeutic drug monitoring)

A
  • itraconazole
  • voriconazole
  • 5-fluorocytosine

1. CP - Core Microbiology (8 decks)

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