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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
What are the different formulations of lipid-associated AmB?
- liposomal AmB (L-AmB) - AmB lipid complex (ABLC) - AmB colloidal dispersion (ABCD)
26
Describe the important clinical points concerning use of Amphotericin B
- not absorbed orally - administered parenterally - serious/systemic infectious - not used, if possible, in patients with existing nephrotoxicity
27
Describe the important clinical points concerning use of Nystatin
- not absorbed orally - too toxic for systemic use - superficial infections
28
Give some examples of fungal infections which Amphotericin B might be prescribed for?
Serious/sytemic infections - aspergillosis - candidiasis - cryptococcosis
29
Give some examples of fungal infections which Nystatin might be prescribed for
Superficial infections - oral candidiasis - vaginal candidiasis
30
Which polyene would be used for systemic infection?
Amphotericin B | Nystatin is too toxic for systemic use
31
What is the mode of action of allylamines?
Inhibit ergosterol synthesis (target = squalene epoxidase)
32
Give an example of an allylamine
Terbinafine
33
What is the spectrum of activity of allylamines (terbinafine)?
Broad spectrum of activity in vitro
34
What are the adverse effects of allylamine?
Liver toxicity (jaundice, hepatitis - rarely fatal)
35
What are the clinical uses of allylamines?
Dermatophyte infections (superficial fungal infections) - topical use - systemic (oral) use
36
For what infections would you use allylamines topically?
- athlete's foot (tinea pedis) - tinea corporis - tinea cruris
37
For what infections would you use allylamines systemically?
- scalp ringworm (tinea capitis) | - onychomycosis
38
What is onychomycosis?
Fungal infection of the nail - it is the most common disease of the nails Also known as tinea unguium
39
What are dermatophytes?
Dermatophytes are fungi that require keratin for growth - these fungi can cause superficial infections of the skin, hair, and nails
40
What are azoles?
Synthetic compounds containing a 5-membered azole ring
41
What characterises an imidazole?
Two nitrogen atoms
42
What characterises a triazole?
Three nitrogen atoms
43
What is the mode of action of azoles?
Inhibit ergosterol synthesis (target = lanosterol 14a-demethylase) - build up of non-ergosterol 14a-sterols in cell membrane
44
What is the spectrum of activity of azoles?
- complex, varies between drugs - essentially broad spectrum (yeasts and filamentous fungi) - exceptions (fuconazole/aspergillus spp.)
45
Which, out of imidazoles and triazoles, is toxic?
Imidazoles = toxic Triazoles = less toxic
46
Which, out of imidazoles and triazoles, is used systemically?
Imidazoles = rarely used systemically - ketoconazole Triazoles = systemic use is common
47
Give some examples of imidazoles
- clotrimazole - miconazole - ketoconazole
48
Give some examples of triazoles
- fluconazole - itraconazole - voriconazole - posaconazole - isavuconazole
49
What are the adverse effects of azoles?
- hepatotoxicity (mild liver enzyme abnormalities eg. 7% with fluconazole, life-threatening hepatitis eg. 1/10,000 patients with ketoconazole)
50
What are the drug interactions of azoles?
Inhibition of cytochrome P450 enzymes = increases concentration of all drugs metabolised by Cy P450 enzymes
51
What is the anti fungal spectrum of fluconazole? (a triazole)
- yeats
52
What is the anti fungal spectrum of itraconazole/voriconazole? (triazoles)
- yeasts | - aspergillus spp.
53
What is the anti fungal spectrum of posaconazole/isauvconazole? (triazoles)
- yeasts - aspergillus spp. - mucoraceous moulds
54
What are the clinical uses of imidazoles?
Superficial infections (topical administration) - candidiasis - dermatophyte infections
55
What are the clinical uses of triazoles?
Systemic infections (oral/parenteral administration) - aspergillosis - candidiasis
56
Triazoles are used for aspergillosis, for treatment and for what else?
Used in treatment and occasionally as prophylaxis
57
Give an imidazole and a triazole used to treat candidiasis
imidazole = clotrimazole (canesten) triazole = fluconazole
58
What is the mode of action of echinocandins?
Inhibition of B-1,3-glucan synthesis Construction of severely abnormal cell wall
59
Give some examples of echinocandins
- anidulafungin - caspofungin - micafungin
60
What is the spectrum of activity of echinocandins?
- aspergillus spp. and candida spp. | - misses certain moulds and cryptococcus spp.
61
What are the adverse effects of echinocandins?
Minimal eg. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug
62
What are the clinical uses of echinocandins?
Systemic infections - parenteral formulations only
63
What is 5-flurocytosine (5-FC)?
Synthetic analogue of cytosine (pyrimidine nucleoside)
64
What was 5-FC originally developed as?
Developed as an anti-cancer drug Has no anti-cancer activity, but was found incidentally to have anti fungal activity
65
What is the mode of action of 5-fluorocytosine?
- enters cell (requiring fungal cytosine permease) - coverted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate - inhibits RNA/protein synthesis and DNA synthesis
66
What allows 5-fluorocytosine to have selective toxicity?
Entry of 5-FC into the cell requires fungal cytosine permease
67
What 2 products is 5-fluorocytosine converted to?
5-fluorouracil and 5-fluorodeoxyuridine monophosphate
68
What does 5-fluorocytosine ultimately do to kill the fungus?
Inhibits RNA/protein synthesis and DNA synthesis
69
What is the spectrum of activity of 5-fluorocytosine?
Yeasts only - candida and cryptococcus spp.
70
What are the adverse effects of 5-flurorocytosine?
Bone marrow suppression - selective toxicity is incomplete - 5-fluorouracil (5FU) is an anti-cancer drug
71
What is the clinical use of 5-fluorocytosine?
Cryptococcal meningitis (in combination with AmB)
72
What is the mode of action of griseofulvin?
Inhibition of fungal mitosis
73
What is the spectrum of activity of griseofulvin?
Dermatophytes
74
What are the adverse effects of griseofulvin?
Minimal
75
What are the clinical uses of griseofulvin?
- dermatophyte infections in children requiring systemic treatment (eg. kerion, onychomycosis)
76
What are the reasons for therapeutic drug monitoring?
- to minimise toxicity (level should remain below a threshold value) - to maximise efficacy (level should exceed a threshold value)
77
Give 3 anti fungal drugs that require TDM (therapeutic drug monitoring)
- itraconazole - voriconazole - 5-fluorocytosine

1. CP - Core Microbiology (8 decks)

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