Antifungals

Question 1

What are the two main types of pathogenic fungi?

Answer 1

Filamentous fungi

Yeasts

Some are dymorphic (exist in both forms)

Question 2

What are the 5 main antifungal targets?

Answer 2

DNA synthesis

Mitosis

Cell membrane: ergosterol

Protein synthesis

Cell wall: Beta-1,3-glucan

Protein synthesis

Question 3

What is ergosterol?

Answer 3

Found mainly in fungal cell membranes
Forms clusters within the phospholipid bilayer
Has a role in the regulation of membrane permeability
Required for normal growth and function of the fungal cell wall, hence fungal viability

Question 4

How is ergosterol biosynthesised?

Answer 4

Squalene is converted into Lanosterol by squalene epoxidase.
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Lanosterol is converted into Ergosterol by Lanosterol 14a demethylase.

Question 5

What are β-1,3-glucans?

Answer 5

Large polymers of UDP-glucose
50 ‑ 60% of the dry weight of the fungal cell wall
Form a fibrous network on the inner surface of the cell wall
Synthesized by β-1,3-glucan synthase

Question 6

What are the 4 main classes of antifungals?

Answer 6

Polyenes
Allylamines
Azoles
Echinocandins

Question 7

What is a polyene’s mode of action?

Answer 7

Association with ergosterol
Formation of pore-like molecular aggregates
- Aqueous vs. non-aqueous pores
Loss of membrane integrity and leakage of K+
Cell death

Question 8

Give 2 examples of polyenes

Answer 8

Amphotericin B

Nystatin

Question 9

Amphotericin B can treat most fungi of medical importance. What are its adverse effects?

Answer 9

Allergic reactions
Nephrotoxicity
- Pores are formed in ergosterol-free membranes

Question 10

How does lipid associated AmB reduce nephrotoxicity?

Answer 10

Delivery targeted to fungal cells and/or reticulo-endothelial system
Liver, spleen, lymph nodes

Question 11

What are the clinical indications for Amphotericin B?

Answer 11

Serious/systemic infections
e.g. aspergillosis, candidiasis, cryptococcosis

Not absorbed orally
Administered parenterally
Not used, if possible, in patients with existing nephrotoxicity

Question 12

What are the clinical indications for Nyastatin?

Answer 12

Superficial infections
e.g. oral/vaginal candidiasis

Not absorbed orally
Too toxic for systemic use

Question 13

What is the mode of action of allylamines?

Answer 13

Inhibit ergosterol synthesis

- specifically squalene epoxidase

Question 14

Give an example of an allylamine

Answer 14

Terbinafine

Question 15

Terbinafine - adverse effects?

Answer 15

Liver toxicity

Jaundice, hepatitis – rarely fatal

Question 16

What are allylamines used for?

Answer 16

Dermatophyte infections (superficial fungal infections)
Topical use
Athletes foot (tinea pedis), tinea corporis, tinea cruris
Systemic (oral) use
Scalp ringworm (tinea capitis), onychomycosis

Question 17

What are azoles?

Answer 17

Synthetic compounds containing a 5-membered azole ring
Imidazoles
 - Two nitrogen atoms
Triazoles
 - Three nitrogen atoms

Question 18

What is the mode of action of azoles?

Answer 18

Inhibit ergosterol synthesis

• Lanosterol 14α-demethylase
• Build up of non-ergosterol 14α-sterols in cell membrane

Question 19

Properties of imidazoles and triazoles?

Answer 19

Imidazoles
 - Toxic
 - Rarely used systemically
     -Ketoconazole
Triazoles
 - Less toxic
 - Systemic use common

Question 20

Examples of imidazoles?

Answer 20

Clotrimazole
Miconazole
Ketoconazole

Question 21

Examples of Triazoles?

Answer 21

Fluconazole
Itraconazole
Voriconazole
Posaconazole
Isavuconazole

Question 22

What are the possible drug interactions with azoles?

Answer 22

Inhibition of cytochrome P-450 enzymes

- Increases concentration of all drugs metabolised by Cy P-450 enzymes

Question 23

What are the clinical uses of azoles?

Answer 23

Imidazoles
Superficial infections (topical administration)
Candidiasis - Clotrimazole
Dermatophyte infections

Triazoles
Systemic infections (oral/parenteral administration)
- Aspergillosis (used in treatment and occasionally as prophylaxis)
- Candidiasis (fluconazole)

Question 24

What is the mode of action of Echinocandins?

Answer 24

Mode of action
Inhibition of β-1,3-glucan synthase
Construction of severely abnormal cell wall

Question 25

Name some examples of Echinocandins

Answer 25

Anidulafungin
Caspofungin
Micafungin

Question 26

What is the spectrum of activity of echinocandins?

Answer 26

Aspergillus and Candida spp.

Misses certain moulds and Cryptococcus spp.

Question 27

What are the adverse effects of Echinocandins?

Answer 27

Minimal

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

Question 28

What is the clinical use of Echinocandin?

Answer 28

Systemic infections

Parenteral formulations only (IV)

Question 29

What is 5-fluorocytosine (5-FC)?

Answer 29

Synthetic analogue of cytosine
- Pyrimidine nucleoside

Developed as an anti-cancer drug
- Has no anti-cancer activity, but was found incidentally to have antifungal activity

Question 30

What is the mode of action of 5-fluorocytosine (5-FC)?

Answer 30

Entry into cell requires fungal cytosine permease
- Selective toxicity
Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate
- Inhibit RNA/protein synthesis and DNA synthesis

Question 31

What is the spectrum of activity of 5-fluorocytosine?

Answer 31

Yeasts only

Candida and Cryptococcus spp.

Question 32

What are the adverse effects of 5-fluorocytosine?

Answer 32

Bone marrow suppression

• Selective toxicity is incomplete
• 5-fluorouracil (5FU) is an anti-cancer drug

Question 33

What is the clinical use of 5-fluorocytosine?

Answer 33

Cryptococcal meningitis (in combination with AmB)

Question 34

Which 3 antifungal drugs require Therapeutic Drug Monitoring? (TDM)

Answer 34

Itraconazole
5-fluorocytosine
Voriconazole