Antifungals

Question 1

What are the three types of pathogenic fungi?

Answer 1

Filamentous

Yeasts

Dimorphic (ie both)

Question 2

How is the fungal cell membrane different to the animal cell membrane?

Answer 2

Consists mainly of ergosterol - potential target.

Question 3

What does the fungal cell wall mainly consist of?

Answer 3

β-1,3-glucan

Question 4

Give an example of a dimorphic fungi.

Answer 4

Candida albicans

Question 5

What is ergosterol?

Answer 5

• 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 6

Describe ergosterol biosynthesis.

Answer 6

Squalene —> (via squalene peroxidase) —> lanosterol lanosterol —> (via lanosterol 1,4 beta demethylase) —> ergosterol

Question 7

What is the mode of action for the polyenes? e.g. Amphotericin B, Nystatin

Answer 7

• Association with ergosterol - Formation of pore-like molecular aggregates - Aqueous vs. non-aqueous pores1 - Loss of membrane integrity and leakage of K+ - Cell death

Question 8

What is the spectrum of activity of Amphotericin B?

Answer 8

• Most fungi of medical importance - Aspergillus spp., Candida spp., Cryptococcus spp.

Question 9

What are the potential side-effects of AmB?

Answer 9

Allergic reactions Nephrotoxicity Pores are formed in ergosterol-free membranes

Question 10

What are the benefits of lipid-associated AmB?

Answer 10

• Minimize delivery of AmB to kidney cells
• Delivery targeted to fungal cells and/or reticulo-endothelial system - Liver, spleen, lymph nodes -

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

Question 11

How are the polyenes used clinically?

Answer 11

Amphotericin B - Not absorbed orally

• Administered parenterally - Serious/systemic infections - e.g. aspergillosis, candidiasis, cryptococcosis
• Not used, if possible, in patients with existing nephrotoxicity

Nystatin

• Not absorbed orally
• Too toxic for systemic use - Superficial infections e.g. oral/vaginal candidiasis

Question 12

What is the mode of action of the allylamines? e.g. terbinafine

Answer 12

Inhibit ergosterol synthesis by inhibiting squalene epoxidase

Question 13

What is the spectrum of activity of the allylamines?

Answer 13

Broad.

Question 14

What are the adverse effects of allyamines?

Answer 14

Liver toxicity

Question 15

How are the allyamines used clinically?

Answer 15

• Dermatophyte infections (superficial fungal infections)

Topical use - Athletes foot (tinea pedis), tinea corporis, tinea cruris - Systemic (oral) use - Scalp ringworm (tinea capitis), onychomycosis

Question 16

What defines the azoles?

Answer 16

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

Question 17

What is the mode of action of the azoles?

Answer 17

• Inhibit ergosterol synthesis by inhibiting Lanosterol 14α-demethylase.
• Build up of non-ergosterol 14α-sterols in cell membrane

Question 18

What fungi are not covered by members of the azole family?

Answer 18

Fluconazole does not cover the Aspergillus spp.

Question 19

How are the azoles used clinically?

Answer 19

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

Question 20

What are the main adverse effects of the azoles?

Answer 20

Liver toxicity

Question 21

What are the drug interactions for the azoles?

Answer 21

• Inhibition of cytochrome P-450 enzymes - Increases concentration of all drugs metabolised by CYP-450 enzymes

Question 22

What is the mode of action for the echinocandins? e.g. Anidulafungin, Caspofungin, Micafungin

Answer 22

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

Question 23

How are the echinocandins used clinically?

Answer 23

Systemic infections

Parenteral formulations only.

Question 24

What are possible adverse effects of the echinocandins?

Answer 24

Minimal - rash, nausea, vomiting etc

Question 25

What is 5-fluorocytosine?

Answer 25

Pyrimidine nucleoside - developed as an anit-cancer drug but found to have anti-fungal activity.

Question 26

What is the mode of action of 5-flourocytosine?

Answer 26

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 27

What is the spectrum of activity of 5-flourocytosine?

Answer 27

Yeasts only

Question 28

What is the spectrum of activity of the echinocandins?

Answer 28

• Aspergillus and Candida spp. - Misses certain moulds and Cryptococcus spp.

Question 29

What are the adverse effects of 5-flourocytosine?

Answer 29

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

Question 30

What are the clinical uses of 5-flourocytisine?

Answer 30

Cryptococcal meningitis (in combination with AmB).

Question 31

What are the features of Grisofulvin?

Answer 31

Mode of action - Inhibition of fungal mitosis

Spectrum of activity - Dermatophytes

Minimal Clinical use - Dermatophyte infections in children requiring systemic treatment e.g. kerion, onychomycosis

Question 32

What are the reasons for therapeutic drug monitoring (TDM)?

Answer 32

To minimize toxicity - Level should remain below a threshold value

To maximize efficacy - Level should exceed a threshold value

Question 33

Which drugs require TDM?

Answer 33

• Itraconazole
• 5-fluorocytosine
• Voriconazole