What are the three types of pathogenic fungi?
Dimorphic (ie both)
How is the fungal cell membrane different to the animal cell membrane?
Consists mainly of ergosterol - potential target.
What does the fungal cell wall mainly consist of?
Give an example of a dimorphic fungi.
What is ergosterol?
- 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
Describe ergosterol biosynthesis.
Squalene ---> (via squalene peroxidase) ---> lanosterol lanosterol ---> (via lanosterol 1,4 beta demethylase) ---> ergosterol
What is the mode of action for the polyenes? e.g. Amphotericin B, Nystatin
- Association with ergosterol - Formation of pore-like molecular aggregates - Aqueous vs. non-aqueous pores1 - Loss of membrane integrity and leakage of K+ - Cell death
What is the spectrum of activity of Amphotericin B?
- Most fungi of medical importance - Aspergillus spp., Candida spp., Cryptococcus spp.
What are the potential side-effects of AmB?
Allergic reactions Nephrotoxicity Pores are formed in ergosterol-free membranes
What are the benefits of lipid-associated AmB?
- 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
How are the polyenes used clinically?
Amphotericin B - Not absorbed orally
- Administered parenterally - Serious/systemic infections - e.g. aspergillosis, candidiasis, cryptococcosis
- Not used, if possible, in patients with existing nephrotoxicity
- Not absorbed orally
- Too toxic for systemic use - Superficial infections e.g. oral/vaginal candidiasis
What is the mode of action of the allylamines? e.g. terbinafine
Inhibit ergosterol synthesis by inhibiting squalene epoxidase
What is the spectrum of activity of the allylamines?
What are the adverse effects of allyamines?
How are the allyamines used clinically?
- Dermatophyte infections (superficial fungal infections)
Topical use - Athletes foot (tinea pedis), tinea corporis, tinea cruris - Systemic (oral) use - Scalp ringworm (tinea capitis), onychomycosis
What defines the azoles?
Synthetic compounds containing a 5-membered azole ring Imidazoles - Two nitrogen atoms Triazoles - Three nitrogen atoms
What is the mode of action of the azoles?
- Inhibit ergosterol synthesis by inhibiting Lanosterol 14α-demethylase.
- Build up of non-ergosterol 14α-sterols in cell membrane
What fungi are not covered by members of the azole family?
Fluconazole does not cover the Aspergillus spp.
How are the azoles used clinically?
Imidazoles - Toxic - Rarely used systemically - Ketoconazole Triazoles - Less toxic - Systemic use common
What are the main adverse effects of the azoles?
What are the drug interactions for the azoles?
- Inhibition of cytochrome P-450 enzymes - Increases concentration of all drugs metabolised by CYP-450 enzymes
What is the mode of action for the echinocandins? e.g. Anidulafungin, Caspofungin, Micafungin
- Inhibition of β-1,3-glucan synthase
- Construction of severely abnormal cell wall
How are the echinocandins used clinically?
Parenteral formulations only.
What are possible adverse effects of the echinocandins?
Minimal - rash, nausea, vomiting etc
What is 5-fluorocytosine?
Pyrimidine nucleoside - developed as an anit-cancer drug but found to have anti-fungal activity.
What is the mode of action of 5-flourocytosine?
Entry into cell requires fungal cytosine permease Selective toxicity Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate Inhibit RNA/protein synthesis and DNA synthesis
What is the spectrum of activity of 5-flourocytosine?
What is the spectrum of activity of the echinocandins?
- Aspergillus and Candida spp. - Misses certain moulds and Cryptococcus spp.
What are the adverse effects of 5-flourocytosine?
- Bone marrow suppression - Selective toxicity is incomplete 5-fluorouracil (5FU) is an anti-cancer drug
What are the clinical uses of 5-flourocytisine?
Cryptococcal meningitis (in combination with AmB).
What are the features of Grisofulvin?
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
What are the reasons for therapeutic drug monitoring (TDM)?
To minimize toxicity - Level should remain below a threshold value
To maximize efficacy - Level should exceed a threshold value
Which drugs require TDM?