1. Antifungal agents Flashcards
What are fungi?
A group of spore-producing organisms feeding on organic matter.
-includes moulds, yeasts, mushrooms.
How do fungi differ in size from bacteria and viruses?
Fungi are generally larger
What are the 2 main pathogenic classifications of pathogenic fungi?
Yeasts
Filamentous fungi
NB. some are dimorphic (exist in both forms)
How do filamentous fungi divide?
Spore-production
How do yeasts divide?
Budding
What is the difference in the structures of filamentous fungi and yeasts?
FILAMENTOUS FUNGI = hair-like structures
YEASTS = large, oval structures
Give 3 examples of dimorphic fungi.
Histoplasma spp (»Endemic mycoses)
Candida albicans
Malasezzia spp.
Give an example of a condition caused by filamentous fungi.
Athlete’s foot
Give an example of a condition caused by yeasts.
Thrush (candida albicans)
What is an important feature for antifungal targets?
Selective toxicity - don’t cause harm to humans.
What is ‘Pneumocystis jirovecii’?
Yeast»_space; pneumonia
especially in immunosupressed
What types of cells do fungi contain? What problem does this cause for antifungal targets?
Eukaryotic
-more similar to human cells, so makes selective toxicity harder
What are the main targets for antifungals, and why?
- CELL WALL (humans don’t have one)
- CELL MEMBRANE (different composition to humans)
- DNA/PROTEIN SYNTHESIS
What is a fungal cell wall composed of?
B-1,3-glucans
not peptidoglycan like bacteria
What do fungal cell membranes contain instead of cholesterol?
Ergosterol
What is the function of ergosterol in fungal cell membranes?
Forms clusters in phospholipid bilayer
»regulates membrane permeability
»required for normal growth & function of cell wall
What is the process of ergosterol biosynthesis?
SQUALENE »_space; LANOSTEROL »_space; ERGOSTEROL
What are the enzymes involved in ergosterol synthesis? (2)
Squalene epoxidase
Lanosterol 14a demethylase
How do antifungal agents act on ergosterol synthesis?
Inhibit the enzymes involved
squalene epoxidase & lanosterol 14a demethylase
What is B-1,3-glucans?
Large polymer of UDP-glucose»_space; fibrous nerwork of fungal cell wall
What is B-1,3-glucans synthesised by?
B-1,3-glucan synthase
antifungal target
What are the 4 classes of antifungals?
- Polyenes
- Allylamines
- Azoles
- Echinocandins
- (Other; 5-fluorocytosine, griseofulvin)
What is the mode of action of polyenes?
Association with ergosterol
» forms pore-like aggregates
» loss of membrane integrity & K+ leakage
» cell death
Give 2 examples of polyenes.
Amphotericin B
Nystatin
What is nystatin used for?
Superficial infections (eg. thrush)
- too toxic for systemic use
- not orally absorbed
What is the spectrum of Amphotericin B?
Broad spectrum - most fungi
What are the adverse effects of Amphotericin B?
- Allergic reactions
- Nephrotoxicity (»pores in human membranes)
What type of Amphotericin B is now used and why?
Lipid-associated AmB
eg. liposomal AmB
- reduced nephrotoxicity
How is Amphotericin B clinically used?
Administered parenterally for serious/systemic infections (eg. pulmonary aspergillosis).
-not absorbed orally
When should Amphotericin B be avoided?
With patients with existing nephrotoxicity
What is the mode of action of allylamines?
Inhibit ergosterol synthesis
-squalene epoxidase
Give an example of an allylamine.
Terbinafine
What is the spectrum of activity of Terbinafine (allylamine)?
Broad spectrum in vitro
What are possible adverse effects of Terbinafine?
Liver toxicity
|»_space;jaundice, hepatitis
What are allylamines used to treat?
DERMATOPHYTE (superficial fungal) infections
- topcial (eg. Athletes foot)
- systemic (eg. scalp ringworm)
What are azoles?
Synthetic compounds containing a 5-membered azole ring.
What are the 2 types of azoles, and how do they differ?
IMIDAZOLES - 2 nitrogen atoms
TRIAZOLES - 3 nitrogen atoms
What is the mode of action of azoles?
Inhibit ergosterol synthesis (lanosterol 14a-demethylase)
|»_space; build up of non-ergosterol 14a-sterols in membrane
What is the spectrum of activity in azoles?
Complex/variable.
- mainly broad
- exceptions; fluconazole»_space; Aspergillus spp.
Which azoles are less toxic, and commonly used systemically?
Triazoles
not imidazoles
Give an example of an imidazole.
Clotrimazole
Give 3 examples of triazoles.
Fluconazole
Itraconazole
Voriconazole
What are possible adverse effects of azoles?
HEPATOTOXICITY
- mild liver enzyme abnormalities (fluconazole)
- life-threatening hepatitis (ketoconazole - rare)
What drug interactions do azoles have?
Inhibition of cytochrome P-450 enzymes.
-increases concentration of drug metabolised by it
Rank the following in order of their antifungal spectrum:
- Itraconazole/voriconazole
- Fluconazole
- Posaconazole/ isavuconazole
NARROW»_space; BROAD:
- Fluconazole
- Itraconazole/voriconazole
- Posaconazole/ isavuconazole
What are imidazoles used for clinically?
Superficial infections (topical)
- candidiasis
- dermatophyte infections
What are triazoles used for clinically?
Systemic infections (oral/parenteral)
- Aspergillosis
- Candidiasis
What is the mode of action of echinocandins?
Inhibit B-1,3-glucan synthase
|»_space;abnormal cell wall
Give 3 examples of echinocandins.
- Anidulafungin
- Caspofungin
- Micafungin
What is the spectrum of activity of echinocandins?
Aspergillus & Candida spp.
-Not Cryptococcus spp
What are possible adverse effects of ecinocandins?
Minimal
-eg. skin rash, nausea, headache
What are ecinocandins used for clinically?
Systemic infections
-parenteral only
What is 5-fluorocytosine (5-FC)?
Synthetic analogue of cytosine
-pyrimidine nucleoside
What was 5-fluorocytosine developed as, and what is it now used as?
Developed as an anti-cancer drug
-now used as an antifungal
What is the mode of action of 5-fluorocytosine?
Enters cell with fungal cytosine permease (selective toxicity)
» converted to 5-fluorouracil & 5-fluorodeoxyuridine monophosphate
» inhibits RNA/protein synthesis & DNA synthesis
What is the spectrum of activity of 5-fluorocytosine?
Yeasts only
-Candida & Cryptococcus spp.
What are the possible adverse effects of 5-fluorocytosine?
Bone marrow suppression
-selective toxicity is incomplete
What is 5-fluorocytosine used for clinically?
Cryptococcal meningitis
in combination with AmB
What is the mode of action of Griseofulvin?
Inhibits fungal mitosis.
What is the spectrum of activity of Griseofulvin?
Dermatophytes
What are the possible adverse effects of Griseofulvin?
Minimal
What is Griseofulvin used for clinically?
Dermatophyte infections in children
- eg. kerion
- NB. only agent licensed for scalp infection in children
What is therapeutic drug monitoring?
Measuring drug concentrations in blood.
What is the purpose of therapeutic drug monitoring?
- Minimise toxicity
- Maximise efficacy
Which antifungal drugs require therapeutic drug monitoring? (3)
- ITRACONAZOLE (make sure it doesn’t decrease too much)
- 5-FLUOROCYTOSINE (bone marrow toxicity if too high)
- VORICONAZOLE (liver toxicity when too high)
