Antifungal Flashcards
Difference between human and fungal plasma membrane
Both require a sterol:
- Human: Cholestrol
- Fungal: Ergosterol
A target for selective toxicity
How is ergosterol synthesized?
- From squalene to lanosterol and then ergosterol
- Via action of Cyt P450 3A and c14a demethylase
- Targeted by azoles
- Via action of Cyt P450 3A and c14a demethylase
Target in fungal cell walls
Glucan
- Requires Glucan synthase
- Which are targeted by echinocandins
MOA for 5-Flucytosine
5-Flucytosine- 5-Fluouracil -Thymidylate synthetase- Nucleic acids
Issues with selective toxicity in antifungals
- Some Polyenes will also bind cholestrol
- Azols can bind to hepatic P450
- Nucleic acid synthesis
Avoided by:
- Topical application
- For serious infections one accepts a degree of toxicity eg. amphotericin B
ADR for Amphotericin B
Acute reactions (30 min post infusion)
- Chills, fever, SOB, drop in BP
- Lasts 4 hours
- induction of prostaglandin E2
- test dose and then escalate dose pre-medicate with paracetomol, brufen or steroids
Renal toxicity
- vasoconstricts afferent renal arterioles
- potassium, magnesium, bicarbonate loss
- decreased erythropoietin production
- loss of nephron units • related to total dose?
electrolyte replacement, amiloride
Avoiding toxicity of AmB
-
Delivery: Conjugate with lipid preparations
- Lipsomal
- Colloidal dispersion
- Lipid complexes
- At site of infection there is inflammation, presence of inflammtory molecules containing phospholipase, breaks down lipid. AmB binds to fungal ergosterol
- Nottingham does not stock non-conjugated AmB anymore
AmB efficienct vs other antifungals
Effective against a very wide range of fungi compared to most
Advantage of AmB in antifungal resistance
For fungi to become resistant to AmB they need to decrease erogsterol production, but this also reduces fungal fitness by lessening fungal wall..
issues in azole resistance
- c14a demethylase mutates and adapts
- Efflux mechanisms Increasing fluconazole resistance amongst C.albicans, C.glabrata, C.krusei, C.norvegensis, C.inconspicua
Issues in 5-Flucytosine resistance
- Resistance rare when used in combination therapy, but common with monotherapy
- Fungi change there surface to avoiddisturabnce of nucelicacid synthesis by:
- Decreased permeability
- Altered phosphorylation
- All other antifungals work on surface (membrane, wall). If you damage these you ensure permeability is maintained
MOA for echinocandins
- Lipopetides that target glucosynthase
- Have to be IV due to GI enzyme breakdown
- Candida -cidal
- Aspergillus -static
- Compared to AmB, similar effectiveness for candida, but less toxicity
- For invasive aspergillus
Define Mycosis
Fungal infection
Athletes foot
= Tinea pedis. Mould
- Predisposition to cellulitis, provide entry point for staph etc
- Topical Terbinafine
Tinea Corpis/capitis
=Ring worm. Mould
- Circulary growth
- Topical clotrimazole
- May have to include a systemic antifungal to “attack from both sides”
