Core Microbiology - Anti-fungal Agents (5) Flashcards Preview

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Flashcards in Core Microbiology - Anti-fungal Agents (5) Deck (42):
1

Fungi classification

1. Moulds/filamentous fungi
2. Yeast

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Dimorphic fungi

Exist as mould and yeast

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Erogsterol

In fungal cell membranes, forms clusters within phospholipid bilayer, regulates membrane permeability

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Ergosterol biosynthesis

Squalene > (Squalene epoxidase) > Lanosterol > (Lanosterol 14a demethylase) > Ergosterol

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B-1,3-glucans

Large polymers of UDP-glucose, form a fibrous network on inner surface of wall, snythesised by B-1,3-glucan synthase

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Antifungal classes

Polyenes, Allylamines, Azoles, Echinocandins, others..

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Polyenes mode of action

Association with ergosterol, forms pore-like molecular aggregates, loss of membrane integrity and leakage of K+, cell death

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Examples of Polygenes

Amphotericin B and Nystatin

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Amphotericin B spectrum of activity

Most fungi - Aspergillus, Candida, Cryptococcus (Parenterally)

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Amphotericin B adverse effects

Allergic reactions, nephrotoxicity (reversible), not completely selective to fungi

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Lipid associated Amphotericin B (AmB) different formulations

Liposomal AmB (L-AmB), AmB lipid complex (ABLC), AmB colloidal disperson (ABCD)

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Lipid associated Amphotericin B (AmB) pros

Minimises delivery of AmB to kidney cells (liver, spleen and lymph nodes)

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Nystatin

Too toxin for systemic use, superficial infections - oral/vaginal candidiasis

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Allylamines mode of action

Inhibit erogsterol synthesis (Squalene epoxidase)

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Allylamines examples

Terbinafine

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Terbinafine spectrum

Broad in vitro

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Terbinafine adverse effects

Liver toxicity (Jaundice, hepatitis)

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Allylamines clinical use

Dermatophyte infections (superficial)

Topical - athletes foot (tinea pedis), tinea corporis (trunk, legs, arm/skin), tinea cruris (groin)

Systemic - scalp ringworm (tinea capitis), onychomycosis (nail)

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Azoles

5-membered ring

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Examples

- Imidazoles (2N)
- Triazoles (3N)

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Azoles mode of action

Inhibit ergosterol synthesis (Lanosterol 14a-demethylase)

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Azoles spectrum

Broad - yeasts and filamentous fungi (except Fluconazole/Aspergillus)

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Imidazoles

Toxic, rarely used systemically (ketoconazole)

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Examples of Imidazoles

Clotrimazole (Canesten), Miconazole, Ketoconazole

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Examples of Triazoles

Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole

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Azoles adverse effects

Hepatotoxicity

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Azoles drug interactions

Inhibition of Cytochrome P-450 enzymes - increases concentration of all drugs metabolised by Cy P-450 enzymes

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Imidazoles clinical use

Superficial infections - Candidiasis or dermatophyte infections

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Triazoles clinical use

Systemic - aspergillosis and candidiasis

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Echinocandins mode of action

Inhibition of B-1,3-glucan synthase, construction of severely abnormal cell wall

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Examples of Echinocandins

Andiulafungin, Caspofungin, Micafungin

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Echinocandins spectrum of activity

Aspergillus and Candida (not certain moulds and cryptococcus) - serious as iv

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Echinocandins adverse effects

Skin rash, nausea, vomiting, headache, diarrhoea

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5-fluorocytosine (5-FC)

Synthetic analogue of cytosine (pyrimidine nucleoside), developed as anti-cancer drug

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5-FC mode of action

Entry into cells requires fungal cytosine permeases, converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate (inhibit RNA/protein synthesis and DNA synthesis)

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5-FC spectrum of activity

Yeasts only (Candida and Cryptococcus)

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5-FC adverse effects

Bone marrow suppression, selective toxicity is incomplete - 5FU anti-cancer

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5-FC clinical use

Cryptococcal meningitis (combination with AmB)

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Griseofulvin mode of action

Inhibition of fungal mitosis

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Griseofulvin spectrum of activity

Dermatophytes

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Griseofulvin clinical use

Dermatophyte infections in children requiring system treatment (kerion, onychomycosis)

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Antifungal drugs that require therapeutic drug monitoring

- Itraconazole
- 5-FC (bone marrow)
- Voriconazole (liver)

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