Fungal Basics and Antifungals Slackers Facts by Mike Ori.
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Transcript of Fungal Basics and Antifungals Slackers Facts by Mike Ori.
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Fungal Basics and Antifungals
Slackers Facts by Mike Ori
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Disclaimer
The information represents my understanding only so errors and omissions are probably rampant. It has not been vetted or reviewed by faculty. The source is our class notes.
The document can mostly be used forward and backward. I tried to mark questionable stuff with (?).
If you want it to look pretty, steal some crayons and go to town.
Finally…
If you’re a gunner, buck up and do your own work.
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What are the two forms a fungus can take?
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YeastMould
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What is a hypha
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A fungal filament (Sherris)
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What is a mould
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An intertwining network of hyphae
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What is a yeast
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A smooth colony of fungi that resembles a bacterial colony. Hyphal forms are not
present.
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What is a conidia
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Asexual fungal reproductive spore-like bodies
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What are spores
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Sexually produced reproductive elements.
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What is the characteristic of all dimorphic fungi?
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They change from yeast to moulds depending on the environmental conditions.
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What is the ploidy of the average fungi?
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Haploid
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When is a fungi diploid
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During the sexual state which usually occurs during times of stress.
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What are the common forms of asexual reproduction
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BuddingFragmentation
Sporulation
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What is the imperfect state
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The haploid/asexual state
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What is the sexual/diploid state referred to as?
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Perfect
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What is an anamorph
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The asexual morphology
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What is the sexual morphology referred to as?
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Teleomorph
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Where do most medically important fungi reside
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The environment
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What fungi is part of the normal flora
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Candida
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What organic compounds are associated with fungi?
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High organic nitrogen
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Which fungi is likely to cause an allergic reaction
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Apergillis
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Why are fungi more difficult to treat then bacteria? (i.e. why are there fewer drugs)
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Fungi are eukaryotic and hence are more closely related to mammalian cells. This substantially increases the risk of toxicity from antifungals.
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What unique cellular compounds are found in fungi?
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Ergosterol (instead of cholesterol?) (plasma membrane)
Chitin (cell wall)Glucans (cell wall)
Mannoproteins (cell wall)
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What is the principal target for antifungals?
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Principally ergosterol (polyene) and its synthesis (azoles). Other unique compounds are also
targeted but these are the big hitters.
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List the common polyene antifungals
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Amphotericin BNystatin (Oral)
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What is the mechanism of action of polyene antimicrobials?
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Interacts with ergosterol to form pores in the plasma membrane that allow electrolytes (K+)
to leak from the cell.
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What is amphotericin’s solubility
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It is insoluble
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What preparations of amphotericin are available?
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IV Preparations that increase its solubility.1. Sodium deoxycholate suspension
2. Lipid formulations
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What are the kinetics of amphotericin B?
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It accumulates in and is released by the peripheral tissues. Its T ½ is therefore
variable.
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What is Amphotericin’s principal systemic toxicity
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Sodium deoxycholate suspensions are nephrotoxic. Lipid preparations are less
nephrotoxic.
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What symptoms might your patient experience during Amphotericin infusion?
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FeverChills
Phlebitis (DVT)Arrhythmia
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What polyene would you prescribe for thrush?
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Nystatin(swish and swallow)
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What is the mechanism of action of azoles?
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Interfere with the synthesis of ergosterol.
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What are the two classes of azoles?
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Imidazoles – two nitrogensTriazoles – three nitrogens
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Which class of azoles is most commonly used
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Triazoles
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Describe the kinetics and bioavailability of azoles
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Varies depending on the individual compound. Physically larger compounds have lower
bioavailability.
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Describe the azoles impact on the cytochrome system
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Both metabolized by and an inhibitor of the cytochrome p450 system particularly of
CYP3A4.
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List the azoles and their class
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Drug Class
Ketoconazole Imidazole
Fluconazole Triazole
Itraconazole Triazole
Posaconazole Triazole
Voriconazole Triazole
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Whats Russian for someone who’s a jerk?
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Whatanazole
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Azole resistance basis
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Ca dependent efflux pumps
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Azole target fungi
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• Dimorphic fungi• Candida
• Cryptococcus
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Echinocandin mechanism
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Block the formation of B-1,3-glucan
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What are the target fungi for echinocandins
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CandidaAspergillus
Ineffective against dimorphic fungi
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List the echinocandins
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CaspofunginMicafungin
Anidulofungin
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Terbinafine mechanism
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Inhibits squalene epoxidase, an ergosterol precursor
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Terbinafine target fungi
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Dermatophytes
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Flucytosine mechanism
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Deamination to the uracil analog 5-fluorouracil thus interfering with RNA synthesis. 5-FU also inhibits thymidylate synthase to interfere with
DNA synthesis.
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Flucytosine resistance caveats
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Resistance rapidly emerges so it must be used in combination
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Flucytosine target fungi
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CandidaCrytococcus
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Flucytosine toxicity
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Metabolite (5-FU) is a uracil analog that is toxic to human cells and damages rapidly dividing
cells.NOTE: 5-FU is a cancer chemotherapeutic.
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Griseofulvin mechanism
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Interferes with microtubule formation by binding tubulin.
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Nikkomycin Z mechanism and notes
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Inhibits chitin synthesis.Orphaned drug. (Seems prime for a social
question.)Phase I/II trial underway for coccidiodal
pneumonia.