Fungal Basics and Antifungals Slackers Facts by Mike Ori

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.

What are the two forms a fungus can take?

Yeast Mould

What is a hypha

A fungal filament (Sherris)

What is a mould

An intertwining network of hyphae

What is a yeast

A smooth colony of fungi that resembles a bacterial colony. Hyphal forms are not present.

What is a conidia

Asexual fungal reproductive spore-like bodies

What are spores

Sexually produced reproductive elements.

What is the characteristic of all dimorphic fungi?

They change from yeast to moulds depending on the environmental conditions.

What is the ploidy of the average fungi?

Haploid

When is a fungi diploid

During the sexual state which usually occurs during times of stress.

What are the common forms of asexual reproduction

Budding Fragmentation Sporulation

What is the imperfect state

The haploid/asexual state

What is the sexual/diploid state referred to as?

Perfect

What is an anamorph

The asexual morphology

What is the sexual morphology referred to as?

Teleomorph

Where do most medically important fungi reside

The environment

What fungi is part of the normal flora

Candida

What organic compounds are associated with fungi?

High organic nitrogen

Which fungi is likely to cause an allergic reaction

Apergillis

Why are fungi more difficult to treat then bacteria? (i.e. why are there fewer drugs)

Fungi are eukaryotic and hence are more closely related to mammalian cells. This substantially increases the risk of toxicity from antifungals.

What unique cellular compounds are found in fungi?

Ergosterol (instead of cholesterol?) (plasma membrane) Chitin (cell wall) Glucans (cell wall) Mannoproteins (cell wall)

What is the principal target for antifungals?

Principally ergosterol (polyene) and its synthesis (azoles). Other unique compounds are also targeted but these are the big hitters.

List the common polyene antifungals

Amphotericin B Nystatin (Oral)

What is the mechanism of action of polyene antimicrobials?

Interacts with ergosterol to form pores in the plasma membrane that allow electrolytes (K+) to leak from the cell.

What is amphotericin’s solubility

It is insoluble

What preparations of amphotericin are available?

IV Preparations that increase its solubility.

1. Sodium deoxycholate suspension 2. Lipid formulations

What are the kinetics of amphotericin B?

It accumulates in and is released by the peripheral tissues. Its T ½ is therefore variable.

What is Amphotericin’s principal systemic toxicity

Sodium deoxycholate suspensions are nephrotoxic. Lipid preparations are less nephrotoxic.

What symptoms might your patient experience during Amphotericin infusion?

Fever Chills Phlebitis (DVT) Arrhythmia

What polyene would you prescribe for thrush?

Nystatin (swish and swallow)

What is the mechanism of action of azoles?

Interfere with the synthesis of ergosterol.

What are the two classes of azoles?

Imidazoles – two nitrogens Triazoles – three nitrogens

Which class of azoles is most commonly used

Triazoles

Describe the kinetics and bioavailability of azoles

Varies depending on the individual compound. Physically larger compounds have lower bioavailability.

Describe the azoles impact on the cytochrome system

Both metabolized by and an inhibitor of the cytochrome p450 system particularly of CYP3A4.

List the azoles and their class

Drug

Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole

Class

Imidazole Triazole Triazole Triazole Triazole

Whats Russian for someone who’s a jerk?

Whatanazole

Azole resistance basis

Ca dependent efflux pumps

Azole target fungi

• • Dimorphic fungi • Candida Cryptococcus

Echinocandin mechanism

Block the formation of B-1,3-glucan

What are the target fungi for echinocandins

Candida Aspergillus Ineffective against dimorphic fungi

List the echinocandins

Caspofungin Micafungin Anidulofungin

Terbinafine mechanism

Inhibits squalene epoxidase, an ergosterol precursor

Terbinafine target fungi

Dermatophytes

Flucytosine mechanism

Deamination to the uracil analog 5-fluorouracil thus interfering with RNA synthesis. 5-FU also inhibits thymidylate synthase to interfere with DNA synthesis.

Flucytosine resistance caveats

Resistance rapidly emerges so it must be used in combination

Flucytosine target fungi

Candida Crytococcus

Flucytosine toxicity

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.

Griseofulvin mechanism

Interferes with microtubule formation by binding tubulin.

Nikkomycin Z mechanism and notes

Inhibits chitin synthesis.

Orphaned drug. (Seems prime for a social question.) Phase I/II trial underway for coccidiodal pneumonia.