Transcript Immunology Stack - University of Arizona

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
Class
Ketoconazole
Imidazole
Fluconazole
Triazole
Itraconazole
Triazole
Posaconazole
Triazole
Voriconazole
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.