Antifungals Flashcards
What is the major difference between bacteria and fungi
Fungi differ from bacteria because they are eukaryotic (80S ribosomes as compared to 70S) - so many antibacterial agents are ineffective
Which are larger, fungi or bacteria?
Fungi are much larger and slower growing
What is the difference in the cell wall of fungi and bacteria?
Fungi have a rigid cell wall made of chitin and glucans - whereas bacteria have mucopeptide cell walls
What is unique about fungi cell membranes?
Fungi contain ergosterol instead of cholesterol
Where are fungal infections common? Why are they difficult to treat?
Poorly vascularized tissues, or skin, nails, and hair
Difficult to treat since antifungal agents are poorly soluble and not distributed or retained well
What sort of response do fungi cause?
They cause a cellular immune response - which may interfere with drug penetration
How do treatments differ between fungi and bacterial infections?
Bacterial = use short term low toxicity therapy Fungal = use long term high toxicity therapy
What are the different types of fungal infections?
Superficial/cutaneous
Subcutaneous
Systemic
Griseofulvin Mechanism
Mitotic Inhibitor
Is Griseofulvin static or cidal?
Static
Griseofulvin selectivity
Taken up by keratinocytes or precursor cells
Griseofulvin Clinical uses
Active against dermatophytes (hair, skin, nails)
Fungi are lost as hair and nails fall out
Used to treat ringworm
Griseofulvin toxicity
Well tolerated, but long term use can lead to headache, memory loss, skin rashes, photosensitivity rxsns, porphyria
Griseofulvin Resistance
Rare, but likely related to decreased transport into cells
5-Flucytosine Mechanism
Inhibits or alters DNA/RNA synthesis
5-Flucytosine static or cidal?
Both
5-Flucytosine Clinical uses
Effective in combo with Amphotericin B to treat cryptococcal meningitis
Use with Amphotericin B also decreases the incidence of resistance
5-Flucytosine Toxicities
Bone marrow depression, neutropenia, throbocytopenia
Careful to monitor patients who ahve renal insufficiency to avoid toxicity
5-Flucytosine Resistance mechanisms
High resistance
Due to transport alterations, cytosine deaminase alterations, and anabolic enzyme alterations
Amphotericin B Mechanism
Interaction with membrane sterols to form a pore and/or alter the membrane fluidity
Binding to ergosterol of fungal cell membrane causes a loss of K, altering Na/K-ATPase activity, permeability, and amino acid uptake
Amphotericin B fungicidal or static?
Fungicidal
Amphotericin B selectivity
Binds to fungal ergosterol much more readily than human cholesterol
Amphotericin B Clinical uses
Best choice for treating systemic fungal infections
- Candidiasis
- Histoplasmosis
- Coccidiomucosis
- Blastomycosis
- Aperigillus
- Cryptococcoses
Amphotericin B Toxicities
A whole bunch
-Nephrotoxicity the main one?
Amphotericin B Resistance mechanisms
Rare - may occur due to alteration of sterol content or composition
Amphotericin B Drug interacitons
Can increase the cytotoxicit of Rifampicin
5-FC plus Amphotericin B can used to treat Cryptococcal meningitis
Syntergism or additivity with Amph B + Triazoles
Nyastatin Mechanism
Interaction with membrane sterols to form a pore and/or alter the membrane fluidity
Binding to ergosterol of fungal cell membrane causes a loss of K, altering Na/K-ATPase activity, permeability, and amino acid uptake
Nyastatin Clinical use
Topical treatment for candidiasis, thrush, esophaginitis, vaginitis
Nyastatin toxicities
Minimal
Azoles Mechanism
Bind through ring nitrogen to heme of cytochrome p450 and inhibit the lanosterol C-dimethylase system
Are Azoles fungistatic or fungicidal?
Fungistatic at low concentrations
Fungicidal at high concentrations
Azoles selectivity
100-fold greater binding affinity to fungal cell lanosterol C14-demethylase compared to mammalian enzyme
Azoles resistance
Overproduction/mutation in C14-demethylase
Dug efflux
Azoles drug interactions
Inhibitors/substrates of liver p450 enzumes change PK effects and have cardiovascular effects
What are the different Allylamines?
Naftifine
Terbinafine (Lamisil)
What are the different Azoles
Imidiazoles
Triazoles
Allylamines Mechanism
Inhibits Sqalene Epoxidase - leading to acucmulation of sqalene
Are Allylamines fungicidal or static?
Fungicidal
Allylamines selectivity
Hose squalene epoxidase is much less effected
Allylamine clinical uses
treatment of skin and nail infections
Topical use for dermatophytes
Allylamine Toxicities
Potential liver toxicity
Echinocandins Mechanism
Osmotic lysis due to loss of cell wall integrity - due to the inhibition of B-glucan synthase
Echinocandins Clinical uses
Systemic candidiases, asperfillosis, antifungal prophylaxis in bone marrow transplant patients
Echinocandinds toxicities
Well tolerated but some fears of allergic histamine release
Travaborole Mechanism
Inhibits the ability of Leucyl-tRNA to be attached to leucine - protein synthesis is inhibited since amino=acyl tRNA for leucine is not formed
Travaborole selectivity
Mammalian enzyme has a different structure than fungal enzume at critical aa recognition site
Travaborole clinical use
Topical for onychomycosis of nail in 10% of formulation along with ciclopirox
