Antifungals

Question 1

What is the major difference between bacteria and fungi

Answer 1

Fungi differ from bacteria because they are eukaryotic (80S ribosomes as compared to 70S) - so many antibacterial agents are ineffective

Question 2

Which are larger, fungi or bacteria?

Answer 2

Fungi are much larger and slower growing

Question 3

What is the difference in the cell wall of fungi and bacteria?

Answer 3

Fungi have a rigid cell wall made of chitin and glucans - whereas bacteria have mucopeptide cell walls

Question 4

What is unique about fungi cell membranes?

Answer 4

Fungi contain ergosterol instead of cholesterol

Question 5

Where are fungal infections common? Why are they difficult to treat?

Answer 5

Poorly vascularized tissues, or skin, nails, and hair

Difficult to treat since antifungal agents are poorly soluble and not distributed or retained well

Question 6

What sort of response do fungi cause?

Answer 6

They cause a cellular immune response - which may interfere with drug penetration

Question 7

How do treatments differ between fungi and bacterial infections?

Answer 7

Bacterial = use short term low toxicity therapy
Fungal = use long term high toxicity therapy

Question 8

What are the different types of fungal infections?

Answer 8

Superficial/cutaneous
Subcutaneous
Systemic

Question 9

Griseofulvin Mechanism

Answer 9

Mitotic Inhibitor

Question 10

Is Griseofulvin static or cidal?

Answer 10

Static

Question 11

Griseofulvin selectivity

Answer 11

Taken up by keratinocytes or precursor cells

Question 12

Griseofulvin Clinical uses

Answer 12

Active against dermatophytes (hair, skin, nails)
Fungi are lost as hair and nails fall out
Used to treat ringworm

Question 13

Griseofulvin toxicity

Answer 13

Well tolerated, but long term use can lead to headache, memory loss, skin rashes, photosensitivity rxsns, porphyria

Question 14

Griseofulvin Resistance

Answer 14

Rare, but likely related to decreased transport into cells

Question 15

5-Flucytosine Mechanism

Answer 15

Inhibits or alters DNA/RNA synthesis

Question 16

5-Flucytosine static or cidal?

Answer 16

Both

Question 17

5-Flucytosine Clinical uses

Answer 17

Effective in combo with Amphotericin B to treat cryptococcal meningitis
Use with Amphotericin B also decreases the incidence of resistance

Question 18

5-Flucytosine Toxicities

Answer 18

Bone marrow depression, neutropenia, throbocytopenia

Careful to monitor patients who ahve renal insufficiency to avoid toxicity

Question 19

5-Flucytosine Resistance mechanisms

Answer 19

High resistance

Due to transport alterations, cytosine deaminase alterations, and anabolic enzyme alterations

Question 20

Amphotericin B Mechanism

Answer 20

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

Question 21

Amphotericin B fungicidal or static?

Answer 21

Fungicidal

Question 22

Amphotericin B selectivity

Answer 22

Binds to fungal ergosterol much more readily than human cholesterol

Question 23

Amphotericin B Clinical uses

Answer 23

Best choice for treating systemic fungal infections

• Candidiasis
• Histoplasmosis
• Coccidiomucosis
• Blastomycosis
• Aperigillus
• Cryptococcoses

Question 24

Amphotericin B Toxicities

Answer 24

A whole bunch

-Nephrotoxicity the main one?

Question 25

Amphotericin B Resistance mechanisms

Answer 25

Rare - may occur due to alteration of sterol content or composition

Question 26

Amphotericin B Drug interacitons

Answer 26

Can increase the cytotoxicit of Rifampicin 5-FC plus Amphotericin B can used to treat Cryptococcal meningitis Syntergism or additivity with Amph B + Triazoles

Question 27

Nyastatin Mechanism

Answer 27

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

Question 28

Nyastatin Clinical use

Answer 28

Topical treatment for candidiasis, thrush, esophaginitis, vaginitis

Question 29

Nyastatin toxicities

Answer 29

Minimal

Question 30

Azoles Mechanism

Answer 30

Bind through ring nitrogen to heme of cytochrome p450 and inhibit the lanosterol C-dimethylase system

Question 31

Are Azoles fungistatic or fungicidal?

Answer 31

Fungistatic at low concentrations | Fungicidal at high concentrations

Question 32

Azoles selectivity

Answer 32

100-fold greater binding affinity to fungal cell lanosterol C14-demethylase compared to mammalian enzyme

Question 33

Azoles resistance

Answer 33

Overproduction/mutation in C14-demethylase | Dug efflux

Question 34

Azoles drug interactions

Answer 34

Inhibitors/substrates of liver p450 enzumes change PK effects and have cardiovascular effects

Question 35

What are the different Allylamines?

Answer 35

Naftifine | Terbinafine (Lamisil)

Question 36

What are the different Azoles

Answer 36

Imidiazoles | Triazoles

Question 37

Allylamines Mechanism

Answer 37

Inhibits Sqalene Epoxidase - leading to acucmulation of sqalene

Question 38

Are Allylamines fungicidal or static?

Answer 38

Fungicidal

Question 39

Allylamines selectivity

Answer 39

Hose squalene epoxidase is much less effected

Question 40

Allylamine clinical uses

Answer 40

treatment of skin and nail infections | Topical use for dermatophytes

Question 41

Allylamine Toxicities

Answer 41

Potential liver toxicity

Question 42

Echinocandins Mechanism

Answer 42

Osmotic lysis due to loss of cell wall integrity - due to the inhibition of B-glucan synthase

Question 43

Echinocandins Clinical uses

Answer 43

Systemic candidiases, asperfillosis, antifungal prophylaxis in bone marrow transplant patients

Question 44

Echinocandinds toxicities

Answer 44

Well tolerated but some fears of allergic histamine release

Question 45

Travaborole Mechanism

Answer 45

Inhibits the ability of Leucyl-tRNA to be attached to leucine - protein synthesis is inhibited since amino=acyl tRNA for leucine is not formed

Question 46

Travaborole selectivity

Answer 46

Mammalian enzyme has a different structure than fungal enzume at critical aa recognition site

Question 47

Travaborole clinical use

Answer 47

Topical for onychomycosis of nail in 10% of formulation along with ciclopirox