Week 2 - Antifungal Drugs & Fungal Skin Infections

Question 0

What is the mechanism of Polyenes (Amphotericin B & Nystatin)?

Answer 0

It binds ergosterol, creating holes in the membrane allowing leakage of electrolytes. It’s fungicidal!

Question 1

What are the 6 antifungals we need to know?

Answer 1

1. Polyenes - Amphotericin & Nystatin
2. Azoles - Fluconazole, Itraconazole, Ketoconazole
3. Allylamines - Terbinafine
4. Flucytosine
5. Griseofulvin
6. Echinocandins - Caspofungin

Question 2

What is the spectrum of Polyenes? What types of patients are they commonly used for?

Answer 2

Broad spectrum. Used for invasive systemic fungal infections in immunocompromised patients. Active against yeast and molds.

Question 3

How are Polyenes distributed through out the body?

Answer 3

A small fraction of drug is excreted and has a long tissue half life. Liposomal form can cross blood-brain barrier.

Question 4

Resistance is rare in polyenes. How does a fungi become resistant to a Polyene?

Answer 4

It has a decreased amount of ergosterol in its membrane.

Question 5

What are the adverse effects of Polyenes?

Answer 5

TOXIC because they’re able to bind cholesterol. This decreases renal blood flow and leads to permanent destruction of the basement membrane. About 80% of patients have nephrotoxicity. Nystatin does NOT have these effects. Nystatin is a topical used for Candida.

Question 6

What are the three Azoles?

Answer 6

Fluconazole, Itraconazole, Ketoconazole

Question 7

What is the mechanism of azoles?

Answer 7

They bind fungal P-450 enzyme (Erg11) and block the production of the membrane protein ergosterol and causes accumulation of lanosterol. It’s fungistatic.

Question 8

What is the spectrum of Azoles?

Answer 8

They’re the most widely used antifungal and the spectrum varies by the agent used.

Question 9

How are Azoles distributed in the body?

Answer 9

They have better oral availability when taken with cola/acid. Cola helps facilitate absorption of itraconazole and ketoconazole.

Question 10

What kind of toxicity do Azoles cause?

Answer 10

Drug-drug interactions, hepatotoxicity, neurotoxicity, alters hormone synthesis - AVOID DURING PREGNANCY (pregnancy class C)

Question 11

How can fungi become resistant to Azoles?

Answer 11

Altered cytochome P-450, upregulation of efflux transporters

Question 12

What is the drug in the Allylamines class?

Answer 12

Terbinafine (Lamisil)

Question 13

What is the mechanism of Terbinafine (Lamisil)?

Answer 13

It inhibits squalene epoxidase, which leads to the toxic accumulation of squalene. This drug is fungicidal.

Question 14

What is the spectrum of Allylamines (Terbinafine - Lamisil)?

Answer 14

Dermatophytes

Question 15

What type of toxicity does Terbinafine cause?

Answer 15

It’s almost always used topically. It can cause drug interactions with CYP2D6 substrates.

Question 16

How can a fungi become resistant to Terbinafine (Lamisil)?

Answer 16

Resistance is rare in human pathogens, but it could include (1) Decreased uptake, (2) Mutant binding site, and (3) Substrate for efflux transporters

Question 17

What is the fungal nucleic acid synthesis inhibitor?

Answer 17

Flucytosine (5-FC)

Question 18

What is the mechanism of Flucytosine?

Answer 18

It’s an antimetabolite selectively taken up and converted to 5-fluorouracil in fungi, interfering with DNA and RNA synthesis. It’s fungistatic.

Question 19

What is the spectrum of Flucytosine?

Answer 19

Narrow spectrum, mostly yeast. (Candida albicans & Cryptococcus)

Question 20

How is Flucytosine taken?

Answer 20

Orally, it penetrates the CNS when distributed in the body.

Question 21

What is the toxicity of Flucytosine?

Answer 21

It is only partially selective for yeast so it can lead to bone marrow suppression - need to follow a patient’s cell counts closely

Question 22

How do fungi become resistant to Flucytosine?

Answer 22

They loose the converting enzyme or transporters.

Question 23

How do we compensate for the resistance some fungi have developed against Flucytosine?

Answer 23

It is rarely used as a monotherapy, often its cotreated with Amphotericin B to increase uptake and minimize the likelihood of developing resistance.

Question 24

What is the mechanism of Griseofulvin?

Answer 24

It binds microtubules and inhibits spindles leading to multinucleate cells. It’s fungistatic.

Question 25

What is the spectrum of Griseofulvin?

Answer 25

Dermatophytes

Question 26

How is griseofulvin distributed in the body?

Answer 26

Lipids increase the oral absorption.

Then the medication concentrates in the dead keratinized layer of the skin.

Question 27

What toxicity does griseofulvin cause?

Answer 27

It is teratogenic, it’s able to disturb the growth & development of an embryo or fetus.

Question 28

How do fungi gain resistance for griseofulvin?

Answer 28

It changes beta-tubulin.

Question 29

How long does a patient need to take Griseofulvin?

Answer 29

They need to take it for months orally, so if the patient is not adherent, resistance mutations are more likely to develop.

Question 30

What is the mechanism of Echinocandins (Caspofungin)?

Answer 30

Its a cell wall inhibitor that blocks the synthesis of Beta (1,3)-d-glucan polysaccharide. It’s fungicidal - Candida and Fungistatic- aspergillus.

Question 31

What is the spectrum of Caspofungin?

Answer 31

Candida albicans, systemic

Question 32

How is caspofungin given to the patient?

Answer 32

It’s given through IV. The large molecular weight prohibits CNS penetration.

Question 33

What toxicity does Caspofungin cause?

Answer 33

Limited - fever, rash at site of injection

Question 34

How can fungi gain resistance to Caspofungin?

Answer 34

It can have a change in the (1,3) beta-D-glucan synthase gene.