Antifungals

Question 1

What is Mycosis?

Answer 1

• mycosis is an infection caused by microscopic fungi
• can infect the body superficially, subcutaneously or systemically

Question 2

What are the 3 different forms of fungi?

Answer 2

1. unicellular yeast-like form (candida)
2. filamentous mold (apergillus and dermatophytes)
3. Yeast-like in the body, filamentous outside the body

Question 3

What are fungal infections and what are the key differences between bacteria and fungi?

Answer 3

• unlike bacteria, fungi are eukaryotic organisms
• this makes fungal infections much harder to attack without affecting the host
  FUNGI DIFFERENCES:
• Cell wall: B-glucan, glycoproteins, chitin; B-glucan varieties can evade the immune system
• Plasma membrane: Ergosterol instead of cholesterol
• DNA synthesis: Cytosine deaminase expression

Question 4

What are the 4 main antifungal drug classes?

Answer 4

1. Polyenes
   Ex: Amphotericin B
   - Broad spectrum fungicidal
   - High systemic toxicity
2. Azoles
   Ex: Itraconazole
   - Broad spectrum, fungistatic
   - Very low toxicity
3. Pneumocandins and echinocandins
   Ex: caspofungin
   - Newest AF drugs
   - fungicidal
   - low toxicity
   - replacing polyenes for systemic therapy
4. drugs used to treat dermatophytosis
   - terbinafine

Question 5

What are the main targets of the AF drugs Terbinafine, Echinocandins and Polyenes (amphotericin B)

Answer 5

Terbinafine = endoplasmic reticulum - inhibit ergosterol synthesis
Echinocandins = cell wall
Polyenes (amphotericin B) = plasma membrane

Question 6

What is Polyenes (Amphotericin B) mechanism of action?

Answer 6

MOA: Plasma membrane disruption
Binds ergosterol in fungal membrane:
- enters membrane → several molecules come together and form a pore → pores cause fungal cell to lyse (FUNGICIDAL)
- unfortunately, also binds cholesterol to some extent → toxic to host cells

Question 7

What is Polyenes (amphotericin B) spectrum of action?

Answer 7

Broad spectrum (greater than the azoles or pneumocandins)
- many serious, systemic mycotic infections, like Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, Aspergillus, etc.
- ineffective against dermatophytes → less serious causes athletes feet and ringworm

Question 8

What is Polyenes (amphotericin B) pharmacokinetics?

Answer 8

long half-life >100h; drug continues to be excreted for weeks after discontinuation of therapy
- don’t need to administer often, but severe side effects - most toxic drug approved in the world

Question 9

What are the adverse effects of Polyenes (amphotericin B)?

Answer 9

• most toxic antimicrobial drug in clinical use
• main problem is dose-dependent nephrotoxicity
• IV administration may cause thrombosis (must be administered over ~4-6h start low and go slow)
• Fungizone (conventional Amphotericin B formulation) causes serious side effects in 80% of patients
• Lipid-complex formulations are safer, but Fungizone (cheaper) is still the treatment of choice for certain infections

Question 10

Lipid-complex formulations for Polyenes: Amphotericin B

Answer 10

various lipid formulations now available:
- lipid complex
- colloidal
- liposomal
much less toxic and can be infused at higher dosages over 1-2h
usually given 3x/week or once prior to azole therapy

Question 11

what are clinical applications of polyenes (amphotericin B)?

Answer 11

• mainly administered IV to patients with life-threatening systemic mycoses (especially in immunocompromised patients, due to the fungicidal nature of the drug)
• for immunocompromised patients → prefer safer azoles even though they are fungistatic
• often given once prior to longer follow up therapy with an azalea (usually not combined → azole may reduce ergosterol binding sites for amphotericin B)

Question 12

what are Azoles and their mechanism of action?

Answer 12

• azoles are the 1st relatively safe class of antifungal drugs; now the most commonly used for systemic antifungal therapy
• azoles inhibit fungal CYP450-mediated conversion of lanosterol to ergosterol
• inhibit fungak membrane synthesis
• fungistatic effect
• fairly broad spectrum not as broad as Amphotericin B
• would not use in severely immunocompromised patients

Question 13

What are the two classes of Azoles?

Answer 13

• Imidazoles and triazoles
• although they are safer than polyenes, azoles are teratogenic (affect fetus)
• for systemic use, older imidazoles (ketoconazole) → less effective and more toxic than newer triazoles (itraconazole→ can treat endocrine disorders)
• for topical use, imidazoles and triazoles are often interchangable based on good efficacy and low toxicity

Question 14

What is an example of a imidazoles (Azoles) and its administration and adverse effects

Answer 14

• Ketoconazole
• topical use for dermatophytosis (ringworm, athletes food, jock itch)
• oral used not recommended due to side effects → use terbinafine instead for more serious dermatophyte infections
  adverse effects:
• systemically, inhibit fungal and mammalian sterol synthesis (e.g. cortisol and testosterone) → endocrine adverse effects
• no side effects if applied topically

Question 15

What is an example of a Triazoles (Azoles) and its administration, use, and adverse effects

Answer 15

• Itraconazole
• good oral absorption (convenient for patient)
• long half life (48h)
• used to treat many non-life-threatening systemic fungal infections
• fairly broad spectrum of activity (not as effective against Aspergillus or Candida as the polyenes or the newer triazole voriconazole)
• sometimes used in place of (or following) amphotericin B for life-threatening infections
  adverse effects:
• interfere with sterol synthesis enzymes of host less than imidazoles → systemic endocrine adverse effects are uncommon

Question 16

adverse effects of all Azoles

Answer 16

• teratogenic (contraindicated in pregnancy)
• all azoles inhibit mammalian hepatic P450 enzymes → inhibit metabolism of many concurrently administered drugs

Question 17

what are Echinocandins mechanism of action

Answer 17

• echinocandins are now the most common IV antifungal drug for the treatment of serious fungal infections worldwide (replaced amphotericin B in a lot of fungal treatments)
• inhibit an enzyme (beta-(1,3)-D-glucan synthase) necessary for the synthesis fo the cell wall of several fungi
• inhibit fungal cell wall synthesis
• Fungicidal effect against Candida and fungistatic effect against Aspergillus

Question 18

what are Echinocandins pharmacokinetics

Answer 18

• half-life of 8-13h (much less than ampho B)
• only available parenterally; limited oral absorption

Question 18

Echinocandins spectrum of action

Answer 18

narrower spectrum than Amphotericin B and azoles; not effective against Cryptococcus (but effective against Candida and Aspergillus species, which itraconazole is not)
- ineffective against dermatophytes

Question 19

what are examples of echinocandins?

Answer 19

Capsofungin, micafungin, anidulafungin
- used for esophageal candidiasis, candidemia, and invasive candidiasis and aspergillosis
- significantly metabolized by the liver, so dose adjustments may be required for patients with moderate hepatic dysfunction
- overall, all agents are well-tolerated (pretty safe) with similar adverse effect profiles and few drug-drug interactions
- expensive

Question 20

What is terbinafine?

Answer 20

• “Tinea” or “ringworm” is caused by dermatophytes that can infect the epidermis, including skin, hair, and nails
• infection is known as “dematophytosis”
• many different varieties
• terbinafine inhibits ergosterol synthesis (different enzyme than azoles, though same result)
• unlike azoles, terbinafine is fungicidal - in dermatophytes, toxic metabolites accumulate and cause cell death
• more effective than itraconazole in treating dermatophytes despite itraconazole’s broad spectrum
• given orally for serious infections (unlike imidazoles)
• half-life is extremely long (>300hrs) bc it accumulates in skin, hair, nails and fat
• generally safe, adverse effects are uncommon (may see GI upset, headache, rash)