Anti-fungals

Question 1

What are the various temperature dependent morphologies of dimorphic fungi?

Answer 1

1) Yeast at body temp

2) Mold at room temp

Question 2

What is the structure and function of the fungal cell wall?

Answer 2

• Structure:
  
  • Polysaccharides (~90%)
  • Proteins and glycoproteins (~10%)
    -Functions:
    Provides shape, rigidity, strength and protection from osmotic shock

Question 3

What is the structure and function of the fungal cell MEMBRANE?

Answer 3

• Structure:
  
  • Phospholipids
  • Sterol (ergosterol)
• Functions:
  
  • Protects cytoplasm
  • Regulates the intake and secretion of solutes
  • Facilitates capsule and cell wall synthesis

Question 4

What is the mechanism of action of Azoles?

Answer 4

Inhibit the rate limiting step in ergosterol synthesis

Question 5

What are the drug interactions associated with Azoles?

Answer 5

• Azole’s increase levels of many drugs including cyclosporine / tacrolimus, antihistamines, oral hypoglycemics, warfarin…
• Rifampin and other CYP 450 enzyme inducers decrease azole levels

Question 6

What are the adverse drug reactions of Azoles?

Answer 6

GI upset, Hepatitis, Rash, Headache

Question 7

How is Fluconazole administered and how is it absorbed?

Answer 7

• Administration: IV, oral tabs and oral soln

- Absorption: GI absorption and CNS penetration (50-60% serum)

Question 8

Which drug has the least drug interactions of all the Azoles?

Answer 8

Fluconazole

Question 9

What toxicity is associated with Fluconazole?

Answer 9

H/A, alopecia, n/v,anorexia, hepatitis (rare), rash

Question 10

What fungi are sensitive to fluconazole?

Answer 10

Drug of choice for Candida albicans, mild to moderate Cryptococcus neoformans

Question 11

Which fungi are resistant to fluconazole?

Answer 11

C. krusei, T. glabrata (usually dose dependant)

Question 12

How is itraconzole administered and absorbed?

Answer 12

• Administratio: IV, oral caps and soln.

- Poor GI absorption (caps are worst) and CNS penetration

Question 13

Which drug has the MOST drug interactions of all the Azoles?

Answer 13

Itraconzaole

Question 14

What toxicities are associated with itraconazole?

Answer 14

• Headache, Nausea/vomiting, diarrhea, rash, hypokalemia, adrenal insufficiency, impotence, gynecomastia,leg edema, hepatitis (rare), CHF (rare)

Question 15

What are the indications for itraconazole?

Answer 15

• Most yeast, many molds and most dimorphics

- Drug of choice for Histoplasma

Question 16

How does voriconazole extend the spectrum of azoles?

Answer 16

Extends spectrum to molds

Question 17

Describe the bioavailability of voriconazole?

Answer 17

Excellent bioavailability and CNS penetration

Question 18

What toxicities are associated with Voriconazole?

Answer 18

Visual disturbances (24%), hepatitis (13%), Rash (6%)

Question 19

What are the indications for voriconazole?

Answer 19

Aspergillus sp., Candida sp., Cryptococcus, dimorphics, Scedosporidium, Fusarium…

• Drug of choice for aspergillus
• Prophylaxis during neutropenia and GVHD

Question 20

What is the mechanism of action of the polyenes?

Answer 20

• Bind to ergosterols in cell membrane and form membrane channels w/ increased permeability causing a resultant leakage of intracellular components

Question 21

What fungi are sensitive to amphotericin B?

Answer 21

• Candida sp, Cryptococcus neoformans, dimorphics, Aspergillus sp, mucormycosis

Question 22

Which fungi are resistant to amphotericin B?

Answer 22

• C. lusitaniae C. guilliermondi, P. boydii and A. terrius

- Less sensitive: C. krusei

Question 23

What drug interactions are associated with amphotericin B?

Answer 23

Concurrent nephrotoxic agents

Question 24

What toxicities are associated with Amphotericin B?

Answer 24

• Renal, infusion related rxn’s (fever and rigors), anemia (↓ erythropoetin)

Question 25

How does Amphotericin B lead to renal toxicity?

Answer 25

1) Direct damage of distal tubular membranes leading to wasting of Na+, K+, and Mg++
2) Tubular-glomerular feedback: Further constriction of arterioles
3) Constriction of the afferent arterioles leading to decreased glomerular filtration

Question 26

What type of Amphotericin B has decreased renal toxicity?

Answer 26

• Lipid Based Amphotericin B

- Require higher doses to achieve the same therapeutic effect as AmphoB

Question 27

What is the mechanism of action of Echinocandin?

Answer 27

• Inhibition of Beta (1,3)-D-glucan synthesis in the fungal cell wall

Question 28

What fungi are sensitive/resistant to Echinocandin?

Answer 28

1) Sensitive: Candida sp., Aspergillus sp.

2) Resistant: Poor activity against Mucor, Cryptococcus

Question 29

What echinocandin is given IV only?

Answer 29

Caspofungin

Question 30

What adverse drug reactions are associated with Caspofungin?

Answer 30

fever, rash, n/v, phlebitis, hepatitis (all rare)

Question 31

What are the indications for caspofungin?

Answer 31

• Third line therapy for invasive Aspergillus sp.

- Option for Candida sp. resistant to azoles or when the patient is intolerant of azoles

Question 32

How is caspofungin eliminated?

Answer 32

hepatically