Anti-fungals Flashcards
What are the various temperature dependent morphologies of dimorphic fungi?
1) Yeast at body temp
2) Mold at room temp
What is the structure and function of the fungal cell wall?
- Structure:
- Polysaccharides (~90%)
- Proteins and glycoproteins (~10%)
-Functions:
Provides shape, rigidity, strength and protection from osmotic shock
What is the structure and function of the fungal cell MEMBRANE?
- Structure:
- Phospholipids
- Sterol (ergosterol)
- Functions:
- Protects cytoplasm
- Regulates the intake and secretion of solutes
- Facilitates capsule and cell wall synthesis
What is the mechanism of action of Azoles?
Inhibit the rate limiting step in ergosterol synthesis
What are the drug interactions associated with Azoles?
- Azole’s increase levels of many drugs including cyclosporine / tacrolimus, antihistamines, oral hypoglycemics, warfarin…
- Rifampin and other CYP 450 enzyme inducers decrease azole levels
What are the adverse drug reactions of Azoles?
GI upset, Hepatitis, Rash, Headache
How is Fluconazole administered and how is it absorbed?
- Administration: IV, oral tabs and oral soln
- Absorption: GI absorption and CNS penetration (50-60% serum)
Which drug has the least drug interactions of all the Azoles?
Fluconazole
What toxicity is associated with Fluconazole?
H/A, alopecia, n/v,anorexia, hepatitis (rare), rash
What fungi are sensitive to fluconazole?
Drug of choice for Candida albicans, mild to moderate Cryptococcus neoformans
Which fungi are resistant to fluconazole?
C. krusei, T. glabrata (usually dose dependant)
How is itraconzole administered and absorbed?
- Administratio: IV, oral caps and soln.
- Poor GI absorption (caps are worst) and CNS penetration
Which drug has the MOST drug interactions of all the Azoles?
Itraconzaole
What toxicities are associated with itraconazole?
- Headache, Nausea/vomiting, diarrhea, rash, hypokalemia, adrenal insufficiency, impotence, gynecomastia,leg edema, hepatitis (rare), CHF (rare)
What are the indications for itraconazole?
- Most yeast, many molds and most dimorphics
- Drug of choice for Histoplasma
How does voriconazole extend the spectrum of azoles?
Extends spectrum to molds
Describe the bioavailability of voriconazole?
Excellent bioavailability and CNS penetration
What toxicities are associated with Voriconazole?
Visual disturbances (24%), hepatitis (13%), Rash (6%)
What are the indications for voriconazole?
Aspergillus sp., Candida sp., Cryptococcus, dimorphics, Scedosporidium, Fusarium…
- Drug of choice for aspergillus
- Prophylaxis during neutropenia and GVHD
What is the mechanism of action of the polyenes?
- Bind to ergosterols in cell membrane and form membrane channels w/ increased permeability causing a resultant leakage of intracellular components
What fungi are sensitive to amphotericin B?
- Candida sp, Cryptococcus neoformans, dimorphics, Aspergillus sp, mucormycosis
Which fungi are resistant to amphotericin B?
- C. lusitaniae C. guilliermondi, P. boydii and A. terrius
- Less sensitive: C. krusei
What drug interactions are associated with amphotericin B?
Concurrent nephrotoxic agents
What toxicities are associated with Amphotericin B?
- Renal, infusion related rxn’s (fever and rigors), anemia (↓ erythropoetin)
How does Amphotericin B lead to renal toxicity?
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
What type of Amphotericin B has decreased renal toxicity?
- Lipid Based Amphotericin B
- Require higher doses to achieve the same therapeutic effect as AmphoB
What is the mechanism of action of Echinocandin?
- Inhibition of Beta (1,3)-D-glucan synthesis in the fungal cell wall
What fungi are sensitive/resistant to Echinocandin?
1) Sensitive: Candida sp., Aspergillus sp.
2) Resistant: Poor activity against Mucor, Cryptococcus
What echinocandin is given IV only?
Caspofungin
What adverse drug reactions are associated with Caspofungin?
fever, rash, n/v, phlebitis, hepatitis (all rare)
What are the indications for caspofungin?
- Third line therapy for invasive Aspergillus sp.
- Option for Candida sp. resistant to azoles or when the patient is intolerant of azoles
How is caspofungin eliminated?
hepatically
