Anti-Fungal Agents Flashcards
What are some factors that allow the overgrowth of fungal infections? Think opportunistic!
1) Alteration in oral flora
- maybe b/c of broad spectrum antibiotics
2) Immunosuppression
- via chemo
- long-term use of SAIDs
- inhaled steroids for asthma
3) Systemic disease
- AIDS, diabetes
- Adrenal suppression
Describe the mechanism of action for amphotericin B
- a polyene => most reliable agent against most fungal pathogens
- Binds ergosterol in fungal membrane => punches holes => cell stuff leaks out => CELL DEATH
Problem: also binds to cholesterol in mammalian cells
How is amphotericin B absorbed?
- IV or topical
- poor PO
Describe the distribution of amphotericin B
- Rapidly sequester in tissues (liver, spleen, lymph nodes, lungs)
- then slowly released
Little CNS penetration
How is amphotericin B elminated?
- Slowly via kidney
- Major route: through biliary tract
t1/2 15 days
Describe the clinical use of amphotericin B
- Most reliable agent against most fungi
- DRUG OF CHOICE for all life-threatening systemic fungal infections – esp immunosuppressed pts
Often used to start therapy but the replaced by less toxic azoles
Describe the adverse rxns associated with amphotericin B
- NEPHROTOXICITY! — in nearly all pts
- ANEMIA (BM depression secondary to the above)
- Fever, chills, vomiting, rigor, hypotension w/ IV use
Describe the mechanism of action of nystatin
Similar to amphotericin B
- a polyene => most reliable agent against most fungal pathogens
- Binds ergosterol in fungal membrane => punches holes => cell stuff leaks out => CELL DEATH
How is nystatin absorbed?
- Topical use ONLY
Cannot be absorbed PO
Describe the clinical use of nystatin when treating fungal infections
Superficial candidal infections
skin, mucous membrane, GI tract
Describe the adverse rxns associated with nystatin
mild GI upset if swallowed
Describe the mechanism of action of echinocandins
- Inhibits synthesis of beta(1,3)-D-glucan (this is an essential component of fungal cell walls)
- Overall => disrupts cell wall
Higher level of selective toxicity b/c mammal’s don’t have cell walls or those enzymes
How is echinocandin absorbed?
IV infusion only
What are the situations in which you would want to adjust the dosage for echinocandin?
- Hepatic insufficiency
- if pt is taking an inducer of P450
No need to adjust for kidney probs
Describe the clinical uses of echinocandins
- Invasive aspergillosis
used in pts who don’t respond to other therapies
Describe the adverse rxns associated with echinocandins
- Histamine-mediated symptoms: rash, facial swelling
- Also fever, n/v, HA
What are some types of triazoles?
- Fluconazole
- Itraconazole
Describe the mechanism of action of triazoles
- Selective inhibition of fungal cytochrome p450
- Prevents synthesis of ergosterol => fungistatic-cidal
Great selectivity for fungal P450 instead of mammalian
How are triazoles absorbed?
PO, IV
- Bioavailability 90-99%
How is fluconazole eliminated?
- Kidneys
May need to adjust dosage w/ renal dysfunction
How is itraconazole eliminated?
Hepatic metabolism
Describe the distribution of fluconazole
Can enter CNS
Therefore => used to treat meningitis
Describe the clinical uses of fluconazole
- Vaginal candidiasis (if topical tx fails)
- Oropharyngeal/esophageal candidiasis
- Tx/prevention of cryptococcal meningitis in pts w/ AIDS
Describe the clinical uses of itraconazole
- Dermatophytoses
- Onychomycosis
Describe the adverse rxns associated w/ triazoles
- Overall very well-tolerated
- GI upset, HA, rash, liver enzyme probs
Can inhibition CYP450 metabolism (more so in itraconazole than fluconazole)
What are some types of imidazoles?
- Ketoconazole
- Clotrimazole
- Miconazole
Describe the mechanism of action of imidazoles
- Inhibits fungal p450 enzyme => decreased synthesis of ergosterol
- Disrupts cell wall synthesis => alter membrane permeability
- Fungistatic/fungicidal => depends on concentration
How is ketoconazole absorbed?
PO, IV
Used systemically
How are clotrimazole and miconazole absorbed?
Topical ONLY
poor PO
How are imidazoles distributed?
- poor CNS
- well-distributed otherwise
- crosses placenta
How are imidazoles eliminated?
- Hepatic metabolism (CYP450 oxidation)
- Also via breast milk
Describe the clinical use of ketoconazole
- Systemic infections like candidiasis => use is decreasing b/c of safer drugs
- Also dermatologic indications
Describe the clinical use of clotrimazole and miconazole
- oral and vaginal candidiasis
- used as creams/troches
Describe the adverse rxns associated with imidazoles
- Anorexia, n/v
- Hepatotoxicity inhibits CYP450 drug metabolism and mammalian testosterone synthesis
