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Polyenes
Amphtericin B, Nyastatin
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Binds sterole moiety (primarily ergosterol)
Forms pores/ channels that increase membrane permeability
Causes leakage of intracellular molecules
Polyenes (Amp B, Nyastatin)
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Mechanism of Resistance to Polyenes (Amp B)
Species with notable resistance?
- Bacteria replaces ergosterol w/ precursor sterols
- Candida lusitaniae
- Aspergillus nidulans
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Which drug is dosed only topically to treat Candida (folds of obese patients with fungal infxns)
Nyastatin
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Amp B is used to treat
Candida, Aspergillus, Coccidoides, Rhisopus, Cryptococcus, Blastomyces, Histoplasma
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Amp B: Fungistatic of Fungicidal?
Fungicidal
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Clinical roles of Amp B?
Meningitis, mucormycosis, neutropenic fever
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Toxicity of AmpB (3)
- Infusion-related rxns (Worst with ABCD)
- Azotemia (Treat w/ K+, Mg2+)
- Anemia (Decreased productionof erythropoietin)
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Name 4 azoles
- Itraconazole
- Fluconazole
- Voriconazole
- Posaconazole
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What drugs work by inhibiting 14-a-sterole demethylase?
Azoles
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Azoles work by inhibiting (2 things)
14-a-sterol demethylase, impairs biosynthesis of ergosterol
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Resistance to the Azoles is by accumulation of mutations in
ERG11
(Protects heme in enzyme pocket from binding)
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Azoles: Fungistatic or Fungicidal?
Fungistatic
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What is the spectrum of action of azoles?
Candida, Blastomyces, Histoplasma, Coccidiodes
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What drug interacts with the CYP450 pathway? (not other drug friendly)
Azoles
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Which azole must have the stomach acidity to be absorbed?
- Itraconazole
- (If they're on an H2 antagonist or PPI, they shouldn't take itraconazole)
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Itraconazole is PO only. What forms? Are these interchangeable?
Capsule and liquid, the dosing levels are different so very hard to interchange
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Adverse effect of Itraconazole?
CHF (also contraindicated in pregnancy)
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Tx of Cryptococcus meningitis or transplant prophylaxis?
Fluconazole
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What does Fluconazole treat?
Cryptococcus meningitis, transplant prophylaxis, candidiasis
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Why is SBECD required with Voriconazole?
It is necessary for absorption of the drug
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Who can't receive Voriconazole? Why?
Pts. w/ decreased renal function because SBECD (which is required for Voriconazole absorption) causes nephrotoxicity
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SBECD is necessary for absorption of?
Voriconazole
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Why is Posaconazole not really clinically useful?
Very difficult to reach therapeutic levels, the drug is cleared too rapidly.
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Which azole causes visual side effects/ hallucinations?
Voriconazole
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N/V/D, Hepatotoxicity, abdominal paint, QT prolongation are adverse effects of what class of drugs?
Azoles
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Echinocandins (3)
- Caspofungin
- Micafungin
- Anidulafungin
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Echnocandins inhibit cell wall synthesis by inhbiting
- 1,3-B-D-glucan synthase
- (Reduces structural integrity, fungal cell wall--> osmotic instability, death)
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Which class of drugs inhibits cell wall synthesis by inhibiting 1,3-B-D-glucan synthase?
Echnocandins
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Mechanism of resistance to Echnocandins is a mutation in
Fks1p (subunit of glucan synthase)
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Echnocandins: Fungistatic or Fungicidal?
Fungicidal
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Echnocandins:
1) Oral bioavailability?
2) Protein bound?
3) Cleared by?
- 1) Not orally bioavailable
- 2) Highly protein bound
- 3) Hepatic clearance
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Treat deeply invasive candidiasis
Caspofungin
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Don't give pts. w:
Renal impairment-
Hepatic impairment-
- Renal impairment- Voriconazole
- Hepatic impairment- Caspfungin
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Treat deeply invasive candidiasis, esophageal candidiasis, prophylaxis HSCT
Micafungin
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Treat candidemia, esophageal candidiasis
Anidulafungin
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Which class of drugs acts on RNA and is the only antifunga that can have synergy w/ other antifungals?
Flucytosine
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