Antifungals Flashcards
Polyenes: Amphotericin B and Nystatin
MOA; Binds ergosterol, creating holes in membrane allowing leakage of electrolytes. Fungicidal.
Spectrum: Broad. Used for invasive systemic fungal infections in immunocompromised patients. Active against yeast and molds.
Distribution: Long half life and can cross blood brain barrier.
Adverse effects: Amphotericin B TOXIC because it can bind cholesterol. 80% have nephrotoxicity. Nystatin is mainly topical candida
Resistance: Rare, decreased ergosterol in membrane.
Azoles- Fluconazole, Itraconazole, Ketoconazole, -azole
MOA; binds fungal p450 enzyme (erg11) blocking production of ergosterol and causing an accumulation of Ianosterol. Fungistatic
Spectrum: Most widely used antifungal; varies by agent
Distribution: Orally available though cola/acid helps facilitate absorbtion of itraconazole, ketoconazole
Toxicity: Drug-Drug interactions, hepatotoxicity, neurotoxicity, alters hormone synthesis. Pregnancy class D.
Resistance: Altered P450, Efflux transporters.
Allylamines- Terbinafine (Lamisil)
Mechanism: Fungicidal, inhibits squalene epoxidase, which leads to toxic accumulation of squalene
Spectrum: Dermatophytes
Toxicity: Topical, drug interactions with CYP2D6 substrates
Resistance: Rare in human pathogens but could include decreased uptake, mutant binding site, and substrate efflux.
Flucytosine (5-FC)
MOA: Antimetabolite selectively taken up and converted to 5-fluorouracil in fungi, interfering with DNA and RNA synthesis. Fungistatic.
Spectrum: Narrow - Yeast
Distribution: Oral, Penetrates CNS
Toxicity: Only partially selective for yeast. can lead to bone marrow suppression - follow patient’s cell counts closely.
Resistance: Loss of converting enzyme or transporters, rarely used monotherapy –> cotreat with amphotericin B to increase uptake and minimize the likelihood of developing resistance.
Griseofulvin
MOA: Binds microtubules inhibits spindle leading to multinucleate cells, fungistatic.
Spectrum: Dermatophytes
Distribution: Lipids increase oral absorbtion and then concentrates in dead keratinized layer of skin
Toxicity: Teratogenic (Pregnancy Class D)
Resistance: change to beta-tubulin, need to take orally for months so if patient is not adherent resistant mutations are more likely to develop
Echinocandins - Caspofungin
MOA: Cell wall inhibitor blocks synthesis of Beta (1-3)-d-glucan polysaccharide. Fungicidal (Candida) and Fungistatic (Aspergillus)
Spectrum: Candida albicans, systemic
Distribution: IV, large molecular weight prohibits CNS penetration
Toxicity: limited, fever, rash at site of injection
Resistance: change in (1,3)-beta-D-glucan synthase gene
