Antifungal Agents

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Targets & Polyenes - Fungal Kryptonite Crew

  • Fungal Drug Targets:
    • Cell Membrane: Ergosterol (primary fungal target)
    • Cell Wall: β-glucans, chitin
    • Nucleic Acid/Protein Synthesis
  • Polyenes: Membrane Disruptors
    • Mechanism: Bind ergosterol → form pores in cell membrane → ion leakage (K⁺, Mg²⁺) → cell death.
    • Amphotericin B (AmB): 📌 "Amphoterrible"
      • Broadest spectrum; IV for systemic mycoses.
      • Toxicities: Infusion reactions, nephrotoxicity (RTA type 1, ↓K⁺, ↓Mg²⁺, dose-limiting), anemia, thrombophlebitis.
      • Lipid formulations (e.g., Liposomal AmB) ↓nephrotoxicity.
    • Nystatin:
      • Topical use only (local candidiasis); systemically toxic.

⭐ Amphotericin B is notorious for causing "shake and bake" (fever and chills) infusion reactions. Fungal cell wall and membrane with drug targets

Azoles - Ergosterol's Enders

  • MoA: Inhibit fungal CYP450 enzyme (14-α-demethylase) → ↓ ergosterol synthesis → disrupts cell membrane integrity.
  • Spectrum: Broad (Candida, Cryptococcus, Aspergillus, dermatophytes); many drug interactions (CYP450 inhibition).
  • Types & Key Uses:
    • Imidazoles (e.g., Ketoconazole): Topical; older systemic (more toxicity).
    • Triazoles (e.g., Fluconazole, Voriconazole, Posaconazole): Systemic; generally preferred.
      • Fluconazole: Candida, Cryptococcus; good CNS penetration.
      • Voriconazole: DOC for Aspergillosis.
      • Posaconazole: Broadest; includes Mucorales.
  • AEs: Hepatotoxicity (class effect), GI upset.
    • Ketoconazole: Endocrine effects (e.g., gynecomastia).
    • Voriconazole: Visual disturbances (reversible), photosensitivity.
  • 📌 Mnemonic: "Azoles zap 14-alpha."

⭐ Voriconazole is the drug of choice for invasive aspergillosis but can cause visual disturbances and requires therapeutic drug monitoring.

Antifungal drug mechanisms of action

Echinocandins & Flucytosine - Wall Breakers & Code Scramblers

  • Echinocandins (-fungins: Caspofungin, Micafungin, Anidulafungin)
    • Mechanism: Inhibit $\beta$-(1,3)-D-glucan synthase → disrupt fungal cell wall. "Wall Breakers".
    • Spectrum: Candida (cidal), Aspergillus (static). IV only.
    • Uses: Invasive candidiasis, aspergillosis (often combination).
    • Side Effects: Well-tolerated; GI upset, flushing (histamine release). Caspofungin inhibits fungal beta-glucan synthesis
  • Flucytosine (5-FC)
    • Mechanism: Converted to 5-FU by fungal cytosine deaminase → inhibits DNA/RNA synthesis. "Code Scramblers". 📌 5-Flies into Cell.
    • Spectrum: Cryptococcus, some Candida.
    • Uses: Combination therapy (prevents resistance).
    • Side Effects: Bone marrow suppression (monitor!), hepatotoxicity, GI issues.

    ⭐ Flucytosine is almost always used in combination with Amphotericin B for cryptococcal meningitis to enhance efficacy and prevent resistance; monitor for bone marrow toxicity.

Allylamines, Griseofulvin & Resistance - Niche Fighters & Foe Evolution

  • Allylamines (e.g., Terbinafine)
    • MoA: Inhibit squalene epoxidase → ↓ ergosterol. Fungicidal.
    • Uses: Dermatophytes (tinea), onychomycosis.
  • Griseofulvin
    • MoA: Mitotic spindle inhibitor (binds tubulin). Fungistatic.
    • Uses: Dermatophytosis (skin, hair, nails).
    • PK: Deposits in new keratin.

    ⭐ Griseofulvin is deposited in newly formed keratin-containing tissues, making it effective for dermatophyte infections of skin and nails, but it is fungistatic and requires long treatment durations.

  • Antifungal Resistance
    • Target modification (e.g., ERG11, FKS genes).
    • ↑ Efflux pumps (e.g., ABC, MFS transporters).
    • Biofilm formation.
    • Reduced drug access/uptake.

Antifungal drug targets and resistance mechanisms

High‑Yield Points - ⚡ Biggest Takeaways

  • Amphotericin B: Binds ergosterol, forms pores; causes nephrotoxicity, infusion reactions.
  • Azoles: Inhibit 14-alpha-demethylase (ergosterol synthesis); drug interactions (CYP450), hepatotoxicity.
  • Echinocandins: Inhibit β-(1,3)-D-glucan synthesis (cell wall); for Candida, Aspergillus; well-tolerated.
  • Flucytosine (5-FC): Converted to 5-FU, inhibits DNA/RNA synthesis; bone marrow suppression, use with Ampho B.
  • Terbinafine: Inhibits squalene epoxidase (ergosterol synthesis); for dermatophytes, onychomycosis.
  • Griseofulvin: Disrupts microtubules; for dermatophyte infections; teratogenic.

Practice Questions: Antifungal Agents

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Which drug should not be given with ketoconazole?

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Flashcards: Antifungal Agents

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_____ is a fungus responsible for causing Pneumocystic pneumonia

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_____ is a fungus responsible for causing Pneumocystic pneumonia

Pneumocystis jiroveci

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