Antifungal Agents

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.

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.

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).
• 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.

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.