Antifungal Agents

Classification - Fungal Foes & Drug Classes

Antifungal agents are classified by their mechanism of action, targeting unique fungal structures: cell membrane (ergosterol, squalene), cell wall (β-glucan), nucleic acids, or mitotic spindle (microtubules).

⭐ Amphotericin B: Binds ergosterol in fungal membranes, forming pores causing leakage & cell death. Broad spectrum; monitor for nephrotoxicity.

Polyenes - Ampho the Terrible & Co.

• Mechanism: Binds ergosterol (fungal membrane) → forms pores → K⁺/Mg²⁺ leakage → cell death.
• Spectrum: Broad: Candida, Aspergillus, Cryptococcus, endemic mycoses (e.g., Histoplasma).
• PK: IV only; poor CNS penetration.
• Toxicities: 📌 Ampho-terrible!
  • Nephrotoxicity (dose-limiting; RTA). Monitor renal function.
  • Infusion reactions (fever, chills, rigors - "shake and bake").
  • Anemia (↓ erythropoietin).
  • Electrolyte loss: ↓K⁺, ↓Mg²⁺.
• Liposomal Preps (LAmB): ↓ Nephrotoxicity & infusion reactions. Preferred if renal issues.

⭐ Conventional Amphotericin B deoxycholate requires a test dose due to potential anaphylactoid reactions.

Azoles - The "-azole" Armada

• Mechanism: Inhibit fungal 14-alpha-demethylase → ↓ergosterol synthesis.
• Types: Imidazoles (e.g., Ketoconazole); Triazoles (e.g., Fluconazole, Voriconazole, Itraconazole, Posaconazole).
• Interactions: Many are potent CYP450 inhibitors.
• Toxicities: Hepatotoxicity (class effect); QT prolongation (some, e.g., Voriconazole).

• Key Triazoles Comparison:

  Azole	Key Spectrum	Key Notes
  Fluconazole	Candida, Cryptococcus	Good CSF; Few DDIs; Renal excretion
  Itraconazole	Aspergillus, Histoplasma, Blastomyces	Potent CYP3A4 inh; CHF risk; Needs acid
  Voriconazole	Aspergillus (DOC), C. krusei/glabrata	Visual issues; Photosensitivity; Good CSF
  Posaconazole	Broadest: Zygomycetes, Aspergillus, Candida	Prophylaxis; Needs high-fat meal

⭐ Voriconazole: Drug of Choice (DOC) for invasive Aspergillosis; Therapeutic Drug Monitoring (TDM) recommended.

📌 All Zoles Often Lead to Elevated SG enzymes (Hepatotoxicity).

Echinocandins - Glucan Wall Wreckers

• Mechanism: Potently inhibit $β-(1,3)$-D-glucan synthase, disrupting fungal cell wall integrity. 📌 "Glucan Wall Wreckers".
• Spectrum: Fungicidal against most Candida spp. (incl. azole-resistant); fungistatic against Aspergillus spp.
  • No activity: Cryptococcus neoformans, Zygomycetes (e.g., Mucor).
• PK: IV administration only. Favorable safety profile; few significant drug interactions (minimal CYP450).
• Agents: Caspofungin, Micafungin, Anidulafungin.

⭐ Echinocandins are often first-line for empiric therapy of invasive candidiasis in critically ill patients, especially if azole resistance is suspected.

Other Antifungals - The Unique Crew

• Flucytosine (5-FC)
  • MOA: Converted by fungal enzymes to $5-Fluorouracil$ ($5-FU$), which inhibits thymidylate synthase → ↓ DNA & RNA synthesis.
  • Use: Synergy with Amphotericin B for cryptococcal meningitis.
  • Toxicity: Bone marrow suppression (dose-related).
• Griseofulvin
  • MOA: Disrupts fungal mitotic spindle by interacting with microtubules.
  • Use: Dermatophytoses (tinea capitis, corporis). 📌 "Greasy" for skin/hair/nails.
  • DDI: Induces CYP450 → ↓ warfarin efficacy.
• Terbinafine
  • MOA: Inhibits squalene epoxidase → ↓ ergosterol synthesis & ↑ toxic squalene.
  • Use: Dermatophytoses, onychomycosis (excellent nail penetration).
  • Toxicity: GI distress, hepatotoxicity (monitor LFTs).

  ⭐ Terbinafine is fungicidal and accumulates in keratinized tissues like skin, hair, and nails, making it highly effective for superficial infections there.

High‑Yield Points - ⚡ Biggest Takeaways

• Amphotericin B: Broadest spectrum; nephrotoxicity is dose-limiting. Liposomal forms reduce toxicity.
• Azoles: Inhibit ergosterol synthesis (14-α-demethylase). Significant drug interactions (CYP450 inhibition).
• Voriconazole: DOC for invasive Aspergillosis. Causes visual disturbances and photosensitivity.
• Echinocandins: Inhibit β-(1,3)-D-glucan synthesis (cell wall). Effective against Candida and Aspergillus.
• Terbinafine: Accumulates in keratin. For dermatophytoses/onychomycosis. Inhibits squalene epoxidase.
• Flucytosine: Converted to 5-FU; synergistic with Ampho B. Risk of bone marrow suppression.