Antifungal pharmacology

Mechanisms: (briefly)

  • Cell wall: echinocandins
  • Cell membrane (ergosterol)
    – Azoles
    a) Imidazoles
    b) triazoles
    – Amphotericin B
    – Terbinafine
  • Antimetabolite: Flucytosine
  • Mitosis inhibitor: griseofulvin

Some pearls on antifungals:

  1. Imidazoles
    – Ketoconazole, clotrimazole, miconazole, econazole
    – The strongest imidazole (comparable to terbinafine) is sertaconazole
    – ketoconazole is famous for causing gynecomastia.
  2. Triazoles
    – Only fluconazole and posaconazole have good oral bioavailibility and CNS penetration
    – Itraconazole and voriconazole have poor oral bioavailibility and CNS penetration.
    – Oral fluconazole does not need acidic pH to be absorbed., itraconazole needs acidic condition to be absorbed; so beware in patients taking PPI/antacid/antihistamine
    – The wider the spectrum, the more chance of drug-drug interaction.
  3. Oral terbinafine
    – First line for tinea unguium (if it spreads proximally involving the lunula) and capitis.
    – However,in kerion griseofulvin is favoured if pityrosporum is the pathogen. Terbinafine is only used if trichophyton is identified as the pathogen.
  4. Griseofulvin
    – Slow onset of action, and has highly variable availibility, making it less effective
    – Concentrates in keratinocytes (skin, nail or hair)
  5. Amphotericin B
    – Nephrotoxicity, and hypersensitivity reaction (before infusion need test dose with antihistamine beside)
  6. Flucytosine
    – Converted to 5-FU by fungal enzyme which blocks DNA formation; therefore mutation in the enzyme can cause resistance
    – Fungistatic
    – Typically used with amphotericin B
  7. Echinocandins
    – Static against Aspergillus but Cidal Against Candidiasis

** Cell membrane inhibitors are fungicidal; BUT griseofulvin is fungistatic

In summary:
Almost all antifungals are cidal except griseofulvin, flucytosine and echinocandins (towards aspergillus).

Spectrum:

Candidiasis

  • Imidazoles are generally okay againt superficial candidiasis.
  • For systemic candidiasis
    Fluconazole < newer triazoles < echinocandins, amphotericin B
  • Fluconazole: C.krusei and glabrata are resistant.
  • For newer triazoles, resistance has been found for C.glabrata.

Cryptococcosis

  • Triazoles and amphotericin B are generally effective.

Aspergillosis

  • Fluconazole DOES NOT cover aspergillus.
  • Newer triazoles, echinocandins > amphotericin B
  • Resistance has been found for A.tereus in amphotericin B.

Mucormycosis

  • Only amphotericin B and posaconazole cover this fungus, with posaconazole > amphotericin B

Histoplasmosis, blastomycosis, coccidiodomycosis

  • Amphotericin B and triazoles are generally okay.

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So for summary

  • Echinocandins or Amphotericin B are the best for candidiasis.
    – Triazoles is also appropriate. Resistance has been found for triazoles in C.glabrata.
    – Fluconazole can be accepted if it’s not C.krusei OR glabrata.
  • Triazoles and echinocandins are the best for aspergillus.
    – Amphotericin B is appropriate unless A.tereus.
  • ONLY posaconazole and amphotericin B cover mucormycosis (posaco > amphotericin B).
  • Cryptococcosis generally responds well to triazoles and amphotericin B.

Reference

Russell E. Lewis, PharmD. Current Concepts in Antifungal Pharmacology. Mayo Clin Proc. 2011 Aug; 86(8): 805–817.

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