Types of Fungi:

• Yeasts (single celled)
• Molds (multicellular, hyphated)
• Dimorphous (can have yeast and mold forms) – very common for human pathogens

Fungal components

• Nucleus (they’re eukaryotes after all, where the DNA lives)
• Cytosol (with organelles, where the proteins are made)
• Cell membrane (regulates transmembrane transport)
• Cell wall (structural integrity to the cell)

Examples of fungi

Yeasts	Molds	*Dimorphic
Candida spp (*) Cryptococcus neoformans	Aspergillus spp Mucorales – Rhizopus – Mucor, etc etc Fusarium spp	Histoplasma Blastomyces Coccidioides

Classes of antifungals, and their targets

• Polyenes – directly bind ergosterol in cell membrane, create pores
• Azoles – Cytosol/Cell Membrane – inhibit ergosterol synthesis (lanosterol demethylase)
• Allylamines – Cytosol/Cell Membrane – inhibit ergosterol synthesis (squalene monoxygenase)
• Echinocandins – Cytosol/Cell Wall – inhibit glucan synthesis
• Others – Nucleus
  • 5-Flucytosine – Inhibit RNA transcription
  • Griseofulvin – Prevent mitotic spindle formation

Drugs in each class

• Polyenes
  • Amphotericin B
  • Nystatin
• Azoles
  • Imidazoles
    • Ketoconazole
    • Miconazole
  • Triazoles
    • Fluconazole
    • Itraconazole
    • Voriconazole
    • Posaconazole
    • Isavuconazole
• Allylamines
  • Terbinafine
• Echinocandins
  • Anidulafungin
  • Caspofungin
  • Micafungin
• Others
  • 5-Flucytosine
  • Griseofulvin

Spectrum of effect

	Ampho-B	Fluconazole	Posaconazole	Echinocandins	5-FC
Candida spp	YES	YES *not krusei *RC glabrata	YES *RC glabrata	YES	RC
Cryptococcus	YES	YES	YES	NO	RC
Aspergillus	YES *not terreus	NO	YES	YES	NO
Mucorales	RC	NO	YES	NO	NO
Fusarium	RC	NO	YES	NO	NO
Dimorphs -Histoplasma – Blastomyces – Coccidioides	YES	YES	YES	NO	NO

Metabolism

• Minimal/none/minor misc
  • Amphotericin B
  • Anidulafungin
  • 5-Flucytosine
• Hepatic
  • Fluconazole (minimal)
  • Itrazonazole
  • Voriconazole
  • Posaconazole (modest)
  • Caspofungin
  • Micafungin

Clearance

• Renal
  • Fluconazole
  • Caspofungin
  • 5-Flucytosine
• Hepatic
  • Itraconazole
• Intestinal
  • Posaconazole
  • Anidulafungin
  • Micafungin

Toxicity

	Ampho-B	Azoles	Echinocandins	Allylenes	5-FC
Hepatic	YES	YES	YES		YES
Renal	YES	?Voriconazole
CNS		Voriconazole
Photopsia		Voriconazole
Cutaneous	YES	YES (esp vori)	YES	YES	YES
GI		Itra/Posa			YES
Cardiac		CM – Itra Long QT
Infusion Rxn	YES		YES
Marrow supp	YES				YES

Source material

• Lewis RE. Current Concepts in Antifungal Pharmacology, Mayo Clin Proc, August 2011;86(8):805-817. doi: 10.4065/mcp.2011.0247
• Oh’s manual, Seventh edition
• Irwin & Rippe’s Intensive Care Manual
• Robbins and Cotran Pathologic Basis of Disease Eighth edition