Antimicrobial agents targeting eukaryotic and heterotrophic microbes. Can be divided by class into:

  • Azoles
    Inhibit erosterol synthesis. Subdivided into:
    • Triazoles
      • Fluconazole
      • Itraconazole
      • Voriconazole
      • Posaconazole
    • Imidazoles
      • Ketoconazole
  • Echinocandins
    Inhibit glucan synthesis.
    • Caspofungin
    • Micafungin
    • Anidulafungin
  • Polyenes
    Disrupt cell membrane.
    • Amphotericin B
    • Nystatin

Common Features

Mechanisms of Antifungal Resistance

Three broad mechanisms:

  • Increased efflux
    Increased expression of transport proteins removing drug from cell.
  • Alteration of target enzyme
    Changes to protein target prevent drug binding or inactivation.
    • Typically only requires changes in a few amino acids
  • Alteration of drug metabolism
    Reduced enzyme activity prevents accumulation of toxic product.

Amphotericin resistance is rare in vivo, and is typically via different mechanisms:

  • Decreased ergosterol content
  • Altered sterol:phospholipid ratio

Comparison of Antifungals

Drug Fluconazole Voriconazole Caspofungin Amphotericin B
Class Azole AzoleEchinocandins Polyenes
Spectrum of Activity Candida albicans (most other species, especially C. glabrataand to a lesser extent C. krusei are resistant), as resistance rapidly develops), cryptococcus, coccidioides, histoplasma, blastomyces, and some aspergillus (resistance may also develop rapidly). At least as good as amphotericin in susceptible organisms. As fluconazole, but broader spectrum of activity Candida (including azole resistant C. glabrata and C. krusei and Candida biofilms), aspergillus. Notably no activity against cryptococcus, fusarium, and trichosporon.

Additionally, echinocandins typically have no cross-resistance with other antifungals
Effective against many fungi, with notable exceptions being Chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium, and some Fusarium.
Pharmaceutics Poor water solubility Poor water solubility Poor water solubility Four different formulations, most common is amphotericin B colloidal dispersion (ABCD)
Dosing 100-800mg OD, adjust in renal failure Typically 70mg loading dose, followed by 50mg daily; dose reduced in hepatic impairment Load with, followed by, reduced in severe renal impairment
Route of Administration IV or PO IV only (high MW) IV for systemic indications
Absorption High PO bioavailability, PO absorption at low pH (interaction with antacids, vitamin supplements) <5% PO bioavailability
Distribution Crosses BBB - good CSF penetration. Very low protein binding (~10%) Not dialysable due to very high protein binding, VD. Good tissue penetration. Essentially no CSF penetration, 97% protein bound in serum Rapid uptake by reticuloendothelial system. Binds to organic anion transporting peptides (important in hepatocyte drug binding), important in key drug interactions (such as tacrolimus)
Metabolism Metabolised by and cause reversible inhibition of multiple hepatic CYP450 enzymes (including 3A4, 2C19, 2C9), leading to increased concentrations of many drugs/metabolites As fluconazole Extensive hydrolysis and N-acetylation to inactive metabolites Minimal metabolism
Elimination 80% of fluconazole renally eliminated unchanged Mostly cleared via liver. Renal of metabolites Renal and faecal elimination of unchanged drug
Mechanism of Action Inhibit ergosterol synthesis by inhibiting CYP450 enzyme As fluconazole Prevent cell wall synthesis by blocking production of beta-glucan Binds sterols, disrupting osmotic integrity of the cell membrane
CVS HTN Long QT Histamine release
CNS Headache, visual disturbances Hallucinations, psychosis
Renal AKI via afferent arteriolar constriction and direct tubular toxicity, hypokalaemia, renal tubular acidosis
GIT Hepatotoxicity Mild hepatotoxicity in up to ~15%
Haeme Thrombophlebitis, normocytic anaemia


  1. Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol. 2005 Jul;3(7):547-56.
  2. Drew RH. Pharmacology of Amphotericin B. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
  3. Ashley ED, Perfect JR. Pharmacology of azoles. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
  4. Lewis RE. Pharmacology of echinocandins. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
  5. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2002 Mar;46(3):828-33.
Last updated 2018-03-03

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