Chapter 37  ·  Module 1
Polyene Antifungals
Amphotericin B and Nystatin — mechanism, formulations, toxicity, and spectrum
AmB = Amphotericin B  ·  IV = intravenous  ·  K&sup+; = potassium  ·  Mg²&sup+; = magnesium
Mechanism of Action
Target
Ergosterol Binding
  • Fungi use ergosterol; mammals use cholesterol
  • Amphotericin B binds ergosterol with ~10x selectivity over cholesterol
  • Drug molecules insert into membrane and self-assemble into pores
  • Pores allow K&sup+; efflux → membrane depolarization → cell death
Activity
Fungicidal vs. Fungistatic
  • Fungicidal: Candida species, Cryptococcus neoformans
  • Fungistatic: Aspergillus and most molds
  • Selectivity is relative, not absolute → explains nephrotoxicity
  • No cytochrome P450 metabolism → no pharmacokinetic drug interactions
Formulation Comparison
Formulation Structure Tolerability Key Note
AmB Deoxycholate Micellar suspension Highest nephrotoxicity; infusion reactions common Sodium-load before each dose; lowest cost
Liposomal AmB Small unilamellar liposomes Best tolerated; lowest nephrotoxicity Preferred when cost is not limiting
AmB Lipid Complex Ribbon-like bilayer structures Moderate; higher than liposomal AmB High liver/spleen/lung uptake via phagocytes
AmB Colloidal Disp. Cholesteryl sulfate disks Highest infusion reaction rate Rarely chosen; approved for refractory cases
Toxicity Management
Infusion Reactions
Fever, Rigors, Hypotension
  • Mechanism: cytokine release (not IgE-mediated)
  • Premedicate: acetaminophen + diphenhydramine
  • Rigors: meperidine IV breaks the shaking episode
  • Reactions diminish with repeat dosing
Nephrotoxicity
Vasoconstriction + Tubular Damage
  • Afferent arteriolar constriction → reduced glomerular filtration
  • Distal tubular pores → K&sup+; and Mg²&sup+; wasting
  • Sodium loading (500 mL normal saline before each dose)
  • Creatinine doubling = switch to lipid formulation
Antifungal Spectrum
Covered
Broad Spectrum
  • Most Candida species (fungicidal)
  • Cryptococcus neoformans (fungicidal)
  • Aspergillus species (fungistatic)
  • Mucorales: Rhizopus, Mucor, Lichtheimia
  • Endemic dimorphics: Histoplasma, Blastomyces, Coccidioides
Not Covered — Intrinsic Resistance
Spectrum Gaps
  • Candida lusitaniae — intrinsic (low ergosterol)
  • Candida auris — variable; test susceptibility
  • Scedosporium & Lomentospora prolificans
  • Trichosporon species
  • Most Fusarium species
Nystatin
Topical and Non-Absorbed Oral Use Only
Nystatin — Same Mechanism, Different Route
  • Same ergosterol-binding mechanism as amphotericin B
  • Insoluble in aqueous solution → cannot be given IV safely
  • Oral suspension: oropharyngeal candidiasis (swish and swallow)
  • Topical: cutaneous and mucocutaneous candidiasis
  • Vaginal suppositories: safe option during pregnancy
  • Not absorbed from gut → no systemic toxicity
Clinical Rule — Lipid Formulation Threshold

Use a lipid formulation from the start (do not begin with amphotericin B deoxycholate) when any of the following are present: baseline creatinine above 2.5 mg/dL, concurrent nephrotoxins that cannot be stopped, solid organ or stem cell transplant recipient, or anticipated treatment duration beyond two weeks. Switching after nephrotoxicity develops is suboptimal because tubular damage is cumulative.