Pharmacology · Antifungal Agents

Polyene Antifungals — Amphotericin B and Nystatin

Ergosterol binding, formulations, nephrotoxicity, and antifungal spectrum

Amphotericin B binds ergosterol with ~10× selectivity over cholesterol — the selectivity is relative, not absolute, which directly explains why nephrotoxicity is an inherent class effect rather than a preventable side reaction.
Lipid formulations do not improve antifungal efficacy over amphotericin B deoxycholate — they deliver equivalent or higher doses with substantially less nephrotoxicity by altering drug distribution away from the kidney and toward phagocytic cells.
Amphotericin B has no CYP-mediated drug interactions — unlike azoles, it does not inhibit or induce cytochrome P450 enzymes, making it the preferred agent when significant drug interactions preclude azole use.
Sodium loading (500 mL normal saline before each dose) is the single most effective nephroprotective intervention — volume depletion dramatically amplifies amphotericin B nephrotoxicity through afferent arteriolar constriction.
Nystatin shares the same ergosterol-binding mechanism as amphotericin B but cannot be given systemically — its aqueous insolubility and toxicity at systemic concentrations confine it to topical and non-absorbed oral applications.

Abbreviations: AmB = amphotericin B · IV = intravenous · K⁺ = potassium · Mg²⁺ = magnesium · CYP = cytochrome P450 · L-AmB = liposomal amphotericin B · ABLC = amphotericin B lipid complex · ABCD = amphotericin B colloidal dispersion · GFR = glomerular filtration rate

Mechanism of Action

Target and Selectivity

Ergosterol Binding

Fungi use ergosterol as primary membrane sterol; mammals use cholesterol — structural difference is the pharmacological basis of selectivity
AmB binds ergosterol with ~10× higher affinity than cholesterol — selectivity is relative, not absolute
Drug molecules insert into the fungal membrane and self-assemble into aqueous pores
Pores allow K⁺ efflux → membrane depolarization → osmotic imbalance → cell death
Residual cholesterol binding explains nephrotoxicity — tubular and glomerular damage from non-selective membrane disruption
No CYP metabolism → no pharmacokinetic drug interactions with azoles, antiretrovirals, or immunosuppressants

Fungicidal vs. Fungistatic Activity

Activity Profile

Fungicidal: Candida species, Cryptococcus neoformans
Fungistatic: Aspergillus and most molds — adequate for clinical use but not eradication
Mucorales: fungicidal; amphotericin B is drug of choice for mucormycosis
Activity is concentration-independent — AUC-driven, not Cmax-driven
Penetrates CSF, vitreous, peritoneal fluid, pleural fluid — distribution sufficient for most deep-seated infections

Formulation Comparison

Formulation	Structure	Nephrotoxicity / Tolerability	Key Clinical Note
AmB Deoxycholate	Micellar suspension with sodium deoxycholate	Highest nephrotoxicity; infusion reactions common (fever, rigors, hypotension)	Sodium-load 500 mL NS before each dose; lowest cost; avoid when nephrotoxins present
Liposomal AmB (L-AmB)	Small unilamellar liposomes encapsulating AmB	Best tolerated; lowest nephrotoxicity; fewest infusion reactions	Preferred when renal protection needed or cost not limiting; higher doses (10 mg/kg) used for CNS fungal infections
AmB Lipid Complex (ABLC)	Ribbon-like bilayer structures with phospholipid	Moderate nephrotoxicity — less than deoxycholate, more than L-AmB	High uptake by phagocytic cells → high liver, spleen, lung concentrations; useful for disseminated infections
AmB Colloidal Disp. (ABCD)	Cholesteryl sulfate disk complexes	Lowest nephrotoxicity but highest infusion reaction rate — rigors and fever very common	Rarely chosen over other lipid formulations; approved for refractory invasive aspergillosis

Toxicity Management

Infusion Reactions

Fever, Rigors, and Hypotension

Mechanism: cytokine release (TNF-α, IL-1β) — not IgE-mediated allergy
Premedicate: acetaminophen + diphenhydramine 30 minutes before infusion
Rigors: meperidine 25–50 mg IV breaks the shaking episode; hydrocortisone also effective
Slow infusion rate (over 4–6 hours) reduces severity
Reactions diminish with repeat dosing — tolerance develops over first week
Lipid formulations substantially reduce infusion reactions (except ABCD)

Nephrotoxicity

Vasoconstriction and Tubular Damage

Afferent arteriolar constriction → reduced GFR → azotemia
Distal tubular pore formation → K⁺ and Mg²⁺ wasting — monitor and replace
Sodium loading (500 mL normal saline before each dose) is the most effective nephroprotective strategy — prevents afferent constriction
Avoid concurrent nephrotoxins (aminoglycosides, NSAIDs, contrast) — synergistic toxicity
Creatinine doubling from baseline → switch to lipid formulation; tubular damage is cumulative and not reliably reversible
Renal tubular acidosis (type 1) may occur with prolonged use

Antifungal Spectrum

Covered — Broad Spectrum

Active Organisms

Most Candida species — fungicidal; drug of choice for invasive candidiasis in unstable patients
Cryptococcus neoformans and C. gattii — fungicidal; used in CNS cryptococcosis induction
Aspergillus species — fungistatic; second-line after voriconazole
Mucorales (Rhizopus, Mucor, Lichtheimia) — drug of choice for mucormycosis; azoles inactive
Endemic dimorphics: Histoplasma, Blastomyces, Coccidioides — preferred in severe/disseminated disease

Not Covered — Intrinsic Resistance

Spectrum Gaps

Candida lusitaniae — intrinsic resistance (reduced ergosterol content); test susceptibility in all invasive isolates
Candida auris — variable; susceptibility testing required; some isolates pan-resistant
Scedosporium apiospermum and Lomentospora prolificans — intrinsically resistant; voriconazole preferred
Trichosporon species — resistant; use voriconazole
Most Fusarium species — intrinsic resistance; voriconazole or combination required

Nystatin

Topical and Non-Absorbed Oral Use Only

Nystatin — Same Mechanism, Different Route

Same ergosterol-binding pore-forming mechanism as amphotericin B — no meaningful cross-resistance
Insoluble in aqueous solution at concentrations required for systemic use → cannot be given IV; systemic toxicity would preclude use even if formulated
Oral suspension (swish and swallow): oropharyngeal candidiasis — effective, well tolerated, cheap
Topical cream/powder: cutaneous and mucocutaneous candidiasis (intertrigo, diaper rash, vulvovaginal)
Vaginal suppositories: safe in pregnancy — not absorbed systemically
Not absorbed from GI tract → no systemic toxicity; not useful for esophageal or invasive candidiasis

Clinical Rule: Lipid Formulation Threshold — Start Upfront, Not After Damage

Use a lipid formulation from the start — do not begin with amphotericin B deoxycholate — when any of the following apply: baseline creatinine above 2.5 mg/dL; concurrent nephrotoxins that cannot be discontinued; solid organ or hematopoietic stem cell transplant recipient; anticipated treatment duration beyond two weeks. Switching after nephrotoxicity develops is suboptimal because tubular damage is cumulative and may not be fully reversible.

Sodium loading (500 mL 0.9% normal saline infused before each dose) is mandatory with amphotericin B deoxycholate and beneficial even with lipid formulations. Volume depletion is the most modifiable risk factor for amphotericin B nephrotoxicity — patients receiving diuretics, on fluid restriction, or with poor oral intake are at highest risk and require proactive sodium supplementation.

Suggested References

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