Polyenes

Mechanism: Polyenes bind ergosterol (unique to fungal cell membranes, analogous to cholesterol in human cells) and form transmembrane pores/channels, increasing membrane permeability and causing leakage of ions (K+) and other cellular contents, leading to fungal cell death. This selectivity for ergosterol over cholesterol underlies their antifungal action, though some binding to human cholesterol accounts for toxicity.

Amphotericin B: Broad-spectrum IV antifungal used for severe, systemic, life-threatening fungal infections including Candida, Aspergillus, Cryptococcus, Mucor, Histoplasma, Blastomyces, and Coccidioides. Often called 'amphoterrible' due to significant toxicity: - Nephrotoxicity (distal RTA, decreased GFR, Mg2+/K+ wasting) - most significant adverse effect; can be reduced by hydration and using liposomal formulations - Infusion-related reactions: fever, chills, rigors ('shake and bake'), hypotension - pretreat with antipyretics, antihistamines, or meperidine - Anemia (decreased erythropoietin production) - Arrhythmias from electrolyte disturbances - Liposomal amphotericin B formulations reduce nephrotoxicity

Intrathecal amphotericin B is used for fungal meningitis (poor CNS penetration otherwise).

Nystatin: Too toxic for systemic use; restricted to topical/oral use for mucocutaneous candidiasis (oral thrush, diaper rash, vaginal candidiasis). 'Swish and swallow' for oral candidiasis, especially in immunocompromised patients (HIV, chemotherapy).

Clinical pearls: Know the difference between azoles (inhibit ergosterol synthesis via lanosterol demethylase/CYP450 inhibition) vs polyenes (bind existing ergosterol). Amphotericin B is first-line for many severe systemic mycoses despite toxicity due to broad spectrum and efficacy. Combination with flucytosine (which inhibits DNA/RNA synthesis) is classic for cryptococcal meningitis treatment.