Polyene Antifungals

Polyene antifungals are amphotericin B (deoxycholate, liposomal and lipid complex formulations) and nystatin. They bind ergosterol, form membrane pores and cause leakage of cell contents, which is rapidly fungicidal. Amphotericin B has the broadest spectrum of any antifungal and remains the drug of choice for severe cryptococcal meningitis, mucormycosis and several endemic mycoses.

Pharmacokinetics. Not absorbed orally; used intravenously for systemic disease. Highly protein bound with a long terminal half-life of about 15 days; penetration into cerebrospinal fluid is low but clinically effective. Nystatin is not absorbed and is used for oral and gut candidiasis.

• Amphotericin B deoxycholate: 0.7 to 1 mg/kg daily (maximum 1.5 mg/kg); cheapest; most nephrotoxic; frequent infusion reactions.
• Liposomal amphotericin B: 3 to 5 mg/kg daily; up to 10 mg/kg daily for mucormycosis or in cryptococcal induction as a single dose; least toxic.
• Amphotericin B lipid complex: 5 mg/kg daily.
• Nystatin: oral suspension 100,000 units/mL, 4 to 6 mL four times daily (swish and swallow) for 7 to 14 days.

Cryptococcal meningitis. Single-dose liposomal amphotericin B 10 mg/kg on day 1 with flucytosine 100 mg/kg daily in 4 divided doses and fluconazole 1200 mg daily for 14 days. If single dosing is unavailable, a 7-day course of amphotericin B deoxycholate 1 mg/kg daily (or liposomal 3 to 4 mg/kg) with flucytosine, followed by fluconazole 1200 mg daily for 7 days. Then fluconazole 800 mg daily for 8 weeks and 200 mg daily maintenance. Use therapeutic lumbar puncture when opening pressure is over 25 cm of cerebrospinal fluid.

Other uses.

• Mucormycosis: liposomal amphotericin B 5 to 10 mg/kg daily with surgery.
• Histoplasmosis, severe: liposomal amphotericin B 3 mg/kg daily for 1 to 2 weeks, then itraconazole.
• Invasive candidiasis or aspergillosis when other drugs cannot be used.
• Visceral leishmaniasis: liposomal amphotericin B is an effective option, with total dose and schedule set by a specialist and regional practice.

Administration.

• Dilute only in 5% glucose, never in saline. Infuse deoxycholate over 4 to 6 hours and liposomal over 1 to 2 hours.
• Pre-hydrate with 500 to 1000 mL of 0.9% saline before deoxycholate, and give potassium and magnesium supplements.
• Paracetamol, an antihistamine or hydrocortisone may be given before the infusion for rigors.

Serious adverse effects. Nephrotoxicity (dose-related), hypokalaemia, hypomagnesaemia, anaemia, infusion reactions with fever and rigors, and cardiac arrhythmia with rapid infusion. Liposomal formulations cause less of each.

Monitoring. Creatinine, potassium and magnesium at baseline and daily during induction (at least twice weekly later), full blood count weekly, liver enzymes weekly. Replace potassium to keep it over 4 mmol/L.

Interactions. Additive nephrotoxicity with aminoglycosides, ciclosporin, tacrolimus, tenofovir and contrast. Hypokalaemia increases the risk of digoxin toxicity and torsades.

Common prescribing errors. Confusing doses between conventional and liposomal forms, which can lead to overdose; diluting in saline; omitting pre-hydration and electrolyte replacement; treating the single liposomal dose as complete therapy without the flucytosine and fluconazole partners.

Special groups.

• Pregnancy: the preferred drug for invasive fungal disease. Breastfeeding: poor oral absorption, acceptable.
• Kidney impairment: prefer a liposomal form and correct volume and electrolytes first; if creatinine doubles, agree any dose or interval change with a specialist rather than stopping.
• Children and older adults: weight-based dosing, with careful fluid balance.

Referral and escalation. Discuss with infectious diseases for rising creatinine, persistent fever, or resistant organisms.