Amphotericin B Deoxycholate

Amphotericin B deoxycholate is a polyene antifungal with the broadest spectrum and fungicidal activity against Candida, Cryptococcus, Aspergillus, Histoplasma, Mucorales and Leishmania. It remains the usual induction drug for cryptococcal meningitis where lipid formulations are unavailable. Infusion reactions, nephrotoxicity and electrolyte wasting limit its use and demand pre-hydration and close monitoring.

Class. Polyene antifungal.

Mechanism. Binds ergosterol in fungal membranes, forming pores and causing leakage of ions; some binding to human cholesterol explains toxicity.

Pharmacokinetics. Not absorbed orally. Highly protein bound, large volume of distribution, poor cerebrospinal fluid penetration but effective in meningitis. Terminal half life about 15 days; slow urinary and biliary elimination. No dose adjustment is needed for dialysis.

Cryptococcal meningitis (induction, HIV-associated). - Amphotericin B deoxycholate 1 mg/kg intravenously once daily for 7 days, with flucytosine 100 mg/kg daily in four divided doses for 7 days. - Then fluconazole 1200 mg daily with flucytosine for a further 7 days. - Then consolidation fluconazole 800 mg daily for 2 weeks, then 400 mg daily to complete 8 weeks, and then 200 mg daily maintenance.

Invasive candidiasis. 0.5 to 1 mg/kg once daily, for at least 14 days after the first negative blood culture.

Other uses. - Severe histoplasmosis: 0.7 to 1 mg/kg daily for 1 to 2 weeks, then itraconazole. - Visceral leishmaniasis (where lipid formulations are unavailable): 1 mg/kg on alternate days for 15 doses. - Maximum: 1.5 mg/kg daily (or alternate day). Loading dose: none; a test dose is not required.

Children. 0.5 to 1 mg/kg daily; neonates up to 1 mg/kg daily.

Pre-hydration and replacement. Sodium chloride 0.9% 1 litre over 2 to 4 hours before each dose (10 to 15 mL/kg in children), potassium chloride 20 mmol and magnesium 8 to 10 mmol added to the fluid.

Main alternative. Liposomal amphotericin B.

Contraindications. Hypersensitivity (unless life-threatening infection), and co-prescription of other nephrotoxins where avoidable.

Serious adverse effects. Nephrotoxicity, hypokalaemia, hypomagnesaemia, normocytic anaemia, cardiac arrhythmia from hypokalaemia, anaphylaxis, thrombophlebitis and bone marrow suppression.

Common adverse effects. Fever, rigors, headache, nausea and phlebitis during infusion.

Interactions. Additive nephrotoxicity with aminoglycosides, vancomycin, ciclosporin, tacrolimus, tenofovir disoproxil fumarate and NSAIDs. Corticosteroids and diuretics worsen hypokalaemia; hypokalaemia increases digoxin toxicity; flucytosine toxicity rises with kidney injury.

Common prescribing errors. Diluting in saline (causes precipitation), infusing too fast, omitting pre-hydration and potassium and magnesium replacement, and poor kidney and electrolyte monitoring.

Special groups. - Pregnancy: used when indicated; no teratogenicity signal, and cryptococcal meningitis outweighs risk. - Breastfeeding: compatible; poor oral absorption in the infant. - Children: well tolerated, with the same pre-hydration. - Older adults: higher nephrotoxicity risk; strict hydration. - Kidney impairment: no fixed adjustment; if creatinine doubles from baseline, switch to alternate-day dosing or a lipid formulation. - Liver impairment: no adjustment.

Regional points. In East Africa, advanced HIV disease and cryptococcal meningitis make this drug central; pre-hydration, potassium and magnesium supplementation and creatinine monitoring determine safe use, and lipid formulations and flucytosine may be limited.

Formulations. Powder for infusion 50 mg vial; store at 2 to 8 degrees C, protect from light.

Administration. Reconstitute with sterile water and dilute in 5% glucose only, to a final concentration of 0.1 mg/mL; infuse over 4 to 6 hours. Pre-medicate with paracetamol; use hydrocortisone or pethidine for rigors if needed.

Baseline. Creatinine, urea, potassium, magnesium, full blood count, liver tests, pregnancy test.

Monitoring. Creatinine, potassium and magnesium daily in the first week, then 2 to 3 times weekly; haemoglobin weekly; vital signs during infusion.

Stopping thresholds. Review for creatinine rising to twice baseline, potassium under 3.0 mmol/L despite replacement, or anaphylaxis (stop).

Referral and escalation. Specialist review for all invasive mycoses, kidney injury or intolerance requiring a lipid formulation.