Amphotericin

Amphotericin B is a polyene macrolide antifungal produced by Streptomyces nodosus. Current US products are intravenous: conventional amphotericin B deoxycholate for injection, liposomal amphotericin B (AmBisome) and amphotericin B lipid complex (Abelcet). No oral amphotericin B product is currently marketed in the US. Lake Hills Pharmacy uses amphotericin B bulk drug substance in compounded oral capsules.

• Conventional amphotericin B for injection: progressive, potentially life-threatening fungal infections, including aspergillosis, cryptococcosis, blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zygomycosis including mucormycosis, and sporotrichosis; also American mucocutaneous leishmaniasis.
• AmBisome: empirical therapy for presumed fungal infection in febrile neutropenic patients; cryptococcal meningitis in HIV infection; Aspergillus, Candida or Cryptococcus infections refractory to or intolerant of conventional amphotericin B; and visceral leishmaniasis.
• Abelcet: invasive fungal infections in patients refractory to or intolerant of conventional amphotericin B.
• Oral use: prescribers use compounded oral amphotericin B for local antifungal action within the gastrointestinal tract. Because it is not absorbed, oral amphotericin B does not treat systemic or invasive infections.

Amphotericin B binds ergosterol in the fungal cell membrane and forms transmembrane pores, causing leakage of potassium and other intracellular contents and cell death. It is fungicidal or fungistatic depending on concentration and organism. Its lower but real affinity for cholesterol in human cell membranes underlies its toxicity, especially in the kidney. Its spectrum includes Candida, Aspergillus, Cryptococcus, the Mucorales and the endemic dimorphic fungi, and it is active against Leishmania.

Oral amphotericin B is negligibly absorbed and is eliminated largely unchanged in the feces, so oral doses act only within the gut lumen. After intravenous dosing, conventional amphotericin B is more than 90% protein bound and distributes extensively into tissues; it is eliminated slowly, with a terminal half-life of about 15 days. It is not removed by hemodialysis. Lipid formulations differ in distribution and dosing and are not interchangeable with the conventional product.

• Hypersensitivity to amphotericin B or any component, unless the condition is life-threatening and treatable only with amphotericin B.

• Intravenous use: infusion reactions (fever, chills, rigors, nausea, hypotension), anaphylaxis, nephrotoxicity, hypokalemia, hypomagnesemia, renal tubular acidosis and anemia.
• Rapid intravenous infusion can cause hyperkalemia and arrhythmia; acute pulmonary reactions have occurred with concurrent leukocyte transfusions.
• Conventional and lipid formulation doses differ substantially; confusion between them has caused fatal overdose.
• Oral use: gastrointestinal intolerance is the main concern; systemic toxicities are not expected at the low levels absorbed.

• Systemic exposure only: other nephrotoxic drugs (aminoglycosides, cyclosporine, tacrolimus, pentamidine, foscarnet) increase renal toxicity.
• Corticosteroids and corticotropin worsen hypokalemia; hypokalemia increases digoxin toxicity and enhances skeletal muscle relaxants.
• Flucytosine toxicity may increase through reduced renal excretion.
• No clinically significant interactions are expected with oral use because of minimal absorption.

Intravenous: fever, chills, rigors, headache, nausea, vomiting, hypotension, thrombophlebitis, renal impairment, hypokalemia, hypomagnesemia, anemia and, rarely, arrhythmia or anaphylaxis. Oral: nausea, vomiting, abdominal cramping and diarrhea, with rash and hypersensitivity reactions uncommon.

Amphotericin B crosses the placenta. Intravenous amphotericin B has long been used in pregnancy for serious fungal infections without evident teratogenicity, but controlled data are limited. Whether it is excreted in human milk is unknown. Systemic exposure from oral use is minimal; the prescriber weighs benefit and risk.

Intravenous: serum creatinine, BUN, potassium and magnesium (frequently during therapy), complete blood count, liver tests and infusion reactions. Oral: gastrointestinal tolerance and clinical response; systemic laboratory monitoring is needed only if systemic absorption is suspected.

• Amphotericin B for Injection, USP, Prescribing Information, X-Gen Pharmaceuticals.
• AmBisome (amphotericin B) liposome for injection Prescribing Information, Astellas Pharma US.
• Abelcet (amphotericin B lipid complex) Prescribing Information, Leadiant Biosciences.
• Clinical Practice Guideline for the Management of Candidiasis: 2016 Update, Infectious Diseases Society of America.