amphotericin B (Fungisone, Ambisone, Amphotec, Fungilin, LAMB, AmBisome)

Introduction

Tradename: Fungizone, AmBisome

Indications

• severe systemic fungal infections & meningitis caused by most fungi including aspergillus, Candida, Coccidioides & Cryptococcus
  • aspergillosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, mucormycosis, disseminated sporotrichosis, candidiasis, cryptococcosis
• not for use with infections caused by Pseudallescheria boydii
• prevention of invasive pulmonary aspergillosis in patients with chronic neutropenia, aerosolized liposomal form
• treatment of leishmaniasis
• used in treatment of
  • pulmonary infection, including ventilator-associated pneumonia
  • intra-abdominal infection including peritonitis
  • fungal urinary tract infection
    • used as bladder irrigant for fungal cystitis (candiduria)

Dosage

(administration)

• test dose: 1 mg slow IV
• then, begin 0.25 mg/kg IV QD & gradually increase to 1-1.5 mg/kg/day.

Amphotericin will precipitate if mixed with electrolyte solutions.

• Premedication:
  • Benadryl 50 mg PO
  • tylenol 650 mg PO
  • Demerol 50-75 mg IV as needed
  • Compazine 10 mg PO as needed
  • give premeds at start of amphotericin B infusion
• PRN medications for chills/shakes
  • Demerol 25-50 mg IV slowly
  • Tylenol 650 mg PO/pr every 4 hours
  • Benadryl 50 mg PO every 4 hours
• 1st day (includes 1 mg test dose)
  • 10 mg amphotericin B in 100 mL D5W
  • infuse 10 mL (1 mg) over 30 minutes, then stop infusion
  • check vital signs every 10 min for 30 minutes for signs of anaphylaxis
  • if no signs of anaphylaxis, infuse remaining 9 mg (90 mL) over 2-3 hours
  • monitor vital signs every 20 min until infusion complete
• 2nd day
  • 20 mg amphotericin B in 200 mL D5W - infuse over 2-3*h
  • vital signs every 20 min until infusion is complete
• 3rd day
  • 30 mg amphotericin B in 300 mL D5W - infuse over 2-3*h
  • monitor vital signs every 20 min until fusion is complete
• 4th day
  • 40 mg amphotericin B in 400 mL D5W - infuse over 2-3*h
  • monitor vital signs every 20 min until fusion is complete
• 5th day
  • 50 mg amphotericin B in 500 mL D5W - infuse over 2-3*h
  • monitor vital signs every 20 min until fusion is complete
• laboratory
  • serum creatinine QOD
  • serum K+ QOD
  • serum Mg+2 QOD
  • CBC weekly
• give amphotericin B daily, highest dose tolerated (up to 1 mg/kg)
  • change to QOD if creatinine nears 3.0

* slower infusion (over 24 hours) may produce fewer adverse effects

Test doses have been advocated to identify patients prone to severe infusion-related adverse effects. A 1 mg test dose may be given over 30 minutes &, if well tolerated, a separate infusion of 0.2-0.5 mg/kg may follow. Dosage can be increased until a therapeutic or maximum tolerated dose is reached, generally 0.5-1.0 mg/kg/day, given over a period of 2-5 hours. 50 mg/day is a standard dose. Dosage may be doubled & given on alternate days, but dose should not exceed 1.5 mg/kg/day.

Intrathecal or intraventricular administration of amphotericin is occasionally used in conjunction with expert consultation.

Bladder irrigation: Continuous irrigation with amphotericin B, 50 mg in 1 liter of sterile water for 3-5 days may be useful in treatment of fungal cystitis.

Topical agent: (oropharyngeal candidiasis) 3% cream/lotion/ointment BID/QID.

aerosolized Liposomal AMphotericin-B (LAMB)

AmBisome; 12.5 mg delivered using an adaptive aerosolized system, or 30 minutes on 2 consecutive days each week until recovery from neutropenia

Pharmacokinetics

• amphotericin is poorly absorbed & must be administered intravenously
• low concentrations are obtained in the CSF.
• metabolism & excretion of amphotericin is not well understood; however, renal excretion is small & dosage need not be adjusted in patients with pre-existing renal failure

elimination via liver

Adverse effects

• Fever, chills, headache, myalgias, nausea, vomiting
  • reduced by premedication with:
    • aspirin or acetaminophen
    • diphenhydramine
  • meperidine for treatment of infusion-related chills
  • hydrocortisone 25-100 mg IV
• thrombophlebitis: reduced by:
  • administration through a central catheter
  • heparin 1000 U with infusion
• nephrotoxicity
  • acute tubular necrosis, generally non-oliguric & slowly progressive
  • distal renal tubular acidosis, RTA IV
  • hypokalemia
  • hypomagnesemia
  • impaired GFR, increased creatinine
  • irreversible renal damage may occur with cumulative doses > 3-4 g
  • sodium & volume depletion potentiate nephrotoxicity. Normal saline infusion 250-500 mL before & after amphotericin therapy may reduce nephrotoxicity.
• anemia
• neuritis & arachnoiditis in patients with intrathecal administration.

Drug interactions

• aminoglycosides, cyclosporine & vancomycin may increase risk of renal failure
• corticosteroid may increase K+ loss
• K+ loss in combination with digoxin & neuromuscular junction blockers may increase toxicity
• flucytosine or zidovudine in combination increases risk of bone marrow toxicity
• itraconazole in combination decreases effect of both agents

• drug interaction(s) of antibiotics with warfarin

Mechanism of action

• binds to fungal sterols (ergosterol)
• alters structure & permeability of fungal membranes
• also binds human cytoplasmic sterols (cholesterol) which accounts for some of its toxicity
• aerosolized liposomal form acts as pulmonary surfactant

Notes

Amphotericin B is a polyene antimicrobial produced by Streptomycetes nodosus M4575 that disrupts fungi via binding to ergosterol in the fungal plasma membrane. Amphotericin is fungicidal.

More general terms

• amphotericin
• antifungal agent
• amebicide

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=451404
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=107892
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5280965
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14956
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=352546