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

Tradename: Fungizone, AmBisome Indications: 1) severe systemic fungal infections & meningitis caused by most fungi including aspergillus, Candida, Coccidioides & Cryptococcus - aspergillosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, mucormycosis, disseminated sporotrichosis, candidiasis, cryptococcosis 2) not for use with infections caused by Pseudallescheria boydii 3) prevention of invasive pulmonary aspergillosis in patients with chronic neutropenia, aerosolized liposomal form [8] 4) treatment of leishmaniasis [10] 5) used in treatment of a) pulmonary infection, including ventilator-associated pneumonia b) intra-abdominal infection including peritonitis [10] c) fungal urinary tract infection - used as bladder irrigant for fungal cystitis (candiduria) Dosage: (administration) 1) test dose: 1 mg slow IV 2) 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. 1) Premedication: a) Benadryl 50 mg PO b) tylenol 650 mg PO c) Demerol 50-75 mg IV as needed d) Compazine 10 mg PO as needed e) give premeds at start of amphotericin B infusion 2) PRN medications for chills/shakes a) Demerol 25-50 mg IV slowly b) Tylenol 650 mg PO/pr every 4 hours c) Benadryl 50 mg PO every 4 hours 3) 1st day (includes 1 mg test dose) a) 10 mg amphotericin B in 100 mL D5W b) infuse 10 mL (1 mg) over 30 minutes, then stop infusion c) check vital signs every 10 min for 30 minutes for signs of anaphylaxis d) if no signs of anaphylaxis, infuse remaining 9 mg (90 mL) over 2-3 hours e) monitor vital signs every 20 min until infusion complete 4) 2nd day a) 20 mg amphotericin B in 200 mL D5W - infuse over 2-3*h b) vital signs every 20 min until infusion is complete 5) 3rd day a) 30 mg amphotericin B in 300 mL D5W - infuse over 2-3*h b) monitor vital signs every 20 min until fusion is complete 6) 4th day a) 40 mg amphotericin B in 400 mL D5W - infuse over 2-3*h b) monitor vital signs every 20 min until fusion is complete 7) 5th day a) 50 mg amphotericin B in 500 mL D5W - infuse over 2-3*h b) monitor vital signs every 20 min until fusion is complete 8) laboratory a) serum creatinine QOD b) serum K+ QOD c) serum Mg+2 QOD d) CBC weekly 9) give amphotericin B daily, highest dose tolerated (up to 1 mg/kg) [9] - 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) [8] AmBisome; 12.5 mg delivered using an adaptive aerosolized system, or 30 minutes on 2 consecutive days each week until recovery from neutropenia [8] Pharmacokinetics: 1) amphotericin is poorly absorbed & must be administered intravenously 2) low concentrations are obtained in the CSF. 3) 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 Adverse effects: 1) Fever, chills, headache, myalgias, nausea, vomiting a) reduced by premedication with: 1] aspirin or acetaminophen 2] diphenhydramine b) meperidine for treatment of infusion-related chills c) hydrocortisone 25-100 mg IV 2) thrombophlebitis: reduced by: a) administration through a central catheter b) heparin 1000 U with infusion 3) nephrotoxicity a) acute tubular necrosis, generally non-oliguric & slowly progressive b) distal renal tubular acidosis, RTA IV c) hypokalemia d) hypomagnesemia e) impaired GFR, increased creatinine f) irreversible renal damage may occur with cumulative doses > 3-4 g g) sodium & volume depletion potentiate nephrotoxicity. Normal saline infusion 250-500 mL before & after amphotericin therapy may reduce nephrotoxicity. 4) anemia 5) neuritis & arachnoiditis in patients with intrathecal administration. Drug interactions: 1) aminoglycosides, cyclosporine & vancomycin may increase risk of renal failure 2) corticosteroid may increase K+ loss 3) K+ loss in combination with digoxin & neuromuscular junction blockers may increase toxicity 4) flucytosine or zidovudine in combination increases risk of bone marrow toxicity 5) itraconazole in combination decreases effect of both agents Mechanism of action: 1) binds to fungal sterols (ergosterol) 2) alters structure & permeability of fungal membranes 3) also binds human cytoplasmic sterols (cholesterol) which accounts for some of its toxicity 4) 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.

Interactions

drug interactions

General

amebicide amphotericin antifungal agent

Properties

MISC-INFO: elimination route LIVER pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 294-95
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 598
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  7. Journal Watch 21(9):72, 2001 Eriksson et al, BMJ 322:579, 2001
  8. Rijnders BJ et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: A randomized, placebo-controlled trial. Clin Infect Dis 2008 May 1; 46:1401. PMID: 18419443
  9. Bicanic T et al, High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: A randomized clinical trial. Clin Infect Dis 2008, 47:123 PMID: 18505387
  10. Deprecated Reference