Amphotericin B
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Contents |
Introduction
- Tradename: Fungizone, AmBisome.
Indications
- severe systemic fungal infections & meningitis caused by most fungi including aspergillus, Candida, Coccidioides & Cryptococcus
- not for use with infections caused by Pseudallescheria boydii
- used as bladder irrigant for fungal cystitis
- prevention of invasive pulmonary aspergillosis in patients with chronic neutropenia, aerosolized liposomal form [8]
Dosage
- Amphotericin will precipitate if mixed with electrolyte solutions.
-
- PRN medications
- 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) [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
- 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
-
- reduced by premedication with:
- 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
- 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
- heterocyclic compound, 2 rings
- antifungal agent
- amebicide
- alcohol
- carboxylate
- prokaryote-specific molecule
Internet Database
PubChem: 451404
PubChem: 107892
PubChem: 5280965
PubChem: 14956
PubChem: 352546
References
- The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
- Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 294-95
- Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 598
- Kaiser Permanente Northern California Regional Drug Formulary, 1998
- Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
- Journal Watch 21(9):72, 2001 Eriksson et al, BMJ 322:579, 2001
- 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: [1]
- 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: [2]
