Course: Opportunistic Fungi in the Immunocompromised Patient
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Therapeutic Approaches to Fungal Disease
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Amphotericin B

The polyene class of antifungals, specifically amphotericin B (AmB) remains the gold standard for the treatment of many invasive or life-threatening mycoses [67]. The drug binds to ergosterol in the fungal cell membrane, resulting in cell-wall disruption and killing. It has a broad spectrum of activity against both yeasts and moulds and is a valuable first-line agent against many species, including Candida, Aspergillus, Zygomycetes, Fusarium, Histoplasma, Cryptococcus, Blastomyces, and Coccidioidomyces, although it is not always effective for Aspergillus or Fusarium infections in severely immunocompromised patients. Treatment failure due to the development of amphotericin resistance is rare, although resistant strains of Candida lusitaniae and C tropicalis have been isolated during treatment.

Amphotericin is not absorbed when given orally, and intravenous formulation must be used to treat systemic disease. The formulation is inconvenient to use and necessitates prolonged intravenous access. The drug has a very narrow therapeutic index. Administration is unfortunately accompanied by a number of harmful side effects and unpleasant reactions that often limit the amount that can be given. Immediate side effects may include headache, fever, chills, and rigors. Nausea and vomiting are less common and, as with fever, often diminish as treatment proceeds. Local phlebitis at the injection site can occur but can be avoided by giving the drug through a central venous catheter. Heparin addition to the infusate has been suggested to improve the tolerability of peripheral injection.

The most serious toxic effect of amphotericin is renal damage likely caused by increased renal vascular resistance leading to decreased glomerular filtration and damage to renal tubular cells [68-70]. Renal loss of potassium and, less commonly, magnesium will in time cause substantial depletion in total body stores. Most patients with invasive fungal infection receive AmB at a daily dose of greater or equal to 0.5 mg/kg/day. This dose is associated with reversal impairment of renal function that occurs early during treatment (within 2 weeks) in up to 80% of patients. Renal tubular acidosis can occur in patients receiving doses of 500 mg to 1 gram or more. It is generally reversible, with renal function returning to pretreatment levels after discontinuation of therapy or (rarely) even with continued use. Irreversible renal damage, with necrosis and calcification of renal tubules, is uncommon unless the cumulative AmB dose exceeds 4 to 5 grams. Patients with preexisting renal impairment and those receiving other nephrotoxic drugs are at increased risk of renal damage. Careful monitoring of renal function during treatment can reduce or prevent renal damage.

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Therapeutic Approaches to Fungal
   Amphotericin B
   Lipid Formulations of Amphotericin B
   Azole Antifungal Agents
   New Azoles Undergoing Clinical Trials
   Echinocandin/Pneumocandin Agents

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Course Number: V035B.043001

This CME Expires on July 1, 2003; no tests will be accepted after this date.

This course is accredited by The University of Pittsburgh School of Medicine, Center for Continuing Education

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