Review article
Clinical pharmacology of antifungal compounds

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Amphotericin B deoxycholate

Amphotericin B is a natural polyene macrolide antibiotic and consists of seven conjugated double bounds, an internal ester, a free carboxyl group, and a glycoside side chain with a primary amino group (Fig. 1). It is not orally or intramuscularly absorbed. For parenteral use, AmB has been solubilized with deoxycholate as micellar suspension.

Flucytosine

Flucytosine (5-fluorocytosine [5-FC]) is a low-molecular-weight water-soluble synthetic fluorinated pyrimidine analogue (Fig. 3). It is taken up by the fungus-specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil, which causes RNA miscoding and inhibits DNA synthesis [37]. 5-FC is relatively nontoxic to mammalian cells because of the absence or very low level of activity of cytosine deaminase. In the United States, 5-FC is available only as

Antifungal triazoles

The antifungal azoles are a class of synthetic compounds that have one or more azole rings and, attached to one of the nitrogen atoms, a more or less complex side chain. The imidazoles miconazole and ketoconazole were the first azoles developed for systemic treatment of human mycoses. Two subsequently developed triazoles, fluconazole and itraconazole, are in current use (Fig. 4).

Echinocandin lipopeptides: anidulafungin, caspofungin, and micafungin

The echinocandins are a novel class of semisynthetic amphiphilic lipopeptides composed of a cyclic hexapeptide core linked to a variably configured lipid side chain. The echinocandins act by noncompetitive inhibition of the synthesis of 1,3-β-glucan, a polysaccharide in the cell wall of many pathogenic fungi (Fig. 5). Together with chitin, the rope-like glucan fibrils are responsible for the cell wall's strength and shape. They are important in maintaining the osmotic integrity of the fungal

Future directions

The past decade has seen a considerable expansion in antifungal drug research and the clinical development of several new compounds and strategies targeted against invasive fungal infections. ITC, voriconazole, and liposomal AmB are acceptable alternatives to AmB-D in neutropenic fever. The newer triazoles offer the tantalizing possibility of oral prophylaxis of mold infections, and seem a viable option to AmB in many cases of aspergillosis. Combination therapy of echinocandins with triazoles

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References (128)

  • D.W. Denning et al.

    Treatment of invasive aspergillosis with itraconazole

    Am J Med

    (1989)
  • P.K. Sharkey et al.

    Itraconazole treatment of phaeohyphomycosis

    J Am Acad Dermatol

    (1990)
  • A.H. Groll et al.

    Antifungal agents

  • J. Brajtburg et al.

    Amphotericin B: current understanding of mechanisms of action

    Antimicrob Agents Chemother

    (1990)
  • J. Brajtburg et al.

    Involvement of oxidative damage in erythrocyte lysis induced by amphotericin B

    Antimicrob Agents Chemother

    (1985)
  • H. Vanden Bossche et al.

    Antifungal drug resistance in pathogenic fungi

    Med Mycol

    (1998)
  • A.H. Groll et al.

    Antifungal pharmacodynamics: concentration-effect relationships in vitro and in vivo

    Pharmacotherapy

    (2001)
  • D. Andes et al.

    Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model

    Antimicrob Agents Chemother

    (2001)
  • A.J. Atkinson et al.

    Amphotericin B pharmacokinetics in humans

    Antimicrob Agents Chemother

    (1978)
  • K.J. Christiansen et al.

    Distribution and activity of amphotericin B in humans

    J Infect Dis

    (1985)
  • T.J. Walsh et al.

    Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group

    N Engl J Med

    (1999)
  • B.P. Sawaya et al.

    Amphotericin B nephrotoxicity: the adverse consequences of altered membrane properties

    J Am Soc Nephrol

    (1995)
  • J.R. Wingard et al.

    Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis

    Clin Infect Dis

    (1999)
  • T.K. Daneshmend et al.

    Clinical pharmacokinetics of systemic antifungal drugs

    Clin Pharmacokinet

    (1983)
  • Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group

    Am J Med

    (1989)
  • J.H. Rex et al.

    Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America

    Clin Infect Dis

    (2000)
  • D.A. Stevens et al.

    Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America

    Clin Infect Dis

    (2000)
  • U. Eriksson et al.

    Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial

    BMJ

    (2001)
  • J.W. Hiemenz et al.

    Lipid formulations of amphotericin B: recent progress and future directions

    Clin Infect Dis

    (1996)
  • A. Wong-Beringer et al.

    Lipid formulations of amphotericin B: clinical efficacy and toxicities

    Clin Infect Dis

    (1998)
  • R. Herbrecht

    Safety of amphotericin B colloidal dispersion

    Eur J Clin Microbiol Infect Dis

    (1997)
  • O. Ringden et al.

    Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients

    J Antimicrob Chemother

    (1991)
  • M.H. White et al.

    Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis

    Clin Infect Dis

    (1997)
  • M.H. White et al.

    Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia

    Clin Infect Dis

    (1998)
  • H.G. Prentice et al.

    A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients

    Br J Haematol

    (1997)
  • J.R. Wingard et al.

    A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group

    Clin Infect Dis

    (2000)
  • M.D. Johnson et al.

    Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature

    Pharmacotherapy

    (1998)
  • A.C. Leenders et al.

    Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections

    Br J Haematol

    (1998)
  • T.J. Walsh et al.

    Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study

    Antimicrob Agents Chemother

    (2001)
  • P.A. Cossum et al.

    Pharmacokinetics of Nyotran (liposomal nystatin) in human patients

  • E.I. Boutati et al.

    Phase I study of maximum tolerated dose of intravenous liposomal nystatin for the treatment of refractory febrile neutropenia in patients with hematological malignancies

  • A.H. Williams et al.

    Multicenter study to evaluate the safety and efficacy of various doses of liposomal encapsulated nystatin in nonneutropenic patients with candidemia

  • Y. Krupova et al.

    Liposomal nystatin (L-NYS) in therapy of pulmonary aspergillosis refractory to conventional amphotericin B in cancer patients

    Support Care Cancer

    (2001)
  • F.C.J Offner et al.

    EORTC-IFCG phase II study on liposomal nystatin in patients with invasive aspergillosis refractory or intolerant to conventional/lipid amphotericin B

  • R. Powles et al.

    Liposomal nystatin (Nyotran) vs. amphotericin B (fungizone) in empiric treatment of presumed fungal infections in neutropenic patients

  • A. Vermes et al.

    Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions

    J Antimicrob Chemother

    (2000)
  • A. Vermes et al.

    Flucytosine: correlation between toxicity and pharmacokinetic parameters

    Chemotherapy

    (2000)
  • A. Polak

    Mode of action studies

  • P. Francis et al.

    Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy

    Clin Infect Dis

    (1992)
  • J.E. Bennett et al.

    A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis

    N Engl J Med

    (1979)
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