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Back To Vidyya The Second NIAID Workshop In Medical Mycology:

Molecular And Immunologic Approaches To The Diagnosis And Treatment Of Systemic Mycoses

STATUS AND LIMITATIONS OF DIAGNOSIS AND
THERAPY OF SYSTEMIC FUNGAL INFECTIONS

Current Status

Culture of body fluids or tissue for fungus continues to be the mainstay of diagnosis of systemic fungal disease. Unfortunately, definitive identification of a fungus by culture may take one to four weeks. A presumptive diagnosis can be made on the basis of characteristic histopathology and special tissue stains such as periodic acid-Schiff (PAS) and Gomori-methenamine silver (GMS). Skin tests with antigens such as histoplasmin or spherulin, while useful in epidemiologic studies, have no role in diagnosis of active disease. Serologic tests have limited values for most fungal diseases because of low specificity and sensitivities; however, there are exceptions which include the latex agglutination test for cryptococcal antigen in patients with suspected cryptococcosis, and the complement-fixation and immunodiffusion tests for coccidioidomycosis and paracoccidioidomycosis. At present, highly specific and sensitive serologic tests are not available for early and rapid diagnosis of candidiasis and aspergillosis, the two most common and clinically important opportunistic fungal diseases in immunocompromised hosts. Investigational approaches to diagnosis and monitoring of systemic mycoses include: (1) detection of unique fungal metabolites by gas liquid chromatography or antigen/antibody based methods; (2) detection of immunodominant fungal antigens by radioimmunoassay, ELISA, latex agglutination or immunoblot; and 3) use of molecular probes such as polymerase chain reaction to detect fungal DNA. While results of some newer tests to identify Candida cell wall mannan, Candida cytoplasmic enolase antigen, and Aspergillus galactomannan are promising, drawbacks persist. For example, these tests often must be performed on multiple sera over time in order to achieve acceptable sensitivity, and have restricted availability because they are not commercially produced, and have low perceived market priority.

At present, the five licensed antifungal drugs which are the most important and commonly used agents against the systemic fungal diseases are amphotericin B, flucytosine, and the three azole drugs, ketoconazole, itraconazole, and fluconazole. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death. The azole drugs inhibit synthesis of ergosterol through an interaction with the cytochrome P450 dependent enzyme, 14 alpha demethylase, necessary for the conversion of lanosterol to ergosterol. By contrast, flucytosine, an oral fluorinated pyrimidine, inhibits both fungal DNA and RNA protein synthesis. While these drugs are effective therapies for many of the systemic mycoses including blastomycosis, candidiasis, cryptococcosis, histoplasmosis, and sporotrichosis, they are only minimally or moderately effective for aspergillosis, coccidioidomycosis, non-albicans candidiasis, and phaeohyphomycosis caused by dematiaceous moulds. Moreover, these drugs are not without other problems. Amphotericin B, considered by some authorities as the "gold standard" because of its broad spectrum of activity and fungicidal action, is available only as an intravenous formulation in the United States, requiring continuous intravenous access, and is associated with significant dose-limiting toxicity, especially nephrotoxicity. Flucytosine also has the potential for considerable toxicity, especially affecting the bone marrow, liver, gastrointestinal tract, and skin. As a result, this drug has never been optimally utilized. Although the azole class of drugs is an important advance and offers effective and safe alternatives to amphotericin B and flucytosine for many of the systemic mycoses, the azoles, too, are not ideal drugs. Only fluconazole is available as both an oral and intravenous formulation. Although amphotericin B and flucytosine, the azoles are potentially hepatotoxic, may inhibit steroid hormone synthesis in humans, and have the potential to interact with many classes of drugs (oral hypoglycemics, oral anticoagulants, phenytoin, cyclosporine, H1 and H2 receptor antagonists, rifampin, etc.) with serious sequelae. In addition, fluconazole-resistant Candida species are an increasing cause of concern in AIDS patients and other compromised hosts exposed to fluconazole and as a prophylaxis over extended periods.

Because of the toxicity and other problems associated with the currently available antifungal drugs, new treatment approaches are needed. Current efforts in antifungal drug development are focused on: (1) drugs with novel fungal cell targets; (2) investigational azole and allylamine drugs; and (3) novel formulations of currently licensed drugs. In addition, recombinant cytokines, both licensed and investigational, have promise. With regard to novel fungal cell targets, an important difference between fungi and mammalian cells is that the fungal cell envelope consists of a cell wall, composed primarily of two carbohydrates, glycan and chitin, and mannoproteins, and cytoplasmic membrane. By contrast, cell walls are not found in mammalian cells and other eukaryotic cells. Available evidence indicates that drugs which target fungal cell wall structures will not adversely affect mammalian cells; thus, the potential for toxicity of such drugs in humans is reduced. Examples of investigational drugs which interrupt formation of the unique fungal cell wall include: (a) nikkomycins which inhibit chitin synthase; (b) the echinocandin/pneumocandin/ lipopeptide class which inhibit glycan synthesis; and (c) pradimicins which exhibit calcium dependent binding to mannan (mannoprotein). The investigational azole drugs under development by several pharmaceutical companies have the potential to outperform the currently licensed azoles, ketoconazole, itraconazole, and fluconazole, in terms of broader spectrum of activity, increased efficacy, and less toxicity. The allylamines, a new class of drug, inhibit squalene epoxidase, another enzyme in the biosynthetic pathway of ergosterol.

Novel formulations of currently licensed drugs are aimed at enhancing the efficacy and reducing the toxicity of the parent compound. There are two classes of drugs in this group. The first class are lipid formulations of amphotericin B including liposomal amphotericin B (AmBisome), amphotericin B colloidal dispersion (Amphocil), and amphotericin B lipid complex (ABLC). Enveloping amphotericin B in liposomes or complexing the drug with lipids offers several advantages of the novel formulations over conventional amphotericin B, which is complexed in desoxycholate, a bile salt. These potential advantages include: (a) up to 5- 10-fold increase in daily dose of amphotericin B, thereby increasing the therapeutic index; (b) less nephrotoxicity, the major limiting toxic effect of conventional amphotericin B; (c) tropism for reticulo-endothelial organs such as lymph nodes, liver and spleen where fungi typically home in contrast to the tropism of conventional amphotericin B for kidneys; (d) preferential binding of lipid formulated drugs to fungal cell membranes; and (e) efficacy in some patients who have failed or cannot tolerate conventional amphotericin B.

New oral and intravenous preparations of itraconazole represent a second class of novel formulations. Itraconazole, currently available only for oral administration, is a weak base which requires an acid environment for optimal solubilization and absorption. The bioavailability of itraconazole is increased when it is formulated in hydroxypropyl- beta-cyclodextrin, a cyclic oligosaccharide carrier molecule that increases the solubility of lipophilic compounds in aqueous solutions. Hydroxypropyl-beta- cyclodextrin itraconazole may be especially helpful in selected clinical situations, such as AIDS patients with achlorhydria or receiving concurrent drugs which impair absorption, or critically ill hospitalized patients who cannot take oral medications.

Immunomodulators may be important adjuncts to therapy of systemic mycoses. Invasive fungal diseases are increasingly observed in immunocompromised patients, especially those with protracted granulocytopenia secondary to neoplastic disease or cytotoxic chemotherapy, transplant recipients receiving immunosuppressive drugs such as high dose corticosteroids and cyclosporine, and AIDS patients with progressively declining CD4+ T cells and other perturbations in immune function. Current evidence indicates that both granulocytes, adequate in number and function, as well as intact cell-mediated immunity, are keys to successful outcome in patients with opportunistic yeast and mould diseases; cellular immunity also plays an important role in the host's containment of the endemic mycoses. Recent in vitro and animal in vivo data suggest a role in the management of fungal diseases for the expanding array of recombinant cytokines, especially interferon-gamma, the colony- stimulating factors, the various interleukins or interleukin antagonists, as well as passive immunotherapy with monoclonal antibodies. To date, only limited trials with these agents have been performed in humans with fungal diseases.

Recommendations

  • Encourage continued investigation of novel approaches to serodiagnosis of systemic mycoses, especially candidiasis and aspergillosis. Evaluation of new diagnostic methodologies should be incorporated into large scale prospective clinical trials.
  • Continue to develop novel antifungal drugs, i.e., new classes of drugs. Pursue new fungal cell targets and new formulations of existing drugs.
  • Give priority to drug development programs which focus on aspergillosis and diseases caused by other moulds, among the most common emerging opportunistic mycoses.
  • Explore more aggressively the role of immunomodulators in the management of systemic fungal diseases. Combinations of immunomodulators plus antifungal drugs should be evaluated in Phase II and III clinical trials.

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Editor: Susan K. Boyer, RN
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