Future directions of antifungal chemotherapy

The number of recognized fungal pathogens and the alternatives for treatment of infections due to these organisms have increased dramatically in the 1980s. Use of the traditional agent, amphotericin B, has been hampered by severe dose-limiting toxicity and variable efficacy, and flucytosine is characterized by a narrow spectrum, rapid emergence of resistance, and significant dose-limiting toxicities. In recent years, the appearance of a variety of azole antifungal drugs has permitted exploration of the use of different agents in a wide range of dosages for treatment of a variety of fungal infections. Even so, the azoles are often ineffective or cannot be used, and major therapeutic gaps still remain, particularly for patients with AIDS and those with severe neutropenia. For those with acute, life-threatening disease, the use of amphotericin B-lipid complex or ampholiposomes offers the potential of delivering much higher doses of amphotericin B safely. However, the efficacy of these formulations compared with that of amphotericin B is as yet uncertain. In addition to treatment of established disease, there has been interest in using antifungal azoles for prophylaxis for mucocutaneous candidiasis and systemic mycoses in patients who are predisposed to these conditions. Recently completed large-scale studies suggest that antifungal prophylaxis can be accomplished with use of azoles; however, the cost versus benefits of the prophylactic use of these agents is not yet defined. The 1990s will see consolidation of the uses of antifungals presently available, exploration of the use of much higher doses of amphotericin B (perhaps other polyenes as well in liposomal form), and perhaps the use of azoles in combination as well as alone or sequentially in the form of polyene/azole antifungal therapy. New entries may include beta-1,3-glucan inhibitors in the mid-1990s and other classes of drugs toward the end of the decade.