Antifungal chemotherapy and drug strategies: Projected clinical needs

Abstract

In recent years, the incidence of systemic fungal infections has increased tremendously, particularly in severely ill and immunocompromised patients. Adequate treatment of these infections when they occur in the normal host is available. Amphotericin B (AmB) is very effective, but its toxicity and inconveniences associated with its intravenous administration are important negative factors associated with its use. Present attempts to decrease toxicity of AmB by combining it with other drugs and/or by developing unique delivery systems are interesting but the results are only preliminary. Azoles are also effective and ketoconazole is particularly attractive because it can be administered orally. The triazoles, itraconazole and fluconazole, represent promising agents in this group because they have a broader range of action, are well absorbed through the gastrointestinal tract, have a prolonged half life, have fever side effects and also penetrate well into the central nervous system and urine in an active form. Despite these advances, significant problems exist. None of the antifungal agents appear to be curative in patients with AIDS. Consequently, life-long suppressive therapy is necessary to prevent recurrence of disease. Drug resistance is an increasing problem with the potential for cross-resistance among the presently available agents which all affect the fungal cell envelopes. Clearly, there is a need to develop antifungal agents which have completely different sites of action to avoid cross resistance. Different classes of drugs affecting different cellular metabolic processes might interact with polyenes and azoles synergistically to enhance therapeutic effects. There is also a need to understand the basis for susceptibility to systemic fungal infections and to devise strategies based on these insights to prevent them.