Antifungal agents: chemotherapeutic targets and immunologic strategies

During the past two decades the frequencies and types of life-threatening fungal infections have increased dramatically in immunocompromised patients (7, 220, 232, 282). Several factors have contributed to this rise: the expansion of severely ill and/or immunocompromised patient populations with human immunodeficiency virus (HIV) infection, with chemotherapy-induced neutropenia, and receiving organ transplant-associated immunosuppressive therapy; more invasive medical procedures, such as extensive surgery and the use of prosthetic devices and vascular catheters; treatment with broad-spectrum antibiotics or glucocorticosteroids; parenteral nutrition; and peritoneal dialysis or hemodialysis (25, 63, 66). The major opportunistic pathogen has been Candida albicans (17, 25, 142); however, the frequency of non-C. albicans Candida species is increasing (232, 287). Invasive pulmonary aspergillosis is a leading cause of attributable mortality in bone marrow transplant recipients (209). HIV-infected patients are particularly susceptible to mucosal candidiasis, cryptococcal meningitis, disseminated histoplasmosis, and coccidioidomycosis (5, 66, 294), while Pneumocystis carinii pneumonia is a leading cause of death in HIV-infected patients in North America and Europe (121). P. carinii was considered, until recently, a protozoal parasite on the basis of its resistance to classical antifungal agents. However, it has been reclassified as being most closely related to ascomycetous fungi on the basis of rRNA and b-tubulin homologies, the presence of the typical fungal cell wall polymers glucan and chitin, and separate dihydrofolate reductase and thymidylate synthase enzymes (in protozoa, both activities reside on a single protein) (74, 163). Treatment of invasive mycoses is complicated by problems in diagnosis (285) and susceptibility testing (8, 79, 90, 230) of fungi. Opportunistic fungal infections are often treated empirically in profoundly neutropenic patients when there is fever of unknown origin refractory to broad-spectrum antibacterial agents (233, 266, 284). Treatment of deeply invasive fungal infections has consistently lagged behind bacterial chemotherapy (27, 178). Amphotericin B, still the ‘‘gold standard’’ for the treatment of most severe invasive fungal infections, was discovered in 1956 (102). One reason for the slow progress is that, like mammalian cells, fungi are eukaryotes, and thus, agents that inhibit protein, RNA, or DNA biosynthesis have greater potential for toxicity. A second reason is that, until recently, the incidence of life-threatening fungal infections was perceived as being too low to warrant aggressive research by the pharmaceutical industry. In the past decade, however, there has been a major expansion in the number of antifungal drugs available (99). Nevertheless, there are still major weaknesses in their spectra, potencies, safety, and pharmacokinetic properties. This minireview briefly discusses the antifungal agents currently in clinical use. It then considers the use of promising new biochemical targets in fungi as well as host-based, immunological approaches as evolving strategies for antifungal therapy.