Therapy for fungal diseases

Penicillium chrysogenum Invasive fungal infections are an increasing threat to human health. In the developed world, these infections predominantly occur in increasingly aggressive immunosuppressive therapies. The overall mortality for invasive diseases caused by Candida spp. and Aspergillus spp. is 30–50%, despite the advent of new diagnostic and therapeutic strategies. In the developing world, there are 1 million cases of cryptococcal disease per year, resulting in 675,000 deaths. Allergic fungal syndromes are increasingly recognised. Continued efforts are required to improve the often suboptimal therapeutic outcomes associated with fungal infections.

The high degree of phylogenetic relatedness between fungi and humans means that there are relatively few differential targets to be exploited for antifungal drug development. Fungi are involved in an interminable struggle for survival with each other and with other microbes. They produce a vast array of extracellular enzymes and secondary metabolites to counteract and digest the external world. Many antimicrobial agents have been isolated from fungi themselves. The best example is penicillin, which was isolated from Penicillium notatum (now Penicillium chrysogenum) by Fleming, and later purified for medical use by Florey and Chain. Similarly, the echinocandins, a novel class of antifungal compounds now in widespread clinical use, are semisynthetic derivatives of fungal-derived cyclic hexapeptides. Currently, five classes of antifungal agents are used orally or intravenously for the treatment of fungal infections in humans: polyenes, pyrimidine analogues, allylamines, azoles and the echinocandins. Each antifungal compound has advantages and limitations related to its spectrum of activity, route of administration, drug interactions and toxicity profile.

This review describes the role and limitations of these agents for the treatment of the most common and medically important syndromes, and provides a perspective on the current status of drug therapy for invasive fungal diseases, together with priorities for the future development of novel compounds. Key opportunities for new drugs include production of orally bioavailable agents for the treatment of invasive aspergillosis, invasive candidiasis, cryptococcal meningitis and mucosal and urinary Candida infections. Orally bioavailable agents for the treatment of chronic pulmonary and allergic aspergillosis are also required, as well as new potent drugs against a range of medically important moulds. Antifungal resistance is a problem in certain contexts, but is generally less of a problem than bacterial infections. Earlier and more complete mycological diagnosis and improvements in underlying risk estimation will improve outcomes.

Therapy for fungal diseases: opportunities and priorities. Trends Microbiol. March 5, 2010

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