ABSTRACT
Based on infection sites, fungal infections in humans are mainly classified into two categories: superficial and systemic infections. In other words, the infections can range from superficial, noninvasive diseases of normal children and adults to life-threatening systemic diseases of immunocompromised individuals. Pathogenic fungi, causing superficial infections inhabit preferably the keratinized tissues such as stratum corneum of the skin, nail, and hair. Among these, dermatophytosis or tinea infections of the skin (tinea pedis and corporis) caused by dermatophytes, cutaneous candidiasis caused by Candida spp., and tinea versicolor caused by Malassezia furfur are commonly found as superficial skin fungal infections, and these infections are generally not life-threatening. These infections are usually treated with topical antifungal agents such as tolnaftate, ciclopirox olamine, clotrimazole, bifonazole, amorolfine, terbinafine, and butenafine. To treat tinea pedis, for example, tolnaftate, ciclopirox olamine, and clotrimazole are usually applied two or three times a day for four or more weeks. Bifonazole is the first drug that is used by once-a-day treatment regimen mainly because of its good retention in the stratum corneum of the skin. Amorolfine, terbinafine, and butenafine have also proved good retention in the stratum corneum so that once-a-day treatment with each of them can be sufficient to exert potent antifungal activity. Recently, as an additional advance in antifungal chemotherapy, successful short-term treatment of tinea infections has been achieved by the use of topical terbinafine. In the case of tinea unguium or onychomycosis (fungal infection of the nails), which is hardly cured by topical antifungal agents, oral griseofulvin had mainly been used until oral terbinafine or oral itraconazole became available. In contrast to superficial fungal infections, systemic fungal infections can be seriously life threatening and can be associated with high mortality. The incidence of disseminated systemic infections has grown in the past two decades, at least in part, as a consequence of the increasing number of immunocompromised people worldwide such as patients with HIV infection, organ transplant recipients, and patients receiving cancer chemotherapy. The immunocompromised patients are confronted with risk of systemic infection from commensal and/or ubiquitous species, primarily Candida spp. and Aspergillus spp. To treat these systemic fungal infections, four groups of agents based on the chemical structures have mainly been used to date: the polyene, the fluoropyrimidine, the imidazole, and the triazole. The polyenes are prototypic antifungal agents including amphotericin B and its analogue nystatin. These agents are effective across a broad spectrum of pathogens, but their utility is tempered by inherent toxicity, particularly nephrotoxicity. The class of fluoropyrimidines includes 5-flucytosine (5-FC) that was
originally discovered as a potential antitumor agent. 5-FC is a nucleoside analogue and exerts antifungal effect by disturbing nucleic acids metabolism in fungal cells. However, the major drawback of the agent is that it creates multiple opportunities for selection of resistance. Thus, the agent is rarely used as a monotherapy. Regarding imidazoles, ketoconazole and miconazole have been used for the treatment of systemic fungal infections. In the case of ketoconazole, although it is effective against a number of medically important fungi, it causes a number of toxic effects including hepatotoxicity. Other imidazoles including miconazole also cause systemic toxicity so that their principal use is generally restricted to the treatment of superficial infections in topical formulations. The triazoles are distinguished from the imidazoles by the presence of a third nitrogen atom in the core structure. Fluconazole and itraconazole have some utility in invasive fungal infections although fluconazole is poorly active against Aspergillus spp. and sometimes causes development of azole-resistant organisms, and oral itraconazole is poorly absorbed in humans. As described previously, all four classes of current antifungal agents for the treatment of systemic infections possess somewhat drawbacks in terms of side effects and/or drug resistance. Thus, the search for new agents for life-threatening systemic fungal infections is continued. This chapter covers the medically important antifungal drugs in terms of historical background, and current and prospective management of fungal infections including problems such as drug-resistance and side effects.
