Overview of Antifungal Agents
Pathogenic fungi affecting animals are eukaryotes, generally existing as either filamentous molds (hyphal forms) or intracellular yeasts. Fungal organisms are characterized by a low invasiveness and virulence. Factors that contribute to fungal infection include necrotic tissue, a moist environment, and immunosuppression. Fungal infections can be primarily superficial and irritating (eg, dermatophytosis) or systemic and life threatening (eg, blastomycosis, cryptococcosis, histoplasmosis, coccidioidomycosis). See also Dermatophytosis and see Fungal Infections.) Clinically relevant dimorphic fungi grow as yeast-like forms in a host but as molds in vitro at room temperature; they include Candida spp, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Sporothrix schenckii, and Rhinosporidium.
Several factors can lead to therapeutic failure or relapse after antifungal therapy. Drug access to fungal targets is often compromised. Host inflammatory response may be the first barrier, followed by location in sanctuaries (brain, eye, etc) as a second barrier for some infections, and the organisms themselves as a third barrier. The fungal cell wall is rigid and contains chitin, which along with polysaccharides, acts as a barrier to drug penetration. The cell membrane contains sterols such as ergosterol, which influences the efficacy and potential resistance to some drugs. Cryptococcus and occasionally Sporothrix schenckii produce an external coating or slime layer that encapsulates the cells and causes them to adhere and clump together. Finally, regarding drug access, most infections are located inside host cells, the lipid membrane of which can present a final barrier.
Discontinuing therapy after clinical signs have resolved but before infection is eradicated also leads to therapeutic failure. Therapy should extend well beyond clinical cure. Once drugs reach the site of action, therapeutic success is impeded by the nature of fungal infections. Fungal growth is slow, yet most antifungal drugs work better in rapidly growing organisms. Likewise, most antifungal agents are fungistatic in action, with clearance of infection largely dependent on host response. As such, the duration of therapy is long, and the "get in quick, hit hard, and get out quick" recommendation for antibacterial therapy is not appropriate for antifungal therapy; care must be taken to not discontinue therapy too early. However, longer duration of therapy contributes to another common cause of therapeutic failure: host toxicity. Because both the antifungal target organism and the host cells are eukaryotic, the cellular targets of fungal organisms are often similar to the host structures. Therefore, as a class, antifungal drugs tend to be more toxic than antibacterial drugs, and the number of antifungal drugs approved for use are markedly fewer than the number of antibacterial drugs. Drugs that can be used locally (including topically) or characterized by distribution to sites of infection (eg, liposomal products) may decrease this risk. The slow growth that characterizes fungal infections means that acquired resistance occurs less commonly than in bacterial infections. Therapeutic failure may also reflect the inability of the immunocompromised host to overcome residual fungal populations inhibited by the drug; those antifungals that are also (positive) immunomodulators may be more effective.
A number of serious systemic fungal diseases are well recognized in several parts of the world (see Fungal Infections). Antifungal agents have greatly reduced previously recorded human mortality rates due to systemic mycoses. A relatively narrow selection of drugs is used in these cases.