Be cancer’s antimatter.
An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host.
Polyene Antifungal Drugs
Amphotericin, nystatin, and pimaricin interact with sterols in the cell membrane (ergosterol in fungi, cholesterol in humans) to form channels through which small molecules leak from the inside of the fungal cell to the outside.
Azole Antifungal Drugs
Fluconazole, itraconazole, and ketoconazole inhibit cytochrome P450-dependent enzymes (particularly C14-demethylase) involved in the biosynthesis of ergosterol, which is required for fungal cell membrane structure and function.
Allylamine and Morpholine Antifungal Drugs
Allylamines (naftifine, terbinafine) inhibit ergosterol biosynthesis at the level of squalene epoxidase. The morpholine drug, amorolfine, inhibits the same pathway at a later step.
Antimetabolite Antifungal Drugs
5-Fluorocytosine acts as an inhibitor of both DNA and RNA synthesis via the intracytoplasmic conversion of 5-fluorocytosine to 5-fluorouracil.
Selection of Antifungal Agents
In vitro susceptibility testing with the fungi is not yet standardized, and the results of in vitro tests do not always compare to the results obtained in vivo. Therefore, preliminary selection of an antifungal agent for clinical use is made primarily on the basis of the specific fungal pathogen involved. The spectrum of activity for the licensed antifungal agents is well defined through the results of preclinical and clinical testing with the most common fungal pathogens. This approach is useful in avoiding selection of antifungals for species of fungi that are known to have primary resistance to the agent, but less useful in selecting antifungals for species that are known to develop secondary (drug induced) resistance to a particular agent.
Antifungal drug resistance has become an increasing problem with the development of a larger compendium of antifungal agents. Drug resistance to the polyene antifungals is almost always primary resistance rather than secondary resistance. That is, the susceptibility profiles for the species are characteristic and inherent, and rarely change in response to exposure to the agent. For example, amphotericin B-resistant species such as Pseudallescheria boydii and Candida lusitaniae are well known, and do not appear to have originated from exposure to the antifungal. Despite decades of widespread clinical use of amphotericin B in Candida albicansinfections, the development of secondary resistance has been exceedingly rare. In contrast, both primary and secondary resistance to 5-fluorocytosine are known to occur for strains of Candida species, serving as the basis for restricting use of this agent to combination therapy with other antifungal drugs.
The question of fungal resistance to the azole drugs is considerably more complex and is currently under evaluation. Examples of both primary and secondary resistance are known for the medically important yeasts and selected azole antifungals. Candida krusei as a species is typically resistant to fluconazole. Candida albicansstrains are typically susceptible to fluconazole and certain other azole antifungals, but there are increasing reports of resistance, especially in HIV-infected hosts having undergone repeated courses of azole antifungal therapy. The question of drug resistance is complicated by the limitations in the available susceptibility testing methodology and the ability to distinguish between microbiological and clinical drug resistance. The latter typically occurs when an inhibitory antifungal agent reaches the limits of its activity in a host with a decreasingly efficient immune system.
With the advent of the polyenes, azoles, and fluorocytosine, previously fatal infections can now be treated. However, as modern medicine continues to extend life through aggressive therapy of other life-threatening diseases such as cancer, there is an increasing population at risk for opportunistic fungal infections. Such patients represent a special challenge because they often are left with little host immune function. Therefore, chemotherapeutic agents should be fungicidal and not just fungistatic. The search continues for fungicidal agents that are nontoxic to the host. Research is also directed toward immunomodulating agents that can reverse the defects of native host immunity.