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Antifungal

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Antifungal medications, also known as antimycotics, are pharmaceutical agents used to treat or prevent mycoses. Mycoses are infections caused by fungi. These infections can range from common skin conditions like athlete's foot and ringworm to serious systemic issues. Examples of serious infections include candidiasis, known as thrush, and cryptococcal meningitis. While some antifungals are available over the counter, most require a doctor's prescription. Using these drugs correctly is vital because the evolution of antifungal resistance is a growing global health threat.

Doctors choose a route of administration based on where the infection is located. For ocular infections in the eye, natamycin is currently the only available antifungal, though other agents can be compounded. If a fungal infection reaches the central nervous system, doctors may use an intrathecal route. This involves injecting medicine like amphotericin B into the spinal fluid because systemic options cannot reach the required concentration there. For skin infections like tinea pedis, topical treatments such as terbinafine are used. Vaginal infections like candida vulvovaginitis are often treated with intravaginal clotrimazole.

Systemic infections can be handled through oral or intravenous (IV) routes. Oral administration is common if the drug has good bioavailability, which means the body can absorb it well. For example, ketoconazole is used orally to treat coccidioidomycosis. If a drug has poor bioavailability, the intravenous route is a better option. An IV injection of amphotericin B allows the drug to reach the bloodstream and distribute quickly throughout the body. This method is particularly useful for treating coccidioidomycosis when oral absorption is not efficient.

Antifungals are categorized into several chemical classes based on how they work. Polyenes are a major class, including drugs like amphotericin B, nystatin, and natamycin. These molecules are amphiphilic, meaning they have both water-loving and fat-loving parts. Polyenes work by binding to sterols in the fungal cell membrane, specifically ergosterol. This binding changes the transition temperature of the membrane. It forces the membrane into a less fluid, more crystalline state. This causes the cell's contents, such as monovalent ions like potassium and sodium, to leak out. This leakage is a primary way the fungal cell dies.

However, polyenes can sometimes affect human cells. Animal cells contain cholesterol instead of ergosterol. At therapeutic doses, some amphotericin B may bind to cholesterol in animal membranes, which increases the risk of toxicity. For instance, amphotericin B is known to be nephrotoxic, meaning it can be harmful to the kidneys when given intravenously. The length of the polyene's hydrophobic chain affects this risk. As the chain is shortened, its ability to bind to sterols increases, which can also increase its binding to cholesterol.

Another large class is the azoles, which includes imidazoles like clotrimazole and triazoles like fluconazole. Azoles work by inhibiting the enzyme lanosterol 14α-demethylase. This enzyme is required to convert lanosterol into ergosterol. By blocking this process, azoles prevent the fungus from building its cell membrane. This leads to an accumulation of 14-α-methylsterols. This buildup disrupts the packing of phospholipids and impairs membrane-bound enzymes, which inhibits fungal growth. Other classes include allylamines, like terbinafine, which inhibit squalene epoxidase, and echinocandins, which stop the creation of glucan in the fungal cell wall.

Echinocandins, such as caspofungin and micafungin, are administered intravenously. They are particularly useful for treating resistant Candida species by inhibiting 1,3-Beta-glucan synthase. Scientists are also studying other types, such as triterpenoids like ibrexafungerp. As of 2021, many novel classes of antifungals were in clinical trials to improve performance. Despite these advancements, doctors must be careful with side effects. Some azoles can interact with other drugs, such as calcium channel blockers or antidepressants, by affecting the cytochrome P450 family of enzymes. This can cause the concentration of those drugs in the body to increase unexpectedly.

Antifungal resistance is a significant challenge for modern medicine. Resistance can happen naturally through genetic mutation or aneuploidy. It can also develop due to external pressures, such as the overuse of clinical antifungals or their use in agriculture. This is considered a "One Health" concern because environmental and host factors all play a role. The emergence of Candida auris is especially concerning. This pathogen can exhibit multi-class drug resistance and has caused outbreaks globally. Because of these risks, the World Health Organization has released a priority fungal pathogen list to track these resistant threats.

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