Antifungal Agents

Fungistatic agents inhibit fungal growth. Fungicidal agents kill the fungal cells. Antifungal resistance arises when fungi alter antifungal target sites and/or reduce access to them, and when the fungal cells produce efflux pumps that prevent accumulation of antifungal agents. We draw a simplified fungal cell with a cell wall, cell membrane, and nucleus. These are the targets of antifungal agents, as follows: – Cell wall: Glucan synthesis inhibitors – Nucleus: DNA/RNA synthesis inhibitors and mitosis inhibitors – Cell membrane; Ergosterol synthesis inhibitors, which include the azoles and allylamines, and cell membrane disruptors, which includes the polyenes. These drugs act by binding ergosterol in the plasma membrane; subsequent damage to the membrane allows for cytoplasmic leakage and causes cell death. Amphotericin B is administered intravenously. It comes in multiple formulations: The conventional formulation is amphotericin B deoxycholate. This was the first antifungal developed; it is highly effective against a wide range of mycoses, but is associated with significant toxicity. We now have multiple lipid formulations, which are less toxic than the conventional form, have since been developed. Although amphotericin B is quite potent against a wide variety of fungi, it is generally reserved for severe mycoses, such as cryptococcal meningitis. It may also be used to treat systemic/endemic mycoses and severe opportunistic mycoses such as aspergillosis, mucormycosis, candidemia, and invasive candidiasis, but other, less-toxic, drugs are generally preferred. It is also used as a bladder wash to treat fungal cystitis. Amphotericin B is associated with severe side effects ("ampho-terrible"): – Nephrotoxic, especially the deoxycholate formulation. – QT prolongation. – Electrolyte disturbances, especially of potassium and magnesium, which increases risk of cardiac arrhythmias. – Acute infusion reactions, which include fever, chills, chest pain, nausea, and other symptoms. – Phlebitis at the IV site. Nystatin is administered orally or topically. It is used to treat oropharyngeal candidiasis – patients are instructed to "swish and spit" or "swish and swallow," depending on how far into the oropharynx the candidiasis develops; it is also used to treat vaginal candidiasis and diaper rash. Largest category of antifungal agents. Azoles block ergosterol synthesis by binding CYP-450 and have fungistatic or slow fungicidal activity. Imidazoles: Ketoconazole, Miconazole, and Clotrimazole (oral or topical). The topical imidazoles are used to treat superficial mycoses, including the dermatophytoses and vaginal and oropharyngeal candidiasis. Triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole (oral and intravenous). Triazoles are the most commonly prescribed antifungals. The triazoles are each used for more specific mycoses, as follows: Fluconazole is used to treat systemic candidiasis (except when caused by Candida krusei), cryptococcosis, and coccidioidomycosis (note that these are all yeasts). Itraconazole is used to treat histoplasmosis, blastomycosis, aspergillosis, fluconazole-resistant candidiasis, and, dermatophytoses, especially of the nail. Voriconazole is used to treat invasive aspergillosis, as well as strains of Candida that are resistant to fluconazole (ex: Candida glabrata). Posacanazole is used to treat aspergillosis, candidiasis, cryptococcosis, mucormycosis, and others. Isavuconazole is used to treat invasive candidiasis, aspergillosis, cryptococcosis, and mucormycosis. Side Effects/Comments: Azoles can impair the metabolism of other CYP-450 drugs, and hepatic toxicity is possible. Azoles are associated with QT prolongation; an important exception is isavuconazole, which shortens the QT interval. Be aware that these drugs are contraindicated during pregnancy. Ketoconazole is associated with gastrointestinal effects and reduced testosterone levels; be aware that this can lead to gynecomastia and impotence in men. Fluconazole has relatively low toxicity, and is distributed to all body systems, which is why it is used to treat cryptococcal meningitis. Itraconazole is known for its erratic absorption from the intestinal tract. – Patients who use the capsule formulation should take the drug with acids, such as orange juice. – Patients who use the solution formulation should take it on an empty stomach. Voriconazole is associated with transient vision disturbances in approximately 30% of patients, as well as hallucinations and rash or peripheral edema. Posaconazole should be taken with a fatty meal, and is known to cause gastrointestinal upset. Isavuconazole is associated with a shortened QT interval and with hypersensitivity reactions. These drugs block ergosterol synthesis by inhibiting squalene epoxidase. Naftifine is administered topically. Terbinafine can be administered orally or topically. They treat dermatophytoses, aspergillosis, and chromoblastomycosis. Side effects are rare with this group. These drugs block glucan synthesis via inhibition of beta 1,3 D-glucan synthesis, thus disrupting the cell wall. The "fungins": caspofungin, anidulafungin, and micafungin. All are administered intravenously. The three Echinocandins are generally interchangeable. Treat invasive candidiasis and candidemia because they are fungicidal to candida species. May be used to treat some cases of aspergillosis, in which case they are fungistatic. These drugs distribute to all body systems, however, concentration is lower in CSF, so these drugs are not generally recommended to treat meningoencephalitis. Side effects: – Generally well-tolerated; few drug-drug interactions. – Infusion reactions can occur, and antihistamines are recommended. – May elevate liver enzymes. Blocks DNA and protein synthesis. Flucytosine is administered orally. Resistance to flucytosine develops rapidly, which limits its use as a monotherapy. Can be combined with amphotericin B for treatment of cryptococcosis (both pulmonary and CNS infections) and candidiasis. Side effects: – Bone marrow suppression, which can lead to cytopenia – Liver toxicity – Gastrointestinal upset and rash are also reported Inhibits fungal cell mitosis by disrupting spindle formation; thus, it is fungistatic. Administered orally. Dermatophytoses, especially ringworm of the scalp and nails, which are difficult to treat topically. Side effects: – Include hypersensitivity reactions, such as rashes or hives. – Hepatic toxicity or neurological effects are reported, but rarely. – May reduce the efficacy of oral contraceptives.