Table 16-23 summarizes common antifungal drugs encountered in ophthalmology practice.
The polyene antibiotics are named for a component sequence of 4–7 conjugated double bonds. That lipophilic region allows these antibiotics to bind to sterols in the cell membrane of susceptible fungi, an interaction that results in damage to the membrane and leakage of essential nutrients. Other antifungals (such as flucytosine and the imidazoles) and even other antibiotics (such as tetracycline and rifampin) can enter through the damaged membrane, yielding synergistic effects.
Natamycin and amphotericin B are 2 examples of polyene macrolide antibiotics. Natamycin is available as a 5% suspension for topical ophthalmic use (once per hour). Local hypersensitivity reactions of the conjunctiva and eyelid and/or corneal epithelial toxicity may occur. Amphotericin B may be reconstituted at 0.25%–0.5% in sterile water (with deoxycholate to improve solubility) for topical use (every 30 minutes). It may also be administered systemically for disseminated disease, although careful monitoring for renal and other toxicities is required. Both drugs penetrate the cornea poorly. They have been used topically against various filamentous fungi, including species of Aspergillus, Cephalosporium, Curvularia, Fusarium, and Penicillium, as well as the yeast Candida albicans. Systemic amphotericin B has been reported as useful in treating systemic Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, and Histoplasma infections. Amphotericin can also be administered intravitreally; however, it has been associated with retinal toxicity.
Imidazoles and triazoles
The imidazole- and triazole-derived antifungal drugs also increase fungal cell-membrane permeability and interrupt membrane-bound enzyme systems. These antifungals act against various species of Aspergillus, Coccidioides, Cryptococcus, and Candida, among others. The triazoles have less effect on human sterol synthesis, as well as a longer half-life, than the imidazoles, and they are being more actively developed. The imidazole miconazole is available in a 1% solution that may be injected subconjunctivally (5 mg/0.5 mL, once or twice daily) or applied topically. Miconazole penetrates the cornea poorly.
Ketoconazole is available in 200-mg tablets for oral therapy (once or twice daily). Ketoconazole normally penetrates the blood–brain barrier and, presumably, the blood–ocular barrier poorly, but therapeutic levels can be achieved in inflamed eyes. The triazole itraconazole, with an expanded antifungal spectrum and less systemic toxicity, has largely replaced ketoconazole. However, there is an extensive and growing list of potentially dangerous drug interactions with itraconazole that should be consulted before instituting systemic therapy. Fluconazole, another triazole, has good bioavailability but limited spectrum and may also increase the plasma concentrations of other medications. Oral voriconazole is rapidly replacing other antifungals because of its excellent bioavailability, intraocular penetration, and broad-spectrum coverage.
Table 16-23 Antifungal Drugs
This class of antifungals inhibits a component (glucan) of the fungal cell wall. Caspofungin and micafungin are the 2 most commonly used agents. Their primary activity is against Candida and Aspergillus species, and they are used prophylactically in stem cell recipients and in patients with candidemia, for whom an ophthalmologist is frequently consulted to rule out ocular involvement.
Flucytosine (5-fluorocytosine) is converted by some species of fungal cells to 5-FU by cytosine deaminase and then to 5-fluorodeoxyuridylate. This last compound inhibits thymidylate synthase, an important enzyme in DNA synthesis. Host cells lack cytosine deaminase activity and are less affected. Only fungi that have both a permease to facilitate flucytosine penetration and a cytosine deaminase are sensitive to flucytosine. Flucytosine is taken orally at 50–150 mg/kg daily, divided every 6 hours. Although the drug is well absorbed and penetrates the blood–ocular barrier well, most Aspergillus and half of Candida isolates are resistant to it. Flucytosine is used primarily as an adjunct to systemic amphotericin B therapy.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.