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86 EW CORNEA October 2012 Voriconazole as salvage or primary therapy? EyeWorld speaks to a microbiologist about the treatment Editors' note: This article discusses the off-label use of voriconazole. F ungal corneal ulcers can be difficult to treat for a vari- ety of reasons, and fungal keratitis ranks among the most difficult. However, a new study1 suggests that topical and systemic voriconazole may be effec- tive as a single agent or in combina- tion with other agents for the treatment of severe Fusarium keratitis or endophthalmitis. Voriconazole is a triazole antifungal used for the treatment of "serious fungal infections" including lung and esophageal infections. Topically, the drug has been used to treat keratitis and ophthalmitis off-label since 2000,2 with some sub- sequent evidence for both efficacy3 and safety in animals4 ; it is generally well tolerated after either intracameral injection or topical instillation of the appropriately diluted intravenous formulation. Fungi of the genus Fusarium are one of the most frequent causes of keratitis, and second generation triazoles have shown more promise in treating these infections than earlier iterations. More commonly prescribed antifungals, including natamycin and fluconazole, report- edly have more limited clinical efficacy against filamentous infec- tions or poor topical penetration. However, because voriconazole has caused visual disturbances after sys- temic administration, its advantages compared to other therapies may not be so clear-cut.1 EyeWorld spoke to one of the compound's developers, Peter Troke, Ph.D., about why this antifungal could be considered as a potential oral and topical treatment in recalci- trant fungal cases. First, "voriconazole has been used for treating patients with keratitis and endophthalmitis since 2000, but has only recently been tested in small clinical trials of keratitis," Dr. Troke and colleagues wrote.1 "Topical therapies for simple (non-penetrating) keratitis are well established (amphotericin, natamycin) with safety and tolera- tion well known and largely man- ageable. They are also cheap and effective and have been used for many years. Experience with voriconazole is relatively limited by comparison. Some studies have sug- gested topical voriconazole alone is no better than topical natamycin alone for treating fungal corneal ulcers," Dr. Troke told EyeWorld. The topical 1% formulation of voricona- zole is an off-label preparation of the appropriately diluted, intravenous formulation, but the oral tablet for- mulation (on-label) has been used successfully in conjunction with other topical antifungal agents to treat both fungal keratitis and endopthalmitis.5 In Dr. Troke's retrospective analysis, the patients came from two sources; one was a database set who were treated before 2002 with topi- cal and/or systemic voriconazole as salvage therapy during the drug's development; the others were treated between 2004 and 2008 in various French hospitals. "Time and experience obviously impact a physician's readiness to use topical voriconazole even where the cost of the intravenous formulation is not an issue," he said. The major- ity of cases—15 of 23—were keratitis patients (the remainder were endophthalmitis), and consisted of both primary and salvage therapy cases. Voriconazole was adminis- tered systemically, topically, and/ or by intraocular injection. "Salvage cases had received between 6 and 78 days of prior therapy," Dr. Troke said. The overall response rate was 67%, higher in the keratitis group (73%) than in the endophthalmitis group (56%). "However, the response rate was 63% for eight primary therapy patients and 69% for 16 salvage therapy patients," he said. For the primary therapy cases, Dr. Troke noted the voriconazole therapy lasted from 7 to 213 days, with two failures (one unknown, one after 7 days of voriconazole use). "The duration of prior therapy (as a surrogate for duration of infec- tion) in the salvage cases is not as well documented," he said. "Six keratitis patients received topical amphotericin, but its duration is unknown," he said. Two other cases also received systemic itraconazole, caspofungin, and/or flucytosine, and the duration of prior therapy for those treatments was between 6 and 78 days. "Voriconazole represents a potential therapy for keratitis or endophthalmitis, especially those due to Fusarium (but also Candida endophthalmitis),6 infections, they are not easy to spe- ciate and some species contain a lot of resistant isolates—including to voriconazole," Dr. Troke said. EW References " Dr. Troke said. "Other fungal infections of the eye also respond, at least based on the increasing number of published case studies and series." He did suggest the findings needed to be corrobo- rated in prospective clinical trials with "well defined" topical and systemic doses and endpoints. "Fusarium infections remains problematic; as there are a number of species capable of causing ocular 1. Troke P, Obenga G, Gaujoux T, et al. The efficacy of voriconazole in 24 ocular Fusarium infections. Infection. Published online 21 June 2012. 2. Reis A, Sundmacher R, Tintelnot K, Agostini H, Jensen HE, Althaus C. Successful treatment of ocular invasive mould infection (fusariosis) with the new antifungal agent voriconazole. Br. J. Ophthalmol. 2000 Aug;84(8):932-3. 3. Sponsel W, Chen N, Dang D, et al. Topical Voriconazole as a Novel Treatment for Fungal Keratitis. Antimicrob Agents Chemother. 2006 January; 50(1): 262–268. 4. Gao H, Pennesi M, Shah K, Qiao X, Hariprasad SM, Mieler WF, Wu SM, Holz ER. Safety of intravitreal voriconazole: electroretinographic and histopathologic studies. Trans Am Ophthalmol Soc. 2003;101:183-9. 5. Hariprasad SM, Mieler WF, Lin TK, et al. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. 2008;92:871-8. 6. Oude Lashof AM, Rothova A, Sobel JD, Ruhnke M, Pappas PG, Viscoli C, Schlamm HT, Oborska IT, Rex JH, Kullberg BJ. Ocular mani- festations of candidemia. Clin Infect Dis. 2011 Aug 1;53(3):262-8. Editors' note: Dr. Troke was previously an employee of, and then a consultant to, Pfizer (New York). He is currently a consultant to industry. Contact information Troke: peter2troke@btinternet.com