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Editor,—Voriconazole is a new, highly potent, triazole with broad spectrum activity against fungi, including moulds as well as fluconazole resistant Candidaspp.1 Like other azole antifungal agents it interferes with ergosterole biosynthesis. Its antifungal activity has been shown in several experimental as well as clinical studies.2-5
In November 1998, a 16 year old girl was transferred to the university eye hospital in Duesseldorf with a severe ulcerative hypopyon keratitis in the left eye, from which she had been suffering for 3 months after swimming in a lake in Italy. Smears, scrapings, and serology gave no hint of the aetiology. Despite intensive topical antibacterial, anti-acanthamoebal, antifungal, and antiherpetic therapy, as well as cryoapplication, her clinical situation had deteriorated continuously before admission to our hospital. As an optical rehabilitation was unlikely, owing to the severely infiltrated cornea, a perforating keratoplasty was performed. Postoperatively, the patient was given systemic as well as topical antibiotics. The first 3 days postoperatively were inconspicuous, but from the sixth day on a hypopyon could again be seen. The hypopyon progressed and we could identify, by ultrasound biomicroscopy the focus at the remaining recipient cornea. We removed this focus which was highly suspected of being a fungal colony and sent it to the microbiology department (an attempt to culture bacteria or fungi failed). Antifungal therapy with systemic fluconazole (200 mg/day intravenously) and topical amphotericin B (0.3% every hour) were started, but the clinical picture still deteriorated. At that time a filamentous fungus was diagnosed histopathologically in the excised corneal button (Fig 1). Because of the morphological similarities betweenAspergillus,Fusarium, andPseudallescheria boydii on histology these potent causes of keratitis could not be differentiated by this technique alone. Immunohistochemical examination of mycelia containing tissue sections with a panel of specific antifungal antibodies, all Grocott methenamine silver positive hyphae were identified asFusarium species because a strong and uniform reactivity was obtained only with a heterologously absorbed polyclonal antibody raised towards somatic antigens ofFusarium solani.6
As the antifungal therapy had no effect whatsoever, the regimen was changed to systemic itraconazole (Sempera) 200 mg twice daily (a triazole which is known to be effective against some amphotericin B resistant mould species) for 3 days again with no clinical effect.
Owing to the lack of response to conventional therapy, we obtained the new antifungal agent voriconazole, from Pfizer, on an compassionate use basis. Voriconazole was started at a dosage of 6 mg/kg intravenously twice on day 1 followed by 4 mg/kg intravenously twice daily. This well tolerated therapy produced a significant clinical improvement. However, after 10 days the disease relapsed (Fig 2). Owing to the initial positive response it was considered that the relapse might be due to suboptimal penetration to the site of infection. Voriconazole therapy was changed to 6 mg/kg by mouth twice daily. Voriconazole was also injected intracamerally, at a dosage of 10 μg/0.1 ml. Topical antifungal therapy was switched from amphotericin B 0.3% every hour to voriconazole 1% every half hour. In addition, any remaining suspicious intraocular material was again excised and the anterior chamber was irrigated with a 3 μg/ml voriconazole solution. After this procedure, healing finally took place, and the patient was released from hospital; voriconazole was discontinued after 8 weeks. The corneal graft remained clear and best corrected vision was 0.9. There were no local or systemic adverse effects during this highly potent therapeutic regimen. A transient elevation of liver enzymes (a known adverse event of azole antimycotic agents) at the end of therapy and after cessation has been attributed to the study drug. Topical administration was well tolerated.
This is the first time that the efficacy of voriconazole in the treatment of ocular invasive fungal infection has been demonstrated. Topical administration has been tolerated well even when injected into the anterior chamber. Its obvious antifungal activity and favourable pharmacological properties, especially the low range of side effects, will make this new drug attractive for future studies on invasive ocular infections.
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