A case of Aspergillus flavus keratitis was successfully treated with oral voriconazole and penetrating keratoplasty after conventional antifungal medical therapy failure.O presente trabalho descreve o emprego do voriconazol sistêmico como adjuvante no tratamento de ceratite micótica grave por Aspergillus flavus.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaHospital Banco de Olhos de Porto Alegre Setor de Córnea e Doenças ExternasUNIFESP, EPMSciEL

Freda, Roberto

Arquivos Brasileiros de Oftalmologia

Freda, Roberto [UNIFESP]

Repositório Institucional UNIFESP

Arq Bras Oftalmol. 2006;69(3):431-4Uso do voriconazol oral como tratamento adjuvante da infecção fúngica graveda córnea: relato de casoTrabalho realizado no curso de Especialização em Oftal-mologia do Hospital Banco de Olhos de Porto Alegre.*Mestre em Oftalmologia pela Escola Paulista de Medici-na, Universidade Federal de São Paulo - UNIFESP;Preceptor do Setor de Córnea e Doenças Externas doHospital Banco de Olhos de Porto Alegre - PortoAlegre (RS) - Brasil.Endereço para correspondência: Rua Araponga, 194- Porto Alegre (RS) CEP 91330-130Recebido para publicação em 07.04.2005Versão revisada recebida em 02.11.2005Aprovação em 08.01.2006Nota Editorial: Depois de concluída a análise doartigo sob sigilo editorial e com a anuência da Dra.Marta Beatriz Filippi Sartori sobre a divulgação de seunome como revisora, agradecemos sua participação nes-te processo.Roberto Freda*Keywords: Fluconazole/therapeutic use; Eye infections, fungal/drug therapy; keratitis;Antifungal agents/therapeutic use; Case reports [publication type]INTRODUCTIONWe present a case of severe fungal infection of the cornea in whichsystemic oral voriconazole was used as an adjunct therapy after conventio-nal antifungal medical therapy failure. This case report may warrant additio-nal investigation on the role of this anti-fungal agent to treat severe myco-tic corneal infection.CASE REPORTA 40-year-old man presented with history of corneal ulcer treatment inthe left eye in the previous week: Tobradex® (0.3% tobramycin - 3 mg, 0.1%dexamethasone - 1 mg, and 0.01% benzalkonium chloride preservative) andMaxitrol® (polymyxin B sulfate, neomycin sulfate, and 0.1% dexamethasone- 1 mg) drops. This regimen was ineffective and the patient was referred toa second opinion.At presentation, visual acuity was normal (20/20) in the right eye and20/200 in the left eye. There was slight lid edema and moderate conjunctivaland pericorneal injection. A corneal epithelial defect measuring 2 x 2 mmwith an infiltrate (abscess) was observed, surrounded by a small amount ofstromal edema, with a small amount of mucopurulent material covering thebase of the ulcer and at the inferior fornix. The ulcer had a deep centralulceration and the abscess with indistinct margins involving the paracen-tral corneal zone. There was anterior chamber reaction (1+/4+) and a discre-te hypopyon of 0.5 mm in height. Lens and fundus examinations werenormal (Figure 1).The patient denied any trauma, systemic disease or use of contact lens.Specimens were collected by scraping the margin of the abscess and bed ofthe corneal ulcer, which were submitted to bacteriological and mycologicalanalysis. Scrapings were inoculated onto blood agar, brain heart infusion(BHI) and Sabouraud agar. Gram stain showed gram-positive cocci. Furtherresults did not identify any culture growth.Use of oral voriconazole as adjunctive treatment ofsevere cornea fungal infection: case reportA case of Aspergillus flavus keratitis was successfully treated with oralvoriconazole and penetrating keratoplasty after conventional antifungalmedical therapy failure.ABSTRACTRELATOS DE CASOS69(3)23.p65 12/6/2006, 16:26431Arq Bras Oftalmol. 2006;69(3):431-4432 Use of oral voriconazole as adjunctive treatment of severe cornea fungal infection: case reportAs suggested by the gram stain, the patient was treatedinitially with fortified antibiotics (50 mg/ml cefazolin and 1 mg/mlamicacin) and fourth generation fluoroquinolone (gatifloxa-cin) hourly. Dilating drops (1% ciclopentolate) every eighthours were also instituted. The patient was examined everyday. As time went by, the corneal condition seemed to impro-ve slightly and treatment with 1% dexametasone twice daily todecrease the inflammation of the eye. However, by day 12 oftreatment (5 days on corticosteroid), the infiltrate seemed tobe growing in extension and some adjacent whitish lesions(satellite lesions) were observed which led to the suspicion offungal infection (Figure 2).Corticosteroid treatment was discontinued immediatelyand the patient started on 0.15% amphotericin B and 5% nata-micin drops hourly and oral ketoconazole (200 mg twice daily).It is worth noting that at that time, laboratory results had notyielded any culture growth and the treatment was based onthe history told by the patient (abrupt onset of symptoms),clinical aspects (compatible with bacterial ulcer) and the gramstain (also compatible with bacterial infection). Despite thisregimen of treatment, the aspect of the cornea had not impro-ved and it was actually enlarged (Figure 3).As the cornea worsened, another scraping was performedfor further analysis. At the same time, a corneal biopsy wasalso performed. The laboratory results revealed filamentousfungal infection (Aspergillus flavus). In three days, infiltra-tion of the cornea and the hypopyon had greatly increased.Intracameral amphotericin B (10 micrograms) was employedtwice. It has been shown that intracameral amphotericin Bdoes not cause corneal or lenticular toxicity and it has beenused with success in anecdotal cases of Aspergillus flavuskeratitis(1). Despite this procedure, the infiltrate extended tothe limbus and the cornea started to melt (Figure 4).Oral voriconazole was initiated (200 mg p.o. daily). In faceof an impending perforation, cornea transplantation was per-formed (Figures 5 and 6). Although the cornea the Eye Bankreleased was meant to be for a tectonic transplantation, thegraft remained clear and with no signs of either infection orrejection, more that 2 months after the corneal transplantation.Initially, the patient was kept on topical cyclosporine twicedaily (Restasis®), due to the fact that corticosteroids were keptuntil there were no signs of fungal relapse.As time passed and there was no sign of fungal infectionremission, low-dose corticosteroid was initiated to minimizeeye inflammation. Alrex® twice daily was started (for 1 week)then switched to Loteprol® twice daily (for 1 week). After therewas confidence that there was no infection, Minidex® twicedaily was initiated (for 1 week) and then switched to Maxidex®Figure 1 - A 2x2 mm corneal epithelial defect with abscess and astromal edema, mucopurulent material covering the base of the ulcer.The ulcer had a deep central ulceration and the abscess showedindistinct margins involving the paracentral corneal zone. There wasanterior chamber reaction and a discrete hypopyon of 0.5 mm in height.Figure 2 - After five days on corticosteroid, the infiltrate extensionincreased and some adjacent whitish lesions (satellite lesions) thatraised the suspicion of fungal infection were observedFigure 3 - Despite the treatment, the aspect of the cornea had not im-proved and the ulcer had enlarged69(3)23.p65 12/6/2006, 16:26432Arq Bras Oftalmol. 2006;69(3):431-4Use of oral voriconazole as adjunctive treatment of severe cornea fungal infection: case report  433twice a day. The patient has been kept on this regimen for 2weeks and cyclosporine has been discontinued.On the last visit, three months after the corneal transplan-tation, the graft remained clear and the best corrected visualacuity with contact lenses was 20/30, though we do not yetintend to fit them. We expect to start fitting contact lens afterat least 12 months of clear graft.DISCUSSIONFungal corneal infection is a vision-threatening conditionthat may present in a challenging way. It has been demonstra-ted that the use of topical corticosteroid may predispose tothe onset and the worsening of the fungal infection of the eye.Despite aggressive treatment, the here described patient, wasirresponsive to the medical therapy.Filamentous fungi are more common in patients with ahistory of trauma of the eye, especially with vegetal material.More rarely, Aspergillus flavus may cause severe infection ofthe cornea after laser in situ keratomileusis(2). It has beenshown that intracameral amphotericin B does not cause cor-neal or lenticular toxicity and has been used with success inanecdotal cases of Aspergillus flavus keratitis(1). On the otherhand, patients with previous use of corticosteroid are moreprone to Candida-like infections.The drugs available to treat infections of the eye withfungi are limited. Moreover, their penetration into the eye islimited. The case of a fungal corneal infection treated with anew antifungal agent (voriconazole) with very good result isreported in this article.Searching the medical literature, a paper reporting the use oforal voriconazole with great success was found, though in thiscase it was not a keratomycosis caused by Aspergillus flavus(3).A study by Hariprasad(4) demonstrated that orally admi-nistered voriconazole reaches therapeutic aqueous and vi-treous levels in the noninflamed human eye and that theactivity spectrum appears appropriately to encompass themost frequent encountered mycotic species involved in thevarious causes of fungal eye infection.We considered that oral voriconazole might be importantin attempting to prevent further spread of the fungus to theinterior of the eye, since the transplantation of the corneaalone would not have been sufficient to keep the fungus in theanterior portion of the eye, because the periphery of the cor-nea was already compromised and Descemet’s membrane hadbeen breached.Some papers demonstrated in the aqueous a concentrationmore than 50% than that in plasma and almost seven timeshigher than the MIC for Scedosporium apiospermum strain.Hua et at(5) demonstrated that intravitreal voriconazole of upto 25 microgram/ml causes no ERG change or histologicabnormality in rat retina. This may indicate that voriconazoleFigure 4 - The infiltrate extended to the limbus and the cornea startedto meltFigure 6 - In face of an impending perforation, a cornea transplantationwas performedFigure 5 - Cornea with an impending perforation69(3)23.p65 12/6/2006, 16:26433Arq Bras Oftalmol. 2006;69(3):431-4434 Use of oral voriconazole as adjunctive treatment of severe cornea fungal infection: case reportis a safe antifungal agent that may be employed by intravitrealinjection in the treatment of fungal infections of the eye.We could not find any study on the topical concentrationof cyclosporine used in this case (0.05%), although higherdoses have shown to be of some clinical effectiveness(6).CONCLUSIONSThis case report shows that severe fungal eye infectionsmay benefit from the use of adjunct systemic voriconazole.Further studies on animal models may determine the appro-priate timing and dose of this promising drug.RESUMOO presente trabalho descreve o emprego do voriconazol sistê-mico como adjuvante no tratamento de ceratite micótica gravepor Aspergillus flavus.Descritores: Fluconazol/uso terapêutico; Infecções ocularesfúngicas/quimioterapia; Ceratite; Antimicóticos/uso terapêu-tico; Relatos de casos [tipo de publicação]REFERENCES1. Kaushik S, Ram J, Brar GS, Jain AK, Chakraborti A, Gupta A. Intracameralamphotericin B: initial experience in severe keratomycosis. Cornea. 2001;20(7):715-9.2. Sridhar MS, Garg P, Bansal AK, Gopinathan U. Aspergillus flavus keratitisafter laser in situ keratomileusis. Am J Ophthalmol. 2000;129(6):802-4.3. Nulens E, Eggink C, Rijs AJ, Wesseling P, Verweij PE. Keratitis caused byScedosporium apiospermum successfully treated with a cornea transplant andvoriconazole. J Clin Microbiol. 2003;41(5):2261-4.4. Hariprasad SM, Mieler WF, Holz ER, Gao H, Kim JE, Chi J, Prince RA.Determination of vitreous, aqueous, and plasma concentration of orally admi-nistered voriconazole in humans. Arch Ophthalmol. 2004;122(1):42-7.5. Hua G, Pennesi M, Shah K, Qiao X, Hariprasad SM, Mieler WF, et al.Safety of intravitreal voriconazole: electroretinographic and histopathologicstudies. Trans Am Ophthalmol Soc. 2003;101:183-9; discussion 189.6. Bell NP, Karp CL, Alfonso EC, Schiffman J, Miller D. Effects of methylpred-nisolone and cyclosporine A on fungal growth in vitro. Cornea. 1999;18(3):306-13.9º Congresso de Oftalmologia e8º Congresso de Auxiliar da USP24 a 26 de Outubro de 2006Centro de Convenções RebouçasSão Paulo - SPINFORMAÇÕES: Tel.: (11) 5575-0254 - Fax: (11) 5539-2186E-mail: info@congressousp.com.brHome page: www.congressousp.com.br69(3)23.p65 12/6/2006, 16:26434

Uso do voriconazol oral como tratamento adjuvante da infecção fúngica grave da córnea: relato de caso

O presente trabalho descreve o emprego do voriconazol sistêmico como adjuvante no tratamento de ceratite micótica grave por Aspergillus flavus.A case of Aspergillus flavus keratitis was successfully treated with oral voriconazole and penetrating keratoplasty after conventional antifungal medical therapy failure.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaHospital Banco de Olhos de Porto Alegre Setor de Córnea e Doenças ExternasUNIFESP, EPMSciEL

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

http://dx.doi.org/10.1590/S0004-27492006000300028

Uso do voriconazol oral como tratamento adjuvante da infecção fúngica grave da córnea: relato de caso

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