Cornea 19(4): 558–560, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

Recurrent Fungal and

Ming X. Wang, M.D., PhD., David J. Shen, O.D., Judy C. Liu, M.A., Stephen C. Pflugfelder, M.D., Eduardo C. Alfonso, M.D., and Richard K. Forster, M.D.

Purpose. To report a case of recurrent fungal sclerokeratitis and gressive and timely medical and surgical treatment can lead to a endophthalmitis with a very successful outcome due to aggressive very good visual outcome. combined surgical and medical therapy. To discuss the manage- ment of this potentially devastating infection. Methods. A 65- year-old man presented with 6 months of left eye redness and CASE REPORT irritation after injury from organic matter propelled from an air- boat. Initially, he had been treated with foreign body removal, A 65-year-old man from southern Florida presented with 6 antibiotics, and steroids. He was diagnosed with reactive sclero- months of left eye redness and irritation after injury from organic keratitis at presentation and was treated with steroids. However, matter propelled from an airboat. Despite scleral foreign body when he did not improve, cultures were obtained and Acremonium removal, gentamicin, and topical steroids started at the time of species filamentous fungi was identified. Despite treatment with appropriate topical and systemic antifungals, his fungal sclerokera- injury, he experienced recurrent flare-ups. His left eye was his only titis progressed to endophthalmitis. Two therapeutic penetrating functioning eye; he had no light perception in his right eye sec- keratoplasties (PKs) with iridectomy and intraocular amphotericin ondary to and repair in the distant past after B were necessary to eradicate the fungal infection. Results. Visual penetrating trauma. On presentation at Bascom Palmer Eye Insti- acuity was restored to 20/25-3 with correction 9 months after tute (Miami, FL, U.S.A.), visual acuity was 20/30 in the left eye, initial presentation. There was no recurrence of fungal infection with an intraocular pressure of 14 mmHg. Slit-lamp examination after the second therapeutic PK. Conclusion. The possible reasons showed a focal superficial infiltrate of the peripheral and for recurrence of fungal infection are discussed. The role of timely with conjunctival injection at the 4 o’clock position. Keratic and aggressive medical and surgical intervention for fungal sclero- precipitates and rare cells were present in the anterior chamber. keratitis and endophthalmitis in restoring excellent vision is em- There was no epithelial defect and the fundus was normal. Due to phasized. an absence of features suggesting fungal infection, the patient was Key Words: Cornea—Fungal keratitis—Infection—Antibiotic— Penetrating keratoplasty—Trauma—Endophthalmitis—Acremo- diagnosed with reactive sclerokeratitis with possible residual for- nium—Filamentous fungi—Antifungal therapy (fungal pupillary eign body. He was started on 1% prednisolone acetate six times a block). day and his symptoms resolved. Approximately 1 month later, he returned complaining that “the white dot in my left eye is getting bigger.” Visual acuity was 20/30 pinhole. Slit-lamp examination showed a corneal infiltrate at the 4 Reported cases of fungal keratitis have increased in recent years o’clock position with surrounding neovascularization, stromal due to heightened awareness, as well as the increased use of topical edema, and an overlying epithelial defect. The corneal infiltrate steroids.1 Progression of fungal keratitis to exogenous endophthal- was scraped with a surgical blade, cultured on Sabouraud’s agar, mitis, however, is relatively uncommon. Endophthalmitis resulting and eventually identified as the Acremonium species (probable from keratitis generally has a poor visual prognosis.2 We present Acremonium kiliense). The patient was started on 5% topical na- a complicated case of recurrent fungal sclerokeratitis with subse- tamycin every hour, 0.3% ofloxacin two times a day, and 100 mg quent endophthalmitis. This case demonstrates that fungal infec- fluconazole by mouth two times a day. tion remains a diagnostic and therapeutic challenge but that ag- The patient returned 1 month later with a decreased visual acuity of 20/80. Physical examination was notable for a perforated cor- neal ulcer plugged with , a shallow anterior chamber, and a Submitted October 1, 1999. Revision received January 8, 2000. Ac- peaked (Fig. 1). Tissue adhesive failed to seal the perfora- cepted January 15, 2000. tion, and the patient underwent an eccentric corneoscleral kerato- From the Vanderbilt University Medical Center (M.X.W., D.J.S.), De- plasty with iridectomy. Fluconazole levels in an aqueous sample partment of , Nashville, Tennessee; the Vanderbilt School ␮ of Medicine (J.C.L.), Nashville, Tennessee; and the Bascom Palmer Eye obtained at the time of surgery ranged 3.1–7.2 g/mL (therapeutic Institute (S.C.P., E.C.A., R.K.F.), Miami, Florida, U.S.A. peak levels, 1.9–16.8 ␮g/mL). The patient’s postoperative course Sources of support: J.C. Davis Foundation, Fight For Sight, Research to was complicated by a associated with pupillary block Prevent Blindness, Ingram Cancer Center, SDRC of Vanderbilt, NIH . Intraocular pressures were maintained between 17–21 (EY-01621). Address correspondence and reprint requests to Dr. M.X. Wang, De- mmHg after several peripheral iridectomies. Postoperative medi- partment of Ophthalmology, 8010 Medical Center East, Vanderbilt Medi- cations included 100 mg fluconazole by mouth two times a day, cal Center, Nashville, TN 37212, U.S.A. 2% dorzolamide three times a day, 0.5% timolol two times a day,

558 FUNGAL KERATITIS AND ENDOPHTHALMITIS 559

ocular implantation. Visual acuity was 20/25-3 with correc- tion 9 months after initial presentation with no recurrence of in- fection. Currently, he has a best corrected visual acuity of 20/25. Biomicroscopy showed a clear cornea 3.5 years after initial pre- sentation (Fig. 3).

DISCUSSION Early recognition of fungal keratitis is important, but fungal infection remains a diagnostic challenge. Risk factors for fungal keratitis include diseased , external and surgical trauma, topical antibiotics and steroids, and use.1 Trauma, however, is by far the most common predisposing factor.3 Fungi are not able to traverse intact corneal epithelium and trauma en- ables the penetration of fungal elements into the stroma. A history of trauma, as in our patient, especially with vegetable or organic FIG. 1. Perforated with extruded tissue adhesive. matter, heightens one’s clinical suspicion for fungal keratitis.4 Formulating an optimal antifungal treatment regimen can also 1% apraclonidine three times a day, and 1% atropine two times a be difficult, but there has been substantial progress in recent years. day. Two weeks after the operation he started a treatment of 1% Advances in medical therapy have made management with anti- prednisolone acetate four times a day. He was switched to 200 mg fungal agents the preferred initial approach. Medical treatment of itraconazole by mouth once a day after 1 month for better Acre- choice includes 5% topical or 0.15% amphotericin B. monium coverage. General guidelines are to use natamycin for filamentous fungi and The patient returned, 7 weeks after corneal grafting, with a amphotericin B for yeast. Therapy should also include cyclople- decreased visual acuity of 20/300. Slit-lamp examination revealed gics and glaucoma medications as necessary.5 Because topical a white infiltrate along the donor–recipient junction, an endothelial antifungals offer poor penetration, oral systemic agents— plaque, and a (Fig. 2). The patient was diagnosed with especially the azoles—need to be considered.6 Treatment with recurrent fungal keratitis. The prednisolone acetate was stopped systemic antifungal agents is recommended if there is severe kera- and natamycin every hour was restarted. Because of continued titis, , and/or endophthalmitis.7 Several clinical and experi- clinical disease progression, he underwent a second penetrating mental studies have reported good results in the treatment of fun- keratoplasty (PK) with iridectomy and 0.1 mL of 10 ␮g intraocular gal keratitis with systemic ketoconazole, miconazole, and flucona- amphotericin B injection into the anterior chamber. Itraconazole zole. Ketoconazole is the most frequently used oral antifungal.8 was discontinued due to elevated liver enzymes; 100 mg flucona- However, recent studies suggest that fluconazole may have better zole by mouth two times a day was restarted based on adequate penetration into the cornea than some other azoles and have fewer anterior chamber concentrations previously measured. The patient systemic side effects.8–10 was placed on 1% prednisolone acetate two times a day, 0.5% PK should be considered when keratitis continues to progress timolol two times a day, scopolamine two times a day, and poly- with increasing hypopyon, peripheral corneal involvement, or im- myxin B/bacitracin ointment at bedtime. pending or frank perforation.5 PK is an effective way to remove Antifungal treatment was stopped 6 weeks after the second infected cornea as well as immune complex precipitates that pro- therapeutic PK due to no signs of recurrence of infection. Within vide a stimulus for inflammation.6 Signs of improvement include a month of antifungal cessation, the patient developed a visually rounding of feathery margins, decreased size or density of the significant and underwent cataract extraction with intra- infiltrate, and disappearance of satellite lesions.4 If these signs

FIG. 2. Biomicroscopy showing a white ring of infiltrate along the FIG. 3. Biomicroscopy showing a clear cornea 3.5 years after initial donor–recipient junction and an enlarging endothelial plaque. presentation.

Cornea, Vol. 19, No. 4, 2000 560 M.X. WANG ET AL. indicating a lack of progression are not apparent after medical management, prompt consideration of surgical approaches is vi- tal.7 In our patient, the first PK was indicated due to corneal perforation with presumed spread of infection into the anterior chamber. The second PK was indicated due to disease progression as evidenced by a growing hypopyon and an endothelial plaque. The desired effect of therapeutic PK is to remove all infected tissue leaving a disease-free margin of at least 1 mm and to restore the integrity of the .4,5 Despite attempts to remove all af- fected tissue, a portion of the iris excised from our patient at the time of the second PK showed numerous filamentous fungal ele- ments on the host side of the host-graft junction (Fig. 4). This was believed to be the source for recurrent infection after the first corneal graft. The pathology specimen demonstrated fungal hy- phae penetrating Descemet’s membrane in an orientation perpen- dicular to the corneal lamellae (Fig. 5). These characteristics in- FIG. 5. The fungal hyphae are oriented perpendicular to the corneal dicate increased pathogenicity.5 lamellae and have penetrated Descemet’s membrane. (Arrowheads The role of steroids in the management of our patient is instruc- indicate Descemet’s membrane.) tive. Use of topical steroids at the time of trauma and at initial mies and glaucoma medications were successful in maintaining presentation at the Bascom Palmer Eye Institute may have inad- normal intraocular pressures in our patient. vertently potentiated fungal growth by suppressing host de- In conclusion, fungal keratitis is a serious complication of fenses.11 There may be a place for corticosteroids in postoperative trauma. The Acremonium species identified in our patient, inter- management, however.7 Corticosteroids are currently the treat- estingly, is not a common cause of fungal keratitis. Fusarium and ment of choice for prevention of corneal graft rejection. In cases Candida species are the most common.3 However, Acremonium is complicated by mycotic keratitis, there is concern that immuno- the second most common cause of fungal exogenous endophthal- suppression may enhance infection if surgical removal of diseased mitis after Fusarium.2 Our case report demonstrates that aggres- tissue is incomplete. It is, therefore, recommended that corticoste- sive and timely medical and surgical therapy can lead to a good roids not be used in the early postoperative period.7 visual outcome despite recurrent infection. Other medications for the maintenance of a clear corneal graft, in lieu of corticosteroids, are being investigated. Bell and col- leagues12 have shown that cyclosporin A has an inhibitory effect REFERENCES on fungal growth in vitro. This, in combination with its well- 1. Mabon M. Fungal keratitis. Int Ophthalmol Clin 1998;38:115–23. established role as an immunosuppressant, may make cyclosporin 2. Pflugfelder SC, Flynn HW, Zwickey TA, Forster RK, Tsiligianni A, A an important alternative to steroids in the future. Culbertson WW, Mandelbaum S. Exogenous fungal endophthalmitis. Finally, it is possible that our patient’s pupillary block was, in Ophthalmology 1988;95:19–30. 3. Rosa RH, Miller D, Alfonso EC. The changing spectrum of fungal fact, a fungal pupillary block. Fungal pupillary block, well- keratitis in south Florida. Ophthalmology 1994;101:1005–13. 13,14 described by Barrie, results when growth of with in- 4. Abad JC, Foster CS. Fungal keratitis. Int Ophthalmol Clin 1996;36: flammatory exudation accumulates around the lens, secludes the 1–15. posterior chamber, and binds the iris to the lens. 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Treatment of presumed fungal endophthalmitis with oral fluconazole. Ophthalmic Surg Lasers 1996;27:628–31. 11. O’Day DM. Fungal keratitis. In: Leibowitz HM, Waring III GO, eds. Corneal disorders: clinical diagnosis and management. Philadelphia: W.B. Saunders Company, 1998:711–8. 12. Bell NP, Karp CL, Alfonso EC, Schiffman J, Miller D. Effects of methylprednisolone and cyclosporin A on fungal growth in vitro. Cor- nea 1999;18:306–13. 13. Jones BR. Principles in the management of oculomycosis. Am J Oph- thalmol 1975;79:719–51. FIG. 4. Histological specimen from the second therapeutic PK show- 14. Okhravi N, Dart JK, Towler HM, Lightman S. Paecilomyces lilacinus ing fungal hyphae on the host side of the host-graft junction. (Arrow- endophthalmitis with secondary keratitis. Arch Ophthalmol 1997;115: head indicates the host side of the host-graft junction.) 1320–4.

Cornea, Vol. 19, No. 4, 2000