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Candida albicans Endophthalmitis after Penetrating Keratoplasty
Candida albicans Endophthalmitis After Penetrating Keratoplasty Michael S. Insler, M . D . , and Lillian F. Urso, B . S . We examined two patients who received contaminated corneas from the same organ donor during penetrating keratoplasty. Both developed Candida albicans endophthalmitis, which responded to surgical and antifungal therapy. On follow-up examination one patient had a visual acuity of hand motions, a pupillary membrane, and a macular scar. The other had a visual acuity of 20/100 and a clear graft. THE TRANSMISSION of infectious agents by donor tissue is a well-known complication of transplantation. 1 In the last decade an increasing number of cases have been reported in which serious ocular or systemic disease developed in the recipient of a corneal transplant. There have been two confirmed instances of donor-to-host transmission of fungal endophthalmitis. The first case involved Cryptococcus neoformans2 and the second Torulopsis glabrata.3 We report herein two cases of Candida albicans endophthalmitis following penetrating keratoplasty in two patients who received corneal grafts from a single donor. Although there have been reports of Candida infection complicating penetrating keratoplasty, we have found no previous reports of C. albicans being transferred by a corneal transplant.
Case Reports Casel A 78-year-old man with aphakic bullous keratopathy and vitreous touch was first examined Accepted for publication April 24, 1987. From the Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana. Reprint requests to Michael S. Insler, M.D., LSU Eye Center, 2020 Gravier St., Suite B, New Orleans, LA 70112.
in February 1984. The patient underwent penetrating keratoplasty, anterior vitrectomy, and secondary anterior chamber intraocular lens insertion one month later, with no complications. An episode of graft rejection occurred in October, which resulted in progressive stromal edema. When the patient was examined in June 1986 he had a visual acuity of 20/400 in the operated on eye. On June 24, 1986, a regraft was performed. Both the donor rim and the McCarey-Kaufman medium were cultured and were found to contain a few yeast cells identified as C. albicans. The patient was admitted on Aug. 11, 1986, with a purulent discharge, conjunctival injection, and multiple fluffy infiltrates at the graft/ host interface. Visual acuity was reduced to hand motions at 1 foot. The next day the patient underwent penetrating keratoplasty, vitrectomy, removal of the intraocular lens, and irrigation of the anterior chamber with a solution containing 5 |xg of amphotericin B and 100 n-g of gentamicin sulfate. Intraocular smears of the anterior chamber material demonstrated budding yeasts and hyphae suggestive of Candida. Postoperatively the patient was placed on topical amphotericin B and oral and topical flucytosine. After postoperative day 5 the oral flucytosine was discontinued. Subsequent postoperative cultures grew C. albicans biotype 557, which were identified by the Centers for Disease Control as identical to the fungi cultured from the donor cornea. On follow-up examination six months later, the endophthalmitis had completely resolved but the patient had a visual acuity of hand motions, a pupillary membrane, and a macular scar. Case 2 The second patient was a 66-year-old man with pseudophakic bullous keratopathy of the left eye. The patient's ocular history included a cataract extraction with an intraocular lens in
©AMERICAN JOURNAL OF OPHTHALMOLOGY 104:57-60, JULY, 1987
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August 1983. An intraocular lens exchange was performed in July 1984, which resulted in a gradual decrease in visual acuity to 20/400. On June 24, 1986, the patient underwent a penetrating keratoplasty of the left eye without complications.In July the patient began experiencing pain in his left eye and he was noted to have an endothelial plaque at the border of the corneal transplant (Figure). On July 21, 1986, the patient underwent a paracentesis of the left eye involving an aqueous and vitreous tap. Examination of the aqueous and vitreous material at that time demonstrated no fungal elements. However, by postoperative day 2, the anterior chamber fluid cultured demonstrated yeast cells. At that time the diagnosis of C. albicans was made and the patient underwent a repeat penetrating keratoplasty, removal of the intraocular lens, and an anterior vitrectomy of the left eye. The patient also received an intraocular injection of 5 u.g of amphotericin B. The patient's condition improved on 600 mg/day of ketoconazole for one week and topical amphotericin B. The best corrected visual acuity achieved to date is 20/100. The graft has remained clear. The Donor The donor was a 30-year-old man who died suddenly of a brain hemorrhage. The eyes were enucleated three hours and 15 minutes after
Figure (Insler and Urso). Case 2. An endothelial plaque at the border of the graft/host interface within four weeks after penetrating keratoplasty. Cultures of the infiltrate and anterior chamber grew Candida albicans identical to the organisms cultured from the donor rim.
death and rated as good. The donor tissue was stored in McCarey-Kaufman medium for four days and I6V2 hours before transplantation in the first patient and three days and 15V2 hours before transplantion in the second patient.
Discussion Postoperative fungal endophthalmitis may originate from several sources including the operative site, contaminated solutions, 4 culture media, and donor tissues. 1,! In our two patients the source of postoperative infection was the contaminated donor corneal tissue, with identical strains of C. albicans cultured from the donor rim and the patient's eye. Even under normal conditions up to 27% of eyes suitable for corneal transplantation have been found to harbor fungi. 5 In a series by Poole and Insler, 6 several donor rims were found to be contaminated with a Candida species. In the previously reported case of postkeratoplasty cryptococcal endophthalmitis, 2 the donor died of disseminated cryptococcosis. The recipient had a mass in the anterior chamber several months after corneal transplant surgery and responded to systemic flucytosine and amphotericin B with apparent sterilization of the anterior chamber. The organ cultured donor rim in the second previously reported case 3 as well as smears from the anterior chamber and vitreous grew Torulopsis glabrata. The patient was treated with a lengthy course of systemic amphotericin B and flucytosine but with a fatal outcome. The infecting organism, C. albicans, in our patients has been a cause of both endogenous and exogenous endophthalmitis. The donor did not appear to be at any increased risk to harbor fungi and no prophylactic antifungal measures were taken. In a study by Stern and associates, 4 Candida parapsilosis endophthalmitis developed in a large group of cataract patients one to 18 weeks after the use of contaminated intraocular irrigating solutions. All the patients underwent vitrectomy combined with intravitreal amphotericin B, intravenous amphotericin B, and oral flucytosine or ketoconazole therapy. In 13 of 15 patients the intraocular lens was retained. 4 ' Most patients had a syndrome of indolent inflammation with mild symptoms and a fibri-
Vol. 104, No. 1
Candida Endophthalmitis
noid anterior chamber exudate with vitreous opacities. Fungal endophthalmitis often has a poor prognosis, which may be attributed to the frequent delay in diagnosis, limited selection of antifungal agents, poor intraocular penetration, and the toxicity of these agents. 8 Successful treatment requires antifungal agents with a broad spectrum of activity and good penetration. 9 Amphotericin B, which possesses a broad spectrum of antifungal activity, is limited in its use by its poor penetrance into the vitreous after systemic administration and its potential tissue toxicity. However, Peyman 10 has shown the beneficial effects of intravitreal injection of the drug. Flucytosine is another antifungal agent used in the successful treatment of fungal endophthalmitis. Although there is the potential for secondary drug resistance and adverse side effects, when used in combination with amphotericin B, satisfactory results have been reported because of the synergistic effects. Ketoconazole, a recently developed imidazole derivative, has also been shown effective in preventing the development of endophthalmitis. It is relatively nontoxic but may be associated with asymptomatic hepatotoxicity. We agree with Goodman and Stern 7 that vitrectomy and intraocular but not systemic amphotericin B may be the treatment of choice in postoperative Candida endophthalmitis and that oral ketoconazole may also prove useful when combined with intravitreal amphotericin B. Repeat keratoplasty and intraocular lens removal in conjunction with vitrectomy are warranted depending on the degree of inflammation, involvement of the lens, and the amount of corneal infection. However, Weiss and Parker 11 described a case of C. albicans endophthalmitis following penetrating keratoplasty without a positive source of infection that cleared with oral ketoconazole alone. Endophthalmitis is an inflammatory response to infected or injured intraocular tissue. The clinical course of fungal endophthalmitis is often indolent and fluctuating. 12 Characteristically, symptoms are not experienced until several weeks after surgery. As described by Theodore, 13 the earliest symptoms are increased redness, pain, and varying degrees of visual impairment. On examination, aqueous flare and cells are seen and are usually followed by a characteristic hypopyon. At the same time, hazy patches appear in the anterior vitreous,
59
adjacent to the pupillary margin. There is progressive involvement of the anterior vitreous associated with increasing vitreous turbidity, which eventually develops into a fibrinopuruleht exudate. The clinical characteristics of our patients demonstrated the usual delay in the onset of symptoms. The use of frequent corticosteroid eyedrops in the early postoperative period may have contributed to this delay. To help reduce the potential for infection we believe that the donor cornea should be irrigated with balanced salt solution before being transferred to the recipient. Our cases show the importance of a thorough microbiologic evaluation of the donor rim and careful follow-up of patients with positive donor rim contamination. Since many donor rims may be contaminated with fungi as well as bacteria, further research is needed on the proper storage and sterilization of donor corneoscleral material.
ACKNOWLEDGMENT
F. C. Odds, Ph.D., Department of Microbiology, University of Leicester, Leicester, England, identified the Candida species.
References 1. Ghandi, S. S., Lamberts, D. W., and Perry, H. D.: Donor to host transmission of disease via corneal transplantation. Surv. Ophthalmol. 25:306, 1981. 2. Beyt, B. E., and Waltman, S. R.: Cryptococcal endophthalmitis after corneal transplantation. N. Engl. J. Med. 298:825, 1978. 3. Larsen, P. A., Lindstrom, R. L., and Doughman, D. J.: Torulopsis glabrata endophthalmitis after keratoplasty with an organ-cultured cornea. Arch. Ophthalmol. 96:1019, 1978. 4. Stern, W. H., Tamura, E., Jacobs, R. A., Pons, V. G., Stone, R. D., O'Day, D. M., and Irvine, A. R.: Epidemic postsurgical Candida parapsilosis endophthalmitis. Clinical findings and management of 15 consecutive cases. Ophthalmology 92:1701, 1985. 5. White, J. H.: Fungal contamination of donor eyes. Br. J. Ophthalmol. 53:30, 1969. 6. Poole, T. G., and Insler, M. S.: Contamination of donor cornea by gentamicin-resistant organisms. Am. J. Ophthalmol. 97:560, 1984. 7. Goodman, D. F., and Stern, W. H.: Oral ketoconazole and intraocular amphotericin B for
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treatment of postoperative Candida parapsilosis endophthalmitis. Arch. Ophthalmol. 105:172, 1987. 8. Jones, D. B.: Therapy of postsurgical fungal endophthalmitis. Symposium. Postoperative endophthalmitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 85:357, 1978. 9. Theodore, F. H., Littman, M. } . , and Almeda, E.: Diagnosis and management of fungus endophthalmitis following cataract extraction. Arch. Ophthalmol. 66:39, 1961. 10. Peyman, G. A., and Sanders, D. R.: Advances in Uveal Surgery, Vitreous Surgery and Treatment of
July, 1987
Endophthalmitis. New York, Appleton-CenturyCrofts, 1975, p. 207. 11. Weiss, J. L., and Parker, W. T.: Candida albicans endophthalmitis following penetrating keratoplasty. Arch. Ophthalmol. 105:173, 1987. 12. Forster, R. K.: Endophthalmitis. In Duane, T. F. (ed.): Clinical Ophthalmology. Philadelphia, Harper & Row, 1984, vol. 4, p. 4. 13. Theodore, F. H.: Etiology and diagnosis of fungal postoperative endophthalmitis. Symposium. Postoperative endophthalmitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 85:327, 1978.
Case Reports Casel A 78-year-old man with aphakic bullous keratopathy and vitreous touch was first examined Accepted for publication April 24, 1987. From the Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana. Reprint requests to Michael S. Insler, M.D., LSU Eye Center, 2020 Gravier St., Suite B, New Orleans, LA 70112.
in February 1984. The patient underwent penetrating keratoplasty, anterior vitrectomy, and secondary anterior chamber intraocular lens insertion one month later, with no complications. An episode of graft rejection occurred in October, which resulted in progressive stromal edema. When the patient was examined in June 1986 he had a visual acuity of 20/400 in the operated on eye. On June 24, 1986, a regraft was performed. Both the donor rim and the McCarey-Kaufman medium were cultured and were found to contain a few yeast cells identified as C. albicans. The patient was admitted on Aug. 11, 1986, with a purulent discharge, conjunctival injection, and multiple fluffy infiltrates at the graft/ host interface. Visual acuity was reduced to hand motions at 1 foot. The next day the patient underwent penetrating keratoplasty, vitrectomy, removal of the intraocular lens, and irrigation of the anterior chamber with a solution containing 5 |xg of amphotericin B and 100 n-g of gentamicin sulfate. Intraocular smears of the anterior chamber material demonstrated budding yeasts and hyphae suggestive of Candida. Postoperatively the patient was placed on topical amphotericin B and oral and topical flucytosine. After postoperative day 5 the oral flucytosine was discontinued. Subsequent postoperative cultures grew C. albicans biotype 557, which were identified by the Centers for Disease Control as identical to the fungi cultured from the donor cornea. On follow-up examination six months later, the endophthalmitis had completely resolved but the patient had a visual acuity of hand motions, a pupillary membrane, and a macular scar. Case 2 The second patient was a 66-year-old man with pseudophakic bullous keratopathy of the left eye. The patient's ocular history included a cataract extraction with an intraocular lens in
©AMERICAN JOURNAL OF OPHTHALMOLOGY 104:57-60, JULY, 1987
57
58
July, 1987
AMERICAN JOURNAL OF OPHTHALMOLOGY
August 1983. An intraocular lens exchange was performed in July 1984, which resulted in a gradual decrease in visual acuity to 20/400. On June 24, 1986, the patient underwent a penetrating keratoplasty of the left eye without complications.In July the patient began experiencing pain in his left eye and he was noted to have an endothelial plaque at the border of the corneal transplant (Figure). On July 21, 1986, the patient underwent a paracentesis of the left eye involving an aqueous and vitreous tap. Examination of the aqueous and vitreous material at that time demonstrated no fungal elements. However, by postoperative day 2, the anterior chamber fluid cultured demonstrated yeast cells. At that time the diagnosis of C. albicans was made and the patient underwent a repeat penetrating keratoplasty, removal of the intraocular lens, and an anterior vitrectomy of the left eye. The patient also received an intraocular injection of 5 u.g of amphotericin B. The patient's condition improved on 600 mg/day of ketoconazole for one week and topical amphotericin B. The best corrected visual acuity achieved to date is 20/100. The graft has remained clear. The Donor The donor was a 30-year-old man who died suddenly of a brain hemorrhage. The eyes were enucleated three hours and 15 minutes after
Figure (Insler and Urso). Case 2. An endothelial plaque at the border of the graft/host interface within four weeks after penetrating keratoplasty. Cultures of the infiltrate and anterior chamber grew Candida albicans identical to the organisms cultured from the donor rim.
death and rated as good. The donor tissue was stored in McCarey-Kaufman medium for four days and I6V2 hours before transplantation in the first patient and three days and 15V2 hours before transplantion in the second patient.
Discussion Postoperative fungal endophthalmitis may originate from several sources including the operative site, contaminated solutions, 4 culture media, and donor tissues. 1,! In our two patients the source of postoperative infection was the contaminated donor corneal tissue, with identical strains of C. albicans cultured from the donor rim and the patient's eye. Even under normal conditions up to 27% of eyes suitable for corneal transplantation have been found to harbor fungi. 5 In a series by Poole and Insler, 6 several donor rims were found to be contaminated with a Candida species. In the previously reported case of postkeratoplasty cryptococcal endophthalmitis, 2 the donor died of disseminated cryptococcosis. The recipient had a mass in the anterior chamber several months after corneal transplant surgery and responded to systemic flucytosine and amphotericin B with apparent sterilization of the anterior chamber. The organ cultured donor rim in the second previously reported case 3 as well as smears from the anterior chamber and vitreous grew Torulopsis glabrata. The patient was treated with a lengthy course of systemic amphotericin B and flucytosine but with a fatal outcome. The infecting organism, C. albicans, in our patients has been a cause of both endogenous and exogenous endophthalmitis. The donor did not appear to be at any increased risk to harbor fungi and no prophylactic antifungal measures were taken. In a study by Stern and associates, 4 Candida parapsilosis endophthalmitis developed in a large group of cataract patients one to 18 weeks after the use of contaminated intraocular irrigating solutions. All the patients underwent vitrectomy combined with intravitreal amphotericin B, intravenous amphotericin B, and oral flucytosine or ketoconazole therapy. In 13 of 15 patients the intraocular lens was retained. 4 ' Most patients had a syndrome of indolent inflammation with mild symptoms and a fibri-
Vol. 104, No. 1
Candida Endophthalmitis
noid anterior chamber exudate with vitreous opacities. Fungal endophthalmitis often has a poor prognosis, which may be attributed to the frequent delay in diagnosis, limited selection of antifungal agents, poor intraocular penetration, and the toxicity of these agents. 8 Successful treatment requires antifungal agents with a broad spectrum of activity and good penetration. 9 Amphotericin B, which possesses a broad spectrum of antifungal activity, is limited in its use by its poor penetrance into the vitreous after systemic administration and its potential tissue toxicity. However, Peyman 10 has shown the beneficial effects of intravitreal injection of the drug. Flucytosine is another antifungal agent used in the successful treatment of fungal endophthalmitis. Although there is the potential for secondary drug resistance and adverse side effects, when used in combination with amphotericin B, satisfactory results have been reported because of the synergistic effects. Ketoconazole, a recently developed imidazole derivative, has also been shown effective in preventing the development of endophthalmitis. It is relatively nontoxic but may be associated with asymptomatic hepatotoxicity. We agree with Goodman and Stern 7 that vitrectomy and intraocular but not systemic amphotericin B may be the treatment of choice in postoperative Candida endophthalmitis and that oral ketoconazole may also prove useful when combined with intravitreal amphotericin B. Repeat keratoplasty and intraocular lens removal in conjunction with vitrectomy are warranted depending on the degree of inflammation, involvement of the lens, and the amount of corneal infection. However, Weiss and Parker 11 described a case of C. albicans endophthalmitis following penetrating keratoplasty without a positive source of infection that cleared with oral ketoconazole alone. Endophthalmitis is an inflammatory response to infected or injured intraocular tissue. The clinical course of fungal endophthalmitis is often indolent and fluctuating. 12 Characteristically, symptoms are not experienced until several weeks after surgery. As described by Theodore, 13 the earliest symptoms are increased redness, pain, and varying degrees of visual impairment. On examination, aqueous flare and cells are seen and are usually followed by a characteristic hypopyon. At the same time, hazy patches appear in the anterior vitreous,
59
adjacent to the pupillary margin. There is progressive involvement of the anterior vitreous associated with increasing vitreous turbidity, which eventually develops into a fibrinopuruleht exudate. The clinical characteristics of our patients demonstrated the usual delay in the onset of symptoms. The use of frequent corticosteroid eyedrops in the early postoperative period may have contributed to this delay. To help reduce the potential for infection we believe that the donor cornea should be irrigated with balanced salt solution before being transferred to the recipient. Our cases show the importance of a thorough microbiologic evaluation of the donor rim and careful follow-up of patients with positive donor rim contamination. Since many donor rims may be contaminated with fungi as well as bacteria, further research is needed on the proper storage and sterilization of donor corneoscleral material.
ACKNOWLEDGMENT
F. C. Odds, Ph.D., Department of Microbiology, University of Leicester, Leicester, England, identified the Candida species.
References 1. Ghandi, S. S., Lamberts, D. W., and Perry, H. D.: Donor to host transmission of disease via corneal transplantation. Surv. Ophthalmol. 25:306, 1981. 2. Beyt, B. E., and Waltman, S. R.: Cryptococcal endophthalmitis after corneal transplantation. N. Engl. J. Med. 298:825, 1978. 3. Larsen, P. A., Lindstrom, R. L., and Doughman, D. J.: Torulopsis glabrata endophthalmitis after keratoplasty with an organ-cultured cornea. Arch. Ophthalmol. 96:1019, 1978. 4. Stern, W. H., Tamura, E., Jacobs, R. A., Pons, V. G., Stone, R. D., O'Day, D. M., and Irvine, A. R.: Epidemic postsurgical Candida parapsilosis endophthalmitis. Clinical findings and management of 15 consecutive cases. Ophthalmology 92:1701, 1985. 5. White, J. H.: Fungal contamination of donor eyes. Br. J. Ophthalmol. 53:30, 1969. 6. Poole, T. G., and Insler, M. S.: Contamination of donor cornea by gentamicin-resistant organisms. Am. J. Ophthalmol. 97:560, 1984. 7. Goodman, D. F., and Stern, W. H.: Oral ketoconazole and intraocular amphotericin B for
60
AMERICAN JOURNAL OF OPHTHALMOLOGY
treatment of postoperative Candida parapsilosis endophthalmitis. Arch. Ophthalmol. 105:172, 1987. 8. Jones, D. B.: Therapy of postsurgical fungal endophthalmitis. Symposium. Postoperative endophthalmitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 85:357, 1978. 9. Theodore, F. H., Littman, M. } . , and Almeda, E.: Diagnosis and management of fungus endophthalmitis following cataract extraction. Arch. Ophthalmol. 66:39, 1961. 10. Peyman, G. A., and Sanders, D. R.: Advances in Uveal Surgery, Vitreous Surgery and Treatment of
July, 1987
Endophthalmitis. New York, Appleton-CenturyCrofts, 1975, p. 207. 11. Weiss, J. L., and Parker, W. T.: Candida albicans endophthalmitis following penetrating keratoplasty. Arch. Ophthalmol. 105:173, 1987. 12. Forster, R. K.: Endophthalmitis. In Duane, T. F. (ed.): Clinical Ophthalmology. Philadelphia, Harper & Row, 1984, vol. 4, p. 4. 13. Theodore, F. H.: Etiology and diagnosis of fungal postoperative endophthalmitis. Symposium. Postoperative endophthalmitis. Trans. Am. Acad. Ophthalmol. Otolaryngol. 85:327, 1978.