Intracorneal Injection of Amphothericin B for Recurrent Fungal Keratitis and Endophthalmitis

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SURGICAL TECHNIQUE Intracorneal Injection of Amphothericin B for Recurrent Fungal Keratitis and Endophthalmitis

Enrique Garcia-Valenzuela, MD, PhD; C. Diane Song, MD

enetrating keratoplasty carries an infectious risk. Its requirement for topical corticosteroid therapy facilitates fungal growth with resulting keratitis. Although progression of fungal keratitis to intraocular infection is uncommon, endophthalmitis resulting from keratitis usually has a poor visual prognosis. Fungal infection under these circum- Pstances remains a diagnostic and therapeutic challenge. We report a complicated case of recurrent fungal keratitis with endophthalmitis following a contaminated penetrating keratoplasty that ul- timately was controlled with a new treatment modality. Intrastromal corneal injections combined with intravitreal injection of amphotericin B led to the eradication of the corneal fungal plaques and the intraocular infection. Intrastromal corneal injections of amphotericin B may offer a less invasive, in-office alternative to repeat penetrating keratoplasty. Arch Ophthalmol. 2005;123:1721-1723

REPORT OF A CASE examination, a posterior corneal plaque, a hypopyon, and vitreous cells were noted. An 85-year-old woman with Fuchs endo- There was no epithelial defect. She was di- thelial dystrophy and a history of pseudo- agnosed as having late-onset endophthal- phakia came to the Emory University Eye mitis. Aqueous and vitreous taps were per- Center, Atlanta, Ga, complaining of de- formed, and an intravitreal injection of creased vision in the right eye of 6 months’ amphotericin B, 5 µg, was given. Admin- duration. She underwent penetrating kera- istration of oral fluconazole, 200 mg once toplasty (PK) for visually significant cor- daily, was restarted and topical cortico- neal edema secondary to Fuchs dystrophy. steroid therapy, 1% prednisolone acetate The donor corneal rim culture yielded the QID, was maintained. Although the aque- yeast Candida glabrata. The patient was pro- ous and vitreous biopsy specimens did not phylactically treated with oral fluconazole, disclose an infectious agent, the intraocu- 200 mg once daily, and topical 5% natamy- lar signs of infection cleared. A residual cin, 4 times daily (QID) for 6 weeks, and small, deep intrastromal white opacity re- she continued treatment with topical 1% mained at the corneal donor-host inter- prednisolone acetate, 5 times daily. When face. The patient’s vision improved to no evidence of infection remained, the an- 20/50 OD with spectacles. tifungal medications were discontinued and On follow-up 12 months after surgery, the topical corticosteroid was tapered to 3 mild anterior inflammation was evident. times daily. Her best-corrected vision was Her visual acuity was 20/70 OD. She was 20/70 OD. treated with 1% prednisolone acetate, QID. Five months after surgery, she re- The patient did not return for follow-up ap- turned with pain and decreased vision. On pointments until 3 months later (15 months after surgery), when she sought care for se- Author Affiliations: Emory University Eye Center, Emory University School of vere worsening of vision to hand motions. Medicine, and Eye Clinic, Atlanta Veterans Affairs Medical Center, Atlanta, Ga. A hypopyon had developed with in- Dr Garcia-Valenzuela is now with the University of Illinois Eye Center, creased vitreous inflammation, and a fi- Department of Ophthalmology and Visual Sciences, University of Illinois at brous plaque was noted to surround the in- Chicago, and Midwest Retina Consultants, SC, Park Ridge, Ill. traocular lens. She underwent vitrectomy

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Figure. Biomicroscopic photographs of the patient’s right anterior segment before intrastromal amphotericin B injection (A) and 1 year after treatment (B). A, Endothelial and deep stromal corneal white plaques with feathery borders are seen at the donor-host interface, accompanied by anterior chamber inflammation and conjunctival vascular reaction. B, The resolution of infectious and inflammatory signs is apparent, with minimal residual localized endothelial fibrosis. (The green coloration is fluorescein, which had been used for tonometry immediately prior to this photograph.)

and removal of the intraocular lens tient had a best-corrected visual acu- organisms in posttransplant cul- implant and capsule, and received in- ity of 20/400 OD. Her macula had tures of donor corneal rim ranges travitreal amphotericin B, 5 µg, and marked traction with edema second- from 4% to 43%, with higher culture oral fluconazole, 200 mg once daily. ary to a visually significant epireti- yields often explained by the use of The vitreous biopsy specimen yielded nal membrane. The patient declined more thorough culture tech- C glabrata. vitrectomy surgery with membrane niques.3,5,6 Despite relatively high rates The corneal plaques initially di- peeling. Biomicroscopic findings had of contamination of donor tissue, the minished in size with an intact epi- been unchanged since 3 months af- clinical occurrence of bacterial kera- thelium, but 18 months after kerato- ter treatment and showed a clear cor- titis and/or endophthalmitis is low. plasty, the plaques grew, with nea with minimal focal fibrosis at the Routine topical antimicrobial therapy extension into the endothelium and donor-host interface (Figure, B). given postoperatively to all patients aqueous and increased intraocular in- after PK probably decreases the inci- flammation (Figure, A). The pa- dence of intraocular infection. Con- tient declined repeat PK. After in- COMMENT tamination with fungus is less fre- formed consent, she chose to undergo quently found in routine cultures of combined intracorneal and intravit- Penetrating keratoplasty carries an in- donor corneal rim, with a reported real therapeutic injections, for which fectious risk. Its requirement for topi- rate of approximately 6.5% of the institutional review board approval cal corticosteroid therapy facilitates identified organisms, although the was obtained. Amphotericin B, 5 µg, fungal growth with resulting kerati- rate can be as high as 50%.6,7 The role was injected intravitreally, after a ret- tis.1 Although progression of fungal of prophylactic treatment is not firmly robulbar block with 2% lidocaine hy- keratitis to intraocular infection is un- established in patients whose graft rim drochloride. In addition, concurrent common, endophthalmitis resulting has been positive for fungi. intrastromal corneal injections were from keratitis usually has a poor vi- The initial therapy for the first epi- performed in the office with the pa- sual prognosis.2 The incidence of en- sode of endophthalmitis in our patient in a supine position, using a dophthalmitis following PK has been tient was intravitreal amphotericin B 1-mL syringe with a 30-gauge needle found to range between 0.2% and and oral fluconazole. This resulted in while viewing the injection site 0.77%,3,4 and the rate of endophthal- resolution of all signs of infection for through surgical loupes. Five mid- mitis increases 22-fold when the do- 7 months. When the patient re- stromal injections were given in the nor rim culture indicates contamina- turned with endophthalmitis, the areas surrounding the corneal tion.3 There is an approximately 50% source of the fungus was thought to plaques. Each time the needle was correlation between the infecting or- be the large feathery, fibrotic white withdrawn after a 1-minute delay to ganism isolated from the endophthal- plaques between the lens capsule and minimize leakage of the drug. A total mitis aspirate and that cultured from the intraocular lens. Because the of approximately 0.05 mL of ampho- the donor tissue.5,6 However, others6 plaques in the cornea were small and tericin B, 5 µg per 0.1 mL, was ad- have offered data questioning whether posterior in the corneal stroma, they ministered, resulting in hydration of rim cultures have any useful value, were considered not to be the source the cornea. Within 3 months the eye since so often no infection develops of recurrence but rather to be sites of became completely quiet and the stro- despite positive culture results. Mi- infection secondary to the endoph- mal corneal plaques cleared. crobial contamination of corneal do- thalmitis. The possibility of concur- On last follow-up, 18 months af- nor tissue is not an infrequent find- rent PK and vitrectomy was thought ter the combined intravitreal and in- ing because of the difficulty in fully unnecessary. Instead, the patient un- trastromal injections, we found no sterilizing the tissue without affect- derwent vitrectomy with removal of signs of fungal recurrence. The pa- ing its viability. Detection of micro- the intraocular lens and lens capsule

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 and received intravitreal amphoteri- elimination of the infection at the last Financial Disclosure: None. cin B and oral fluconazole. follow-up (18 months after treat- Funding/Support: This study was At the third recurrence of endoph- ment). Corneal clarity was not com- supported in part by a Jahnigen thalmitis, frank white corneal plaques promised further by intrastromal am- Scholars Award from the American were also evident. These sites of cor- photericin B. Recently, we studied the Geriatrics Society, New York, NY; an neal growth then became the primary toxicity of intrastromal corneal am- award from the Knights Templar suspects behind the fungal relapses. photericin B in rabbits (Henia Lichter, Educational Foundation, Schaum- Penetrating keratoplasty is often con- MD, Batool Jafri, MD, Hans E. burg, Ill; and an unrestricted re- sidered when keratitis continues to Grossniklaus, MD, Chris Banning, search grant from the Research to progress with increasing hypopyon MD, C.D.S., E.G.-V., Henry Edel- Prevent Blindness, New York. and peripheral corneal involvement.8 hauser, PhD; unpublished data; Sep- Penetrating keratoplasty is an effec- tember 2004). Consistent with our ex- tive way to remove infected cornea, as perience reported herein, intrastromal REFERENCES well as immune-complex precipitates injections of amphotericin B at a con- that provide a stimulus for inflamma- centration of 5 µg per 0.1 mL do not 1. Mabon M. Fungal keratitis. Int Ophthalmol Clin. tion. The desired effect of therapeu- appear to be deleterious to corneal 1998;38:115-123. 2. Pflugfelder SC, Flynn HW Jr, Zwickey TA, et al. tic PK is to remove all infected tissue keratocytes or endothelial cells. Exogenous fungal endophthalmitis. and leave a disease-free margin of at In summary, we present a case of Ophthalmology. 1988;95:19-30. 8 least 1 mm. Our patient was offered Candida endophthalmitis with mul- 3. Leveille AS, McMullan FD, Cavanagh HD. Endoph- PK combined with vitrectomy and in- tiple recurrences due to an inability thalmitis following penetrating keratoplasty. travitreal amphotericin B, but she de- to clear the corneal stromal infiltrate. Ophthalmology. 1983;90:38-39. clinedtohaveanycomplexocularpro- To our knowledge, this is the first re- 4. Cameron JA, Antonios SR, Cotter JB, Habash NR. Endophthalmitis from contaminated donor cor- cedures. port of intracorneal delivery of a thera- neas following penetrating keratoplasty. 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Intracorneal drug ther experience is required, intrastro- 7. Hagenah M, Bohnke M, Engelmann K, Winter R. Incidence of bacterial and fungal contamination delivery has been performed previ- mal corneal injections of amphoteri- of donor corneas preserved by organ culture. ously on animals in an experimen- cin B may offer a less invasive, in-office Cornea. 1995;14:423-426. 9 tal setting. A literature search pro- alternative to repeat PK. 8. Soong HK, Meyer RF, Sugar A. Small, overlap- duced one report of a bioassay in ping tectonic keratoplasty involving graft-host junc- rabbits in which several antifungal Submitted for Publication: Febru- tion of penetrating keratoplasty. Am J Ophthalmol. agents were evaluated in an effort to ary 3, 2004; final revision received 2000;129:465-467. 10 9. Claudio C, Gino G. Homologous antilymphocyte achieve therapeutic corneal levels. January 19, 2005; accepted January antibodies synthesized by limbocorneal lym- Our patient received several am- 19, 2005. phoid foci during the delayed hypersensitivity photericin B intrastromal injections Correspondence: Enrique Garcia- phase: analysis of the limbal immunologic reac- in addition to concomitant intravit- Valenzuela, MD, PhD, University of tion after intracorneal injection of homospecific real amphotericin B to ensure that all Illinois Eye Center, Midwest Retina spleen homogenate [in Italian]. Riv Anat Patol Oncol. 1968;33:336-350. fungal plaques were properly sur- Consultants, SC, 1875 Dempster Rd, 10. O’Day DM, Head WS, Robinson RD, Williams TE. rounded by the medication. This ap- Suite 640, Park Ridge, IL 60068 An evaluation of intrastromal injection of antifun- proach proved effective, with total ([email protected]). gal agents. J Ocul Pharmacol. 1991;7:325-328.

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