FUSARIUM KERATITIS AND REFRACTIVE SURGERY CORNEAL COLLAGEN CROSS-LINKING BY MINAS CORONEO, AO, BSc(Med), MBBS, MSc Syd, MD, MS, UNSW, FRACS, FRANZCO; RAJESH FOGLA, DNB, FRCS(Edin), MMed(Ophth); WILLIAM B. TRATTLER, MD; ASHIYANA NARIANI, MD, MPH; COMPLEX CASE MANAGEMENT GARGI KHARE VORA, MD; AND ALAN N. CARLSON, MD

CASE PRESENTATION

A 42-year-old white man is referred to the Duke University Eye Center Cornea Service for a central corneal ulcer with a hypopyon in his right eye. The patient sustained the ocular injury while mowing the lawn, with debris getting into the eye while he was wearing contact lenses. He was diagnosed with culture-positive Fusarium species by the referring ophthalmologist and was treat- ed with oral voriconazole 200 mg twice daily and frequent topical natamycin 5% and voriconazole 10 mg/mL. The patient under- went epithelium-off corneal collagen cross-linking (CXL) approxi- Figure 1. Initial evaluation of the eye with a Fusarium corneal mately 4 weeks after diagnosis of the ulcer and was treated with infiltrate and hypopyon. a loteprednol steroid taper after the procedure. His condition subsequently progressed, with increasing eye pain, a nonhealing epithelial defect, and a worsening corneal infiltrate. Upon evaluation, the patient has a large corneal infiltrate with necrotic stroma, which is approaching the limbus, and a hypopyon (Figure 1). His UCVA measures 20/70-1. B-scan ultrasound of the right eye shows no evidence of posterior segment involvement. Reculturing of the corneal infiltrate is negative for bacteria, fungus, and Acanthamoeba. Confocal microscopy reveals no evidence of hyphae or cysts. Given the worsened infiltrate with broad antifungal and antibacterial coverage and its proximity to the corneal limbus, Figure 2. The same eye 3 months after PKP with corneal the patient undergoes a therapeutic penetrating keratoplasty (PKP). neovascularization and an inferior fungal infiltrate. After surgery, the patient is maintained on oral voriconazole, topi- cal natamycin 5%, and topical amphotericin B 1.5 mg /mL. Pathology The patient’s UCVA gradually improves to 20/70, with a pinhole of the host cornea reveals diffuse fungal penetration through visual acuity of 20/40. Scarring and deep neovascularization are pres- Descemet membrane into the anterior chamber. The postoperative ent on examination (Figure 2). A repeat PKP to improve visual acuity course is complicated by a recurrence of the infiltrate in the corneal is planned once the infection and associated inflammation com- graft. This is treated with subconjunctival and intracameral injections pletely resolve. of voriconazole (1 mg/mL) administered once weekly on average as With the recent FDA approval of the KXL System (Avedro) and well as two intracameral voriconazole injections performed over the the anticipated usage in refractive surgery, what additional role will next 11 weeks. Resulting corneal neovascularization is treated with CXL offer in the management of active microbial keratitis? What are topical tacrolimus 0.3% ophthalmic solution. After discussion with possible unintended consequences that may develop from the limita- an infectious diseases specialist, polyhexamethylene biguanide 0.02% tions in treatment depth or tissue changes that may affect antimicro- ophthalmic solution and voriconazole 10 mg/mL ophthalmic solu- bial penetration? tion are added, and notable consolidation in the fungal infection is —Case prepared by Ashiyana Nariani, MD, MPH; visible on clinical examination. Gargi Khare Vora, MD; and Alan N. Carlson, MD.

MAY 2017 | CATARACT & REFRACTIVE SURGERY TODAY 29 REFRACTIVE SURGERY COMPLEX CASE MANAGEMENT 30

CATARACT & REFRACTIVE SURGERY TODAY CATARACT &REFRACTIVE SURGERY evidence of its effectiveness for fungal keratitis is lacking. for bacterial keratitis has been noted in published studies, of a CXL procedure. Although some positive effect of CXL rigorous studies. requires the development of better guidelines derived from is a significant inflammatory tissue response. thinning and corneal perforation, particularly where there tended consequences of PACK-CXL are accelerated corneal reactivation of herpes simplex virus, other potential unin helpful. use of topical steroids and tacrolimus may not have been compromise the outcome of future graft procedures. The damage (with evidence of corneal neovascularization) will dictated a different approach. raphy might have indicated the depth of the infection and microscopy or anterior segment optical coherence tomog might have been suboptimal. the stroma. If the Dresden protocol was used, PACK-CXL tary fungal keratitis where there is deep penetration into so the procedure may not be suitable for cases of filamen titis (PACK) CXL effects are limited to the anterior cornea, ered, because voriconazole-resistant cases may respond. such as intravenous micafungin could have been consid testing can guide treatment. pathogen identification and in vitro antifungal susceptibility to get high tissue levels of antifungal treatment. is considered to be more effective than topical treatment intrastromal voriconazole (with or without debridement) is likely that the infection was deep-seated, and repeated Patients’ and surgeons’ improved access to PACK-CXL Apart from limbal and possible endothelial damage and Fifth, unless the limbus was protected, it is possible that Fourth, prior to PACK-CXL, imaging with confocal Third, photoactivated chromophore for infectious kera Second, in a setting of recalcitrant disease, molecular timal, which can be a factor in eye loss. It and subsequent treatments were subop in this case. First, it appears that the initial ing quarterback, I would list five concerns From the perspective of a Monday morn FRACS, FRANZCO MBBS, MS MINAS CORONEO,AO,BS form a therapeutic PKP in this case instead intervention. I would have preferred to per rapid progression often necessitate surgical A limited response to antifungal agents and species ( Managing fungal keratitis from filamentous MM RAJESH FOGLA,DNB,FRCS(E ed (O Fusarium phth

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Other antifungal treatments Other antifungal treatments MAY 2017 5

6 S ) yd ) is clinically challenging. , MD,MSUNSW, 6 1,2 c (M din ed ), ), - 4 ), ), ------is necessary to establish the procedure’s efficacy for this keratitis. Further research with randomized clinical trials ment of superficial infectious keratitis, especially bacterial could also be responsible for the worsening keratitis. recommended in fungal keratitis, and their use after CXL ing keratitis after CXL in this case. Steroids are usually not making it more compact. This could explain the worsen tends to induce structural changes in the corneal stroma, etration, an issue potentially exacerbated by CXL, which tiveness of CXL. Antifungal drugs have poor corneal pen deeper location of fungal infiltrates can reduce the effec one-third of the cornea, however, so in fungal keratitis, the radical production. This action is limited to the anterior melting, and (2) offering the antimicrobial effect of free tance to enzymatic digestion, thereby reducing corneal not eliminate the infection. can reduce the load of micro-organisms but, by itself, may should do so with the understanding that the procedure however, clinicians who employ CXL for infectious keratitis to eliminate certain corneal infections. In the meantime, tions in the CXL procedure will allow a single treatment ate antimicrobial therapy. Perhaps in the future, innova infectious keratitis, the patient should continue appropri potentially even an adjunctive role in the therapy of bacterial, fungal, and nate the fungal infection from the cornea. thickness, so the CXL procedure could not effectively elimi time, however, the CXL was employed early in the patient’s course. At the the depth of effect is limited. In the case described herein, microbial keratitis that is deep within the cornea, because limitations. In particular, the procedure is not effective for the management of fungal corneal ulcers. early bacterial corneal ulcers and that it may have a role in keratitis. Moreover, studies suggest that CXL can help with an effective adjunctive therapy for patients with microbial nus after corneal transplantation. CXL also appears to be totomy or astigmatic keratotomy, and recurrent keratoco indication. Currently, CXL seems to hold promise for the treat CXL is supposed to help by (1) increasing tissue resis On the positive side, there is evidence that CXL can play Despite CXL’s promise, surgeons must understand its degeneration, ectasia following radial kera ectatic conditions such as pellucid marginal LASIK ectasia, CXL can help patients with the treatment of keratoconus and post- to US patients. In addition to its role for tant therapeutic treatment widely available The FDA’s approval of CXL made an impor WILLIAM B.TRATTLER,MD Acanthamoeba Fusarium infection was already full keratitis. 5 5 If CXL is used for ------REFRACTIVE SURGERY COMPLEX CASE MANAGEMENT 32

CATARACT & REFRACTIVE SURGERY TODAY CATARACT &REFRACTIVE SURGERY linking. 6. AbboudaA,EstradaAV,RodriguezAE,etal.Anteriorsegmentopticalcoherencetomographyinevaluationofseverefungalkeratitisinfectionstreatedbycornealcross 5. TabibianD,MazzottaC,HafeziF. PACK-CXL:cornealcross-linkingininfectiouskeratitis. 4. NikiM,EguchiH,HayashiY,etal.Ineffectivenessofintrastromalvoriconazoleforfilamentousfungalkeratitis. terns. 3. TaylanSekerogluH,ErdemE,YagmurM,etal.Successfulmedicalmanagementofrecalcitrant Fusariumsolanikeratitis:molecularidentificationandsusceptibilitypat man]. 2. GuberI,BerginC,MajoF.Repeatedintrastromalinjectionsofvoriconazoleincombinationwithcornealdebridementforrecalcitrantfungalkeratitis-acaseseries[inGer tis. 1. PrakashG,SharmaN,GoelMetal.Evaluationofintrastromalinjectionvoriconazoleasatherapeuticadjunctiveforthemanagementdeeprecalcitrantfungalkerati more challenging. microbial penetration that could make the treatment of infectious microbial keratitis CXL alters corneal tissue in a manner that contributes an additional barrier to anti therapeutic treatment of corneal infection. is important to recognize the limitations of this procedure regarding the depth of Am JOphthalmol n n Section Editor Alan N. Carlson, MD n n n FRANZCO MSc Syd, MD, MS UNSW, FRACS, Minas Coroneo, AO, BSc(Med), MBBS, n Section Editor William F. Wiley, MD n n Section Editor Karl G. Stonecipher, MD n Section Editor Stephen Coleman, MD n           Mycopathologia Klin MonblAugenheilkd Ophthalmology, University of New South Ophthalmology, UniversityofNew South Cleveland, Ohio Greensboro, NorthCarolina University ofNorthCarolina,ChapelHill New Mexico carlsonmd.com Center, Durham,NorthCarolina departmental development, DukeEye [email protected] Wales, SydneyAustralia financial interest:noneacknowledged +61 293999211; professor andchairman,Departmentof private practiceatClevelandEyeClinic, director ofrefractivesurgery,TLCin clinical associateprofessorofophthalmology, director ofColemanVision,Albuquerque, financial interest:noneacknowledged (919) 684-5769;[email protected]; alan professor ofophthalmologyandvicechair, Eur JOphthalmol . 2008;146:56-59. . 2012;174:233-237. . 2014;24:320-324. . 2016;233:369-372. n

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MAY 2017 - What remains uncertain is whether or not What remains uncertain is whether or not Eye Vis(Lond) n n Gargi Khare Vora, MD n n n William B. Trattler, MD n n Ashiyana Nariani, MD, MPH n n n n MMed(Ophth) Rajesh Fogla, DNB, FRCS(Edin),            Durham, NorthCarolina interest inCXLO Eye Care,Miami North Carolina Colombo, SriLanka Hyderabad, India surgeon atApolloHospitals,JubileeHills,in and cataract,cornea,laserrefractive financial interest:noneacknowledged assistant professor,DukeEyeCenter, financial disclosure:consultanttoAvedro; (305) 598-2020;[email protected] director ofcornea,CenterforExcellence in financial interest:noneacknowledged clinical associate,DukeEyeCenter, Durham, financial interest:noneacknowledged +91 9866076750;[email protected] visiting consultant,LankaHospitals, senior consultant;director, CorneaClinic; US surgeons awaited access to CXL. over a lengthy period of time, while expertise that they have accumulated have done a wonderful job sharing Drs. Coroneo, Fogla, and Trattler AND ALANN.CARLSON,MD GARGI KHAREVORA,MD; ASHIYANA NARIANI, MD, MPH; . 2016;3:11. Clin

Ophthalmol . 2014;8:1075-1079.

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