Fungal keratitis is a rare but vision-threatening complication after endothelial keratoplasty (EK). (See “Diagnosing Fungal Keratitis”). Thus, corneal specialists should remain vigilant of strategies for its prevention and management.
Here, we discuss the strategies for prevention and management of fungal keratitis after EK.
Benjamin Franklin once famously said, “an ounce of prevention is worth a pound of cure.” Although, he wasn’t speaking about fungal keratitis after EK, this sentiment does, indeed, apply. The biggest risk factor for fungal keratitis after EK is corneal donor contamination. How might this occur?
• Corneal storage media. In the United States, hypothermic storage media for corneal donor tissue is supplemented with broad-spectrum antibiotics, though not routinely with antifungals. This may allow fungi to flourish.
Of note, the report from the Eye Bank Association of America Medical Advisory Board Subcommittee on Fungal Infection After Corneal Transplantation did not show a significant association between fungal infections and the preparation of corneal donor tissue by the surgeon or the eye bank.3
Another study suggested that preparation of precut donor tissue for EK procedures by a properly trained technician did not significantly increase the risk of either bacterial or fungal donor rim contamination.4
Due to these potential risks for fungal infections, alterations to the preparation and storage of donor corneal tissue have been investigated. These investigations have yielded these strategies thus far:
• A double soak of 5% povidone-iodine at the time of donor harvesting (two 5-minute soaks separated by 5 minutes with irrigation). This significantly reduced the rate of positive donor rim fungal cultures (2.9% to 0.6%) and decreased the clinical infection rate to zero.4
The use of antifungal supplementation in storage media is under assessment. Thus far, the addition of both voriconazole and amphotericin B to Optisol-GS (Bausch + Lomb), and Kerasave (Alchimia), a storage medium that utilizes an amphotericin-B tablet for prolonged shelf-life, have been investigated.7-11 The ideal agents must maintain their efficacy during corneal storage, must not cause endothelial cell toxicity and, ideally, should be cost effective.
In terms of intraoperative risk factors, the use of venting incisions in the recipient is also thought to pose a risk for interface keratitis.12,13 The use of a lenticle inserter may reduce the risk of infection by minimizing contact between the graft and the incision and ocular surface.14
• Medical management. Initial medical management of fungal keratitis after EK includes a combination of oral antifungal therapy (voriconazole 400 mg b.i.d. or fluconazole 100 mg to 200 mg daily) and topical antifungal therapy (natamycin 5% [Natacyn, Santen Pharmaceuticals], voriconazole 1%, or amphotericin B 0.15%).
Topical medications are initiated at a frequency of 1 drop every hour and tapered according to clinical response over several weeks. That said, the infiltrates in keratitis after EK are sequestered deep between the graft and the recipient stroma, so topical and oral therapies alone may not always be effective.
Additionally, intracameral therapy appears to be insufficient in eradicating interface infections.15 Intrastromal injection of both amphotericin B (5 ug/0.1 ml) and voriconazole (50 ug/0.1 ml)16,17 have been shown to resolve fungal keratitis. In these cases, the infection was confined to the interface and adjacent stroma, and patients were progressing on topical and oral therapy. Intrastromal injection delivers high concentrations of the medications to the adjacent stroma and can be repeated every 1 week to 2 weeks until clinical resolution. This approach can preserve the graft and allow for time until surgery can be performed.
Topical antifungals are relatively well tolerated. Generally, side effects of oral medications can be more severe and include skin rashes, hepatotoxicity, gastritis, headache, bone toxicity, and visual disturbances. It is important to note that systemic amphotericin B does not reach therapeutic levels in the eye and can cause renal failure and hepatotoxicity, so it should not be used for the treatment of fungal keratitis.
• Therapeutic keratoplasty (TKP). This removes the infected tissue without exposing the AC to infectious micro-organisms. It carries a high rate of rejection, due to active inflammation and corneal neovascularization, though patients who have undergone EK for Fuchs’ endothelial dystrophy or pseudophakic bullous keratopathy are less likely to have such comorbidities if surgery is performed early enough.
Visual rehabilitation following a TKP is extensive, so this option may not be desirable for patients who have experienced rapid visual recovery after EK. In counseling patients, emphasis should be made on eradication of infection and prevention of endophthalmitis.
• Prophylaxis in the setting of positive donor rim cultures. When faced with a positive donor rim fungal culture, a surgeon can either treat with empiric antifungal prophylaxis (covering Candida spp) or follow the patient more closely and treat only if clinical infection develops. The case for antifungal prophylaxis can be made with evidence that it significantly reduced the incidence of infectious keratitis after a positive rim culture.
Vislisel and colleagues report adopting a protocol of treating patients with oral prophylaxis for 3 months; however, an optimal route and duration of treatment remains to be determined.18 The initiation of a systemic medication with potential adverse effects is not a decision that should be made lightly. Ultimately, a course of action should be determined after honest discussion with the patient and consideration of their medical and ocular comorbidities, their capacity to follow up regularly, and their personal preferences and risk tolerance. Surgeons should also be sure to notify the eye bank of a positive donor rim fungal culture and should consider adjusting the topical steroid regimen.
DIAGNOSING FUNGAL KERATITIS
Fungal keratitis after EK often presents clinically as 1 or more white infiltrates at the interface with minimal inflammation. Additionally, it may mimic epithelial ingrowth, infectious crystalline keratopathy, or graft rejection, delaying diagnosis.19 The location of infection deep at the interface makes it difficult to biopsy the lesion or obtain specimens for culture without potentially releasing the pathogen into the anterior chamber (AC). Anterior-segment OCT can be used to evaluate the depth and extent of the lesion and to monitor its progression or resolution over time.19
Confocal microscopy can aid in the diagnosis as well, as the size and morphology of fungal organisms enable them to be visualized and differentiated from normal structures. A caveat: The quality of imaging and accuracy of diagnosis is highly user and observer dependent.19
Culturing the donor corneoscleral rim at the time of corneal transplantation can yield valuable information in the setting of possible keratitis. Candida species (spp) are the most commonly isolated pathogens in cases of fungal infection.1,2,15,20 In a report from the Eye Bank Association of America, 3/4 of the mates of corneas that led to infection in the recipient were fungal culture positive, and 2/3 of these corneas resulted in fungal infections in their respective recipients.3
However, the utility of routine culture of donor corneoscleral rims remains a controversial topic.21 The overall incidence of positive fungal cultures from donor rims (for all keratoplasties) is 1% to 2.1%.15,22 Also, the absence of a positive donor rim culture does not rule out infectious keratitis in a patient who has a suspicious clinical presentation. Further, the incidence of clinical infection after a positive rim culture has been reported to be low, ranging from 6% to 10%.18,23,24
Because fungal keratitis after EK can result in blindness, corneal specialists should continue to be vigilant regarding the strategies for its prevention and management. Additionally, they should immediately report cases of fungal keratitis after EK to their eye banks, along with treatment outcomes, so that evidence-based guidelines for management can be developed. CP
- Edelstein SL, DeMatteo J, Stoeger CG, Macsai MS, Wang CH. Report of the Eye Bank Association of America medical review subcommittee on adverse reactions reported from 2007 to 2014. Cornea. 2016;35(7):917-926.
- Aldave AJ, DeMatteo J, Glasser DB, et al. Report of the Eye Bank Association of America medical advisory board subcommittee on fungal infection after corneal transplantation. Cornea. 2013;32(2):149-154.
- Brothers KM, Shanks RMQ, Hurlbert S, Kowalski RP, Tu EY. Association between fungal contamination and eye bank-prepared endothelial keratoplasty tissue: temperature-dependent risk factors and antifungal supplementation of optisol-gentamicin and streptomycin. JAMA Ophthalmol. 2017;135(11):1184-1190.
- Rauen MP, Goins KM, Sutphin JE, Kitzmann AS, Schmidt GA, Wagoner MD. Impact of eye bank lamellar tissue cutting for endothelial keratoplasty on bacterial and fungal corneoscleral donor rim cultures after corneal transplantation. Cornea. 2012;31(4):376-379.
- Tran KD, Clover J, Ansin A, Stoeger CG, Terry MA. Rapid warming of donor corneas is safe and improves specular image quality. Cornea. 2017;36(5):581-587.
- Clover J, Ansin A, Stoeger CG, Terry MA, Tran KD. Reduction of donor cornea exposure to repeat warming cycles and evaluation times after implementation of a rapid warming protocol. Cornea. 2018;37(7):829-833.
- Layer N, Cevallos V, Maxwell AJ, Hoover C, Keenan JD, Jeng BH. Efficacy and safety of antifungal additives in Optisol-GS corneal storage medium. JAMA Ophthalmol. 2014;132(7):832-837.
- Tran KD, Aldrich BT, D’Amato Tóthová J, et al. Efficacy and safety of various amphotericin B concentrations on Candida albicans in cold storage conditions. Cornea. 2020;39(1):110-117.
- Perry I, Peterson K, Tóthová JD, Tramber M, Botsay S, Tremblay D. Performance of new hypothermic corneal storage media with an antimycotic tablet in comparison to traditional hypothermic media during simulated eye bank processing. Cornea. 2020;39(8):1031-1039.
- Mistò R, Giurgola L, Pateri F, Limongelli A, Ragazzi E, D’Amato Tóthová J. A new storage medium containing amphotericin B versus Optisol-GS for preservation of human donor corneas. Br J Ophthalmol. 2022;106(2):184-189.
- Tran KD, Ellison M, Straiko MMW, et al. Prospective in vitro comparison of Kerasave and Optisol-GS corneal storage solutions. Cornea. 2023;42(5):630-638.
- Hannush SB, Chew HF, Eagle RC Jr. Late-onset deep infectious keratitis after descemet stripping endothelial keratoplasty with vent incisions. Cornea. 2011;30(2):229-232.
- Chew ACY, Mehta JS, Li L, Busmanis I, Tan DTH. Fungal endophthalmitis after descemet stripping automated endothelial keratoplasty--a case report. Cornea. 2010;29(3):346-349.
- Yamazoe K, Den S, Yamaguchi T, Tanaka Y, Shimazaki J. Severe donor-related Candida keratitis after Descemet’s stripping automated endothelial keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2011;249(10):1579-1582.
- Vislisel JM, Goins KM, Wagoner MD, Roos BR, Fingert JH. Incidence and outcomes of positive donor corneoscleral rim fungal cultures after keratoplasty. Ophthalmology. 2017;124(1):36-42.
- Wong BM, Bonnet C, Ghaffari R, et al. Fungal infection after Descemet membrane endothelial keratoplasty: incidence and outcomes. Cornea. 2023;42(6):687-698.
- Tu EY, Hou J. Intrastromal antifungal injection with secondary lamellar interface infusion for late-onset infectious keratitis after DSAEK. Cornea. 2014;33(9):990-993.
- Tu EY, Majmudar PA. Adjuvant stromal amphotericin B injection for late-onset DMEK infection. Cornea. 2017;36(12):1556-1558.
- Sahay P, Singhal D, Nagpal R, et al. Pharmacologic therapy of mycotic keratitis. Surv Ophthalmol. 2019;64(3):380-400.
- Koenig SB, Wirostko WJ, Fish RI, Covert DJ. Candida keratitis after descemet stripping and automated endothelial keratoplasty. Cornea. 2009;28(4):471-473.
- Hsu YJ, Huang JS, Tsai JH, Hu FR, Hou YC. Early-onset severe donor-related Candida keratitis after descemet stripping automated endothelial keratoplasty. J Formos Med Assoc. 2014;113(11):874-876.
- Mian SI, Aldave AJ, Tu EY, et al. Incidence and outcomes of positive donor rim cultures and infections in the Cornea Preservation Time Study. Cornea. 2018;37(9):1102-1109.
- Weng CY, Parke DW 3rd, Walter SD, Isom RF, Chang JS, Flynn HW Jr. Candida glabrata endophthalmitis transmitted from graft to host after descemet stripping automated endothelial keratoplasty. JAMA Ophthalmol. 2014;132(11):1381-1383.
- Ortiz-Gomariz A, Higueras-Esteban A, Gutiérrez-Ortega ÁR, González-Méijome JM, Arance-Gil A, Villa-Collar C. Late-onset Candida keratitis after Descemet stripping automated endothelial keratoplasty: clinical and confocal microscopic report. Eur J Ophthalmol. 2011;21(4):498-502.