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Corneal Physician

Article

Cross-linking for Infectious Keratitis

A look at the history, research, and anecdotal experience

By: JAIME D. MARTINEZ, MD, DIEGO ALTIMIRANO, MD, Guillermo Amescua, MD
Corneal Physician July 1, 2020 Vol 24, Issue July 2020 Page(s): 18-20

The growing prevalence of antimicrobial resistance has led to the increased use of fortified antimicrobial drops that can cause significant toxicity to the ocular surface and also require a compounding pharmacy.1 Even with proper medical management, some cases of infectious keratitis (IK) can evolve into corneal perforation (Figure 1). In some of these cases, a therapeutic corneal transplant is required. However, corneal grafts on an infected and/or inflamed ocular surface have a guarded prognosis.2 Thus, alternative treatments are needed for the management of IK.


FIGURE 1. A 60-year-old female patient had a diagnosis of Acanthamoeba keratitis, by positive culture. (A) Her clinical appearance at presentation showed a deep corneal infiltrate, with superior thinning, and hypopyon. The patient did not respond to standard medical treatment. (B) At 8 weeks after treatment, her cornea started to melt, and inferior descemetocele with perforation developed
FIGURE 1. A 60-year-old female patient had a diagnosis of Acanthamoeba keratitis, by positive culture. (A) Her clinical appearance at presentation showed a deep corneal infiltrate, with superior thinning, and hypopyon. The patient did not respond to standard medical treatment. (B) At 8 weeks after treatment, her cornea started to melt, and inferior descemetocele with perforation developed

 

A recent addition to the armamentarium against IK is the use of corneal collagen cross-linking (CXL), which is a procedure based on a photosensitizer chemical (riboflavin) and a light source with a specific wavelength to excite the chemical (UV light). CXL results in the formation of stronger chemical bonds among adjacent fibrils.3 In addition, the cornea becomes more resistant to enzymatic digestion by collagenases.3

History

In the 1960s, Tsugita et al reported that the application of riboflavin and UVA light led to the inactivation of the tobacco mosaic virus.4 Since then, this knowledge has been used to eradicate microorganisms in many applications, including in the sterilization of water, surfaces, and blood products. The first to publish its use in human corneal infections was Iseli et al.5 Since then, there have been several case reports, case series and prospective non-randomized studies on the use of CXL for corneal infections, and the term photo-activated chromophore (PACK-CXL) has been used in many recent publications.6-11

Research

The first randomized controlled clinical studies comparing PACK-CXL as an additional procedure to medical therapy, by Said et al and Kasetsuwan et al, did not show a significant difference in corneal healing and final visual outcome compared to standard antibiotic treatments in patients with severe IK.12,13 Nevertheless, PACK-CXL did reduce late complications, such as corneal perforation. Additionally, Bamdad et al demonstrated a faster recovery of epithelial defects and infiltrates when PACK-CXL was added to standard antibiotic treatments.14

The use of PACK-CXL in fungal keratitis is debatable. Li et al reported a successful use of PACK-CXL for eight cases of fungal keratitis.15 However, Uddaraju et al and Venkatesh Prajna N et al, in a prospective randomized clinical trial, found that PACK-CXL was not helpful in deep stromal fungal keratitis.16,17

Interestingly, modifying parameters of the Dresden protocol, such as using higher fluence, may lead to better outcomes in IK patients.18,19 On the other hand, Richoz, et al. reported that, “fluorescein staining competes with riboflavin for the absorption of UVA during PACK-CXL and reduces the antimicrobial effect of the procedure.20

Anecdotal Experience

Our group reported three cases of IK treated with PACK-CXL as an adjunct treatment to standard antibiotic treatments with good long-term follow-up and results.21 We also experienced good results with another case of biopsy-proven fungal keratitis. (Figure 2, unpublished).

FIGURE 2. A 58-year-old male patient had a diagnosis of fungal keratitis, diagnosed by corneal biopsy on pathology. (A and B) His clinical appearance at presentation showed deep, severe corneal infiltrates, paracentral melting and thinning, with 360° of corneal neovascularization. Riboflavin cross-linking using the Dresden protocol was performed, due to the patient not responding to standard medical treatment. (C and D) At 2 and 4 weeks after the procedure, corneal melting and thinning stopped, the patient’s conjunctiva was more quiet, and the infiltrate was smaller. (E) At 6 weeks after riboflavin CXL, his corneal epithelium healed, and steroid drops were started. (F) A corneal transplant was performed, and the patient’s cornea was clear 2 years after the cornea transplant.
FIGURE 2. A 58-year-old male patient had a diagnosis of fungal keratitis, diagnosed by corneal biopsy on pathology. (A and B) His clinical appearance at presentation showed deep, severe corneal infiltrates, paracentral melting and thinning, with 360° of corneal neovascularization. Riboflavin cross-linking using the Dresden protocol was performed, due to the patient not responding to standard medical treatment. (C and D) At 2 and 4 weeks after the procedure, corneal melting and thinning stopped, the patient’s conjunctiva was more quiet, and the infiltrate was smaller. (E) At 6 weeks after riboflavin CXL, his corneal epithelium healed, and steroid drops were started. (F) A corneal transplant was performed, and the patient’s cornea was clear 2 years after the cornea transplant.

As an alternative to PACK-CXL treatment for IK, research by our group has focused on in vitro antimicrobial efficacy of photodynamic antimicrobial therapy (PDAT) using Rose bengal as a photosensitizer, activated by a green light (RB-PDAT). Specifically, our team demonstrated the in vitro antimicrobial efficacy of PDAT comparing Rose bengal and riboflavin as two different photosensitizers against a variety of microbes, including multiple species of bacteria and fungi.22-24 Others have demonstrated a possible role for RB-PDAT on Acanthamoeba infections.25

The safety of RB-PDAT has been established in, in vivo animal models.26,27 Resistance to treatment has also not been observed with RB-PDAT.28 Thus far, at our institution, we have relied on these in vitro and in vivo results to use RB-PDAT to treat patients who have progressive IK who were unresponsive to standard medical therapy (Figure 3 and Figure 4). The first successful reported case of RB-PDAT was in a patient who had Fusarium keratoplasticum keratitis.29,30 Our group published a retrospective pilot study using RB-PDAT as an adjunct treatment for severe IK, with a total of 18 patients. A surgical treatment was avoided in 72% of the patients.31

FIGURE 3. RB-PDAT with computer-controlled 525 nm light-emitting diodes console. This photo demonstrates the actual procedure during the green light phase.
FIGURE 3. RB-PDAT with computer-controlled 525 nm light-emitting diodes console. This photo demonstrates the actual procedure during the green light phase.
FIGURE 4. A 56-year-old female patient had a diagnosis of Acanthamoeba keratitis, by positive culture. (A and B) Her clinical appearance at presentation showed a deep central severe corneal infiltrate, with melting and thinning, and hypopyon. Rose bengal PDAT was performed, due to the patient not responding to standard medical treatment. (C and D) At 4 and 8 weeks after the procedure, the corneal melting and thinning stopped, her conjunctiva was more quiet, and her infiltrate and hypopyon were smaller. (E) At three months after Rose bengal PDAT, her corneal epithelium healed, and a corneal scar was left. (F) A corneal transplant was performed, and her cornea was clear 2 years after the cornea transplant.
FIGURE 4. A 56-year-old female patient had a diagnosis of Acanthamoeba keratitis, by positive culture. (A and B) Her clinical appearance at presentation showed a deep central severe corneal infiltrate, with melting and thinning, and hypopyon. Rose bengal PDAT was performed, due to the patient not responding to standard medical treatment. (C and D) At 4 and 8 weeks after the procedure, the corneal melting and thinning stopped, her conjunctiva was more quiet, and her infiltrate and hypopyon were smaller. (E) At three months after Rose bengal PDAT, her corneal epithelium healed, and a corneal scar was left. (F) A corneal transplant was performed, and her cornea was clear 2 years after the cornea transplant.

Areas of Potential

In summary, the use of a light-activated photosensitizer agent for IK continues to be a challenge, but an area of opportunity. Novel potential treatments, such as PACK-CXL and RB-PDAT, show success, but still need to be evaluated in prospective clinical trials. New improvements in technology, as well as better understanding of the mechanism of action will help improve patient outcomes. CP

References

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  15. Li Z, Jhanji V, Tao X, Yu H, Chen W, Mu G. Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol. 2013;97(5):669-671.
  16. Uddaraju M, Mascarenhas J, Das MR, et al. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial. Am J Ophthalmol. 2015;160(1):131-134.e5.
  17. Prajna NV, Radhakrishnan N, Lalitha P, et al. Cross-linking-assisted infection reduction: a randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis. Ophthalmol. 2020;127(2):159-166.
  18. Richoz O, Kling S, Hoogewoud F, et al. Antibacterial efficacy of accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK-CXL). J Refract Surg. 2014;30(12):850-854.
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  21. Martinez JD, Arboleda A, Naranjo A, et al. Long-term outcomes of riboflavin photodynamic antimicrobial therapy as a treatment for infectious keratitis. Am J Ophthalmol Case Rep. 2019;15:100481.
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  25. Atalay HT, Dogruman-Al F, Sarzhanov F, et al. Effect of riboflavin/rose bengal-mediated PACK-CXL on acanthamoeba trophozoites and cysts in Vitro. Curr Eye Res. 2018;43(11):1322-1325.
  26. Zhu H, Alt C, Webb RH, Melki S, Kochevar IE. Corneal crosslinking with rose bengal and green light: efficacy and safety evaluation. Cornea. 2016;35(9):1234-1241.
  27. Naranjo A, Pelaez D, Arrieta E, et al. Cellular and molecular assessment of rose bengal photodynamic antimicrobial therapy on keratocytes, corneal endothelium and limbal stem cell niche. Exp Eye Res. 2019;188:107808.
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  29. Amescua G, Arboleda A, Nikpoor N, et al. Rose bengal photodynamic antimicrobial therapy: a novel treatment for resistant fusarium keratitis. Cornea. 2017;36(9):1141-1144.
  30. Martinez JD, Naranjo A, Amescua G, et al. Human corneal changes after rose bengal photodynamic antimicrobial therapy for treatment of fungal keratitis. Cornea. 2018;37(10):e46-e8.
  31. Naranjo A, Arboleda A, Martinez JD, et al. Rose bengal photodynamic antimicrobial therapy for patients with progressive infectious keratitis: a pilot clinical study. Am J Ophthalmol. 2019;208:387-396.

 

DR. MARTINEZ is an assistant professor of Clinical Ophthalmology at Bascom Palmer Eye Institute, in Naples, FL. He focuses on corneal and external disease, ocular surface disorders, keratoprosthesis, and cataracts, Disclosures: none.

 

 

DR. ALTAMIRANO is a clinical fellow of corneal and external diseases at Bascom Palmer Eye Institute, in Miami, FL. Disclosures: none.

 

 

DR. AMESCUA is an associate professor of Clinical Ophthalmology and Medical Director of the Ocular Surface Program at the University of Miami, in Miami, FL. He focuses on corneal and external disease, high-risk corneal transplantation, keratoprosthesis and cataracts. Disclosures: none.

 

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