Corneal cross-linking (CXL) is a procedure that uses riboflavin and ultraviolet A (UVA) to strengthen the bonds between corneal collagen fibers. It is widely used for keratoconus and other progressive corneal ectasias 2). Although CXL itself has antimicrobial effects through the production of reactive oxygen species (ROS), like any corneal surgery, there is a risk of postoperative infection 1).
The incidence of infectious keratitis after CXL varies across reports. Shetty et al. reported an extremely low incidence of 4 eyes out of 2,350 (0.0017%) 1), while a large series from South India reported 11 eyes out of 3,842 (0.21%), and an Iranian series reported 6 eyes out of 4,863 (0.12%).
On the other hand, CXL is also being studied as a treatment for infectious keratitis. This application, called PACK-CXL (Photo Activated Chromophore for Keratitis), was first reported by Iseli et al. in 2008 1). It is an adjunctive therapy for microbial keratitis resistant to medical therapy, aiming to suppress corneal melting and provide bactericidal effects 1).
Infectious keratitis after CXL typically develops 1–5 days postoperatively. The main complaints are eye pain, redness, and decreased vision.
The prognosis of reported cases varies. In mild cases (e.g., Staphylococcus epidermidis), corrected visual acuity of 20/22 has been achieved after treatment, while in severe cases (e.g., Pseudomonas aeruginosa, MRSA, Acanthamoeba), corneal transplantation was required and vision was significantly limited.
Causative Organisms
Staphylococcus aureus (MSSA/MRSA): The most common causative organism. It has the ability to adhere to corneal cells via fibronectin-binding proteins.
Pseudomonas aeruginosa: Associated with contact lens use. It secretes seven types of proteases, causing severe corneal damage.
Others: Staphylococcus epidermidis, Escherichia coli, Aspergillus, Acanthamoeba, Herpes simplex virus.
Risk Factors
Epi-off procedure: Loss of the epithelial barrier increases the risk of infection2).
Protective contact lens: The bandage CL used postoperatively can become a reservoir for infection.
Fluoroquinolone resistance: Most post-CXL infections have been reported to be fluoroquinolone-resistant.
In eyes with a history of herpes simplex virus, there is a risk of viral reactivation due to UV irradiation, and CXL is contraindicated1). Kymionis et al. reported a case of herpes simplex keratitis after CXL, with geographic epithelial defect, stromal edema, and anterior chamber inflammation appearing on postoperative day 5, and herpes simplex virus DNA detected by PCR.
Compared to the epithelium-off method, the transepithelial method preserves the corneal epithelium, so theoretically the infection risk is lower. However, Rana et al. reported cases of bacterial keratitis after transepithelial CXL. The epithelial barrier is an important protective factor but does not guarantee complete prevention of infection.
PACK-CXL is being studied as an adjunctive therapy for infectious keratitis refractory to medical treatment1).
| Infection type | Efficacy | Notes |
|---|---|---|
| Bacterial (superficial) | High | Most effective1) |
| Fungal | Moderate | Less effective than for bacteria1) |
| Acanthamoeba | Limited | Used adjunctively1) |
In the initial report by Iseli et al. (2008), progression of corneal melting was halted in all 5 eyes with antimicrobial-resistant infectious keratitis, and emergency corneal transplantation was avoided1). Makdoumi et al. reported that PACK-CXL monotherapy without antibiotics cured bacterial keratitis in 14 of 16 eyes1).
PACK-CXL has been considered for microbial keratitis resistant to standard antimicrobial therapy. Previous reports indicate that it is more effective in superficial bacterial keratitis, while its effect is limited in cases with deep infection or endothelial plaques1).
In cases with deep keratitis or endothelial plaques, the effect of PACK-CXL is limited1). Because UVA energy is absorbed in the anterior corneal stroma, it is difficult to reach deep infections1).
In CXL, photoactivated riboflavin enters an excited state and reacts with environmental oxygen to produce reactive oxygen species (ROS)1). ROS exert bactericidal effects through the following mechanisms:
Additionally, the cross-linking reinforcement of collagen fibers by CXL makes the corneal stroma more resistant to enzymatic degradation, suppressing the progression of microbial collagen melting1).
Despite the antimicrobial effect of CXL, infection may occur due to the following reasons:
PACK-CXL is attracting attention as a promising adjunctive therapy for infectious keratitis1). While relatively good results have been reported for bacterial keratitis, the effects are inconsistent for fungal infections and deep infections1). To overcome the limitations of efficacy in deep infections, optimization of irradiation protocols is underway.
Regarding the prevention of post-CXL infection, the issue of fluoroquinolone-resistant bacteria is important. It has been pointed out that options other than fluoroquinolones should be considered as postoperative antimicrobial agents. With the spread of transepithelial methods, procedures that preserve the epithelial barrier are increasing, but long-term data are needed on the effect of reducing infection risk.
