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Today's Practice | May 2014

Crosslinking for Infectious Keratitis

A proposed therapy with potential to treat a global problem.

Infectious keratitis is a leading cause of global blindness, with an estimated 5 million new cases occurring every year in developing countries.1,2 Whereas contact lens wear is often responsible for ulcers in developed countries, minor corneal injuries along with insufficient access to ophthalmologic care and medication are the main reasons for vision loss attributable to severe corneal infections in developing nations. Corneal infections, which are most often caused by bacteria, fungi, or mixed infections, are a diagnostic and therapeutic clinical challenge.


Corneal collagen crosslinking (CXL) with riboflavin and ultraviolet-A (UV-A) light has been in clinical use since 1999. The proven effect of CXL is an induced increase in the biomechanical stiffness of the corneal stroma. The main indications for CXL are progressive keratoconus, pellucid marginal degeneration, and postoperative ectasia.

CXL also has an indirect biochemical effect. The enormous quantity of reactive oxygen species generated during CXL may directly damage the cell walls of pathogens.3 Additionally, a change occurs in the tertiary structure of the collagen fibers, making it harder for collagenases to dock to the cleavage sites and exert their digestive function during corneal melting.3

Photoactivated riboflavin has been used to reduce the microbial load of liquids for many years. An excellent example can be found in the field of transfusion medicine, where platelet concentrates are routinely treated with UV-A light and riboflavin.4 These biochemical characteristics have been studied in the cornea in vitro and in animals,5 and a proof-of-concept study was conducted in a series of five patients in 2008.6 The term photoactivated chromophore for infectious keratitis-CXL (PACK-CXL) has been created to differentiate this form of treatment from conventional CXL.


In a phase 1 clinical study, all 16 eyes treated with PACK-CXL responded with improvement in symptoms and signs of reduced inflammation.7 Epithelial healing was achieved in all eyes, and only two required additional antimicrobial treatment. In a study of 40 eyes of 40 patients with advanced infectious keratitis and corneal melting, 21 received PACK-CXL plus antimicrobial medication and 19 received antimicrobial medication alone (control group).8 Although healing times were comparable between both groups, the rate of complications (perforation, recurrence of infection) was 23% in the control group and 0% in the PACK-CXL group.


PACK-CXL is a promising approach for treating infectious keratitis in the presence or absence of corneal melting. If the safety and efficacy of PACK-CXL is validated in large clinical studies, this therapy could be a solution to a global problem. Ideally, PACK-CXL would enable comprehensive ophthalmologists to treat corneal infiltrates and ulcers at early stages.

Unpublished data from my laboratory indicate that novel activated chromophores might be able to kill more than 99% of bacterial and fungal pathogens in 150 seconds; a treatment at the slit lamp might be possible once miniaturized technology is available.

The questions I pose are these:

1. Have you performed PACK-CXL on eyes with corneal infections?
2. If large clinical trials validate PACK-CXL as a safe and effective therapy, would you incorporate this therapeutic modality into your daily practice for the treatment of corneal infections?

Farhad Hafezi, MD, PhD, is Professor and Chairman of the Department of Ophthalmology at the University of Geneva, Switzerland, and a Clinical Professor of Ophthalmology at the Keck School of Medicine, University of Southern California, Los Angeles. Dr. Hafezi states that he is a named co-inventor of PCT/ CH 2012/000090 application (UV light source). He may be reached at e-mail: farhad@hafezi.ch.

  1. Gonzales CA, Srinivasan M, Whitcher,JP, Smolin G. Incidence of corneal ulceration in Madurai district, South India. Ophthalmic Epidemiol. 1996;3(3):159-166.
  2. Upadhyay MP, Karmacharya PC, Koirala S, et al. Epidemiologic characteristics, predisposing factors, and etiologic diagnosis of corneal ulceration in Nepal. Am J Ophthalmol. 1991;111(1):92-99.
  3. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res. 2004;29(1):35-40.
  4. Goodrich, RP. The use of riboflavin for the inactivation of pathogens in blood products. Vox Sang. 2000;78 Suppl 2:211-215.
  5. Spiess BM, Pot SA, Florin M, Hafezi F. Corneal collagen cross-linking (CXL) for the treatment of melting keratitis in cats and dogs: a pilot study. Vet Ophthalmol. 2014;17(1):1-11.
  6. Iseli HP, Thiel MA, Hafezi F, et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008;27(5):590-594.
  7. Makdoumi K, Mortensen J, Sorkhabi O, et al. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012;250(1):95-102.
  8. Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting [published online ahead of print February 25, 2014]. Ophthalmology. doi:10.1016/j.ophtha.2014.01.011.