CXL vs antimicrobials

Corneal cross-linking alone shows promise as a first-line treatment in microbial keratitis

Roibeard O’hEineachain

Posted: Saturday, May 1, 2021

Photo-activated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL) appears to be as effective as antimicrobial agents as a standalone treatment for infectious corneal infiltrates and early corneal ulcers, according to the results of a phase III clinical trial presented by Emilio Torres-Netto MD PhD, at the 25th ESCRS Winter Meeting.
“Our findings challenge the dogma that antimicrobials should always be used as a first line of treatment in microbial keratitis and show that PACK-CXL could be a viable alternative,” said Dr Torres-Netto, University of Zurich, Zurich, Switzerland.
The prospective, multi-centre, randomised controlled trial involved 39 patients with infectious keratitis. Participants were recruited from five centres in Egypt, India, Iran, Israel and China. All had infiltrates and early ulcers up to 4.0mm in diameter and 350μm in depth. In 28 cases the infections were due to bacteria, with Gram-positive cocci being the most commonly identified pathogens. There were also 11 cases of filamentous fungal keratitis associated with Aspergillus species, Fusarium species and also Candida albicans.
Dr Torres–Netto – on behalf of the PACK-CXL Working Group – randomised patients to undergo standard antimicrobial treatment or PACK-CXL. Those who were already receiving antibiotic or antifungal therapy stopped their treatment at least one day before undergoing their assigned treatment. Prior to treatment, there was no significant difference between the medication group and the PACK-CXL group in terms of the mean infiltrate size, 2.3mm and 2.7mm, respectively. Median corrected distance visual acuity (CDVA) were also similar, logMAR 0.73 and logMAR 0.76, respectively.
In the PACK-CXL group, the researchers removed the epithelium around the borders of the ulcerations and then applied riboflavin and irradiated the corneal infiltrates or ulcers with UV-A using a total energy up to 7.2J/cm2, Dr Torres-Netto explained. They excluded four cases due to treatment failure. This included two eyes in the Medication group that required corneal transplantation due to descemetocele and corneal perforation and two eyes in PACK-CXL group that needed additional antimicrobial therapy.
He noted that the mean time to re-epithelialisation was 7.0 days the both treatment groups. In addition, there was no significant difference in terms of improvement in BCVA, with a final median BDVA of logMAR 0.54 in the medication group and logMAR 0.53 in the PACK-CXL group. Furthermore, the cumulative distribution favoured PACK-CXL in terms of re-epithelialisation. Moreover, even when including the cases excluded from the analysis there was an 89% healing rate among eyes in the PACK-CXL group without antimicrobial treatment.
Dr Torres-Netto noted that infectious keratitis due to corneal infection is a major cause of global blindness and severe visual impairment, with immense socioeconomic costs. In addition, antibiotic resistance has become a global problem and the development of new antibiotics has been at a virtual standstill for decades.
“Even though in different circumstances, in some series, our group has already found fourth-generation fluoroquinolone-resistant bacteria in up to 50% of our patients receiving a chronic prophylactic regime with moxifloxacin (American Journal of Ophthalmology, 2018),” he said.
He noted that PACK-CXL does not require the massive expense involved in the development of new antibiotics and their manufacture, but instead is fairly simple technology requiring only vitamin B2 solution and a light source. Moreover, the combination of UV-A+ riboflavin has already been used as for disinfectant purposes in blood banks and also as a method to purify water in some remote areas of the world.
Dr Torres-Netto explained that there are three hypotheses for the potential mechanisms by which PACK-CXL achieves its effect in infectious keratitis. First there is the oxidative stress the treatment induces which would cause a disruption in cell membranes, second, there is the direct damage to microbial genes through the intercalation of their DNA and RNA, and third, there is steric hindrance that may increase the corneal collagen’s resistance to digestion by microbial enzymes.
He noted that PACK-CXL is more effective in bacterial keratitis than in fungal keratitis but he pointed out that studies showing very poor results with fungal keratitis have used low UV-A energy (Ophthalmology, 2021). However, recently published in vivo studies he and his associates have carried out show that the germicidal efficacy increases as fluence is increased (Cornea, 2020).
In fact, they were able to demonstrate that using fluence rates of 15 J/mm2resulted in a 99% kill rate of some strains of bacteria. Although that is approximately three times the fluence used in the Dresden CXL protocol, there are now many studies reporting good results with acceptable safety using 15 J/mm2at the thinnest area of the cornea in customised CXL treatments for keratoconus.
“PACK-CXL might be an alternative first-line treatment for infectious corneal infiltrates and early corneal ulcers. While the results of this multi-centre randomised controlled trial are promising, a larger sample is needed to further investigate the efficacy and safety of this treatment modality, especially in fungal infections,” he concluded.
References on request
Emilio Torres-Netto:

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