Racing against microbial keratitis

Microbial keratitis (MK) is a serious condition that can lead to blindness if not treated quickly and effectively. Early intervention is key to successful treatment, leveraging a ‘window of opportunity’ to control microbial invasion and prevent the escalation to stromal necrosis, melt and perforation. Traditional treatments often fail due to difficulties in identifying the infection-causing pathogen and the increasing problem of antimicrobial resistance with drug-resistant pathogens.

Figure 1. The surgical team addressed limbal stem cell deficiency in preparation for grafting.

Figure 2. The patient’s condition remained unstable, with recurrent epithelial defects.

Figures 3, 4. A year after the last surgical attempt, the patient suffered another microbial keratitis episode, which manifested as a large abscess with near-total epithelial defect.

MK poses a significant treatment challenge, especially in patients with complex ocular surface pathology. This challenge is amplified in the paediatric population, where aggressive attempts to salvage the eye and vision are often pursued before considering definitive but irreversible procedures such as evisceration. The following case demonstrates the challenges encountered when managing recurrent and resistant MK in a young patient with complex ocular surface pathology.

Case

At 9 years of age, our patient suffered devastating firework injury to his left eye (LE), which resulted in extensive ocular surface thermal injuries, eyelid trauma, total limbal stem cell deficiency (LSCD), corneal scarring and secondary glaucoma. Over the following years, he underwent multiple surgical procedures across various international centers, including one penetrating keratoplasty (PK) and one lamellar keratoplasty, amniotic membrane transplants (AMTs) and various eyelid reconstruction procedures, all of which were unsuccessful in stabilising his ocular surface. Upon his referral to our department, the patient’s visual acuity was light perception (LP) in the injured eye and 6/6 unaided in the unaffected right eye. His journey through our care began with eyelid correction surgery to restore function and protect the ocular surface, as well as fornix reconstruction and buccal mucosa grafting. Subsequently, we performed cultivated oral mucosal epithelial cell transplantation (COMET) to address the LSCD, in preparation for corneal grafting
(Figure 1). At 7 months post COMET, he developed MK that rapidly advanced to corneal perforation, necessitating a third tectonic PK, AMT and tarsorrhaphy. Unfortunately, the following month the graft showed evidence of melting amidst uncontrolled surface inflammation, prompting a fourth PK with lensectomy and further AMTs. Despite these interventions, his condition remained unstable, with recurrent epithelial defects managed with bandage contact lenses, dry and multilayered fresh AMT and insulin drops against a backdrop of prophylactic antibiotic and anti-inflammatory therapy (Figure 2). The patient’s visual acuity remained LP.

A year after the last surgical attempt, the patient suffered another MK episode which manifested as a large corneal abscess with extensive infiltrate and near-total epithelial defect (Figures 3, 4). Intensive antimicrobial therapy ensued, including hourly gentamicin, vancomycin drops and oral doxycycline, along with the addition of natamycin upon the appearance of new satellite infiltrates.

Figure 5. Ophthalmologists decided against further grafting in favour of photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL). Despite initial signs of improvement, the patient presented 10 days later with a large central corneal melt and perforation.

Figure 6. Imaging confirmed the patient also suffered a completely collapsed globe following PACK-CXL.

Corneal scrapes were again not helpful in identifying the pathogen. Despite the rigorous regimen, the infection persisted, and significant ocular surface toxicity developed due to prolonged antibiotic treatment.

Faced with a clinical dilemma, we decided against further grafting in favour of photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL)¹ using a total energy of 7.2 J. However, despite initial signs of improvement, the patient presented 10 days later with a large central corneal melt and perforation, with a completely collapsed globe (Figures 5, 6).

Intraoperatively, the risks associated with open sky tectonic keratoplasty were too great, and therefore we opted for tectonic epikeratoplasty (TEK) using an ethanol-preserved corneal button². This was sutured onto the recipient’s sclera following a conjunctival peritomy fully covering the damaged area (Figure 7). This less common approach, supported by literature as a practical interim solution, aims to maintain the structural integrity of the eye when the usual keratoplasty is not viable. TEK can potentially serve as a bridge to more definitive corneal transplantation, once the ocular surface is more stable and the risks associated with surgery are reduced.

However, TEK comes with its own set of challenges. Our patient’s postoperative period was marked by delayed epithelialisation, suture issues, and increased vascularisation of the graft, leading to another episode of severe MK. The inflammation was profound, and the patient’s vision regressed to no LP.

Confronted with the reality of recurrent graft failure and vision loss, and after much consideration of the physical and emotional burden endured, the patient and his family opted against further attempts at corneal transplantation, and chose evisceration, bringing to a close a long, complex medical journey.

Figure 7. The author performed tectonic epikeratoplasty using an ethanol-preserved corneal button sutured onto the sclera, following a conjunctival peritomy fully covering the damaged area. (Images courtesy of Artemis Matsou)

Discussion

An emerging trend of antimicrobial resistance complicates the already intricate management of MK. Despite timely and intensive antibiotic therapy, patients may still progress to corneal melt, perforation, and even endophthalmitis, mandating further surgical intervention. Performing keratoplasty on a “hot eye” carries an elevated risk of disease recurrence, uncontrolled intraocular pressure, and graft failure. With no major new classes of antibiotics developed since the 1980s and increasing antimicrobial resistance to existing treatments, there is a pressing need for alternative or adjunctive treatments to supplement current therapies, especially treatments that effectively tackle both infection and inflammation.

PACK-CXL has emerged as a promising option. The inherent antimicrobial activity of UV light and reactive oxygen species can address various pathogens, reducing reliance on antibiotics and increasing corneal resistance to enzymatic degradation. This makes PACK-CXL an attractive adjunct^3,4 in managing MK. It has been suggested as a potential first-line treatment in some cases of MK, offering the dual benefit of reducing bacterial load while reinforcing the corneal stroma. Since it does not rely on identifying a specific pathogen or using antibiotics, it can be particularly useful when facing drug-resistant infections. Early research has shown that PACK-CXL works particularly well for bacterial infections and is more effective on smaller ulcers. However, the evidence supporting its use especially in severe and fungal keratitis cases remains limited, with few randomised controlled trials and heterogenous patient cohorts, necessitating further high-quality studies to establish its efficacy and safety fully.

Conclusion

This challenging case of a young patient with complex ocular surface pathology showcases the relentless nature of keratitis and its profound impact on quality of life. Despite a sequence of surgical interventions and innovative treatments like PACK-CXL, the battle against recurring complications ended with the difficult choice of evisceration. This outcome highlights the inherent complexities of managing intricate ocular surface conditions, particularly in paediatric patients, who not only face the prospect of vision loss but also the disruption of their developmental and educational experiences.

The use of PACK-CXL demonstrated potential as an adjunctive treatment, underscoring the necessity for new modalities in the fight against MK. Meanwhile, TEK served as a valuable interim option to maintain globe integrity when traditional grafting methods were deemed too risky. However, the case also brought to light the limitations of current treatments and the urgent need for continued research and development of new therapies, especially as we face the growing challenge of antimicrobial resistance.

It is critical that as ophthalmologists we continue to pursue personalised care strategies that weigh aggressive treatment options against their long-term implications for patients’ well-being. This case reinforces the need for a thoughtful, evidence-based approach to treatment, and it calls for ongoing innovation and research to expand our therapeutic armamentarium for the preservation of the eye and vision in cases of severe infectious keratitis.

References

1. Hafezi F, Hosny M, Shetty R, et al. PACK-CXL Working Group. PACK-CXL vs. antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022 Jan 7;9(1):2. doi:10.1186/s40662-021-00272-0

2. Lazaridis A, Brouzas D, Sekundo W, et al. Tectonic epikeratoplasty with ethanol-stored donor corneas. Cell Tissue Bank. 2018 Dec;19(4):637-644. doi:10.1007/s10561-018-9714-1

3. Zloto O, Barequet IS, Weissman A, Ezra Nimni O, Berger Y, Avni-Zauberman N. Does PACK-CXL change the prognosis of resistant infectious keratitis? J Refract Surg. 2018 Aug 1;34(8):559-563. doi:10.3928/1081597X-20180705-01

4. Ting DSJ, Henein C, Said DG, Dua HS. Photoactivated chromophore for infectious keratitis - corneal cross-linking (PACK-CXL): a systematic review and meta-analysis. Ocul Surf. 2019 Oct;17(4):624-634. doi:10.1016/j.jtos.2019.08.006

Artemis Matsou, MD, MRCP(UK), FEBO | E: art.matsou@gmail.com

Miss Matsou is a consultant ophthalmologist and cataract lead at Queen Victoria Hospital, England, UK. She is a fellow of the European Board of Ophthalmology and a member of the Royal College of Physicians of London. She presented this case study as “Cornea in Crisis: A Tale of Relentless Keratitis” at the 2023 congress of the United Kingdom and Ireland Society of Cataract and Refractive Surgeons.