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Original Study

Microbial Keratitis After Corneal Collagen Cross-Linking for Corneal Ectasia

Khoo, Pauline BSc (Hons); Cabrera-Aguas, Maria MIPH, MBBS, PhD; Watson, Stephanie L. PhD, FRANZCO∗,†

Author Information
Asia-Pacific Journal of Ophthalmology: July/August 2021 - Volume 10 - Issue 4 - p 355-359
doi: 10.1097/APO.0000000000000379
  • Open

Abstract

INTRODUCTION

The introduction of corneal collagen cross-linking (CXL) has changed the way ophthalmologists manage certain corneal diseases such as keratoconus, post-LASIK ectasia, and pellucid marginal degeneration. These conditions cause progressive corneal thinning that leads to reduced vision1 and a poor quality of life.2,3 Corneal cross-linking aims to prevent or halt progressive vision loss due to the evolution of the pathology and to delay or avoid invasive surgical procedures such as corneal transplantation.4 Overall CXL is relatively safe but sight-threatening complications can occur, such as microbial keratitis.5,6

Randomized controlled trials have evaluated the effectiveness of CXL in halting the progression of keratoconus,7–12 but only 2 trials have reported a total of 2 cases of microbial keratitis post-CXL.9,11 Ten case reports,13 1 case series (4 patients),14 and an open-label clinical trial (8 patients)15 all treating keratoconic patients have documented post-CXL microbial keratitis from several countries, including Australia, Germany, India, Italy, Spain, Switzerland, Turkey, and the United Kingdom. Small patient numbers have been included in each report and series, such that data are lacking on the spectrum of infection in large patient cohorts. Early diagnosis and appropriate management are needed to ensure good outcomes from keratitis post-CXL. To inform clinicians, there is a need for current data on the microbiology spectrum, management strategies, and patient outcomes in these patients.

Contemporary local data on microbial keratitis post-CXL and assisting diagnosis and management informs data on global trends.16 To the best of our knowledge, this study represents the largest cohort of patients with microbial keratitis after CXL for corneal ectasia and the first from Australia. This study reports the clinical and microbiological features of patients that developing microbial keratitis post-CXL for the treatment of various corneal diseases in a large quaternary hospital in Sydney, Australia.

METHODS

A retrospective case series study was conducted including all adult patients with microbial keratitis, a history of CXL, and a corneal scrape performed between January 1, 2012 and December 31, 2019, presenting to the Sydney Eye Hospital (SEH), Sydney, Australia. Patients were identified from hospital coding and pathology data. The study adhered to the tenets of Declaration of Helsinki and was approved by the South Eastern Sydney Local Health District Human Research Ethics Committee (HREC ref 14/282 and HREC 14/315).

Medical records were reviewed, and the following data were collected: sociodemographic information, ocular and systemic history, clinical presentation (eg, best spectacle-corrected visual acuity, epithelial defect, hypopyon, and corneal thinning), pathology, management, and outcomes. Patient outcome was classified according to Khoo et al.17 Study data were collected and managed using REDCap (Research Electronic Data capture, Nashville, TN) hosted at The University of Sydney. Ulcer size was defined as the geometric mean of the longest diameter of the epithelial defect and infiltrate, and its perpendicular diameter.

Definition of Microbial Keratitis

The identification of microbial keratitis was determined by the treating clinician and based on the patient's medical history and clinical signs at the initial presentation at Sydney Eye Hospital. Furthermore, all suspected infectious corneal infiltrates and ulcers were scraped for microbial culture and antibiotic sensitivity analysis.

Microbiology

Corneal scrapes were taken in accord with local protocols from patients who had a clinical diagnosis of keratitis at presentation to the Sydney Eye Hospital.18 Briefly, samples were collected using sterile surgical blades or disposable needles. Superficial corneal samples were directly plated onto 2 glass slides for microscopy and culture media (2 blood agars, chocolate agar, Sabouraud's agar slope, and cooked meat medium) in the clinic. Corneal swabs were also taken for polymerase chain reaction (PCR) testing for detection of herpes simplex virus (HSV) and Acanthamoeba DNA. At our institution, separate corneal swabs are used for HSK and Acanthamoeba PCR and the swabs are taken from the edge and base of the ulcer. Samples were then delivered to New South Wales Health Pathology. A positive culture was defined as any bacterial or fungal growth of an organism in the inoculating streak of any culture medium, as previously detailed.19

CXL Procedure

At our center, CXL was performed in the operating theaters. The CXL procedure used involved the application of povidone iodine 5% followed by the removal of the corneal epithelium with 20% alcohol followed by 0.1% riboflavin (Peschke H, Compounded 0.1% Hypotonic, Compounded 0.1% Isotonic) every 2 minutes for 30 minutes. Corneas were then irradiated with ultraviolet A 365 nm light using the UVX (IROC Innocross UV-X 2000, Zug, Switzerland) at an irradiance of 9 mW/cm2 for 10 minutes, delivering a cumulative energy dose of 540 J/cm2. The procedures were performed in an aseptic room and strict hygiene and sterilization rules were followed. A bandage contact lens (BCL) (Purevision, Bausch and Lomb, USA) was placed at the end of the procedure.

Statistical Analysis

Statistical analysis was performed using SPSS software (version 24 for Mac, IBM). Descriptive statistics summarized the sociodemographic, clinical characteristics, pathology, and treatment for this case series.

The incidence of microbial keratitis after CXL at our institution was calculated by dividing the total number of microbial keratitis cases by the total number of CXL procedures performed at SEH over the 8 years (n = 246). Only eyes that had CXL surgery at the SEH were included in the incidence analysis (ie, 6/11 cases were performed at SEH).

RESULTS

Over the 8 years, microbial keratitis occurred in 10 eyes of 10 patients (2 females and 8 males) after CXL surgery. Patient number 4 had 2 episodes of microbial keratitis during the study period. The incidence of microbial keratitis after CXL at our institution was 2.4% (6/246). Nine of the patients were treated with epithelium-off CXL and 1 was unknown as their procedure was performed elsewhere. The majority of patients had CXL for keratoconus (n = 8 patients, 80%) (Table 1). The mean age ± standard deviation was 29 ± 11 years (range 16–48). The median time to infection after CXL surgery was 4 days [interquartile range (IQR) 3–83). The median initial Visual acuity (VA) at presentation was 1.30 logMAR (IQR 0.94–2), and final VA was 0.83 logMAR (IQR 0.56–1.18) (P = 0.056). The change from initial VA to final VA was 0.4 logMAR (0.13–0.60). All patients were admitted to hospital with a median hospital admission of 9 days (IQR 7.5–16) (Table 1). The median healing time was 30 days (IQR 15–53).

TABLE 1 - Demographics and Clinical Characteristics of Patients With Microbial Keratitis Following CXL
Patient No. Age, y, Sex Diagnosis Type of Procedure Initial VA (logMAR) Final VA (logMAR) Days of Hospital Admission
1 42, M Keratoconus Epi off 1.30 1.7 9
2 27, M Keratoconus Epi off 2.00 0.48 6
3 31, M Keratoconus Epi off 0.50 0.78 8
4a 35, M Keratoconus Unknown 0.86 0.58 17
4b 36, M Keratoconus Unknown 0.88 1.0 9
5 32, M Pellucid marginal corneal degeneration Epi off 1.00 0.48 7
6 17, M Keratoconus Epi off 2.30 CT 15
7 48, F Post-LASIK ectasia Epi off 1.20 1.7 5
8 16, M Keratoconus Epi off 2.00 1.7 21
9 18, M Keratoconus Epi off 1.70 0.88 12
10 27, F Keratoconus Epi off 2.00 CT 25
CT indicates corneal transplantation; CXL, corneal collagen crosslinking; Epi off, epithelium off; F, female; M, male.Note: Patient 4 had 2 episodes of microbial keratitis. Final VA was not recorded in patients who had a corneal transplant.

After CXL, 81% of cases were administered topical fluoroquinolone (ie, ofloxacin, 75% of cases) and topical steroids (ie, dexamethasone) for postoperative CXL treatment. The majority of our patients with microbial keratitis post-CXL were treated with fortified antibiotics (a combination of gentamicin and cephalothin, 82%). Based on results from the microbiological sample, treatment was then modified in 73% of patients; with moxifloxacin most commonly prescribed (n = 4, 36%).

Topical steroids for postoperative treatment for CXL were ceased in all patients at their initial microbial keratitis visit and reintroduced in 82% of cases after identification of the causative organism and under appropriate antibiotic cover. The median duration of commencing topical steroid post corneal scrape was 4 days (IQR 3–7) with unpreserved prednisolone prescribed in 75% of patients.

Predisposing risk factors for microbial keratitis were reported in all 11 cases. The most common risk factors were BCL wear (82%) and topical steroids which were given for post-CXL treatment (73%). Additional possible associations observed included corneal hydrops (n = 1, 9%), eczema (n = 1, 9%), previous refractive surgery (n = 1, 9%), and previous bacterial keratitis (n = 1, 18%).

A total of 11 corneal scrapes were performed (1 patient had a re-scrape). There was a positive culture from 11 of 12 corneal scrapes (92%), which identified 13 isolates. There was a positive culture from 11 of 12 corneal scrapes (92%), which identified 13 isolates, mainly Coagulase-negative Staphylococcus (n = 6, 50%) and Staphylococcus aureus (n = 3, 25%) (Table 2). Patient 10 had a re-scrape and corneal biopsy performed, identifying Staphylococcus capitis and Pseudomonas synxantha, respectively. HSV, Herpes zoster ophthalmicus, and Acanthamoeba PCR results were negative for all patients.

TABLE 2 - Microbiology Profile of Patients With Microbial Keratitis Following CXL
Patient No. Corneal Scrape Result Antimicrobial Sensitivities Antimicrobial Resistance
1 Staphylococcus aureus Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin, Vancomycin
2 Staphylococcus capitis Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin, Vancomycin
Streptococcus milleri Chloramphenicol, Ciprofloxacin, Gentamicin, Moxifloxacin Vancomycin
3 Staphylococcus epidermidis Cephalothin, Vancomycin Chloramphenicol, Ciprofloxacin, Gentamicin
4a Micrococcus luteus Chloramphenicol, Ciprofloxacin, Gentamicin, Vancomycin Cephalothin
4b Staphylococcus capitis Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin, Vancomycin
5 Serratia marcescens Chloramphenicol, Gentamicin Cephalothin
6 Staphylococcus aureus Cephalothin, Chloramphenicol
7 Staphylococcus epidermidis Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin
Moraxella osloensis Chloramphenicol, Moxifloxacin
8 No growth
9 Staphylococcus epidermidis Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin
10 Staphylococcus aureus Cephalothin, Chloramphenicol, Ciprofloxacin, Gentamicin
Staphylococcus capitis Cephalothin, Chloramphenicol
CXL indicates corneal collagen crosslinking.

At final follow-up, 45% of eyes had a moderate outcome (VA between 6/12 and 6/60), and 55% had a poor outcome (VA worse than 6/60). Two patients required corneal transplantation (patients 6 and 10). Patient 6 required penetrating keratoplasty 8 days after CXL, and patient 10 required a deep anterior lamellar keratoplasty 46 days post-CXL. Both patients required the transplant for tectonic purposes due to severe keratitis that could not be controlled via medical treatment alone (Table 1).

DISCUSSION

Cross-linking is one of the most widely used treatment strategies for progressive corneal ectasia. Despite the safety profile of the procedure, there has been an increase in reports of microbial keratitis after CXL.13,14,20 Our study is the largest cohort of patients with post-CXL keratitis. We identified contact lens wear (BCL) and previous topical steroid use for post-CXL treatment to be the most common predisposing risk factors and Staphylococcus species to be the main causative organism. We also found microbial keratitis after CXL surgery resulted in moderate to poor patient outcomes, as vision was impacted, with final visual acuity ranging from 6/18 to counting fingers.

Collagen CXL is a minimally invasive procedure but requires the removal of the epithelium and exposure of the corneal stroma for the delivery of riboflavin then irradiation. The resultant epithelial defect can take from 2 to 5 days to heal. An intact corneal epithelium is important for defence against infection, and only a number of bacteria can penetrate an intact corneal epithelium (eg, Neisseria gonorrhoeae, Corynebacterium diphtheriae). A compromised epithelium due to CXL is a likely predisposing risk factor for microbial keratitis. From the data available, all of our cases had epithelial off CXL. In our study, 42% of the causative organisms were Coagulase-negative staphylococcus (CoNS). Bacteria such as CoNS (eg, Staphylococcus epidermidis) are common components of the normal ocular flora.21 Ocular flora is important for ocular health because nonpathogenic floral bacteria reduce the risk of opportunistic pathogenic stains gaining a foothold. Riboflavin/ultraviolet A has antibacterial activity and is effective in inhibiting bacterial growth that is found as part of the ocular flora.22 However, CXL may change the normal ocular flora, possibly increasing the risk of infection, especially when the corneal epithelium is compromised.17

Infectious keratitis exists in all geographic regions of the world23 and knowledge of the pathogenic patterns of the infections is important for clinicians who treat keratitis empirically. Our study found the most common causative organism to be CoNS, which aligns with a 5-year retrospective study performed in Sydney, Australia.24 However, in countries such as the United States where CoNS and Streptococcus25 are the most common causative organisms or India where Fusarium spp26 is the most common, empirical treatment of keratitis should be given based on their pathogenic patterns.

The causative organisms identified in case reports of post-CXL keratitis have ranged from bacteria to herpes virus, fungal, and even Acanthamoeba.13,27–29 Shetty et al reported 4 patients with moxifloxacin-resistant S aureus.14 In Tzamalis et al, S aureus was the only organism isolated in all 9 cases.15 The microbiological cultures from these studies were identified through corneal scrapings, contact lens culture, PCR analysis of tears, corneal swabs, conjunctival swabs, and nose swabs. As laboratory sampling and geographic location varied among studies, a comparative analysis was difficult to perform. In our study, all corneal scrape cultures were bacterial. It is possible that some of our cases may have had polymicrobial infections. However, routine testing at our institution for HSV, fungal, and acanthamoeba made this unlikely.

In previous studies, patients with Pseudomonas aeruginosa, acanthamoeba, and fungal infections had poor patient outcomes as these patients required corneal transplantation. In our study, all causative organisms were bacteria, with S aureus infection cases having worse patient outcomes. Two of the 3 cases required corneal transplantation and the third patient's vision decreased from 6/120 at presentation to count fingers. These data from this study inform clinicians that early and prompt treatment is needed with patients identified with gram-positive organisms, such that postoperative antibiotic prophylaxis should include gram-positive cover.

Indeed, in our case series, most patients received a fluoroquinolone (specifically ofloxacin) postoperatively. Fluoroquinolones are bactericidal against a broad spectrum of bacteria including some generally resistance species such as S aureus.30,31 Abbouda et al suggest patients’ behavior as the most common risk factor associated with postoperative infection.13 Due to the retrospective nature of our study, we were unable to determine patients’ behavior particularly in terms of postoperative treatment compliance and hygiene. However, this suggests that the risk of infection is not due to antibiotic coverage but possibly due to noncompliance of treatment. Clinicians should communicate to patients the need for good postoperative compliance and hygiene.

The median healing time (ie, reepithelization time) of our patients differed from other published studies on microbial keratitis. Existing literature on microbial keratitis reported a median healing time between 7 and 9 days.32,33 In our study, the median healing time was 30 days. Studies evaluating microbial keratitis in patients with a history of ocular surface disease have proposed that post-CXL patients have more severe keratitis due to the disruption of the corneal epithelium, which creates possible openings for microbial invasions and may delay healing.17,34 The exposed cornea during CXL could explain the delay in reepithelization in our cohort.

For many years, the CXL protocol involving epithelial debridement (epi-off) has been the standard practice due to its efficacy. But there are disadvantages of epithelial debridement, including the risk of infection, postoperative pain, delayed epithelial healing, stromal haze and corneal melting.35,36 Over the last decade, the CXL technique has advanced. The epi-on technique has been postulated to shorten the duration of discomfort and lower the risk for corneal infection and haze through leaving the epithelium intact.37,38 However, although epi-on CXL has fewer complications than epi-off, it is not as effective in stabilizing or improving keratoconic corneas.37 The epi-on technique could reduce the incidence of microbial keratitis; however, further modifications and standardization of the technique are needed before it is seen in clinical practice. Techniques such as iontophoresis and enhanced riboflavin formulations may improve the efficacy of epi-off CXL.

It is worthwhile to note CXL has recently been used as a treatment option for corneal ulcers; however, as we have shown it can also lead to infections. Epithelial debridement before riboflavin application removes the cornea's natural barrier to microbial infiltration. Keratitis can occur after CXL due to the presence of an epithelial defect, use of BCL, and/or topical steroids in the immediate postoperative period. In cases of infection post-CXL, the microbial invasion is likely to occur during the postoperative period rather than during surgery as CXL not only damages keratocytes but also kills bacteria and fungi.39

Post-CXL treatment typically includes the use of topical antibiotic and steroids. It is known that topical steroids can be used to control inflammation, improving clinical outcomes.40 However, their immunosuppressive effect may promote bacterial replication and slow the recovery, exacerbating the infection. Tzamalis et al investigated the role of BCLs and topical steroids in the development of microbial keratitis after CXL in a comparative open clinical trial.15 They found delaying the use of topical steroids until the epithelium healed, reduced the likelihood of infection.15 Our study showed >70% of patients had used topical steroids and worn a contact lens (ie, BCL) within 1 month prior to infection. Tzamalis et al showed microbial keratitis developed in 9 cases wherein both BCL and topical steroids were given compared to no infections occurring in topical steroid only. However, due to their study design, it was not possible to determine whether the use of a BCL, topical steroid, or their combination led to an increase in infection.

This study has several limitations such as the retrospective study design and the setting of where the study took place. The Sydney Eye Hospital is a quaternary referral hospital, which may have an overrepresentation of more severe cases of microbial keratitis. Nevertheless, our study highlights the potential risks associated with CXL and suggests these patients are more likely to have more severe keratitis and poor outcomes. Understanding the impact of CXL with respect to microbial keratitis will assist with management and patient outcomes. Future studies should perform prospective clinical trials to investigate the effects of the use of BCL and topical steroids and patient compliance and hygiene post-CXL.

To the best of our knowledge, this study represents the largest cohort of patients with microbial keratitis after CXL. For most of our patients, microbial keratitis occurred in the immediate postoperative period and their outcomes were moderate to poor. We recommend clinicians stress the importance to their patients to avoid touching and rubbing their eyes, washing their hands before instilling eye drops, and promote postoperative treatment compliance to avoid infections.

Acknowledgements

The authors acknowledge the corneal unit at the Sydney Eye Hospital who managed the patients with microbial keratitis in this case series.

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Keywords:

corneal cross-linking; corneal infection; keratitis; microbial keratitis

Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.