Dr. Pranita Sahay, Dr. PRAFULLA KUMAR MAHARANA, Dr. Jeewan S Titiyal, Dr. Namrata Sharma
Abstract
Purpose:
To assess pattern of microbial keratitis following accelerated corneal collagen cross-linkage (aCXL) in keratoconus (KC) patients.
Method:
Medical record review of cases of KC that underwent aCXL from June 2014 – May 2018.
Results:
Seven cases of microbial keratitis were noted with median age 11 years and associated vernal kerato-conjunctivitis in 57.1%. Median time of onset was 3 days following aCXL. Microbiology revealed mixed infection in three cases [Coag. negative Staph. (CoNS) + Asp. fumigatus, Staph. aureus and Mucor spp., Staph. aureus and Acanthamoeba], Staph. aureus in 2, CoNS and Alternaria spp. in 1 case each. Resistance to 4th generation floroquinolone(FQ) was seen in 83.3%. One case required therapeutic keratoplasty. At 6 months, the corrected distance visual acuity was >6/60 in 3 cases only.
Conclusion: Microbial keratitis following aCXL is rare, however the infection tends to be severe with high preponderance of mixed infection and resistance to 4th generation FQ.
Introduction
Corneal collagen cross-linking (CXL) is the gold standard treatment for halting the progression of keratoconus.1Though CXL is a safe procedure, visually disabling complications such as corneal haze and infectious keratitis have been reported in the past.2 AcceleratedCXL (aCXL) is a relatively new protocol of CXL that delivers high power of UV-A radiation in a short span of time to achieve comparable results to the standard Dresden protocol. Most of the reports on microbial keratitis following CXL have been reported with Dresden protocol.3-6Shetty et al. reported an incidence of 0.0017% microbial keratitis following CXL using Dresden protocol.5 There is only a single case report of microbial keratitis following aCXL. Herein we report a series of seven cases of microbial keratitis following aCXLperformed at a single centre over a period of three years for cases of progressive keratoconus.
Material and methods
A retrospective review of records of 532 aCXLprocedures (412 iso-osmolar and 120 hypo-osmolar)performed over a period of 4 years(June 2014to May 2018) at a tertiary eye care Centre in North India, for cases of progressive KC was performed. Various parameters that were analyzed include epidemiological features, onset of keratitis, visual acuity at presentation and last follow-up, treatment received, organism isolated, drug sensitivity patterns, treatment outcomes, healing time, complications and scar size at last follow-up. The study adhered to the declaration of Helsinki. Approval for conducting the study was obtained from institutional review board/ethics committee of All India Institute of Medical Sciences, New Delhi, India.
Iso-osmolar aCXL was performed for case with thinnest pachymetry >400 µm while hypo-osmolar aCXL was done for cases with pachymetry <400 µm.
Accelerated CXL was performed under topical anesthesia, proparacaine hydrochloride 0.5% (Paracain, Sunways Pvt. Ltd., India) under sterile condition. Subsequently20% ethyl alcohol was applied onto the central 8mm zone to loosen the epithelium followed by epithelium debridement. Riboflavin phosphate (0.1%; 10 mg of riboflavin-5-phosphate in 10 mL of dextran-T-500, 20% solution for iso-osmolar cases and 0.1% riboflavin in 0.9% saline instead of dextran for hypo-osmolar cases) was applied every 2 minutes for 20 minutes followed by UV-A exposure (365 nm wavelength), from a distance of 50 mm, at 18 mW/ cm² for 6 minutes with continuous application of riboflavin 0.1% drops every 30 seconds. At the end of the procedure, a bandage contact lens (Purevision, Bausch &Lomb, Bangalore) was applied in all cases. Post-operatively all patients were prescribedtopicalmoxifloxacin hydrochloride 0.5% (Vigamox,Alcon,Texas) TDS and carboxymethyl cellulose 0.5% 6 times a day. All the cases were followed up on day 1, day 4, 1 week, 1 month, 3 months and 6 months.
The bandage contact lens (BCL)was removedafter complete healing of the epithelium was observed. Alow potency topical steroid, fluorometholone0.1% TDS (FML, Allergan India Pvt. LTD) was started and tapered over next 3 weeks. If there was any suspicion of keratitis on follow up then as a standard protocol the BCL was removed and sent for culture and sensitivity testing (bacterial, fungal and acanthamoeba). Corneal scraping was performed with Kimura spatula and sample was sent for microbiological assessment- smear examination (Gram stain, 10% KOH fresh mount and Calcoflour white), culture (Blood agar, Sabouraud’s dextrose agar and Non- nutrient agar with E.coli overlay) and sensitivity testing. Confocal microscopy was performed in all cases.
Results
Seven cases developed post aCXL microbial keratitis. The baseline characteristics of all cases have been described in Table-1. Medianage ofpatients was11 years (8 to 17 years) includingfive male and two female patients. The median time from procedure to presentation was 3 days (range 1 to 4 days). Association with vernal kerato-conjunctivitis (VKC) was noted in 57.1% of cases (n=4/7).
The presenting visual acuity ranged between 6/18 to finger counting close to face (FCCF).The ulcer size ranged between 2×2 mmto 4.5×5 mmwith infiltrate size varying from 2x2mm to 6×7 mm. [Table-1] all cases except one resolved with scarring. The depth of the ulcer varied from superficial to deep stromal involvement. The scar size ranged between 2×2 mm to diffuse corneal scar involving the visual axis in almost all cases.[Table 2]The visual acuity at last follow up ranged between FCCF to 6/18.
Microbiological reports revealedpresenceof mixed infection in three cases [Coagulase-negative Staphylococcus (CoNS) andAspergillus fumigatus, Staph. aureus andMucor spp., Staph. aureus andAcanthamoeba], Staph. Aureus in two,CoNSandAlternaria spp. in one case each. Culture of BCL was positive in three of the seven cases. Confocal microscopy revealed presence of double walled cyst in one case. All cases were initially managed with empirical topical antibiotic treatment (concentrated cefazolin 5% and tobramycin 1.3%) which was later tailored basedon themicrobiological reports (Table-3).The culture sensitivity reports revealed resistance to fourth generation floroquinolones in 83.3% cases (n=5/6) with all cases being sensitive to chloramphenicol and tetracycline. In one case, the ulcer progressed despite maximal anti-microbial therapy and eventually required therapeutic penetrating keratoplasty (TPK) for corneal perforation.At 6 months follow up, uncorrected distance visual acuity was >6/60 in 3 cases while 4 cases were <6/60.
Discussion
Microbial keratitis is a sight threatening complication of CXL. On review of literature, we found17 cases of post CXL keratitis with 11 isolated case reports and one case series (Table 4).3-14
In our study, we report the first case series of microbial keratitis post aCXL. The mean age of the cases was 12.3 years (range 8 – 14 years), which was less compared to the previous reported cases (mean 24.2 years, range 15-24 years). In addition, the median time for presentation in our study was 3 days (range 1-4 days), which was less compared to the previous literature (mean 5 days, range 2-21 days). The presence of associated VKC was noted in 57.1% of our cases. Due to the high incidence of pediatric keratoconus in our region in association with VKC, we deal with numerous pediatric cases undergoing aCXL for progressive keratoconus. Thereby our patients are much younger than the cases previously reported. We hypothesize that young age is itself a risk factor for post CXL infection in developing countries where hygiene and environmental factors are of significant concern. In addition, the poor understanding and compliance with the post- operative precautions in children is an additional problem.
The incidence of microbial keratitis post aCXL in our study was 1.3% in comparison to 0.0017% post CXL. The higher incidence of infection observed in our series can be largely attributed to the poor compliance and post-operative care of the eye by the patients. In addition, a higher proportion of young patients and association of VKC that frequently requires prolonged topical steroid therapy might have contributed to the higher incidence in our series.
Bacterial keratitis was the most common type of corneal infection reported in literature (68.75%, n= 11/17) post CXL. We report a 60% incidence of polymicrobial infection in culture proven cases in our study, while only one case report of polymicrobial bacterial infection has been previously reported by Zamora et al.12This highlights the need for keeping a high suspicion for polymcrobial infection if there is poor response to the antibiotic regimen and microbiological reports are inconclusive. The exact reason for a higher proportion of polymicrobial cases is difficult to ascertain in our series. However, the higher proportion of mixed infection can be due to the different demographic profile of our patients. Associated VKC,which is quite common in our set up, often requiring long-term steroid therapy, may predispose to mixed infection.
A review of the microbiology of the reported cases suggestsStaphylococcusaureus the most common bacteria isolated in such cases. In our series,Staph.aureus was the most common isolated bacteria as well. Shetty et al reported 4 cases (100%) of Moxifloxacin resistantStaphylococcus aureus (MXRSA) in their series. We also found similar results with 83.33% of our cases showing resistance to Moxifloxacin,
which were sensitive to broad-spectrum antibiotics like tetracycline and chloramphenicol. The rampant and irrational use of fourth generation floroquinolones in our country may very well explain the above finding. Another factor that might have contributed to this increased resistance pattern is high power of the UV radiation used in aCXL can induce mutation and drug resistance in the commensal microorganisms. It is a common practice by private practitioner, at least in our country, to start with a fourth generation floroquinolone as the initial antibiotic therapy. The results of this study suggest thatfourth generation floroquinolonesshould be avoided in such cases. A combination of concentrated topical cephalosporin and tobramycin may be the best option in such cases.
In one of our case, the patient developed keratitis on 3rd day that was positive for Alternaria spp. The ulcer progressed despite maximal therapy ultimately resulting in corneal perforation within next 5 days for which a TPK was performed. Rana et al reported 2 cases of post CXL microbial keratitis that ultimately perforated despite optimal therapy.8 The first case was positive for Staph. aureus while the second case was positive for Methicillin resistant staphylococcus aureus (MRSA). Both the cases were managed with corneal gluing. Similarly Rama et al reported a case of post CXL microbial keratitis in a 32 years old male with Acanthamoeba keratitis that responded poorly to anti-acanthamoeba therapy and the patient eventually underwent TPK for corneal perforation on day 11.9
The patient had history of washing his eyes with tap water on the day following CXL while the BCL was in situ. Thus, an overall analysis suggests a higher rate of perforation 16.6% (n= 4/24) in such cases. This may be due to multiple factors such as a large epithelial defect to begin with, concomitant use of BCL and use of steroids and NSAIDs in the immediate post-operative period. This highlights that the course of post CXL infection can be fulminant and patients must be counseled about this grave complication.
Shetty et al.in 2014 reported the largest case series of post CXL microbial keratitis wherein 4 cases of Moxifloxacin resistantStaphylococcus aureus (MXRSA) were found.5All cases in this study developed infiltrate on third post-operative day and were treated with increased frequency of topical Moxifloxacin while culture sensitivity reports were awaited. All cases developed worsening over the next two days when the antibiogram reports were awaited. Microbiological reports revealed MXRSA following which cases were immediately shifted to fortified antibiotics. Complete clinical resolution was noted by 6 weeks. Two cases were advised optical penetrating keratoplasty, one case was rehabilitated with RGP lens while 1 case underwent amniotic membrane grafting for stromal melting. Use of long term pre-operative oral/topical steroids for chronic allergic disorder was thought to be an important predisposing factor for infection in this study as it leads to a state of immunocompromise.
Reactivation of Herpes simplex virus has been implicated for microbial keratitis following CXL.3,7Exposure to UV-A radiation, use of steroids in the immediate post-operative period and mechanical trauma to the corneal epithelium during epithelium debridement may be the contributing factors.3The other reported organisms were Pseudomonas aeruginosa by Sharma et al, 4 E. coli by Pollhamer et al, 6Microsporidia by Gautam et al.10Pseudomonas infection is often considered as the most common organism associated with CL use. It is surprising to see the rare isolation of pseudomonas in literature in post-CXL keratitis cases (only one report).
This implicates, BCL use may not be the single most important factor in post-CXL keratitis, as hypothesized previously. All our cases presented with features as seen in any case of keratitis. Garcia-Delpech et al have reported a case of fusarium keratitis following CXL that presented with features of infectious crystalline keratopathy.
Kodavoor et al reported the first case of microbial keratitis post accelerated CXL.13 The patient was a 15 years old male who presented on 2ndday after the procedure with a central deep stromal infiltrate and hypopyon for which he was started on topical moxifloxacin and tobramycin along with systemic antibiotic. Complete resolution was noted at 3 weeks following which a short course of topical steroid was given. BCVA of 20/40 was noted at 6 months follow up. This is the first case series of post aCXL keratitis to the best of our knowledge.
To summarize, the incidence of microbial keratitis following aCXL is rare. Young age, long-term use of steroids, use of BCL, association withVKCandpoor compliance to the post-operative regimen may contribute to an increased risk of microbial keratitis following CXL. Multiple risk factors such as large epithelial defect, use of steroid and BCL in the immediate post-operative period may predispose the cornea to polymicrobial infection and a poor outcome. It is difficult to comment upon the increased resistance to 4th generation floroquinolones seen in our study, in view of the smaller sample size. However, we recommend that physicians must be careful while selecting these drugs as they may lose an important option while treating vision threatening complications such as microbial keratitis.
References
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a–induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–7.
- Sykakis E, Karim R, Evans JR, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev. 2015;3:CD010621.
- Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg. 2007;33:1982–4.
- Sharma N, Maharana P, Singh G, et al. Pseudomonas keratitis after collagen crosslinking for keratoconus: Case report and review of literature. J Cataract Refract Surg. 2010;36:517–20.
- Shetty R, Kaweri L, Nuijts RM, et al. Profile of microbial keratitis after corneal collagen cross-linking. BioMed Res Int. 2014;2014:340509.
- Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg. 2009;35:588–9.
- Al-Qarni A, AlHarbi M. Herpetic Keratitis after Corneal Collagen Cross-Linking with Riboflavin and Ultraviolet-A for Keratoconus. Middle East Afr J Ophthalmol. 2015;22:389–92.
- Rana M, Lau A, Aralikatti A, et al. Severe microbial keratitis and associated perforation after corneal crosslinking for keratoconus. Contact Lens Anterior Eye J Br Contact Lens Assoc. 2015;38:134–7.
- Rama P, Di Matteo F, Matuska S, et al. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. J Cataract Refract Surg. 2009;35:788-91.
- Gautam, Jhanji V, Satpathy G, et al. Microsporidial keratitis after collagen cross-linking. OculImmunolInflamm. 2013;21:495–7.
- Garcia-Delpech S, Díaz-Llopis M, Udaondo P, et al. Fusarium keratitis 3 weeks after healed corneal cross-linking. J Refract Surg. 2010;26:994–5.
- Zamora KV, Males JJ. Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report. Cornea. 2009;28:474–6.
- Kodavoor SK, Sarwate NJ, Ramamurhy D. Microbial keratitis following accelerated corneal collagen cross-linking. Oman J Ophthalmol. 2015;8:111.
- Pérez-Santonja JJ, Artola A, Javaloy J, et al. Microbial keratitis after corneal collagen crosslinking. J Cataract Refract Surg. 2009;35:1138-40.
Table Legends
Table-1: Baseline Characteristics of the Study Cohort
Table-2: Microbiology and Outcome of the study cohort
Table-3: Antibiotic Sensitivity Pattern in Bacterial keratitis
Table 4: Review of Literature
Table-1: Baseline Characteristics of theStudy Cohort
| S.No | Age
(in years) |
Sex | Day of presentation*
(in days) |
Eye involved | UDVA
(at presentation) |
Associations | Ulcer location | Ulcer Size
(in mm) |
Infiltrate Size
(in mm) |
Hypopyon |
| 1 | 14 | M | 3 | OD | 6/18 | – | C | 2×3 | 3×3 | Absent |
| 2 | 17 | M | 2 | OS | FCCF | – | C+S | 4X3.5 | 4X5
|
Present |
| 3 | 14 | M | 2 | OS | 1/60 | VKC | C | 2.4X3
|
2X2.8 | Absent |
| 4 | 8 | M | 1 | OS | FCCF | – | D | 3.5X5 | 7X6 | Present |
| 5 | 11 | F | 3 | OS | 6/60 | VKC | C | 2X2 | 3X2 | Absent |
| 6 | 11 | F | 3 | OS | FCCF | VKC | C | 4.5X5 | 6X5 | Absent |
| 7 | 11 | M | 4 | OS | FCCF | VKC | C | 3X3 | 6X6 | Present |
Footnotes
M- male, F- Female; UDVA- Uncorrected distance visual acuity; OD- right eye; OS- left eye; HMCF- hand movement close to face; FCCF- finger count close to face; VKC- vernal keratoconjunctivitis; C- central cornea; S- superior cornea; D- diffuse cornea; * Day of presentation (in days) from day of accelerated corneal collagen crosslinking
Table-2: Microbiology and Outcome of the study cohort
| S.No | Smear report | BCL culture | Corneal scraping culture | Confocal microscopy | Ulcer Healing (in days) | Time to resolution (in days) | Final BCVA | Outcome | Scar Size
(in mm) |
Scar Type | Complication | Rehabilitation |
| 1 | Gram +ve cocci | – | Staph. epidermidis
Asp. fumigatus |
– | 7 | 21 | 6/18 | Corneal scar | 2×2 | LCO | – | CL |
| 2 | Gram +ve cocci | Staph. aureus | Mucor | – | 9 | 24 | 6/36 | Corneal scar | 4×3 | LCO | – | CL |
| 3 | Gram +ve cocci | – | Staph. aureus | – | 5 | 10 | 6/18 | Corneal scar | 2×3 | LCO | – | CL |
| 4 | Gram +ve cocci | Staph. aureus | – | Cyst present | 15 | 35 | 1/60 | Corneal scar with cataract | Diffuse | NMCO | Cataract | Triple Procedure |
| 5 | Gram +ve cocci | – | Staph. epidermidis | – | 7 | 10 | 2/60 | Corneal scar | 2X2 | MCO | – | CL |
| 6 | Hyphae | – | Alternaria spp. | – | – | – | 3/60 | Therapeutic keratoplasty | TPK | TPK | Perforation | TPK |
| 7 | Negative | Staph. aureus | – | – | 10 | 22 | FCCF | Corneal scar | 5×4.5 | LCO | CL |
Footnotes
BCL- bandaged contact lens; CL- contact lens; BCVA- best corrected visual acuity; FCCF- finger count close to face; TPK- therapeutic penetrating keratoplasty, LCO- leucomatous corneal opacity, NMCO- nebulomacular corneal opacity, MCO- macular corneal opacity, TPK- therapeutic penetrating keratoplasty
Table-3: Antibiotic Sensitivity Pattern in Bacterial keratitis
| Case No | Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | Case 7 |
| Organism | Staph. epidermidis | Staph. aureus | Staph. aureus | Staph. aureus | Staph.epidermidis | Staph. aureus |
| Ciprofloxacin | S | R | R | R | R | R |
| Tobramycin | S | S | S | S | S | S |
| Chloramphenicol | S | S | S | S | S | S |
| Tetracycline | S | S | S | S | S | S |
| Gentamycin | S | S | S | S | S | S |
| Cefazolin | S | S | S | R | S | S |
| Erythromycin | S | – | – | – | – | R |
| Clindamycin | S | – | – | – | – | S |
| Vancomycin | S | – | – | S | – | S |
| Moxifloxacin | S | R | R | R | R | R |
| Gatifloxacin | S | R | R | R | R | R |
| Amikacin | S | – | – | – | – | S |
| Oxacillin | – | R | R | R | R | R |
Footnotes
S- sensitive; R- resistant
Table 4: Review of literature
| Author | Type of study | n | Follow up | Age/ Sex | Sex | Type of CXL | CDVA at presentation | Time to presentation | Post operative regimen | Microbiology | CDVA on last follow up | Outcome |
| Kymionis at al [3] | Case report | 1 | 2 | 21 | F | CXL | 20/25 | 5 | Tobramycin–dexamethasone | HSV | 20/25 | Residual haze
|
| Pollhammer et al [6] | Case report | 1 | 4.5 | 42 | – | CXL | 20/400 | 3 | – | E. coli | 20/63 | Stroma l scar |
| Rama et al [9] | Case report | 1 | 2 | 32 | M | CXL | – | 5 | Ofloxacin
Flurbiprofen |
Acanthamoeba | 20/40 | TPK |
| Pe´rez-Santonja et al [14] | Case report | 1 | 5 | 29 | F | CXL | 20/20 | 2 | Cyclopentolate
Ciprofloxacin
|
Staph. Epidermidis | 20/22 | Mild residual haze
|
| Zamora et al [12] | Case report | 1 | 2 | 32 | F | CXL | Counting fingers | 3 | Ketorolac tromethamine
Ciprofloxacin |
Mixed infection* | 20/50 | Stromal haze
|
| Sharma et al [4] | Case report | 1 | 2 | 19 | F | CXL | HMCF | 3 | Prednisolone
Moxifloxacin 0.5% 3 times a day |
P. aeruginosa | 20/200 | Leucomatous
corneal opacity |
| Gautam et al [10] | Case report | 1 | 42 | 36 | M | CXL | FCCF | 6 | Fluorometholone, Moxifloxacin, lubricants | Microsporidia | 20/60 | Corneal scar |
| Shetty et al [5] | Case series | 4 | – | 27
18
25
16
|
F
M
M
M |
CXL | – | 3
3
3
3
|
Moxifloxacin | Staph. aureus | 20/20
20/30
20/120
20/200 |
–
AMG |
| Rana et al [8] | Case report | 2 | – | 19
18 |
F
F |
CXL
|
– | 3
5 |
– | MRSA |
FCCF |
Perforation-corneal glue for both cases |
| Awad Al-Qarni [7] | Case report | 2 | – | 18
21 |
M
M |
CXL | – | 6
9 |
Predinsolone acetate
Ofloxacin Cyclopentolate |
HSV
|
– | Corneal opacity |
| Garcia-Delpech [11] | Case report | 1 | – | 23 | F | CXL | – | 21 | – | F. solani | – | |
|
Kodavoor et al [13]
|
Case report | 1 | 6 | 15 | M | aCXL | 20/400 | 2 | – | Staph. aureus | 20/40 | NMCO |
Footnotes
n- number of cases, CXL- collagen crosslinking; aCXL- accelerated corneal collagen crosslinking, M- male, F- Female; CDVA- corrected distance visual acuity; HMCF- hand movement close to face; FCCF- finger count close to face; FEK- Femtosecond Enabled penetrating eratoplasty; RGP- Rigid Gas Permeable; AMG- Amniotic Membrane Graft; PK- Penetrating keratoplasty; HSV- Herpes simplex virus; MRSA- Methicillin resistant staphylococcus aureus; NMCO- Nebulomacular corneal opacity
* Mixed infection- Streptococcus salivarius,Streptococcus oralis, andcoagulase-negativestaphylococcus spp.
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