Microbial keratitis in Stevens-Johnson syndrome: Clinical and microbiological profile

Accepted Manuscript Microbial keratitis in Stevens-Johnson syndrome: Clinical and microbiological profile Bhupesh Bagga, Swapna Reddy Motukupally, Ashik Mohamed PII:

S1542-0124(18)30038-7

DOI:

10.1016/j.jtos.2018.07.002

Reference:

JTOS 311

To appear in:

Ocular Surface

Received Date: 5 February 2018 Revised Date:

1 June 2018

Accepted Date: 3 July 2018

Please cite this article as: Bagga B, Motukupally SR, Mohamed A, Microbial keratitis in Stevens-Johnson syndrome: Clinical and microbiological profile, Ocular Surface (2018), doi: 10.1016/j.jtos.2018.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Microbial keratitis in Stevens-Johnson syndrome: Clinical and microbiological

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profile

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Authors: Bhupesh Bagga1,*, Swapna Reddy Motukupally2, Ashik Mohamed3.

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Microbiology Centre, L V Prasad Eye Institute, Hyderabad, India; 3Ophthalmic

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Biophysics, L V Prasad Eye Institute, Hyderabad, India.

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*Corresponding author/Address for reprints:

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Dr. Bhupesh Bagga

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Tej Kohli Cornea Institute

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L V Prasad Eye Institute

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L V Prasad Marg, Banjara Hills

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Hyderabad – 500034

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Telangana, India.

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Telephone: +91-40-30612616

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Fax: +91-40-23548271

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E-mail: [email protected]

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Short title: Microbial keratitis in Stevens-Johnson Syndrome

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Tej Kohli Cornea Institute, L V Prasad Eye Institute, Hyderabad, India; 2Jhaveri

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Abstract

22 Purpose. To study the clinical and microbiological profile of microbial keratitis in

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Stevens-Johnson syndrome (SJS).

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Study design. Case series

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Participants. Patients with SJS who developed microbial keratitis.

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Methods. Medical records and microbiological data of patients with SJS who developed

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microbial keratitis from January 1991 to December 2012 were reviewed. We analysed

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the type of causative organisms and their antibiotic susceptibility along with the clinical

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pattern and responses to medications in this group of patients.

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Main Outcome Measure. Clinical and microbiological profile of microbial keratitis.

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Results. We reviewed 65 eyes of 60 patients seen between January 1991 and

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December 2012. Positive microbiological culture results were obtained in 45 eyes

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(69.2%). Isolated bacterial infections were noted in 27 eyes (60%) while isolated fungal

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growth was seen in 1/45 eyes (2.2%). Polymicrobial infections were noted in 17/45 eyes

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(37.8%). The most common bacteria isolated were Staphylococcus species (35%). The

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median duration of SJS before presentation was 5 months (IQR, 2 months to 7 years)

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with 50% presenting within four months of the onset of SJS. Twenty-eight eyes (43%)

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needed treatment in addition to antibiotics for resolution of tarsorraphy, epilation, tissue

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adhesive application, and amniotic membrane grafting or punctal cautery. The average

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time for resolution was 25 days.

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Conclusion- Microbial keratitis in SJS patients is different from patients without SJS in

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presentation and the response to medications. It requires a multi-disciplinary approach

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for healing.

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Introduction

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Stevens-Johnson syndrome (SJS) is a rare and serious disorder characterized by acute

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blisters in the skin and mucous membranes.(1) Ocular complications of SJS include lid

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margin ulceration, keratinization, entropion, distichiasis and severe meibomian gland

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dysfunction.(2-6) Lid margin abnormalities are associated with corneal complications

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which can vary from non-healing epithelial defects in the early stages to severe corneal

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thinning or corneal perforations.(7-10). The severity of SJS was graded by Sontozono et

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al(11) based on corneal complications and adnexal tissue status. Microbial keratitis in

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SJS can behave differently due to unique causative organisms, their increasing

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resistance and associated ocular complications.(12-15). In association with SJS,

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increased incidence of methicillin resistant Staphylococcus Aureus induced keratitis has

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been reported(16)

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Conjunctival flora from patients with SJS and their antimicrobial susceptibility have been

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studied previously. Changes in conjunctival flora along with changes in antibiotic

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susceptibility in SJS are suspected due to the persistent use of antibiotics and a hostile

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environment.(15, 17) Chronic use of antibiotics can lead to emergence of resistant

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organisms(16). In the present study, we describe the clinical and microbiological profile

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of patients with SJS who developed microbial keratitis and also highlight the multi-

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disciplinary approach(18) towards such cases.

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Materials and methods

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This is a retrospective cohort study of the medical records of all consecutive patients

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seen from Jan 1991 to Dec 2012 with a diagnosis of both SJS and microbial keratitis.

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The study was approved by the Institutional Ethics Committee, L V Prasad Eye Institute,

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Hyderabad, India. We collected included demographic information, laterality, duration of

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initial insult to the day of presentation and the data on clinical characteristics of corneal

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ulcers along with adnexal (lid margin and conjunctival congestion) involvement. All eyes

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were further sub-divided into 3 groups based on the grading scores developed by

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Sotozono et al(11). Their outcomes were studied accordingly.

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Every corneal scraping was subjected to a direct microscopic examination, culture and

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antibiotic susceptibility testing. The microscopic examination included Gram stain and

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potassium hydroxide with calcofluor mount. The samples were inoculated directly onto

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5% sheep blood agar, chocolate agar, Sabouraud dextrose agar, potato dextrose agar,

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brain heart infusion broth and thioglycollate broth as part of the standard institutional

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protocol. All bacterial isolates were identified to the species level using the Vitek II

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Compact System (bioMérieux Inc., Hazelwood, MO), while the fungal isolates were

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identified by gross morphology and microscopic examination of lactophenol cotton blue

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mount. Bacterial isolates were further subjected to antibiotic susceptibility testing by the

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Kirby Bauer disc diffusion method.

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The visual acuity was expressed in units of the logarithm of the minimum angle of

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resolution (logMAR). Statistical analysis was performed using the statistical software

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Origin v7.0 (Origin Lab Corporation, Northampton, MA, USA). The Shapiro-Wilk test

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was used to assess the normality of continuous data which were described using either

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mean and standard deviations for parametric data or median and inter-quartile ranges

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(IQR) for non-parametric data. Categorical data were described in proportions.

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Results

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Data were collected on a total of 60 patients (65 eyes) from the a total of 2,013 patients with SJS seen during this period. The median age at presentation was 25 years (IQR,

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25 to 35 years) with 32 males and 28 females. The most common drugs responsible for

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SJS were sulphur-containing medications followed by phenytoin (Table 1). Twenty-

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seven (45%) cases were not aware of the drug having caused SJS with 6 patients

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having had an episode of viral fever contributing SJS as a cause. Based on the scoring

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system by Sotozono(11), outcomes in the 3 groups are mentioned in Table 2. The

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median duration of the disease before presentation was 5 months (IQR, 2 months to 7

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years) with 50% presenting within four months of the disease.

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Among the affected eyes, 14 were able to perceive light (21.5%), two did not perceive

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light (3.1%) and one was able to perceive light with accurate projection (1.5%). The rest

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had a median visual acuity of 1.31 (IQR, 0.80 to 1.79). Five (8.3%) patients presented

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with bilateral involvement. The size of the epithelial defect varied from <3 mm (n = 22,

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33.9%), 3-6 mm (n = 27, 41.5%) to >6 mm (n = 16, 24.6%). Corneal perforations were

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seen in nine eyes (13.9%) at the time of presentation. Fifty-four eyes (83.1%) presented

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as an infiltrate and Three eyes (4.6%) had stromal thinning more than 50%. One patient

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was wearing a bandage contact lens at the time of presentation but he presented with

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large staphyloma and could not be salvaged so evisceration was performed. Deep

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stromal vessels were noticed in 12 eyes (18.5%). Lid margin keratinization (Figure 2)

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was seen in 34 (52%) eyes. Meibomitis was documented to be present in 50 (76%)

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eyes. Schirmers value were recorded in 23 eyes; 14 eyes (60.9%) had <5 mm, five

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(21.7%) had between 8-10 mm and remaining four (17.4%) had between 25-28 mm.

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Conjunctival congestion was seen in all the eyes. Fifteen eyes (23.1%) had

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symblepharon with three eyes having total symblepharon along with ankyloblepharon.

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Trichiasis with distichiasis was found to be present in fifteen (23.1%) eyes.

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Initial treatment was based on smears which included topical fortified Cefazolin 5% and

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Ciprofloxacin 0.3% ophthalmic solution in hourly dose in all cases with smears showing

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either gram positive bacteria, gram negative bacteria or no organisms. We started

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topical fortified Cefazolin (5%) in 17 eyes (26.2%), Ciprofloxacin (0.3%) in 25 eyes

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(38.5%) and Gentamicin (0.3%) in 7 eyes (10.8) in intensive medication hourly doses.

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Ophthalmic lubricants were started as an initial treatment in 12 eyes (18.5%). In those

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12 eyes, Choramphenicol (0.5%) was started 4 times daily. Topical Natamycin (5%)

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ophthalmic solution was started if smears showed the presence of fungus. Steroids

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were added in 7 eyes after seeing the initial response of treatment for 2-3 days.

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Treatment was changed based on the growth on culture media and drug susceptibility.

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In cases where no organisms were seen in smears or cultures, continuation of

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antibiotics was based on the clinical response. Topical Carboxy methyl cellulose (0.5%)

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was added in 12 eyes (18.5%) in addition to the antibiotics for healing.

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During the course of therapy the size of the epithelial defect remained constant in 28

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eyes (43.1%) leading to non-resolution of infected ulcer, in spite of treatment with

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antibiotics started at presentation. These were diagnosed to have persistent epithelial

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defects (PED), edges of which were well defined, rounded and raised. The type of

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infiltrate was whitish in colour and granular in appearance in these eyes. PED was seen

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more frequently in moderate to severe SJS cases (n = 20/28, 71.4%) than in mild SJS

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(n = 8/28, 28.6%) cases. In eyes where there was no PED, ten belonged to mild SJS

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(27%) and 27 eyes (73%) had moderate-severe SJS. The severity of SJS had no

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influence on the development of PED (p = 0.89, Chi-square test). After intensive

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medication with topical antibiotics for 1 week, the dose of antibiotics was reduced to 4

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hourly. In 15 eyes, after seeing the initial response, it was converted to chloramphenicol

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ophthalmic solution due to its lower epithelial toxicity and helpful nature in promoting

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epithelial healing. These 28 eyes needed additional treatment which included tissue

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adhesive (9 eyes), tarsorraphy (8 eyes) and amniotic membrane graft (5 eyes), these

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measures are performed to protect them from perforation and to stop progressive

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thinning of non-healing epithelial defects. Three patients needed mucous membrane

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grafting (Figure1,3) for complete resolution and 5 eyes needed additional tissue

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adhesive and bandage follow-up.

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Punctal cautery and epilation were performed as an additional procedure to treat severe

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dry eye, trichiasis (12 eyes) and distichiasis (2 eyes). In cases where worsening was

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noted after medical treatment, penetrating keratoplasty was performed (3 eyes). One

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eye was eviscerated due to severe involvement and rapid worsening. The average time

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of resolution was 25 days, (range 14 to 55 days). (Figure 2)

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Positive microbiological culture results were obtained in 45 eyes (69.2%). Infection with

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single bacterial species was noted in 27 eyes (60%). Infection with single fungal species

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was seen in only one eye (2.2%). Polymicrobial infections were noted in 17 (37.8%)

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eyes. There was a total of 59 bacterial isolates (Table 3) and Staphylococcus spp. was

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the most common (35%). In five eyes where either isolated (1 eye) or polymicrobial

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infection (4 eyes) was seen, fungal growth occurred out of which three belonged to

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Candida spp, one Aspergillus spp and one Cladosporium species. Analysis of microbial

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susceptibility (Table 2) showed 100 % of the Gram positive bacteria were susceptible to

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vancomycin, while only 76.5 % were susceptible to cefazolin and 72.6% to

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chloramphenicol, whereas among the Gram negative bacteria, 75% of the isolates were

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susceptibile to aminoglycosides and only 62.5% of the isolates were susceptible to

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ceftazidime.

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Discussion

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This study demonstrated that the clinical profile and outcome of microbial keratitis in

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Stevens-Johnson Syndrome is multifactorial, as it not only depends on the organism

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and its virulence but also the adnexal tissue health. Most commonly, it occurs during

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early (1-3 month) or late (>1year) stages of SJS. In acute SJS, this can be explained by

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the poor epithelium, increased inflammation, poor blink rate and exposure keratopathy

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along with use of steroids. In chronic stages, it is associated with lid margin

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keratinisation, distichiasis, entropion or ectropion and severe dry eye.(2, 16)

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Microbial keratitis is commonly seen due to bacterial causes(6) which is similar to our

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observations in SJS. The change of flora(15, 19) and the changed drug susceptibility

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has been reported previously. In both studies by Frizon et al and Gupta et al, the

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differences were shown in the conjunctival flora in SJS patients. The difference in

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microbiome may be responsible for the unique clinical picture of microbial keratitis in

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this sub-set of patients. This is similar to our previous experiences (authors’

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unpublished data) where we collected and compared prospectively conjunctival flora

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between SJS and no SJS eyes and found the difference in the drug susceptibly pattern.

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This can be explained by a hostile environment and use of long term antibiotics(11, 20).

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All patients were referred from elsewhere to our institute and were on mixed treatment

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regimens of broad spectrum antibiotics and antifungals. The most common organism

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was Staphylococcus species which is similar to other microbiological studies(21) from

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our tertiary eye care centre. Interestingly, the incidence of fungal keratitis (7%) was

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lower compared to patients who had microbial keratitis not associated with SJS

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(38%)(21). This can be explained by the fact that the most common cause of microbial

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keratitis in the latter is trauma(22) with vegetative matter leading to a fungal infection.

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The difference in the sample size and cohort could be the explanation for the difference

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of aetiologies.

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With respect to antimicrobial susceptibility, the organisms in those previous studies(21,

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23) had increased drug resistance. Our study showed that 76.5 % of the Gram positive

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bacteria were susceptible to Cefazolin, 72.5 % to Chloramphenicol, 33.4% to

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Ciprofloxacin and 47.1% of the isolates were susceptible to Gentamicin, compared to

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previous studies that reported (21, 23) them to be 92.3%, 75.5%, 70.2% and 68.8%

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susceptible to the drugs, respectively. Similarly, seventy-five percent of Gram negative

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bacteria were susceptible to Gentamicin, 37.5% of the isolates were susceptible to

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Ciprofloxacin, and 50% were susceptible to Chloramphenicol in this study while

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previous studies showed that 86.9%, 85.8% and 27.3% of the isolates were susceptible

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to Gentamicin, Ciprofloxacin and Chloramphenicol respectively. The susceptibility for

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Ciprofloxacin appears to lower in the study group. These data suggest the empirical first

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line medication for microbial keratitis in SJS.

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The healing of corneal ulcers depends on the aetiology and ocular adnexal health. The

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time to resolve bacterial keratitis in otherwise healthy eyes is usually 3 to 7 days, while

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in this SJS cohort, the response was slow due to persistent non-healing epithelial

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defects which took an average of 25 days (range 14 to 55 days). Since changing the

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medication or increasing the frequency of antibiotics adds to the toxicity on the ocular

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surface, emphasis should be based on adopting the measures to improve the ocular

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surface.(24, 25). As similar was done in few of our cases with non-healing ulcers,

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lubricants were started and Chloramphenicol, as considered to be less epitheliotoxic

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also added as a prophylactic treatment to avoid secondary infection.

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Inability to extrapolate the data on drug sensitivity and making comparisons with the

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previous literature is a limitation of the present study due to a different cohort and the

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current time period; Moreover trends in antibiotic susceptibility have been changing over

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the past two decades. Additional measures taken to improve the ocular surface were

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primarily targeting the healing of an epithelial defect such as tarsorraphy (paramedian or

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central). This needs a multi-disciplinary approach targeting not only the organisms but

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also towards dry eye, lid margin treatment, inflammation and associated exposure.

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Conclusion

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This study highlighted the importance of a comprehensive approach towards

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management of microbial keratitis in SJS. To find and treat the causative organism

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based on drug susceptibility, keeping a balance in treatment and surface toxicity along

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with managing epithelial healing should be the correct approach.

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Legends

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Figure

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Figure.1A shows representative photos of a corneal ulcer in a patient with SJS with

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inferior located yellowish infiltrate with raised well defined edges (Yellow arrow) of the

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ulcer along with deep and superficial vessels.

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1 B. The same eye with the resolved ulcer after antibiotics and the amniotic membrane

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on the epithelial defect and mucus membrane graft on the lid margin (Red arrow). A

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thick area of MMG at the temporal area is also visible.

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Figure 2. shows corneal photos of a patient who had SJS and developed microbial

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keratitis (A) caused by E.coli which was susceptible to colisitin only and healed (B) in 14

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days with intensive medical therapy. Lid margin (showed in magnification) had lid

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margin keratinisation.

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Figure 3. Shows a corneal photo of patient with SJS in whom PED (Green arrow)

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resolved after application of MMG (Yellow arrow).

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Tables

Table 1: The culprit drugs responsible for SJS

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Table 2: Categories of eyes based on the scoring system into three groups and

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the outcomes of Microbial keratitis

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Table 3: The various bacteria grown from all the cases of microbial keratitis

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Table 4: Antibiotic susceptibility of both gram positive and gram negative

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bacteria

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Acknowledgements/Disclosure

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a. Funding/Support: None.

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b. Financial Disclosures: No financial disclosures.

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Declarations of interest: none

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298 299 300 References

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1. Narang P, Mohamed A, Mittal V, Sangwan VS. Cataract surgery in chronic StevensJohnson syndrome: aspects and outcomes. The British journal of ophthalmology. 2016;100(11):1542-6. 2. Kaido M, Yamada M, Sotozono C, Kinoshita S, Shimazaki J, Tagawa Y, et al. The relation between visual performance and clinical ocular manifestations in Stevens-Johnson syndrome. Am J Ophthalmol. 2012;154(3):499-511 e1. 3. Saeed HN, Chodosh J. Ocular manifestations of Stevens-Johnson syndrome and their management. Curr Opin Ophthalmol. 2016;27(6):522-9. 4. Goldberg D, Panigrahi D, Barazi M, Abelson M, Butrus S. A case of rofecoxibassociated stevens-johnson syndrome with corneal and conjunctival changes. Cornea. 2004;23(7):736-7. 5. Cher I. Blink-related microtrauma: when the ocular surface harms itself. Clin Exp Ophthalmol. 2003;31(3):183-90. 6. Vera LS, Gueudry J, Delcampe A, Roujeau JC, Brasseur G, Muraine M. In vivo confocal microscopic evaluation of corneal changes in chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. Cornea. 2009;28(4):401-7. 7. Di Pascuale MA, Espana EM, Liu DT, Kawakita T, Li W, Gao YY, et al. Correlation of corneal complications with eyelid cicatricial pathologies in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis syndrome. Ophthalmology. 2005;112(5):904-12. 8. Isawi H, Dhaliwal DK. Corneal melting and perforation in Stevens Johnson syndrome following topical bromfenac use. J Cataract Refract Surg. 2007;33(9):1644-6. 9. Tabbara KF, Shammas HF. Bilateral corneal perforations in Stevens-Johnson syndrome. Can J Ophthalmol. 1975;10(4):514-7. 10. Wang F, Li S, Wang T, Gao H, Shi W. Modified tectonic keratoplasty with minimal corneal graft for corneal perforation in severe Stevens--Johnson syndrome: a case series study. BMC Ophthalmol. 2014;14:97. 11. Sotozono C, Ang LP, Koizumi N, Higashihara H, Ueta M, Inatomi T, et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Ophthalmology. 2007;114(7):1294-302. 12. Sachdev R, Bansal S, Sinha R, Sharma N, Titiyal JS. Bilateral microbial keratitis in highly active antiretroviral therapy-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a case series. Ocul Immunol Inflamm. 2011;19(5):343-5.

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Table 1. Culprit drugs responsible for SJS∗Numbers of patients

Carbamezepine

2

Sulfa-Containing Drugs (not specified)

10

Phenytoin

4

Gatifloxacin,Ofoxacin,ciprofloxacin (one

3

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Name of Culprit drug

each) Tetracycline

3

Thiacetazone

1

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Antivirals Homeopathic Medicine

1

Baclofen

1

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Chloramphenicol

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Ampicillin with cloxacillin

2 1

Paracetamol

2

Dexamethasone

1

Nimesulide

1

∗ (27(45%) cases were not aware of the drug causing SJS, 6 patients had fever and contributing SJS as a cause.

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Table 2

three groups and outcome

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Categorisation of eyes based on the scoring system into

Outcome of

Mild SJS (n=18 Moderate SJS

Severe SJS

Microbial

eyes) (27.6%)

(n=20 eyes)

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(41.5%)

Responded

17

Therapeutic PK (3)/

1

(30.7%)

24

19

3

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Evisceration

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Keratitis

(n=27 eyes)

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Table 3: Shows the various bacteria grown from all the cases of microbial keratitis Bacteria grown Staphylococci Streptococci Corynebacteria Brevibacterium

N 21 (35%) 14 (24%) 15 (25.5%) 1 (1.69%)

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4 (6.7%) 4(6.7%)

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Pseudomonas aeruginosa Escherichia coli

Table 4:

Antibiotic Susceptibility of Both Gram Positive and Gram

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Negative Bacteria

Gram Negative Bacteria

Susceptibility

Susceptibility

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Gram Positive Bacteria

Susceptible%

Antibiotic

Susceptible%

Vancomycin

100

Aminoglycosides

75%

Cefazolin

76.5

Ceftazidime

62.5%

Chloramphenicol

72.6

Chloramphenicol

50%

Ciprofloxacin

33.4

Gatifloxacin

50%

Gentamicin

47.1

Ciprofloxacin

37.5%

AC C

EP

TE D

Antibiotic

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT