Corneal Infections from A-Z Disclosures (Acanthamoeba to Zoster) Allergan Pharmaceutical Advisory Panel Joseph P

Home , Acanthamoeba keratitis, Fumagillin

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Corneal Infections from A-Z Disclosures (Acanthamoeba to Zoster) Allergan Pharmaceutical Advisory Panel Joseph P. Shovlin, OD, FAAO AMO Global Medical Advisory Panel

Scranton, PA -Acanthamoeba Outbreak Panel (ad hoc)

Bausch & Lomb Scientific Advisory Panel

-Global Steering Committee I. Risk Factors In Ulcerative Keratitis -Panel On Fusarium Keratitis (ad hoc)

II. Differential Diagnosis of Infiltrative Keratitis Ciba Vision Post-Market Surveillance Study Group

-Johns Hopkins Adjudication Committee (ad hoc) III. Treatment and Management of Ulcerative Keratitis Center for Disease Control & Prevention- Contact Lens Advisory Panel

IV. Fungal and Protozoan Infection of the Johnson & Johnson Global Professional Advisory Panel

Cornea Shire, Ophthalmic Advisory Panel

Speaker’s Bureau: Vistakon, Ciba Vision, CooperVision, Bausch & Lomb, AMO, Alcon, V. The Herpes Family Genzyme, Shire

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“Swine Flu”: H1N1 Infectious Keratitis

Amoebic Herpes Keratitis Fungal Bacterial Keratitis Keratitis Keratitis

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Case 7 -- corneal haze

Stem Cell Deficiency Tear Film Defenses

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Epidemiology: Relative Risk Risk Factors for Ulcerative Keratitis

¤ Population at risk: approximately 44 million in US and 120 million worldwide ¤Exogenous ¤ Overnight wear the overwhelming risk factor ¤Ocular Adnexal Dysfunction ¤ Relative risk of extended wear v. daily wear: 10- ¤Corneal Abnormalities 15:1 ¤Systemic Disease ¤ Overnight wear of disposable lenses equal risk ¤ Additional risks: aphakia, smoking, lens case, ¤Immunosuppressive Therapy minimal protective effect of hygiene

Incidence Rates for Microbial Keratitis Microbial Keratitis Rates for Orthokeratology/Corneal Reshaping Any MK Severe MK

¤ Daily Wear GP 1.2 (1.1-1.5), 1.2 ¤ Incidence for microbial keratitis is estimated @ 7.7/10,000

¤ Daily Wear DDCL 2.0 (1.7-2.4), .5 ¤ Children carry a higher rate @ 13.9/10,000 ¤ Overall, the infection rate is similar to overnight soft lens ¤ Occasional CW 2.2 (2.0-2.5), 1.8 use.

¤ CW soft 19.5 (14.6-29.5), 13.3 ¤ CDC MMWR Report: 37 GP cases of AK (2005-2011); nearly 25% Ortho-K wearers and 50% used tap water to store lenses overnight ¤ CW silicone 25.4 (21.2-31.5), 16.9

From: Stapelton F. et al, The incidence of contact lens related microbial keratitis in Australia, Ophthalmol, 2008. Bullimore M, Sinnott LT, and Jones-Jordan LA: The risk of microbial keratitis with overnight corneal reshaping lenses. Optom & Vis Sci. 2013; 90(9):937-944.

The Incidence of Microbial Keratitis among Associated Publication: Wearers of a 30-Day Silicone Hydrogel Extended-Wear Contact Lens

Oliver D. Schein, MD, MPH,1 John J. McNally, OD,2 Joanne Katz, ScD,3 Robin L. Chalmers, OD,4 James M. Tielsch, PhD,3 Eduardo Alfonso, MD,5 Mark Bullimore, MCOptom, PhD,6 Denis O’Day, MD,7 Joseph Shovlin, OD8

Purpose: To estimate the incidence of presumed microbial keratitis with and without loss of visual acuity among wearers of a silicone hydrogel contact lens (Lotrafilcon A, Night & Day, CIBA Vision, Inc., Duluth, GA), recently approved for up to 30 days of continuous wear. Design: Prospective cohort postmarket surveillance study. Participants: Contact lens wearers (recruited from 131 practices) who had been prescribed the lens for intended continuous wear of as many as 30 nights. Methods: The occurrence of a corneal infiltrate was ascertained through a combination of center report and direct contact with participants at 3 and 12 months. Whenever a corneal infiltrate was suspected, study and treatment medical records were systematically reviewed by an Endpoints Committee using a predetermined classification scheme for corneal infiltration. Cases of presumed microbial keratitis were determined based on the constellation of presenting signs and symptoms and clinical course. Main Outcome Measures: The incidence of presumed microbial keratitis with and without loss of visual acuity. Results: A total of 6245 participants were recruited between August 13, 2002 and July 2, 2003. Of these, 4999 subjects (80%) completed 12 months of follow-up, and these participants contributed a total of 5561 person years of lens wearing experience. Approximately 80% of participants routinely wore their lenses contin- uously for 3 or more weeks. The overall annual rate of presumed microbial keratitis was 18 per 10,000 (95% confidence interval (CI): 8.5–33.1). There were 2 cases of presumed microbial keratitis with loss of visual acuity, an annual rate of 3.6 per 10,000 (95% CI: 0.4–12.9), and an additional 8 cases without loss of visual acuity, an annual rate of 14.4 per 10 000 (95% CI: 6.1–28.4). The rate of presumed microbial keratitis was lower for users reporting typical wear of 3 or more weeks than for those wearing the lens for less than a 3-week continuous period (P ϭ 0.02). Conclusions: The incidence of loss of visual acuity due to microbial keratitis among users of the silicone hydrogel contact lens was low. The overall rate of presumed microbial keratitis with the wearing schedule of as many as 30 nights was similar to that previously reported for conventional extended-wear soft lenses worn for fewer consecutive nights. Ophthalmology 2005;112:2172–2179 © 2005 by the American Academy of Ophthal- December 2005 Publication mology. Ophthalmology In 1981, the United States Food and Drug Administration potential complication of contact lens extended wear is (FDA) approved the first of a series of soft contact lenses for ulcerative keratitis causing loss of vision. This condition is extended wear for as many as 30 days. The most serious presumed to be of microbial origin, although corneal cul- Journal of the American Academy of Ophthalmology

Originally received: June 9, 2005. sity School of Medicine, Nashville, Tennessee. Accepted: September 8, 2005. Manuscript no. 2005-518. 8 Northeastern Eye Institute, Scranton, Pennsylvania. 1 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland. This study was supported by a research grant from CIBA Vision Corpo- ration, Duluth, Georgia, to the Johns Hopkins University School of Med- 2 CIBA Vision Corporation, Duluth, Georgia. icine. Dr Chalmers is a paid consultant to CIBA Vision, and Dr McNally 3 Department of International Health, Johns Hopkins University Bloomberg is a full-time employee of CIBA Vision. Dr O’Day was supported in part School of Public Health, Baltimore, Maryland. by a challenge grant from Research to Prevent Blindness, New York, New 4 Clinical Trials Consultant, Atlanta, Georgia. York. None of the other authors has a consultative or proprietary interest in the product or company. 5 Bascom Palmer Eye Institute, University of Miami, Miami, Florida. 6 Correspondence to Oliver D. Schein, MD, 116 Wilmer Building, Johns Ohio State University College of Optometry, Columbus, Ohio. Hopkins Hospital, 600 N Wolfe Street, Baltimore, MD 21287-9019. E-mail: 7 Department of Ophthalmology and Visual Sciences, Vanderbilt Univer- [email protected].

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Modifiable Risk Factors for MK Non-Modifiable Risk Factors ¤ Occasional CW Use: 1.87-3.96X ¤ Regular CW Use: 5.28X ¤ < 6 Months CL Use: 4.42X ¤ Smoking: 2.96X ¤ High Socioeconomic Class: 2.66X ¤ Poor Hygiene: 3.7X ¤ Hyperopia 1.77X ¤ Purchase Lens from Internet/Mail Order: 4.76X ¤ Age >50: .45X (protective) ¤ Not Always Washing Hands: 1.49X ¤ Male: 1.48X From: Stapelton F. et al, The incidence of contact lens related microbial keratitis in ¤ >2 Days Wear/Wk.: 3.46X Australia, Ophthalmol, 2008.

From: Stapelton F. et al, The incidence of contact lens related microbial keratitis in Australia, Ophthalmol, 2008.

Pathogenesis of Contact Lens Can We Prevent MK? Associated Microbial Keratitis

¤ Lens wear: 80X relative risk ¤Lack of basic knowledge on how the ocular ¤ Rate of infection has not changed over the past 20 years surface defends itself ¤ Longer wearing times, poor lens care hygiene are modifiable risks. ¤ Would it help if patients were more compliant?

¤ Daily disposable lens wear is associated with a reduction in ¤ Why is EW a risk factor? severity of infection and silicone hydrogel wear materials in disease duration. ¤ Does fluorescein staining predict risk of infection? ¤ Why Pseudomonas aeruginosa? ¤ Severe cases of infection tend to be associated with environmental organisms, a delay in seeking treatment and ¤ What is the relationship between infection and travel overseas. inflammation? ¤ Higher daytime temperatures carry a higher risk for severe Fleiszig SM and Evans DJ. Pathogenesis of contact lens associated microbial infection. keratitis. Optometry & Vision Science 2010;87(4):1-7. From: Stapelton F-BCLA Medal Address, 2015.

Measures for Preventing Microbial Keratitis Lens Storage Cases and Risk for Infection

¤Minimize overnight wear ¤ Hall BJ and Jones L. Contact lens cases: The missing link in CL safety?. Eye & Contact Lens ¤Monitor contact lens induced changes: 2010;36(2): 1-5. surface temperature, epithelial compromise, tear film stagnation, and reduced oxygen ¤ Wu Y, Carndt N, Wilcox M and Stapleton F. Contact surface changes lens and lens storage case cleaning instructions: Whose advice should we follow?. Eye & Contact ¤Minimize lens care contamination: wash hands, remove lenses at pre-determined Lens 2010;36(2): 6-10. interval, small bottles of saline, lens case ¤ Wu Y, Zhu H, Harmis NY, et al. Profile and frequency replacement, antibiotic prophylaxis usually not recommended of microbial contamination of contact lens cases. Optometry & Vision Science 2010;87(3):152-158.

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Common Organisms Encountered Bacterial Flora of the Normal Eye

Staphylococcus epidermidis 75-90%* ¤ Northeast: Staph. species, Moraxella, Diphteroids (C. xerosis) 20-33% Pseudomonas aeruginosa, Streptococcus Staphylococcus Aureus 20-25%* pneumonia Streptococcus (S. viridan) 2-6% ¤ Southeast: Pseudomonas aeruginosa common Hemophilus influenza 3% or more ¤ Pseudomonas aeruginosa still a common Streptococcus pneumoniae 1-3%* organism in contact lens wear. Also Gram negative rods 1% or more* commonly found in burn patients, patients Pseudomonas aeruginosa 0-5%* with exposure keratopathy and those on ventaltory assistance. * Dominant organisms in microbial keratitis

Classification of Infiltrates Common Organisms Encountered

¤Corneal injury including foreign body: Serratia, Proteus, Azotobacter, Neisseria, Bacillus species ¤Concern for organisms that can penetrate an intact epithelium: N. gonorrhoeae, Corynebacterium diphtheriae, Listeria, Hemophilus aegyptius

Ambiguity in Diagnosis of CIEs

vAnalysis assuming 70% of clinical descriptors must be met for a given CIE subtype to be diagnosed o Only 20% could be classified unambiguously as a single CIE subtype o 69% could be classified as 2 or more CIE subtypes o 11% could not be classified Venn diagram show how the 111 CIEs as any of the CIE subtypes are classified based on the categorization proposed by Sweeney 2003. Each dot represents a single CIE.

Efron N, Morgan PB. Cornea. 2006;25(5):540-4.

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Solution Related Keratopathy

Before insertion After 2 hours of lens wear

Solution Related Keratopathy

Before insertion After 2 hours of lens wear

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CORNEAL INFILTRATE STUDIES

Factor Associated Not Associated Known Association with CIEs

Improper lens care Bates 1989; Mah-Sadorra 2005; Matthews 1992; McNally, Chalmers ARVO 2004; Mely 2001

Lens Bioburden Corrigan 2001; Holden 1996; Key 2000; Kiernan 2009; Ozkan 2010; Sankaridurg 2000; Sweeney ARVO 2003; Szczotka-Flynn IOVS 2010

Case contamination Bates 1989; Holden 1996; Kiernan 2009 Overnight/EW Bates 1989; Chalmers 2010; Cutter 1996; Donshik 1995; Efron 2005; Grant 1998; Mah-Sadorra 2005; Morgan BJO 2005, IOVS 2005; Nilsson 1994; Santodomingo-Rubido 2007; Stapleton 1992; Suchecki 1996; Vikoren 1990 Smoking Chalmers 2007 (trend); Cutter 1996; Morgan IOVS 2005; McNally 2003; Szczotka-Flynn 2010 Suchecki 1996 Tight fit/reduced movement Carnt ARVO 2007; Gordon 1985; Mertz 1990; Ozkan 2010; Stein 1988; Sweeney ARVO 2003 McNally 2003 No Association with CIEs

Asymptomatic corneal staining Szczotka-Flynn Arch Ophthalmol 2007 Szczotka-Flynn IOVS 2010; Carnt IER Matrix 2007; Chalmers 2010

PATH Carnt 2007 Carnt 2009; Willcox FDA 2008 Gender Morgan IOVS 2005 Chalmers 2007, OVS 2010; Forister 2009; McNally 2003; Nilsson 1994; Sweeney ARVO 2003; Szczotka-Flynn IOVS 2010

Rx Chalmers 2007 McNally 2003; Chalmers OVS 2010; Sankaridurg 1999 No Conclusive Consensus

Age Chalmers 2007, ARVO 2010; McNally 2003; McNally, Chalmers ARVO 2004 Morgan IOVS 2005; Sankaridurg 1999; Sweeney 2003; Szczotka-Flynn IOVS 2010

Lens care solution Carnt ARVO 2007, 2009; Chalmers ARVO 2010; Diec ARVO 2009, ARVO 2010; Kiernan 2009; Donshik 1995; Morgan IOVS 2005; Roseman Kislan ARVO 2010, ARVO 2011; Mely CLAO 2001; Reeder GSLS 2011; Reindel AOA 2009; Sacco 1994; Zigler 2007 GSLS 2011, CLS 2011; Willcox FDA 2008 Soft contact lens material Brennan 2002; Carnt 2009; Chalmers 2010; Fonn 2002; Forister 2009 (trend); Keir 2010; Morgan Dillehay 2007; Efron 2005; Fonn 2002, US FDA, BJO 2005, IOVS 2005; Santodomingo-Rubido 2007; Sweeney 2003; Szczotka-Flynn 2007; US CIBA Vision 2001 (US) FDA, Bausch & Lomb 2001 (US); US FDA, CIBA Vision,2001; US FDA, Vistakon 2005 Solution/Lens combinations Carnt 2007, 2009; Keir 2010; Kislan ARVO 2010 Diec ARVO 2009; Zigler 2007 Mucin balls Carnt ARVO 2007; Sweeney ARVO 2003; Szczotka-Flynn ARVO 2010 (protective) Dumbleton AAO 1999; Tan AAO 1999

Season Chalmers OVS 2010; Morgan IOVS 2005

Duration of lens wear Chalmers 2007 Nilsson 2001 Swimming Chalmers AAO 2004; McNally, Chalmers ARVO 2004 Morgan IOVS 2005 Prior inflammatory event, CL- Chalmers 2007; Ionides 1997; McNally 2003 Morgan IOVS 2005 related issues, or injury Conjunctival or limbal redness Szczotka-Flynn Arch Ophthalmol 2007 Carnt 2007; Sweeney ARVO 2003

Contamination with Gram- negative bacteria

100%

90% ve - 80% P<0.001 70% P<0.001 60% P<0.001 50% 45%

40% 29% 30% 20% 20% 7% 9% Rate of contamination with Gram 10% 6%

0% ®2 1 1 1 1 1 RevitaLens Aquify Clear Care Express Renu Multi Replenish

MPDS

1. Willcox MD, Carnt N, Diec J, Naduvilath T, Evans V, Stapleton F, Iskandar S, Harmis N, de la Jara PL, Holden BA. Contact lens case contamination during daily wear of silicone hydrogels. Optom Vis Sci. 2010; 87:456-64 2. Brien Holden Institute Follow-up studies – Jan-Aug 2011 2011.09.13- ME3999

G Model

CLAE-601; No. of Pages 5 ARTICLE IN PRESS

Contact Lens & Anterior Eye xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Characterization Of Bacteria From Contact Lens Storage Contact Lens & Anterior Eye

Cases Of Corneal Infiltrative Event Patients

jou rnal homepage: www.elsevier.com/locate/clae

Simon Kilvington1, Joseph P. Shovlin2, Marina Nikolic1.

Identiﬁcation and susceptibility to multipurpose disinfectant

1Corneal R&D Microbiology, Abbott Medical Optics, Santa Ana, CA; 2Northeastern Eye Institute, Scranton, PA.

solutions of bacteria isolated from contact lens storage cases of

Of the 18 CLSC studied:

4 8 Conclusions patients with corneal inﬁltrative events Ø 16/18 (89%) showed TVBC of ≥10 – 10 /mL. The efficacy of the MPDS solutions against bacteria isolated from the storage cases after 6 hour (hr) and 14 day (d) exposure is shown in Table 3.

Ø 13/18 (72%) had TVBC of 106 – 108 /mL. a, b c

Simon Kilvington ∗, Joseph Shovlin , Marina Nikolic Ø 2/18 were dry but yielded TVBC of 104 – 105 /mL when sterile Ø Contact lens storage cases from CIE

saline added. a

patients can be grossly Department of Infection, Immunity & Inﬂammation, University of Leicester, Leicester, United Kingdom

contaminated with Gram negative b

Acanthamoeba was not isolated. Northeastern Eye Institute, Scranton, PA, United States

bacteria. c

Corneal Research & Development, Abbott Medical Optics Inc., Santa Ana, CA, United States All bacterial isolates were Gram negative rods of which 10/18 cases 10 Bacteria log reduction (56%) contained 13 strains of Achromobacter spp., 4/18 Ø Predominant bacteria such as Stenotrophomonas Achromobacter, Stenotrophomonas maltophilia (22%), 3/18 Serratia marcescens (17%), 2/18 Delftia spp. Achromobact (11%), and 6/18 (33%) Elizabethkingia spp. (3), Chryseobacterium sp. S. maltophilia Delftia spp. and Delftia can be resistant to the

er spp.

(2) and Sphingobacterium sp. (1) (Table 1). (10 strains) (4 strains) (2 strains) MPDS used by the patient and able a r t i c l e i n f o a b s t r a c t Table 1. Bacteria identified from storage cases of CIE patients to proliferate to high numbers.

Solution 6 hr 14 d 6 hr 14 d 6 hr 14 d

Article history:

Ø The resulting microbial bioburden Corneal inﬁltrative events (CIEs) are being reported with increasing frequency in lens wearers and may be

Received 7 December 2012

® may initiate an im m unological related to speciﬁc multipurpose disinfecting solution (MPDS), contact lens type or bacterial bio-burden.

CLSC +ve Organism present % b

OPTI-FREE <1 -

® a Received in revised form 30 January 2013

<1 <1 <1 - 2 <1 - 2 <1 response resulting in CIE, either Here, the efﬁcacy of MPDS’s against bacteria from contact lens storage cases (CLSC) of patients with

RepleniSH >4

directly or from the presence of Accepted 2 February 2013

10 Achromobacter spp. 56 CIEs was investigated. Eighteen CLSC from patients with CIEs were cultured. All reported using the same

Table 3. Efficacy of MPDS solutions against storage case bacteria endotoxins (e.g .

RevitaLens c MPDS based on PQ-1 + Aldox + nonanoyl-EDTA prior to experiencing CIEs. Bacteria were identiﬁed and 2 – >4 ≥4 >4 >4 ≥4 ≥4 lipopolysaccharides) derived from

4 Stenotrophomonas maltophilia 22 Keywords:

Ocutec™

the bacterial outer cell membrane. tested for sensitivity to MPDS-1 and three other MPSDs. 16/18 CLSC (89%) contained bacterial counts of

Corneal inﬁltrate events 4 8

d 10 –10 /mL. Achromobacter spp. was most frequently identiﬁed and was found in 11/18 cases (61%).

Contact lens storage case

3 Serratia marcescens 17 Biotrue™ <1 – >4 ≥4 >4 >4 ≥4 ≥4 Ø The significance of MPDS usage, ≥

This was followed by 4/18 (22%) Stenotrophomonas maltophilia, 3/18 (17%) Serratia marcescens, 3/18 (17%) degree of contact lens storage case Bacteria

a,b

Delftia spp., 2/18 (11%) Elizabethkingia spp., 2/18 (11%) Chryseobacterium indologenes and 1/18 Sphingob- Regrowth by 1-2 log for 2 strains of S. maltophilia and both Delftia spp. contamination and bacterial species Disinfection

2 Delftia spp. 11 C D

90% strains ≥4 log kill. 50% strains ≥4 log kill present in the etiology of CIE Multipurpose disinfection solution acterium spiritivorum. Acanthamoeba was not isolated. All of the Achromobacter strains were resistant to

warrants further investigation. MPDS-1 with <1 log10 kill up to 14 days exposure and the solution also showed reduced efﬁcacy against the

other isolates at the manufacturer’s recommended disinfection time of 6 h. Two strains of S. maltophilia

Elizabethkingia sp. Ø Use of disinfection systems with

6 Chryseobacterium sp. 33 broad antimicrobial efficacy, and Delftia spp. grew in the solution over 14 days. Factors responsible for causing adverse events such

Sphingobacterium sp.

combined with good lens storage as CIEs in contact lens wearers remain unclear. However, the presence of signiﬁcant bio-burden in the

case hygiene, may help prevent CIE

contact lens storage case and lens may initiate an immunological response resulting in CIEs either directly

and also reduce the incidence of

4-5 microbial keratitis. or through the release of endotoxins (e.g. lipopolysaccharides) from the bacterial outer cell membrane. © 2013 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Contact: Simon Kilvington ([email protected])

1. Introduction on the lenses which can afford protection from disinfectant activ-

ity and provide a suitable environment for colonisation by primary

Contact lens wear is a risk factor for microbial keratitis and pathogenic species [3,8–12]. Furthermore, the bacteria can serve

occurs at an incidence rate of approximately 40 cases per 100,000 as a food source for the free-living amoeba Acanthamoeba which

users [1–5]. Bacteria are the most common cause of infection, with can cause severe keratitis, with 90% of reported cases occurring in

Staphylococcus spp., Pseudomonas spp. and Serratia spp., notably contact lens wearers [13,14].

P. aeruginosa, and Serratia marcescens, commonly reported as the Accordingly, good hygiene practices, including the correct use

primary causes of infection in this group [6,7]. Routine contact of disinfection systems, are fundamental to safe contact lens wear.

lens wear can result in colonisation of the contact lens storage Multi-purpose disinfecting solutions (MPDS) are most commonly

case by substantial numbers of bacteria and this may be encour- used for soft contact lens care and represent a single solution for the

aged through poor lens care hygiene practices [8,9]. Such bacteria, rinsing, disinfection and storage of lenses [15,16]. Typically, they

although not directly pathogenic, can result in a substantial bio- are composed of biocidal preservatives, buffer system and other

burden (including bioﬁlm production) inside the storage case and agents to aid lens comfort and cleaning [15–17]. To qualify as a

MPDS, such solutions must satisfy the requirements of ISO 14729

and produce a 3 log10 reduction in reference strains of the bacte-

ria P. aeruginosa, S. marcescens and S. aureus, and a 1 log10 for the 8

∗ Corresponding author at: Department of Infection, Immunity & Inﬂammation, yeast Candida albicans and the mould Fusarium solani within the

University of Leicester, Maurice Shock Building, University Road, Leicester LE1 9HN,

manufacturer’s recommended contact lens disinfection time [18].

United Kingdom. Tel.: +44 0116 252 2942; fax: +44 0116 252 5030.

However, there is no requirement to establish efﬁcacy against other

E-mail address: [email protected] (S. Kilvington).

http://dx.doi.org/10.1016/j.clae.2013.02.001

Please cite this article in press as: Kilvington S, et al. Identiﬁcation and susceptibility to multipurpose disinfectant solutions of

bacteria isolated from contact lens storage cases of patients with corneal inﬁltrative events. Contact Lens Anterior Eye (2013), http://dx.doi.org/10.1016/j.clae.2013.02.001 8/28/16

Risk Factors for Infiltrative Events and Does Lens Material Affect Pathogenesis? Contact Lenses ¤ Bioburden on eyelid ¤ May be greater bacterial adhesion to silicone hydrogel lenses ¤ 5X higher ¤ P aeruginosa and S Aureus ¤ Prior CIE’s ¤ Lens-attached bacteria form biofilms ¤ 7X higher ¤ Enhance resistance to anti-microbial agents ¤ Patient age ¤ Adapt gene-expression ¤ <25 or >50 3X higher ¤ May be factor for increased infiltrative events ¤ Smoking ¤ Lens material may: ¤ 3X higher ¤ Suppress innate corneal epithelial defense mechanisms ¤ MPS vs H2O2 ¤ Decrease epi proliferation and renewal(> ¤ 2X higher with MPS for low Dk)

¤ DW DD lenses ¤ Solution interactions ¤ 12.5X lower risk ¤ Volume of postlens tear film/ composition ¤ Bioburden on CL or storage case ¤ Absorption/ adsorption ¤ 6.4% higher ¤ Posterior tear fluid loses antimicrobial activity during wear Optom Vis Sci. 2015 Jun;92(6):659-64 ¤ Sihy vs hydrogel ¤ Sihy 2X higher IOVS January 2015, vol 56, No1, pp 654- 663 Eye Contact Lens. 2013 Jan; 39(1): 73–78.

Prevalence of Risk Behaviors

Material properties that Influence TABLE 2. Prevalence of risk behaviors for eye infections* among contact lens wearers, stratified by type of contact lens — United States, 2014

Bacterial Adhesion Risk factor/Behavior % of wearers, by type of contact lens Daily disposable Planned replace, Overnight, Rigid Overall (n = 154) soft (n = 730) soft† (n = 85) (n = 1,141) (n = 182)

§ ¤ Lens surface hydrophobicity Sleeping overnight in contact lens (ever) (48.7) (45.1) (88.6) (17.3) (50.2) influences bacterial adhesion Napping in contact lens (ever) (85.1) (86.9) (96.4) (74.1) (87.1) Topping off solution (ever) (72.0) (51.3) (59.3) (60.5) (55.1) Replacing lenses at interval longer than (39.0) (48.5) (47.4) NA¶ (49.9) ¤ Bacteria have higher affinity recommended ¤ to low energy hydrophobic or when problem surfaces than high energy hydrophilic surfaces. Not using contact lens case (39.6) (1.9) (13.4) (0.0) (8.9) ¤ Rougher surfaces Replacing contact lens case at interval longer (83.9)** (81.1) (82.0) (91.4) (82.3) than recommended ¤ Material dependent- some SiHy rougher than others Storing lenses in tap water (ever) (28.0)** (12.4) (20.9) (33.3) (16.8) ¤ Worn lenses are rougher surface ¤ Both SiHy and HEMA Rinsing lenses in tap water (ever) (40.3) (27.2) (38.3) (91.4) (35.5) ¤ Absorption/ Adsorption Showering in contact lens (ever) (85.1) (84.6) (94.6) (67.5) (84.9) Swimming in contact lens (ever) (59.1) (61.7) (64.9) (50.6) (61.0) ¤ Tear film components (mucin, IgA, Increased inflammatory cells in cornea of Lysozyme, Lactoferrin) Infrequently or never washing hands (1.3) (4.8) (2.4) (2.5) (3.7) asymptomatic DW sihy wearer ¤ Preferential binding to deposits before inserting lenses Infrequently or never washing hands before (19.5) (12.5) (9.0) (17.3) (13.3) removing lenses

Center for Disease Control: August 21, 2015 64(32); 865-870

% of wearers, by type of contact lens

Daily disposable Planned replace, Overnight, soft† Rigid Overall (n = 154) soft (n = 730) (n = 182) (n = 85) (n = 1,141) Lens-Solution Combinations

Where lenses were purchased ¤ Solution Induced Provider office (66.9) (64.7) (67.5) (84.0) (66.9) Corneal Staining Retail store (8.4) (11.8) (7.5) (8.6) (10.4) ¤ Greater risk of low without eye exam grade inflammation ¤ Increase tear cytokines Internet (23.4) (21.3) (24.4) (4.9) (20.8) ¤ Poor tear quality ¤ Deposits

Had a (29.2) (29.3) (35.3) (28.9) (30.2) red/painful eye ¤ MPS higher incidence while wearing of inflammatory contact lens that required a events than H2O2 doctor's visit (ever) ¤ Incidence depends on lens/ solution combination

Center for Disease Control: August 21, 2015 64(32); 865-870

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Characterizing Corneal Infiltrates from a 2010

Case Control Study of SCL Wearers ¤Eye & Contact Lens, April 2012. Published ahead of print.

1RL Chalmers, OD; 2L Keay, PhD; 3J Kern, PhD; 4M Jansen, OD, MS; 5D Lam, OD, MS; 6B Kinoshita, OD; 7H Wagner, OD, MPH; 8G Sorbara, OD, MS; 9Mark Bullimore, PhD; 10Joseph Shovlin, OD; and 11L Sczcotka-Flynn, OD, PhD Eye & Contact Lens, April 2012. Published ahead of print.

¤Study estimated the economic burden of illness 1Clinical Trial Consultants, Atlanta, GA, 2The George Institute for Global Health, Sydney, imposed by contact lens associated corneal infiltrative Australia, 3Alcon Research, Ltd, Ft. Worth, TX, 4Indiana University School of Optometry, 5Southern California College of Optometry, 6Pacific University College of Optometry, events (CL-CIEs) on both the healthcare system and 7NOVA Southeastern University School of Optometry, 8University of Waterloo, 9Ohio State individual patients in the U.S. University, 10 Northeastern Eye Institute, Scranton, PA, 11Case Western Reserve ¤The cost per non-severe and severe CL-CIEs was estimated to be $1,002.90 and $1,496.00, respectively. Overall, the total estimated direct and indirect cost of This study was designed by Robin L Chalmers and funded by Alcon Research, Ltd non-severe CL-CIEs and severe CL-CIEs in the U.S. in 2010 was estimated to be $58 million. Minor revision submitted to Optometry & Vision Science Sept 6, 2011

Potential Risks & Results of Patient Behavior

¤ Patients are poorly compliant even though they often believe they are not.

¤ Disposable lens replacement schedules (Dart, et al.-DDCL), Dumbleton, et al. ¤ Benefits of rub & rinse ¤ Case care and accoutrement issues

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Tarantula Hairs

What’s Missing Here?

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Clinical Features of Ulcerative Keratitis

Symptomotology: pain, photophobia, decreased acuity, foreign body sensation

Signs: significant lid edema and reactive ptosis, conjunctival and ciliary injection, discharge, papillary response, stromal infiltration, surrounding edema, epithelial defect, anterior chamber reaction, cellular debris of tear meniscus and hypopyon

Differential Diagnosis of Ulcerative Lesions

¤ Herpes simplex keratitis

¤ Neurotrophic keratitis

¤ Peripheral marginal infiltrates ¤ Chemical keratopathy

¤ Keratoconjunctivitis sicca

Culture Media

¤ Blood: aerobic organisms, saprophytic fungi ¤ Chocolate: Neisseria, Moraxella, Hemophilus ¤ Sabouraud’s: fungi ¤ Thioglycolate broth: aerobic and anaerobic bacteria ¤ Lowenstein–Jensen or Middlebrook 7H-9: Nocardia, Mycobacteria species

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When To Culture Corneal Ulcers

¤ History of organic trauma ¤ Atypical ulcer or if a rare infection is suspected ¤ Infiltrate/suppuration involves the visual axis, infiltrate at 25% depth, 50% corneal thinning or scleral extention ¤ Immunocompromised or hospitalized patient ¤ Unresponsive to seemingly appropriate treatment

Post Lasik Infiltrate

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Laboratory Work-up Corneal Scrapings

Up to 50% of properly performed cultures will reveal no ¤ Useful to use two solid media (blood and chocolate). growth in the setting of an actual bacterial keratitis (false negative) Tissue biopsy after treatment may be Helps to R/O contaminants and aids in ID if there’s sparse necessary! growth If only one is used chocolate is preferred. ¤ Direct inoculation of solid and liquid media is best method to increase the culture yield. ¤ Add Lowenstein/Jensen, amoeba culture or HSV swab if necessary. ¤ Kimura spatula: culture the edge and base of the ulcer, serves to debreed the lesion ¤ Hold fungal cultures longer! ¤ Gram stain: only 12-60% accurate at predicting organism ¤ If you use non-solid medias such as thioglycolate broth ¤ Giemsa stain: provides better morphologic characteristics of use a cotton-tip applicatot that’s plastic, not wood organisms and helps to distinguish bacteria from fungi broken into the tube.

Additional Clinical Features of Bacterial Keratitis

Gram Positive Organisms

¤ localized

¤ round or oval gray-white infiltrates

¤ distinct borders

¤ minimal surrounding edema Gram Negative Organisms

¤ increased suppuration

¤ adherent exudate to base

¤ larger, less defined infiltrate

¤ more rapid progression and stromal necrosis/excavation

Principles of Treatment

¤ Utilize broad spectrum of coverage: single agent v. multiple agents (with or without culture)

¤ Use rapid, intensive topical therapy. Best to avoid “heavy” pain medication.

¤ Daily evaluation until significant improvement is shown.

¤ Tailor antibiotic choice by culture results and clinical impression.

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Treatment and Management

¤ In-patient v. out-patient therapy depends on patient profile ¤ Initial treatment should be broad spectrum despite gram stain results with severe infections ¤ Reasons for systemic medications: N. gonorrhoeae ¤ Fortified antibiotics v. fluoroquinolone use ¤ Strep. is a deficiency, low toxicity, good corneal penetration, greater duration of use, off-the-shelf availability, cost, prolonged tear film concentration

Design for Drug Penetration Modification Of Therapy

Topical: every 15 min.-1 hr. for initial 24-48 Objectives: eliminate replicating bacteria, hrs. or an altered loading dose avoid adverse reaction to the medication, control the destructive components of the Subconjunctival injection: once or twice inflammatory process daily for 1-2 days Guidelines: avoid abrupt changes in therapy Intravenous/oral antibiotics: only for until the response can adequately be impending perforation or scleral suppuration assessed and until the sensitivity tests are completed at the lab

Termination of Therapy Fourth Generation Fluoroquinolones

¤ Provide greater gram+ coverage and ¤ Measures of improvement: blunting of the equivalent gram- coverage perimeter of stromal suppuration, reduction in density of suppuration, reduction in ¤ Alternatives: fortified tobramycin 14mg/ml or cellular infiltrate and surrounding edema, ceftazidime 50mg/ml with adequate gram+ reduction in anterior chamber reaction, coverage of vancomycin 30mg/ml or cefazolin. progressive re-epithelialization ¤ Decreased chance for resistance ¤ Reducing anti-microbials and adjuvants: ¤ “quorem sensing and auto-induction” avoid abrupt cessation, prolonged therapy ¤ hydrophobic regions limit bacterial efflux needed for Pseudomonas, Mycobacterium, ¤ attacks and binds DNA gyrase (gram-) and Nocardia, anaerobes topoisomerase II/IV (gram+)

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Resistant Bacteria Fluoroquinolone Resistance

¤ Methicillin resistant Staphylococcus aureus ¤ Enterococcus Fecalis (group D ¤ UCSF Study (1996) Hwuang et al.: topical ciprofloxacin qid. S. Streptococcus) aureus resistance rose from 12%-50% with in-vitro testing

¤ Aminoglycoside resistant Pseudomonas ¤ Wills Eye Hospital Study (1996) Rodman: aeruginosa ¤ S. aureus resistance - Strep. resistance ¤ Beta lactamase producing Neisseria 1992-4% 1992-20% ¤ Atypical Mycobacteria 1996-13% 1996-26%

Gram positive: Vancomycin 20-30 mg/ml, ¤ LV Prasad Institute (1999) Kunimoto et al: ¤ 30.7% corneal isolates not sensitive to ciprofloxacin .28% Lysostaphin, IV Linezolid (Zyvos) Bascom Palmer Eye Institute (1999) Chaudry et al: P. Gram negative: Amikacin 20 mg/ml, .19% Colistin aeruginosa resistance rose from .44% (1991-1994) to 4.1% (1995-1998)

Newer Generation Fluoroquinolone Causes of Antimicrobial Resistance Trends Resistance

¤ Ocular Trust data found 3rd and 4th generation ¤Inappropriate use of antibiotics fluoroquinolone effective against 30% of MRSA isolates, while Polytrim effective against 95% of ¤Tendency to use broader spectrum the same isolates antibiotics ¤ McDonald & Blondeau Cat & Ref Surg 36(9): 2010 ¤Use of antimicrobials in an agricultural ¤ Up to 85% MRSA strains resistant to moxifloxacin & setting gatifloxacin ¤ Besifloxacin showed greater efficacy against multi- ¤Spread of resistant organisms by drug resistant S. aureus increased international travel

ARMOR Surveillance Data Ocular TRUST 2: Overview ¤ Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) initiated in 2009-2013 ¤Methicillin resistance in staphylococci marker ¤ S. aureus and CoNS were non-susceptible to oxacillin/methicillin for multi-drug resistance (43-59%), ciprofloxacin (33-43%) and azithromycin (60-63%) >3 ¤Fluoroquinolones most consistently active drug resistance increased (38-39%). agents across ocular pathogens ¤ Besivance was one-fold less effective than vancomycin for MRSA/MRSE. Ciprofloxacin was 100 fold less effective than ¤Fluoroquinolone susceptibility profile vancomycin. Twenty-five-thirty-seven percent of S. aureus and 50% of CoNS is MR (ARVO 2105). l Gatifloxacin = Levofloxacin = Moxifloxacin l Modest diminution in S. pneumoniae ¤ 4th generation fluroquinoloes show “holes” in Pseudomonas susceptibility to ciprofloxacin coverage. Ciprofloxacin faired reasonably well. ¤Polymixin B and penicillin most limited activity ¤ Overall, updated data (2014) showed multi-drug resistance among CoNS and MRSE increased, but slightly decreased among S. aureus and MRSA

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After 3 days of Abx MRSA ¤ MRSA must be a consideration in any external ocular infection unresponsive to standard antibiotic therapy over 2 weeks. ¤ Suspicion for ocular MRSA must increase with: ¤ Malignancy ¤ Debilitating systemic disease ¤ History of ocular surface disorder ¤ Resistance to fluoroquinolones is increasing, even with 4th generation. ¤ Vancomycin and gentamicin remain effective treatments. ¤ Community-associated MRSA is an evolving ocular pathogen most often found in “hospital- naive” patients.

CA-MRSA MRSE

¤ S. epidermidis and MRSE are ubiquitous commensal organisms in the human body. Most common cause of bacterial endophthalmitis. ¤ Among ophthalmic S. epidermidis isolates, MRSE rates may exceed 50%. ¤ Resistance to fluoroquinolones is common among MRSE isolates. ¤ Biofilm formation fortifies S. epidemidis against antimicrobial therapies and immune defenses. ¤ Biofilms enable adhesion of bacteria to artificial surfaces such as IOLs and contact lenses. ¤ Additional therapies include quorem sensing and immunotherapy against biofilm antigens and anti- biofilm activity.

New Antimicrobials Adjuvant Therapy

¤ 4th and 5th Generation Fluoroquinolones and Isothiozoquinolones (ITQs): ¤ Cycloplegia Trovofloxacin (Pfizer), Moxifloxacin (Bayer, Alcon), Gatifloxacin (Bristol- Myers/Squibb, Allergan), Temafloxacin (Allergan), Gemifloxacin (Pharmacia) ¤ Collagenase inhibitors ¤ Peptide Antimicrobials and Inhibitors: ¤ deformylase, quorum sensing and efflux pump inhibitors ¤ Steroids ¤ Exazolidinones ¤ NSAIDs/Analgesics ¤ Pleuromutulins ¤ Tissue adhesives ¤ Oxazalidone linezolid ¤ Glaucoma medications ¤ Bacteriophages- new classes of viruses ¤ Recombinant bacterial/permeability increasing protein ¤ Aganocides

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Adjuvant Therapy (cont.)

¤ Debridement/biopsy

¤ Cryotherapy ¤ Bandage lens therapy/Pro-Kera/Bio-Tissue ¤ Continuous antibiotic infusion devices ¤ Therapeutic keratoplasty ¤ Bio-erodible mini tablets (fluoroquinolone) ¤ Hyperbaric oxygen

¤ Collagen cross linkage (Riboflavin/UV)

Guidelines: The Use of Topical Steroids in Bacterial Keratitis Collagen Cross-linking

¤ Risks vs. Benefit: - the rationale for and the case against using topical steroids

¤ For: Steroids do not interfere with the ability of a bactericidal antibiotic (in sufficient concentration) to kill susceptible organisms.

¤ Against: Difficult to quantify scarring, therefore it’s never been proven that steroids minimize scarring. If you kill the organisms, patients are “cured”. “The anti-inflammatory effects of an effective antibiotic are frequently sufficient in treating bacterial ulcers.” (Baum)

Guidelines: The Use of Topical Wilhelmus (50 year review): Indecision about Steroids in Bacterial Keratitis corticsteroids for bacterial keratitis: An evidence based update ¤ Meta-analysis of past studies: ¤ (2002) This study did not demonstrate a clear ¤ Steuhl et al. underscores the potential benefit and cut beneficial effect of topical steroids on justification for anti-inflammatory therapy. course of bacterial keratitis. ¤ Leibowitz and Kupferman: cytokine induced expressions significantly down-regulated by corticosteroids. ¤ Results: (1) steroid use before the diagnosis of bacterial keratitis significantly predisposes eyes with pre-exiting ¤ Vemuganti et al.: HLA-DR down-regulated and may inhibit disease to severe ulcerative keratitis [odds ratio: 2.63], keratocyte apoptosis induced by bacterial infection. (2) once microbial keratitis occurred, prior steroid use significantly increased the odds of antibiotic treatment ¤ Flesizig et al.: Pseudomonas shows an invasive v. failure or other infectious complications [odds ratio: 3.75], (3) the effect of topical steroid use with cytotoxic genotype and respond diffferently to steroids antibiotics after the onset of bacterial keratitis was (invasive best response). unclear.

** 24 studies summarized- 37.5% beneficial; 50% neutral and 12.5% adverse

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Guidelines: The Use of Topical Steroids for Corneal Ulcers Trial Steroids in Bacterial Keratitis (SCUT) ¤ Topical steroids offer no significant benefit (or risk) in treating bacterial keratitis.* Randomized Clinical Trial is sorely needed (NEI/NIH funded RO1): similar to the ¤ Adjunctive steroid therapy may improve visual herpetic eye disease study outcome in severe bacterial ulcers (and may be most beneficial when used early).** Pilot study: Srinivasan M, Lalitha P, Mahalakshmi R, et al: Corticosteroids for bacterial corneal ulcers. BJO: Oct, 2008. ¤ Steroids should not be used in Nocardia infections. ¤ Cochrane Systematic Review: only 1 randomized ¤ MIC correlates with clinical results; antibiotics with clinical trial to date with “ major methodological lower MIC are associated with better outcomes. inadequacies”. Challenges include: type of *Srinivarsan M, Mascarenhas J, Rajaraman R et al: Corticosteroids for bacterial keratitis: The Steroids for organism, severity of infection, antibiotic and Corneal Ulcers Trial (SCUT). Arch Ophthalmol (2012); 130(2):143-150.

steroid selection, length of time before treatment, **Ray KJ, Srinivasan M, Mascarenhas J et al: Early addition of topical corticosteroids in the treatment of location of ulcer and additional patient factors. bacterial keratitis. JAMA Ophthalmology (2014); 132(6):737-41.

Steroids for Corneal Ulcers Trial Guidelines: The Use of Topical (SCUT) Update Steroids in Ulcerative Keratitis

¤ 12 month SCUT data published on BSCVA and corneal scar size in ¤ Principles for successful use of corticosteroids: (1) scrapings 399 cases from the original sample. for stain and culture, (2) use of adequately dosed bactericidal ¤ Myofibroblasts and fibroblasts, which are active during wound healing, antibiotics, (3) delay initiation of steroids until a clearly may help restore corneal transparency. beneficial effect to antibiotic has been determined, (4) ¤ Topical corticosteroid benefit may be delayed but little benefit shown continue concurrent use of antibiotic with steroids, and (5) after 12 mos.. delay use of steroids if causative organism is not identified. USE 2-5 days after appropriate antibiotic therapy. ¤ Immune-mediated tissue damage may be reduced, corneal remodeling may occur and scar density may be reduced long ¤ Avoid if fungal infection or atypical mycobacterium is after steroid use has been discontinued. suspected, if there is severe thinning, enlarging epithelial defect, poor wound healing (diabetes), or immuno- ¤ There may be a benefit with adjunctive topical corticosteroids if suppression. application occurs earlier in the course of bacterial corneal ulcers.

Srinivasan M, Mascarenhas J, Rajaaraman R, et al. The steroids for corneal ulcers trial: secondary 12-month clinical ¤ In Acanthamoeba keratitis, steroids may increase potential for outcomes of a randomized controlled trial. Am J Ophthalmol. 2014;157(2):327-33. pathogenicity and steroids likely cause an increase in the rate

Ray K, Srinivasan M, Mascarenhas J et al. Early addition of topical corticosteroids in the treatment of bacterial keratitis. of excystment and suppress macrophages. JAMA Ophthalmol. 2014; 132(6):737-41.

Non-Bacterial Corneal Ulcers Fungal Infections

¤Bascom Palmer Series (Alphonso et al.): CLASSIFICATION/MOST COMMON ORGANISMS ¤ 1986: 3.1% of corneal ulcers treated were not bacterial ¤ Filamentous Fungi; Molds ¤ 2004-05: 64.7% of corneal ulcers treated were ¤ Septated: pigmented, non-pigmented not bacterial ¤ Non -Septated

¤ Yeasts ** some of the increase shift is due to 4th generation fluoroquinolone usage

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Risk Factors for Fungal Keratitis

¤ MOLDS: corneal injury, soft contact lens wear, chronic topical medications, systemic steroid usage, diabetes, radial keratotomy

¤ YEASTS: protracted healing, topical steroids, penetrating keratoplasty, bandage contact lenses

Clinical Features of Fungal Infections

¤ MOLDS - epithelium can be intact or ulcerated, usually non-suppurative with feathery infiltrates (focal or multi-focal / satellite)

¤ YEASTS - epithelium is usually ulcerated, generally suppurative (focal or diffuse)

Specific: infiltrates with gray/brown pigmentation, elevated edges with rough texture

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Diagnosis of Keratomycoses

¤ Clinical Suspicion ¤ Corneal Scrapings and Suture Passes ¤ Smears: gram, giemsa, acridine orange, calcofluor white ¤ Cultures: blood agar, Sabouraud’s media ¤ Polymerase chain reaction ¤ Superficial Keratectomy/Biopsy ¤ Paracentesis ¤ Confocal Microscopy

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Initial Anti-fungal Treatment Antifungal Drugs ¤ Hyphae: Natamycin 5% suspension*, topical and oral Voriconazole, oral Ketoconazole, Fluconazole or Itraconazole ¤Sterol Binding ¤ Yeast or Pseudo-hyphae: Amphotericin B, ¤Inhibition of Sterol Synthesis Natamycin, Miconazole, Clotrimazole, Posaconazole or Flucytosine ¤Interference of RNA Synthesis Subconjunctival injections of Fluconazole or intrastromal ¤Inhibition of Mitosis injection of Amphotericin B are helpful in recalcitrants. *generally most effective especially in Fusarium treatment ¤Cationic Antiseptic MIC values (sensitivity) may be predictive of outcome for Natamycin.

Treatment and Management of Fungal Keratitis Surgical Therapy

¤SUPPORTIVE AND ADJUNCT THERAPY ¤Biopsy ¤ Debridement ¤Keratectomy ¤ Heat (40 degrees C) ¤ Conjunctival Flaps ¤Penetrating keratoplasty ¤ Debulking Procedures / Excimer ablation ¤ Drug Delivery Devices ¤Conjunctival flaps ¤ Cycloplegics ¤ Glaucoma Medications ¤Cryotherapy ¤ Tissue Glue ¤Excimer ablation

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Prevention of Fungal Infections in CL Wear

¤Minimize use of overnight wear including bandage lenses ¤Avoid indiscriminate use of topical medications ¤Stress proper maintenance and care of lenses and case

Unusual Outbreaks of Fusarium Keratitis CDC Fusarium Keratitis Update

¤ Background: Fusarium keratitis is a relatively rare infection around the world, except in humid ¤ 86 cases are confirmed, 9 listed a ”possible” climates and especially in contact lens wearers and 96 are under investigation (about 5%-Bascom Plamer) ¤ Complete data are available in 58 cases (56 are contact lens wearers) ¤ Disproportionate number of ReNu with Moisture Loc users (Singapore, Hong Kong) ¤ Products used were: ¤ 32 B&L ReNu with MoistureLoc™ ¤ Alphonso series: 2005-about 50% CL wear and ¤ 15 B&L ReNu® MultiPlus™ 2006-over 70% CL wear ¤ 7 B&L ReNu (unspecified) ¤ 3 Advanced Medical Optics (AMO) ¤ Script trac experienced a 150% increase in ¤ 3 Alcon product (unspecified) Natamycin prescriptions written in 2005. * Total adds up to more than 56

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Fusarium Keratitis: CDC/MMWR Dispatch “The Perfect Storm” 05-19-06

¤ Focus on: ReNu with MoistureLoc™ ¤ 130 confirmed cases (onset after June, 2005, no (disinfectant/surfactant), system failure history of trauma and positive culture) unlikely, cross contamination likely ¤ Median age: 41 (12-83); Sex: 67% female ¤ Pathogenesis: repeated inoculation not enough, epithelial micro-dehiscense is necessary ¤ 37/120 (31%) evaluated have been grafted ¤ Multifactorial etiology: (lens type, lens case and ¤ 125/130 were CL wearers bottle tips, biofilm/mycelium, “polymer film”/surfactant, environment/natural disasters) ¤ 118 identified their CL solution(s): 75 (64%) ReNu ¤ Similarities to the protozoan mini-epidemic: with MoistureLoc™, 14 (12%) MoistureLoc™ with (uptick, recognition, morbidity, inoculation, masking another solution, 8 (7%) unspecified B&L product, antigens, attack rate, host defenses) 21(18%) using another product

CDC Case Control Study CDC Case Control Study Results

¤ CDC enrolled a sub-set of patients (50 cases and 79 ¤ Adjusted odds ratio: controls) to evaluate relative risk [April, 2006] ¤ ReNu with MoistureLoc™-19 (2.4-944.9) p<.001 ¤ “For the most stringent test for product ¤ ReNu®MultiPlus™-3.6 (0.3-189) p=0.5 association analysis was limited to 25 cases and 37 controls.” Conclusion: “ReNu®MultiPlus™ was not significantly associated with the recent outbreak of Fusarium keratitis; Cause of strong association with ReNu with MoistureLoc™ ¤ Multivariable analysis: after controlling for poor is unclear”. compliance and reported exposure within 1 On-going studies looking at environmental and formulation month prior to symptoms under stress risks are continuing.

Medical Management of Fusarium Keratitis Fusarium Outbreak: Is It Over?

¤ Topical: Natamycin 5%, Voriconazole 10mg/ml, Chlorhexidine 0.2% ¤ Oral and IV: Voriconazole (Vfend/Pfizer) 200mg ¤4 case reported since the ReNu BID ®MoitureLoc recall ¤None of the patients reported using ¤ Surgical: debridement, full thickness grafting ReNu®MoistureLoc *if unresponsive, systemic posaconazole or liposomal or lyophilized Amphotericin B ¤Associated with other MPDS ** Natamycin may respond better than Voriconazole in monotherapy especially in filamentous infections. (Mycotic BBJeng, G Hall, L Schoenfield, and D Meisler: Fusarium Outbreak: Not done Yet? Arch Ophthalmol, 2007, 125(7):981-982. Treatment Trial, JAMA Ophthalmol. 131/4:422-29)

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Paecilomyces lilacinus

Uptick in recently reported cases in Florida in contact lens wearers

¤Responds to Natamycin and Voriconazole ¤Important to realize that unusual infections do occur in non-lens wearers.

Protozoan Infections in CL Wear

¤ ACANTHAMOEBA-at least 7 species show ocular parasitology, 23 species show systemic parasitology

[A.castellani, A.guina, A.culbertsoni, A.lugdunesis, A.polyphaga, A.hatchetti, A.rysades, A.griffini]

¤ Genotype (15)- 97% of isolates are of the T4 genotype

¤ Forms- 2 different life cycles

Acanthamoeba Morphology

Acanthamoeba Acanthamoeba trophozoite cyst

Image from: Hughes R, Kilvington S: Comparison of Hydrogen Peroxide Contact Lens Disinfection Systems and Solutions against Acanthamoeba polyphaga. Antimicrobial Agents and Chemotherapy: 2038-2043, 2001.

† Tests follow FDA/ISO stand-alone criteria but are not FDA-required.

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Acanthamoeba Keratitis can be an Outbreak disease: History in the USA Annualized Incidence Rate of

Time period Total Cases average Comments Acanthamoeba Keratitis cases Per year

1974-1983 31 50% wore contact lenses but no 3 ¤ One case/ 30,000-million contact lens wearers/ year (new infection hard correlation made; this is the beginning normal disease rate to diagnose) ¤ Mathers data following Iowa floods (1/10,000) 1984-1991 1150 115 85% soft contact lens wearers, ¤ England incidence study: 17.53-21.42/mil. Outbreak estimate (6 x normal rate) nearly all used non-Sterile (1990=200 cases) solutions to soak lenses due to ¤ Chicago data-19/mil. (Joslin); 1/8-10,000 CMP users (Schein) FDA approved salt tablets 1994-2003 190 19 excludes 137 cases in the ¤ Proctor increase: 1.8/yr (2000-2005) to 5/yr. (2005-2006) (June ‘03) estimate Iowa flooding outbreak ‘93-’96; this is the normal disease rate ¤ Higher prevalence in Scotland and S. Korea June 2004- 485 121 Outbreak cause? EPA June 2007 Data (2008 continues at decrease of water disinfection Outbreak from 85 cases/yr or 4.5x level and a constant small Seals D: Incidence of acanthamoeba keratitis in contact lens wearers. Eye, 2003; 17:893 CDC the normal rate) number of patients using water in their lens care regimen?

Chicago-Gary-Kenosha 2000 Metropolitan Statistical Area

Kenosha Uptick of Acanthamoeba Keratitis

McHenry Lake Incident AK Cases: ¤ 40 confirmed cases from 6/03-11/05 in the 6/03 – 6/05 Chicago area.* ¤ Clinical and demographic factors: chlorine Kane Cook DeKalb levels in municipal water supplies, change in pathogenicity, environmental shifts in biofilms, DuPage attachment to new materials

nactual = 33 Kendall ¤ 88% hydrogel wearers, 12% RGP wearers Nexpected* = 3.7 – 4.4 Porter Will Lake *Schaumberg DA et al, Cornea 1998 ¤ Orthokeratolgy incidence: 30% of cases of microbial keratitis Grundy ¤ Kids may lack antibodies needed to ward off - Kankakee the infection 0 10 20 40 Miles

* *Joslin CE, Tu EY, McMahon TT et al: Epidemiologic characteristics of a Chicago-area acanthamoeba keratitis outbreak. Am J Ophthalmol, 142(2), 2006.

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Insurgence of Acanthamoeba AMO Recall of Complete Keratitis in Contact Lens Wear Moisture®Plus™ Solutions June 25, 2007

¤Background: Acanthamoeba keratitis ¤ CDC interview of 79 soft lens wearers with AK: 45 (60%) reported at least some use of remains a relatively rare infection among Complete® MoisturePlus™ in the month prior to contact lens wearers with recent reports of symptom onset. outbreaks in some geographic areas. ¤ Patients who used Complete® MoisturePlus™ ¤ CDC reports a disproportionate number of had a relative risk of 16X or greater for Complete® MoisturePlus™ users in data set. contracting acanthamoeba keratitis ¤ Complete®Moisture Plus™ contains ¤ Complete®Moisture Plus™ contained propylene glycol, taurine and surfactants with a lower propylene glycol, taurine and new EDTA concentration. surfactant and lower concentration of EDTA

Parallels with Fusarium Keratitis 2006 Outbreak Acanthamoeba Keratitis Case Control Studies: Relative Risk

¤ CDC: Complete® MoisturePlus™- 16.9, "top off" ¤ Concurrent outbreaks of keratitis among CLU solution 2.8, <5 years wear 2.8

Verani JR, Lorick SA, Yoder JS, et al. National outbreak of Acanthamoeba keratitis associated with the ¤ Multi-purpose solution implicated use of a contact lens solution. Emerg. Infect. Dis. 2009;15(8):1236-1242. ¤ Fusarium: Bausch & Lomb ReNu with MoistureLoc ¤ Joslin: Complete® MoisturePlus™- 18.51, Re-use ¤ No contamination ¤ Insufficient anti-microbial efficacy of solution (.5/mo.)- 3.17, "rub" (<10/mo.)- 9.05, showering with lenses (>5/mo.)- 9.07, case ¤ “Topping off” solution in case common risk factor replacement (>3 mos.)- 2.79 ¤ Reduce anti-microbial efficacy

Joslin CE, Tu E, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol 2007;29(5):1-8. ¤ Concern about safety of multi-purpose solutions

Epidemic Intelligence Acanthamoeba Keratitis Among Conference CDC, April, 2012 RGP Lens Wearers

¤ Elevated Acanthamoeba Keratitis Incidence Despite a ¤ 37 patients in 2 investigations (case control study) 2007 Outbreak-Associated Product Recall-A Multi-State ¤ Significant risk factors: ortho-keratology (OR-undefined), Investigation, 2008-2011 Brown AC, Ross J, Yoder J, Ayers sleeping while wearing lenses (OR-8.00), storing lenses in T, Roy S and Beach M. tap water (OR-16.0), and topping-off care solution in ¤ Multiple CL hygiene practices were associated with increased risk of case (OR-4.80) AK. The observed persistence of AK might be due to enhanced disease awareness and clinical suspicion following the 2007 ¤ “Nearly one quarter of patients were ortho-keratology investigation. wearers. Using tap water and topping off care solutions ¤ To prevent infection, CL wearers should observe recommended CL were identified as modifiable risks. RGP wearers should care practices. avoid exposing their lenses to tap water.”

RISK FACTORS: topping off solutions 4.54X, recently starting CL ¤ Cope JR, Collier SA, Schein OD, et al: Acanthamoeba keratitis among RGP contact lens wearers in the United States, 2005 through 2011. Ophthalmol.; use 3.22X, storing CL in water 5.37X, and handling CLs with June,2016. wet hands 2.17X

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MANNOSE-BINDING PROTEIN (MBP) IS A CRUCIAL LIGAND FOR ADHESION TO THE CORNEAL EPITHELIUM Acanthamoeba Proxy

¤Legionellosis- live inside amoeba ¤Increased reporting in Japan (2004) ¤Causes Legionnaires’ disease (gram negative bacteria)

Neil K. Acanthamoeba and its association with Legionellosis. Clin Infect Dis, 14(9), 2000

Symptomotology in Acanthamoeba “Wheat and Rice” Food Source Keratitis

¤ Stenotrophomonas maltophilia and Delftia acidovorans are bacteria commonly found in cases ¤ Symptoms: Usually unilateral,* pain disparate to where there is contamination with Acanthamoeba. findings, history to trauma and/or contact lens wear, symptoms wax and wane with chronicity ¤ Strategies in designing new MPS: minimizing encystment (1.5X evaporation from “topping off” *Large series shows 7-11% bilaterality at time of initial doubled encystment rate with presentation or a few months later. (Tu et al.) Complete®MoisturePlus)

Nikolic M, Kilvington S, Cheung S, et al. Survival and growth of Stenotrophomonas maltophilia, ARVO abstract #1540-D831, May 2010, Fort Lauderdale.

Clinical Features of Comparison of Clinical Features With Early vs. Late Diagnosis Acanthamoeba Keratitis

Early(%) Late (%)

¤ EPITHELIAL: patchy epithelial involvement (stellate, ¤ Punctate keratitis 46 21 irregular or pleomorphic epitheliopathy) “bull’s eye” ¤ Dendritiform ulcer 14 4 lesion, white spots, persistent epithelial defect, elevated corneal lines ¤ Epithelial loss 38 75

¤ Perineural infiltrates 57 29 ¤ STROMAL: lack of vascularization, granulomatous or non-suppurative inflammation, radial nerve ¤ Limbitis 95 96 infiltrates (“lightning flash”), ring infiltrate ¤ Ring infiltrtate 19 83 ¤ OTHERS: pseudoguttata, hyphema, hypopyon, ¤ Uveitis 5 79 pseudomembrane, scleritis, episcleritis, adenopathy, decreased corneal sensation (initial) Dart JK, Saw VP and Kilvington S: Perspective: Acanthamoeba keratitis-diagnosis and treatment update 2009. Am J Opththalmol 2009;487-500. **poor response to therapy may suggest co-infection

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Diagnostic Confusion With Other Corneal Dendritiform

¤ Acanthamoeba elevated corneal line ¤ Herpes simplex dentrite ¤ Herpes zoster keratopathy ¤ Contact lens “pseudo-dendrite” ¤ Thygeson’s superficial keratopathy ¤ Tryosinemia (Richner-Hanhart) ¤ Other corneal fascinations-edematous formations, verticillata, filaments, stromal dystrophy, post PK hypertrophic epitheliopathy

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Diagnosis of Acanthamoeba Keratitis

¤ Clinical Suspicion

¤ Corneal Scrapings

¤ Superficial Keratectomy / Biopsy

¤ Paracentesis

¤ Confocal Microscopy and SD-OCT

¤ Soft Lens Inspection

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Higher resolution OCT can visualize pathogens

Acanthamoeba in 0.25% agar

Confocal Images of Trophs and Cysts

Post-Surgical TISSUE Analysis Therapy for Acanthamoeba Keratitis

¤ ANTI FUNGALS (anti-trophozoite agents) ¤ ANTIPARASITICS / Aromatic Diamidines ¤ BIOCIDES / CATIONIC ANTISEPTICS

Note: No one case acts in the same manner

**aminoglycosides have now shown increased neomycin resistant strains with an increased preponderance for trophozoite transformation; concentration of BAK in antibiotic can be therapeutic.

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Treatment and Management of Recalcitrant Disease Acanthamoeba Keratitis

¤ Can result from drug resistance, polymicrobial infection, ¤ SUPPORTIVE AND ADJUNCT THERAPY infectious/non-infectious inflammation, neurotrophic ¤ Debridement** epithelial disease ¤ Conjunctival Flaps/Amniotic Membrane Transplants ¤ Bandage Lenses ¤ Treatment: increase dosage/concentration, change ¤ Debulking Procedures medications, add medication(s) ¤ Cryotheraphy ¤ Steroids ¤ Additional secondary therapy: voriconazole ¤ Cycloplegics (topical/oral), pentamide, miltefosine ¤ Pain Medications

Note: Steroids increase pathogenicity by suppressing macrophages and accelerating trophozoite proliferation.

Clinical Outcome In Treating Acanthamoeba Keratitis Acanthamoeba Keratitis Outcomes

¤ Propamidine and neomycin: 9/19 (47%) Meisler ¤ Keratoplasty was 5X more likely in pts. > 40 years old. ¤ Propamidine and PHMB: 8/10 (80%) McCulley ¤ Ring infiltrate pts. were 40X more likely to proceed to 105/111 (96%) Wilhelmus keratoplasty and also predicted worse acuity with 3x risk ¤ Propamidine and chlorhexidine: 40/42 (96%) of blindness. Seals ¤ Any sign of stromal invasion was 10X more likely to ¤ Miltefosine and PHMB: (unknown) Cope/MMWR proceed to keratoplasty. ** Role of corticosteroid treatment is controversial! ¤ More advanced disease (late diagnosis) equates to Robaei D et al: Ophthalmology. 2014 [Epub ahead of print]-30 days or > of steroid use: 7.92X risk for poorer outcomes. poor visual outcome; any steroid use nearly 4X. Ross J, Roy SL, Mathers WD, et al: Clinical characteristics of Acanthamoeba Intensive monotherapy with either PHMB or chlorhexidine may be equally as effective (Wills Series), but oral Voriconazole may be beneficial with deep corneal disease. (Tu et al.) keratitis infections in 28 states, 2008-2011. Cornea, 2013 (12).

Prevention of Acanthamoeba Keratits in CL Wear Additional Protozoan ¤Avoid use of saliva, distilled and tap/well water. ¤Avoid swimming and hot tubs while wearing contact lenses. ¤Naegleria ¤Precautions while showering with lenses in place. ¤Hartmanella ¤Hygiene related variables: proper maintenance and care of lenses includes a ”rub and rinse”, not ¤Vahlkampfiid “topping off”, and replacing lenses and cases regularly. ¤Microsporidia ¤Oxidative disinfection has reasonably good cysticidal effects. ¤Rhinosporidia

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Microsporidia Keratitis

¤ Presents as a superficial punctate, multifocal keratitis and a stromal keratitis is possible following trauma

¤ Nasopharyngeal or urinary colonization in HIV infected patients

¤ Improvement with voriconazole, albendazole and topical fumagillin bicyclohexyl ammonium salts ¤ Repeated debridement (perhaps even swabbing) seems to be therapeutic especially in immunocompetent patients.

*may be best classified as a fungus

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The Herpesviridae Family

¤ 8 distinct DNA viruses

¤ HSV and HZV are the most common; Epstein Barr is also found to cause corneal insult.

¤ HSV-1 is the most common ocular pathogen; HSV-2 is more responsible for genital infections.

¤ Neonates often infected with HSV-2.

¤ Healthcare costs for the herpes group are over $1 billion each year.

Herpes Simplex Features Herpes Simplex Prevalence ¤ Initial ocular presentation occurs on lid and conjunctiva 50% of the time. (anterior cornea 60% and stroma 6%).

¤ Unilateral follicular conjunctivitis is always suspicious for HSV ¤ 25% are seropositive by age 4, nearly 100% are affected infection. Steroids will trigger infectious keratitis. by age 60. ¤ Conjunctival dendrites may be present without corneal findings. An iritis with high IOP is concern for HSV! ¤ Most are asymptomatic on primary infection. ¤ In children, primary infection manifests with fever and cutaneous ¤ Skin eruptions are not common after primary infection. outbreak around the lids. Outbreak is prolonged and less responsive to therapy.

¤ Recurrent HSV is commonly found along the oral or nasal ¤ Bilateral involvement or prolonged HSV suggests comorbid disease mucosa. (i.e. atopy, immunodeficiency or immunosuppression). Two or more atopic conditions increases risk 8.9 fold for HSV (2.9 fold for HZO)*

* Borkar DS et al: Association between atopy and herpetic eye disease results from the Pacific Ocular Inflammation Study. JAMA Ophthalmol. 2013; 132(3):326-41.

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Corneal Presentations

¤ Four clinical presentations: epithelial, stromal, endotheliitis, and neurotrophic keratopathy

¤ Epithelial (Infectious): corneal vesicles, dendritic ulcer, geographic ulcer, marginal ulcer

¤ Stromal (Immune): infiltration, vascularization and scarring/ necrotizing

¤ Endotheliitis: an infectious and inflammatory reaction (HSV or CMV); use anti-viral orals and topical steroids ¤ Neurotrophic: results from altered corneal innervation and decreased tear production

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Case 14 - painless Herpes Simplex Both Stains ?? Additional Value (not a classic dendrite)

Eczema Herpeticum Viral Detection ¤ Manifests as a rash, fever with typical viral lab results; buccal mucosal swabs will likely show ¤ Cell Cultures active virus.

¤ ELVIS (enzyme-linked virus inducible system)** ¤ Bilateral eye involvement (simultaneous) includes disciform corneal findings and atopic ¤ PCR (polymerase chain reaction/DNA detection)- dermatitis or other pre-existing skin disorders. Intelligent MDx ¤ Diagnosis: culture for HSV, secondary bacterial HSV can be recovered by swabbing an untreated dendrite infections are common with a soft tipped applicator inoculating it into viral transport media or a viral culturette. ¤ Treatment: compresses, antiviral therapy (topical and systemic); anti-pruritics; patients ** high degree of sensitivity and specificity within 24 hrs. are in great need of desensitization therapy.

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Pediatric Herpes Simplex Herpes Simplex Masquerades

¤ Frequently misdiagnosed as simply blepharitis or ¤ Various conditions present with branching lesions conjunctivitis. (dendritiform): Acanthamoeba, healing abrasions, stromal dystrophy, Fabry, tyrosinemia, HZV, and Darrier. ¤ Recurrence rates are higher than adults (50%). ¤ Drug Corneal Toxicty ¤ Generally show severe inflammation and stromal disease; adults most commonly have dendritic keratitis. ¤ HSV is the only ulcerative lesion; the rest are excavated!

¤ Managed best with adjusted oral doses of acyclovir.

Liu S, Pavan-Langstan D, Colby KA, Pediatric herpets simplex of the anterior segment, Ophthalmology; 119(10):2003-8, 2012.

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Tyrosinemia (Type II)

¤Richner-Hanhart syndrome: rare protein and amino acid metabolic disorder. ¤Characterized by: corneal dendriform lesions, painful planar and plantar hyperkerotosis and retardation. ¤Treatment: dietary restrictions of tyrosine and phenyalanine

Indolent Ulcerations of the Cornea

¤Sterile ulcerations: vitamin A deficiency, vernal shield ulcers, HSV, other corneal irritants ¤Must be differentiated from an infectious process ¤Often difficult to manage without surgical intervention that includes flaps, tarsorrhaphy, autologous serum, or amniotic membrane transplant.

Crack Keratopathy

¤ Neurotrophic ulcer results from: ¤ hypesthesia and reduced tearing (inherent), chemical burn (alkali), direct toxic irritant to the cornea (smoke), and mechanical rubbing due to eye irritation. ¤ Ulceration is oval with smooth, rolled edge. ¤ Diagnosis by exclusion when suppuration is present and pain is not proportional. ¤ Persistent ulcers may continue even after cessation. ¤ Treatment: tarsorrhaphy, amniotic membrane transplant or Pro-Kera graft, support for chemical dependency

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Treatment and Management of HSV

¤ Topical and orals can be used for any infectious process.

¤ Steroids are the mainstay for stromal/immune disease ¤ Avoid prolonged use of topical agents beyond 14-21 days. Limbal deficiency and conjunctival scarring are possible due to toxicity. At >10-14 days, a neurotrophic state is playing a role.

¤ Debridement is only indicated if there are new epithelial lesions with a history of stromal disease in the past. ¤ Oral prophylaxis is indicated with 2 or more episodes of infectious keratitis. Must monitor renal function.

Treating Principles HEDS Studies

¤ Treat the epithelial disease first (virtually ignoring the ¤ Oral Acyclovir 400mg BID for one year significantly reduced the risk for immune/stromal response) and then treat stromal disease. recurrence of ocular HS, stromal keratitis (only in those who had a history of stromal disease)and oro-facial HSV. Can be adjusted peri- operatively. ¤ When using steroids, use a prophylactic dose of orals to hopefully prevent epithelial recurrence. ¤ No benefit of oral prophylaxis to prevent progression from surface (epithelial) involvement to stromal disease. ¤ Taper steroids using a “full” dose of orals and/or topicals until the dendrite has cleared watching for medicamentosa effects. Steroids ¤ Oral antivirals are considered for epithelial disease to reduce the viral can be increased with a prophylactic oral dosing (Valtrex 500mg load in the ciliary ganglion and associated nerves. Its value in acute disease is still being debated. daily, ACV 400mg BID, Famvir 500mg daily).

¤ When stromal disease is controlled taper steroid gradually. You might never be able to DC completely to control stromal disease. Herpetic Eye Disease Study (Barron et al, 1994) Prophylactic orals may be required indefinitely. The Herpetic Eye Disease Study Group (1997)

Neurotrophic Keratopathy HSV Resistance

¤ If viral resistance is suspected, send a viral culture for PCR and ¤ Loss of trigeminal innervation in recurrent HSV and HZV sensitivities.

¤ Full range of corneal signs: PEK/PEE to frank ulceration/melt ¤ “Super” strains (TK mutants)do encode for key enzyme and prolonged prophylactic use of orals may play a role. Consider Vira A under these ¤ Management: D/C meds that are toxic, taping at night to circumstances. ensure adequate closure (tarsorrhaphy may be necessary) ¤ Non-compliance can certainly mimic resistance.

¤ Topical Treatment: glue, autologous serum, amniotic ¤ GI absorption of polar medications, even with a pro-drug may limit serum concentrations of antiviral medications (especially with lactose membrane application (multi-layer), scleral lenses intolerant). In this case, IV ACV may be helpful.

¤ Experimental: Substance P and insulin-like growth factor with ¤ Viral resistance in an immuno-competent patient is rare, but if suspected HSV-DNA polymerase inhibitors can be injected intavenously nerve growth factor (i.e. Foscarnet) Any resistance raises the concern for immuno-supression or compromised state.

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Herpes Zoster: Shingles Herpes Zoster: Shingles

¤ HZV is the etiologic agent of both varicella (chickenpox) ¤ Exposure to cases of chickenpox may serve as a “booster vaccine”. and reactivation (shingles) ¤ Recurrent disease: concern for reduced cell mediated immunity…..HIV, thymoma, occult CA (especially lymphoid malignancies), etc. ¤ Unlike HSV, HZV typically happens once in life (30% of ¤ Most common diseases associated with HZV infection are pulmonary, adults). Half of adults who live to age 85 will get zoster. diabetes mellitus and cardiovascular. IBD increases risk and certain The rate rises sharply after 50. medications are independent risks such as corticosteroids, thiopurines and ant-TNF.

¤ HZV established latency in the sensory root ganglia ¤ **Overall, increased risk for CA (lymphatic tumors) among HZV patients. Risk for multiple myeloma is increased in older women; risk for bone and (maintained by a T-cell immune response that wanes soft tissue cancers in men following HZV infection. with advancing age) **Does Herpes Zoster Increase Cancer Risk? CME Medscape Education

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Zoster Sine Herpete

¤ Atypical episode of HZV: chronic radicular pain/sensitivity without rash and vanes from sub-acute to chronic.

¤ Reactivation may result in meningitis, cerebellitis, isoalted cranial nerve palsies (ophthalmoplegia or Ramsey Hunt), vasculopathy, myelopathy and various inflammatory disorders of the eye.

¤ VZV DNA in cerebrospinal fluid or blood mononuclear cells or the presence of IgG antibody in CSF or IgM antibody in CSF or serum.

¤ Continuing challenge is establishing a diagnosis at a time when treatment will still provide a benefit. Can have a severe uveitis.

Gilden D, Cohrs RJ, Mahalingam R and Nagel MA: Neurological disease produced by VZV reactivation without a rash. Curr Top Microbiol Immunol. 2010: 342:243-253.

Herpes Zoster Ophthalmicus

¤ Involves the ophthalmic division of the fifth cranial nerve.

¤ Without oral antivirals, 50% of HZV patients will experience ocular involvement. 30% will be chronic ¤ Long list of ocular complications including: persistent keratitis, uveitis, acute retinal necrosis, cranial nerve palsies and optic neuropathy.

¤ ASSOCIATED COMPLICATIONS- HZO increases the risk of stroke by 4.5X within one year of infection; varicella zoster vasculopathy causes stroke secondary to chronic viral infection of large and small cerebral arteries; VZV has been associated with temporal arteritis (possible trigger?).

Pseudodendrites in Herpes Zoster

¤ Part of the list of corneal complications of acute/chronic infectious and immune keratitis (4-13%).

¤ Can be found in the acute stages or months to years later (Herpes zoster pseudodendrites, dendritic plaques, or late Varicella zoster dendritiform keratitis).

¤ The lesions harbor viral DNA and warrant antiviral treatment to prevent further corneal damage. ¤ CASE SERIES: Pavan-Langstan et al.): topical 0.15% ganciclovir gel (and maybe a repeat of orals) is an effective treatment for persistent pseudodendrites.

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Zoster Kerato-uveitis

¤ Complications are similar to HSV keratitis and include: punctate or pseudo dendritic keratitis (mucous plaque), stromal infiltrates, endotheliitis and neurotrophic keratopathy.

¤ Uveitis is not uncommon in severe cases.

Acute Retinal Necrosis

¤ A rare presentation of herpetic or other viral disease; varicella zoster is most common cause, but possible in HSV, EBV, CMV infections.

¤ Characterized by large areas of retinal whitening and necrosis that spreads centripetally with a high rate of accompanying detachment and vascular occlusion.

¤ Can be seen in patients with some level of immune dysfunction.

¤ PCR analysis of the vitreous is confirmatory, but diagnosis is generally made by clinical assessment.

¤ Treatment includes IV acyclovir 10-15mg/kg TID for 5-10 days followed by oral regimen for 6-12 weeks. Intra-vitreal injection of foscarnet or ganciclovir can be considered.

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Post Herpetic Neuralgia Antivirals

¤ A neuropathic pain syndrome that persists or develops ¤ Oral Agents after shingles’ rash has resolved (10-18%). Acyclovir Valacyclovir* ¤ Most frequent and debilitating complication of HZV Famciclovir* regardless of the dermatomal distribution. Penciclovir*

¤ Main PHN risks: advancing age (>60), severity of acute ¤ Topical Agents zoster pain and rash, a painful prodrome and ocular or Trifluridine (Viroptic/non-selective) upper body involvement. Ganciclovir (Zirgan/selective)

¤ Treatment: cool compresses, topical capsaicin, *Better bioavailability and longer intracellular half-life than analgesics, lidocaine patch, cimetidine, amitriptyline, Acyclovir gabapentin, nerve block, and acupuncture Interferon has been used as an adjunct

Zostavax (Merck & Co.) Vaccine Prevention Through Vaccination

¤ Vaccination does not confer lifelong immunity (most studies suggest 5-7 years, but exact duration is unknown). ¤ Controversies….. Protection likely wanes significantly after 5 years. ¤ Should healthcare providers be vaccinated? ¤ When is vaccination appropriate after having the shingles? ¤ About a 50% reduction in HZV occurrence after vaccination. Only a 60% reduction of the risk of experiencing post- ¤ Is vaccination appropriate for the high risk groups in certain herpetic neuralgia. cancer protocols/therapies. ¤ When should one stop antivirals before/after vaccination? ¤ Should probably be avoided in individuals who are experiencing any significant post-HZV corneal/intraocular ¤ Should patients with active kerato-uveitis or corneal inflammation. dendritiform be vaccinated? ¤ FDA recommendation over 50 yrs. of age and CDC is 60.(age for neuralgia is >60 and concern for duration without a booster). However, average age of onset is 52 and half are under 60.

Recurrent Herpes Zoster New Vaccine for Shingles (HZ/su)

¤ Recurrent episodes (different locations) are somewhat atypical and practitioners must consider ¤ Phase 3 sub-unit herpes zoster vaccine consisting of a single protein heat inactivated virus a sinister etiology.

¤ Unlike the live attenuated vaccine the HZ/su vaccine has ¤ Patients should be worked up for occult malignancy an efficacy of 97.2% without decline as one ages. or other reduced cell mediated immunity concerns (body scans, T4 and T8 subsets may be needed). ¤ HZ/su is adjuvanted with AS01B that activates antigen- specific CD4+ T cells and antibody. ¤ HIV/CMV titers are suggested. ¤ Single protein that doesn’t replicate and may be suitable for immunosuppressed and compromised patients. ¤ Thymus gland imaging may reveal a thymoma. .

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Key Points to Remember…….. Key Points to Remember……..

• New “bugs” are emerging and showing variable resistance with significant geographic differences (Nocardia, Cladosporium, Paecilomyces, Microsporidia, Rhinosporidia) • Bilateral HSV and recurrent HZV may signal a more sinister • There’s a paucity of anti-fungals and most penetrate the cornea poorly. Consider frequent corneal debridement. condition due to reduced cell mediated immunity. • Polymicrobial infection is not uncommon. • Poor treatment responses may be due to resistant conditions (including prolonged prophylaxis), poor • It’s important to culture the edge and base of most compliance and a neurotrophic state. infiltrates/ulcers using assorted media. Suture-pass technique may be required for best yield. • Vaccine concerns include inoculating corneal graft patients, those already taking oral antivirals, and patients • Secondary glaucoma is not unusual due to the direct effect on the trabecular meshwork and carries a poor prognosis with persistent ocular disease following an initial HZV especially in fungal disease. infection. This doesn’t impart life-time immunity. Varivax for kids reduces immunity exposure for adults. ü5 DAY RULE: a CL related non-specific keratitis should show significant improvement with seemingly appropriate therapy • Antiviral suppression therapy (prolonged) may have a after 5- 7 days. role in chronic HZV as in HSV.

Key Points to Remember……..

• A “spider bite” is often MRSA or shingles, and not a bug bite.

• A review of systems is paramount. Be concerned for systemic viral dissemination in those with debilitating diseases (ie. diabetes, rheumatoid conditions, etc.), especially when oral steroids are used.

• Acute retinal necrosis may not be as obvious as expected in an immuno-compromised or suppressed individual.

• Avoid the use of Valtex in HIV+ patients (concern for TTP/HUS).

• Iritis with high IOP is generally HSV until proven otherwise!