Keratitis

1. Seeing Red An Overview of Infectious Keratitis Libby Daugherty, PharmD Candidate Matthew Post, PharmD , BCPPS Children’s Healthcare of Atlanta at Scottish Rite University of Georgia – APPE 4 – Emergency Medicine

2. Keratitis Infection of one or many layers of the cornea Mostly due to contact lens use, especially with improper use or hygiene Distinguishing the causative agent is important and difficult Vision-threatening Early consultation with ophthalmology is important Aggressive treatment is warranted

3. Cornea Anatomy Layer of clear columnar cells that covers the front part of the eye. Consistent with the sclera Covers the anterior chamber which includes the iris/pupil. Corneal epithelium is only 1-2 cells thick Stroma is made of keratin

4. Pathology

5. Presentation Early/Common Redness Rapid onset of mild-moderate pain Decreased/blurry vision Photophobia Tearing Late/Severe Visible infiltrate(s) Eyelid edema Conjunctival inflammation Hypopyon Discharge

6. Diagnosis Fluorescein Stain Binds to keratin Cannot penetrate corneal epithelium Only binds to the part of the cornea that has lost its epithelium Illuminates under fluorescent light Corneal Scraping Provide anesthesia first Bacterial and fungal cultures

7. Infectious Etiologies

8. Bacterial Keratitis

9. Bacterial Keratitis Most common form of Keratitis (90-95% of all cases) Rapidly progressive (2-3 days) Sight-threatening Pathogens Streptococcal spp. Pseudomonas Staphylococcus spp. Atypical bacteria Anaerobes

10. Risk Factors LASIK surgery Contact lens use Extended wear Improper hygiene Sleeping with contacts Swimming with contacts Ophthalmic corticosteroids Corneal injury Enropion Chronic dry eye

11. Presentation Symptoms Redness Changes in vision Pain Photophobia Cornea may be clear or hazy Hypopyon may be present Complications Corneal thinning Increases risk for further infection Increases risk for perforation Perforation Infection of the inner eye Often results in permanent loss of sight May result in loss of eye entirely

12. Management Ophthalmology consult Corneal scrapings sent for culture, staining and analysis Topical bactericidal antibiotics Broad Spectrum 4 th Generation Fluoroquinolone Fortified Cephalosporin + Aminoglycoside Frequent Administration Every hour for at least 24 hours May reduce to every 2 hours while awake after signs of improvement Tapered per clinical improvement (per ophthomologist ) Cycloplegia as needed for pain Atropine 1% 1-2 drops 4 times daily Cylopentolate ( Cyclogyl ) 0.5-2% 1-2 drops every 5-10 minutes Cyclopentolate /Phenylephrine ( Cyclomydril ) 0.2% 1 drop every 5-10 minutes

13. Fluoroquinolones 2 nd Generation Ciprofloxacin 0.3% ( Ciloxan ) Ofloxacin 0.3% ( Ocuflox ) 3 rd Generation Levofloxacin 0.5% 4 th Generatoin Moxifloxacin 0.5% ( Moxeza , Vigamox ) Gatifloxacin 0.5% ( Zymaxid )

14. Fortified Antibiotics Aminoglycosides Gentamicin 14mg/ml (1.4%) Tobramycin 14mg/ml (1.4%) Amikacin 2.5 % Cephalosporins Cefazolin 50mg/ml (5%) Ceftazidime 50mg/ml (5 %)

15. Fortified Antibacterial Eyedrops Aminoglycosides Tombramycin and Gentamicin 1.4% Add 2ml (80mg) of the parenteral solution to the commercially available eyedrops Stable for 7 days in the fridge (4 °C) Stable for 4 days at room temperature Amikacin 2.5% Add 2ml (250mg) of the parenteral solution to 8ml of artificial tears Stable for 7 days in the fridge (4 °C ) Cephalosporins Cefazolin 3.3% (33mg/ml) Reconstitute 500mg with 2ml 0.9% NaCl and add to 13ml of artificial tears Stable for 4 days at room temperature Ceftazidime 5 % (50mg/ml) Reconstitute 1g with 10ml sterile water Mix 7.5ml of solution with 7.5ml sterile water Stable for 7 days in the fridge

16. Fortified Antibacterial Eyedrops Vancomycin 31mg/ml (3.1%) Reconstitute 500mg with 5ml sterile water Stable for 28 days in the fridge (4°C) Colistin 0.19% Add 10ml sterile water to 75mg Colistimethate sodium ( Xylistin ) powder to make 7.5mg/ml solution Add 1 ml of the 7.5mg/ml solution to 3ml distilled water to make topical 0.19% drops Linezolid 2ml/ml (0.2%) Use the 200mg/100ml parenteral solution directly Imipenem- Cilastin 1% Add 10ml sterile water to 500/500mg parenteral solution to make a 50mg/ml solution. Add 1ml of the 50mg/ml solution to 4ml sterile water to make topical 1% drops Stable in an amber bottle for 3 days in the fridge (4 °C )

17. Adjunctive Therapy Steroids Controversial Decreases inflammation Minimizes scarring Reduces stromal necrosis Delays wound healing/epithelium regrowth May increase risk of perforation Regimens Dexamethasone 0.15 Q2H Prednisolone 1% QID If used, should not be started until after signs of clinical improvement on antibacterial therapy (24-48 hours) Oral Antibiotics Indications Juxtalimbal ulcer Perforation Atypical infections Regimens Fluoroquinolones Cephalosporin/Aminoglycoside Macrolides

18. Fungal Keratitis

19. Fungal Keratitis Difficult to distinguish from bacterial based on visual exam alone May be more fuzzy/feathered May be extra satellite lesions Often results in more severe disease Fungal growth is slower, but uninhibited by epithelial membranes Delays in diagnosis Pathogens Candida Aspergillus Fusarium

20. Fungal Keratitis Risk Factors Vegetation Ocular trauma Particles Tropical climate Immunodeficiency Management Topical antifungals Amphotericin B 0.15 % Voriconazole 1% Natamycin 5 % ( Natacyn ) Oral antifungals Fluconazole Ketoconazole Cycloplegia Topical antibiotics

21. Fortified Antifungals Eyedrops Amphoteracin B 0.15% Add 10ml sterile water to 50mg powder for injection. Add 3ml of solution to 7ml artificial tears Stable for 7 days in fridge Stable for 4 days at room temperature Voriconazole 1% Mix 2ml Ringer’s Lactate with 200mg lyophilized powder Stable for 30 days in fridge (4°C ) Intrastromal Injection Amphoteracin B 5-10 μ g/0.1ml Voriconazole 50 μ g/0.1ml For severe disease only Intensely painful High risk of systemic absorption/toxicity

22. Viral Keratitis AKA “Herpetic Keratitis”

23. Viral Keratitis Herpetic Keratitis Caused by Herpes simplex virus (HSV-1) Easily identifiable “dendritic” appearance Adenoviral Keratitis Caused by Adenovirus Occurs most often following adenoviral conjunctivitis Ocular reaction to adenovirus particles Small sub-epithelial infiltrates Self-limiting

24. Herpetic K eratitis Background Most common cause of infectious blindness worldwide Presentation is exactly the same as bacterial keratitis, except: Characteristic lesions initially present in a dendritic pattern Good prognosis if treated Management Topical antivirals Ganciclovir ( Zirgan ) Trifluridine ( Viroptic ) Systemic antivirals Acyclovir ( Zovirax ) Valacyclovir (Valtrex) Cycloplegia Atropine Cyclopentolate (+/- Phenylephrine ) NO STEROIDS !

25. Parasitic Keratitis AKA “ Acanthamoebic Keratitis”

26. Acanthamoebic Keratitis Extremely Rare Generally associated with contact lens use while swimming Has been associated with contaminated contact lens solution Poor prognosis Delay in diagnosis Limited/ineffective therapies Resilient infection (cysts)

27. Acanthamoebic Keratitis Systemic antifungals Voriconazole Ketoconazole Topical Biguanides Chlorhexadine 0.02% Polyhexamethylene biguanide (PHMB) 0.02% +/- Topical antiprotozoals ( diamidines ) Pentamidine isethionate ( Pentam ) 0.1% Propamidine isethionate ( Brolene ) 0.1% Hexamidine ( Desmodine ) 0.1% Topical antifungals Natamycin ( Natacyn , Pimaricin ) Neomycin (Neo- Polycin ) Cycloplegia Steroids Check the CDC website!

28. References " Acanthamoeba - Granulomatous Amebic Encephalitis (GAE); Keratitis." Centers for Disease Control and Prevention, 22 Oct. 2013. Web. 04 Oct. 2016. DeLoss , Karen S. "Complications of Contact Lenses." Ed. Jonathan Trobe and Janet L. Wilterdink .  UpToDate . Wolters Kluwer, 17 Sept. 2016. Web. 4 Oct. 2016. Forooghian , Farzin . "Oral Fluoroquinolones and the Risk of Retinal Detachment."  Journal of the American Medical Association  307.13 (2012): 1414. Web. Gangopadhyay , N. "Fluoroquinolone and Fortified Antibiotics for Treating Bacterial Corneal Ulcers."  British Journal of Ophthalmology  84.4 (2000): 378-84. Web. 4 Oct. 2016. Goldstein, Michael H., Regis P. Kowalski, and Y.jerold Gordon. "Emerging Fluoroquinolone Resistance in Bacterial Keratitis."  Ophthalmology  106.7 (1999): 1213-318. Web. 4 Oct. 2016 .

29. References Hillenkamp , Jost , Rainer Sundmacher , and Thomas Reinhard . "Treatment of Adenoviral Keratoconjunctivitis ."  Essentials in Ophthalmology Cornea and External Eye Disease  ( n.d. ): 163-72. Web. Jacobs, Deborah S., Jonathan Trobe, and Janet L. Wilterdink . "Evaluation of the Red Eye."  UpToDate . Wolters Kluwer, 24 Feb. 2016. Web. 4 Oct. 2016. Keratitis . Perf. Paul Bolin.  Keratitis . CRASH! Medical Review Series, 21 Nov. 2015. Web. 4 Oct. 2016. Shah, Sushmita G., and Dikhil S. Gokhale . "Instruction Manual for Preparation of Fortified Antimicrobial Eye Drops." Bombay Ophthalmologists' Association, n.d. Web. 4 Oct. 2016. Sugar, Alan. "Herpes Simplex Keratitis." Ed. Jonathan Trobe and Jennifer Mitty .  UpToDate . Wolters Kluwer, 17 Aug. 2016. Web. 4 Oct. 2016. Thompson, Andrew M. "Ocular Toxicity of Fluoroquinolones."  Clinical & Experimental Ophthalmology Clin Exp Ophthalmol  35.6 (2007): 566-77. Web.

30. Questions? Thank you for your time and attention!