1. SEEING REDA N O V E R V I E W O F I N F E C T I O U S K E R A T I T I S
L I B B Y D A U G H E R T Y , P H A R M D C A N D I D A T E
M A T T H E W P O S T , P H A R M D , B C P P S
C H I L D R E N ’ S H E A L T H C A R E O F A T L A N T A A T S C O T T I S H R I T E
U N I V E R S I T Y O F G E O R G I A – A P P E 4 – E M E R G E N C Y M E D I C I N E
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
Damage to the
corneal epithelium
introduces
microflora to the
stroma
Microflora infect
the keratin of the
stroma
Corneal
inflammation
attracts neutrophils
to the cornea
Enzymes released
by neutrophils
exacerbate
inflammatory
necrosis
Progressive
inflammation
quickly leads to
corneal perforation
Wound healing
often leaves
scarring
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
Fluorescein stain
applied to eye and
washed out with
saline.
Viewed under cobalt
lamp to visualize
defects in the corneal
epithelium.
7. INFECTIOUS ETIOLOGIES
Bacterial
• Singular infiltrate
• Solid border
Fungal
• Large hypopyon
• Feathered/fuzzy
border
• Satellite infiltrates
Herpetic
• Dendritic lesion
Acanthamoebi
c
• Variety of
infiltrates
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
• 4th 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
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
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
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 5-10μg/0.1ml
• Voriconazole 50μg/0.1ml
• For severe disease only
– Intensely painful
– High risk of systemic
absorption/toxicity
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)
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?T H A N K Y O U F O R Y O U R T I M E A N D
A T T E N T I O N !
Editor's Notes
Layers…
Infections generally start on the outer layers
Quickly will cause ulcers and penetrate down into deeper layers
AKA “Ulcerative Keratitis” or “Corneal Ulceration”
Corneal Ulcer vs Corneal Abrasion
Abrasions
Non-infectious
Heal spontaneously within 24-48 hours as the epithelium grows back
Will never have an infiltrate
Associated with recent mechanical trauma (fingernail to eye)
Columnar cells similar to collagen, mainly made of keratin.
Immune system is somewhat of an enemy here
Killing the infection erodes cell layers
Allows for deeper penetration into the eye
Corneal perforation = blindness, systemic infection
Keratitis pain is not severe, usually just irritating (3-4/10). Foreign body sensation.
Red Eye has large differential
Conjunctivitis = infection of mucous membranes inside eyelids/around eyes; no change in vision
Uveitis = miosis
Glaucoma = severe pain (10/10), ↓IOP
Damage to the cornea is hard to see because the cornea is clear
Very difficult to tell just from visual examination
Conjunctivitis = generalized eye redness
Keratitis = circumferential pattern, especially right around sclera cornea transition (circumcorneal redness)
Hypopyon = collection of pus in the anterior chamber
Large hypopyon in fungal infections due to slow-growing infection with early penetration into the anterior chamber (fungi grow slow, but they grow deep)
Atypicla bacteria = Neisseria, Listeria, Mycobacterium, Nocardia, etc.
Neisseria, Corynebacterium, H. flu and Shigella can all cross Bowman’s Layer and infect an intact cornea (no abrasion required)
Anaerobes/Oral flora from people using saliva to clean their contact lenses
LASIK = remolding of the cornea = trauma
Risk of blindness warned about before surgery, keratitis is a major concern
Corticosteroids inhibit the immune system
Using them increases the risk of bacterial colonization
Enropion = genetic condition in which a portion of the eyelid is inverted or folded inward
Bactericidal is important
Quick killing
Take burden away from immune system
Pseudomonal coverage is very important
These directions differ from the recommendations on Lexicomp which are more appropriate for Conjunctivitis
Unlike conjunctivitis, bacterial keratitis is a rapidly progressing, sight-threatening infection and requires extremely aggressive treatment.
You can use ointments instead of drops to allow patients time to sleep, but ointments have very poor corneal penetration. Not recommended in severe infections.
Source of pain is ciliary body spasms.
Cycloplegia relaxes/paralyzes the ciliary body.
Cyclopentolate with phenylephrine (Cyclomydril) is preferred in infants due to lower cyclopentolate concentration and lower risk of systemic absorption.
Apply finger pressure to lacrimal sac for 1-2 minutes after administration to decrease risk of systemic absorption.
Monotherapy
4th generation FQs have better penetration into the cornea than previous generations
Also better GP coverage
Local toxicities (dose dependent)
Corneal precipitates/crystallization delay healing and result in corneal perforation in up to10% of cases
Retinal detachment
FQs have destructive effect on connective tissue (e.g. tendonopathy)
Increased incidence of retinal detachment is a consequence of degeneration of ocular connective tissue and collagen
FQ monotherapy is associated with shorter duration of (intensive) care and shorter hospital stays
However, serious complications from antibiotic use occur much more often with FQs
Fortified antibiotics are created by adding the intravenous formulation of an antibiotic to
The commercially prepared ophthalmic solution
Higher concentration
Better penetration into the cornea
Artificial tears
To create an ophthalmic solution that is otherwise not commercially available
Cephalosporins
Cefazolin is most commonly used for GP coverage in Keratitis
Ceftazidime used with pseudomonas keratitis
Topical product not available commercially because they are unstable in solution and must be re-prepared every 4-5 days
Aminoglycosides
Pseudomonas coverage (double coverage when used with ceftazidime)
The main toxicity of these preparations is the retardation effect of the epithelial-healing rate (aminoglycosides, vancomycin) and the corneal and conjunctival toxic effects (aminoglycosides). However, fortified antibiotic drops remain the standard therapy for severe bacterial keratitis, given their corneal penetration and the possibility of the synergic and combined effect of an antibiotic association.
Fortified antibiotics are created by adding the intravenous formulation of an antibiotic to
The commercially prepared ophthalmic solution
Higher concentration
Better penetration into the cornea
Artificial tears
To create an ophthalmic solution that is otherwise not commercially available
Cephalosporins aren’t available commercially as ophthalmic solutions because
Insoluble
Poor stability (3-4 days)
Alternative preparations:
Cefazolin and Ceftazidime 5%
Reconstitute 500mg parenteral solution with 2ml sterile water and add to 8ml of artificial tears
Stable for 7 days in the fridge
Stable for 3 days at room temperature
For MRSA
Linezolid and Vancomyin are bacteriostatic
(Argument over whether Vanc is static or cidal per mechanism, but functionally it is static)
Colistin and Cabapenems are bactericidal
Alternative preparation:
Vancomycin 50mg/ml (5%)
Reconstitute 500mg with 2ml sterile water and add to 8ml of artificial tears
Stable for 28 days in the fridge (4°C)
If used, corticosteroids should not be started until after signs of clinical improvement on antibacterial therapy (24-48 hours)
Macrolides for atypical infections
Erythromycin is least toxic and most tolerable but has worst penetration into cornea
Juxalimbal = near border with sclera
Candida = Yeast
Fusarium/Aspergillus = Fillamentous
Fusarium linked to recent contamination of contact lens solution
Associated with vision loss in 26-63% of cases due to delay in diagnosis
Coinfection with bacteria occurs in ~20% of cases
Prophylactic topical antibiotics are often used
Oral antifungals for deep eye infections
Both Fluconazole and Ketoconazole have good levels in the anterior chamber
Amphoteracin B is DOC for yeast infections (Candida)
Voriconazole is DOC for filamentous fungi (Aspergillus)
Natamycin is the only commercially available ophthalmic antifungal – great for filamentous fungi, esp Fusarium
Amphoteracin B 5-10μg/0.1ml
Voriconazole 50μg/0.1ml
HSV-1 is the “non STD” herpes
Can also be caused by HSV-2 though
Adenovirus is by far the most common cause of viral conjunctivitis
Ganciclovir: Apply 1 drop in affected eye 5 times daily (approximately every 3 hours while awake) until corneal ulcer heals, then apply 1 drop 3 times daily for 7 days
Viroptic: Instill 1 drop into affected eye(s) every 2 hours while awake, to a maximum of 9 drops/day, until re-epithelialization of corneal ulcer occurs; then use 1 drop every 4 hours while awake for another 7 days
Acyclovir also available as an ointment that can be used while patient sleeps
Other topical antivirals (no dosing information)
Vidarabine
Idoxuridine
Steroids have no benefit in viral infection and are likely to cause harm
Steroids prolong viral replication
Worsen infection
High chance of perforation
High likelihood of blindness
Good outcomes when treated early before deep penetration can occur (rarely happens)
Acanthamoeba spp. implicated as human pathogens:
A. culbertsoni
A. polyphagia
A. castellanii
A. astronyxis
A. hatchetti
A. rhysodes
A. divionensis
A. lugdunensis
A. lenticulata
Treatment for 6-12 months
Antimicrobial treatment is controversial and poorly-studied
Investigational “new” drug for FLA (Free Living Amoeba) infections: Miltefosine.
Naegleria, Balamuthia, Acanthamoeba
Call the CDC Emergency Operations Center at 770-488-7100
None of these drugs (except systemic antifungals) is commercially available or approved for use in the US, but they can be obtained from compounding pharmacies. Leiter’s Park Avenue Pharmacy, San Jose, CA (800-292-6773; www.leiterrx.com) is a compounding pharmacy that specializes in ophthalmic drugs. Propamidine is available over the counter in the UK and Australia. Hexamidine is available in France.
The combination of chlorhexidine, natamycin (pimaricin) and debridement also has been successful.
Debridement is most useful during the stage of corneal epithelial infection. Most cysts are resistant to neomycin; its use is no longer recommended.
Azole antifungal drugs (ketoconazole, itraconazole) have been used as oral or topical adjuncts.
Use of corticosteroids is controversial
