7/28/13 1

7/28/13 Un-invited Guests of the Cornea: Rare
and Unusual Infections
Michael D. DePaolis, OD, FAAO
Rochester, NY
RISK FACTORS FOR ULCERATIVE
KERATITIS
 Exogenous
 Ocular Adnexal Dysfunction
Joseph P. Shovlin, OD, FAAO
Scranton, PA
 Corneal Abnormalities
 Systemic Disease
 Immunosuppressive Therapy
Bacterial Flora of the Normal Eye
Staphylococcus epidermidis
75-90%*
Diphteroids (C. xerosis)
20-33%
Staphylococcus Aureus
20-25%*
Streptococcus (S. viridan)
Hemophilus influenza
2-6%
3% or more
Streptococcus pneumoniae
1-3%*
Gram negative rods
1% or more*
Pseudomonas aeruginosa
0-5%*
* Dominant organisms in microbial keratitis
Common Organisms Encountered
Common Organisms Encountered
 Northeast: Staph. species, Moraxella,
Pseudomonas aeruginosa, Streptococcus
pneumonia
 Southeast: Pseudomonas aeruginosa common
 Pseudomonas aeruginosa still a common
organism in contact lens wear. Also commonly
found in burn patients, patients with exposure
keratopathy and those on ventaltory assistance
Classification of INFILTRATES
 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
1 7/28/13 CORNEAL INFILTRATE STUDIES
Factor
Associated
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
Not Associated
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
Asymptomatic corneal staining
Szczotka-Flynn Arch Ophthalmol 2007
Szczotka-Flynn IOVS 2010
PATH
Carnt 2007
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
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 2007, 2009; Chalmers ARVO 2010; Diec ARVO 2009, ARVO 2010; Kiernan 2009; Kislan
ARVO 2010; Mely CLAO 2001; Willcox FDA 2008
Donshik 1995; Morgan IOVS 2005; Roseman
1994; Zigler 2007
Soft contact lens material
Brennan 2002; Carnt 2009; Chalmers 2010; Fonn 2002; Forister 2009 (trend); Keir 2010; Morgan
BJO 2005, IOVS 2005; Santodomingo-Rubido 2007; Sweeney 2003; Szczotka-Flynn 2007; US
FDA, Bausch & Lomb 2001 (US); US FDA, CIBA Vision,2001; US FDA, Vistakon 2005
Dillehay 2007; Efron 2005; Fonn 2002, US FDA,
CIBA Vision 2001 (US)
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
Tight fit/reduced movement
Sweeney ARVO 2003; Ozkan 2010
Duration of lens wear
Chalmers 2007
Nilsson 2001
Swimming
Chalmers AAO 2004; McNally, Chalmers ARVO 2004
Morgan IOVS 2005
Prior inflammatory event, CLrelated issues, or injury
Chalmers 2007; Ionides 1997; McNally 2003
Morgan IOVS 2005
Conjunctival or limbal redness
Szczotka-Flynn Arch Ophthalmol 2007
Carnt 2007; Sweeney ARVO 2003
Known Association with CIEs
Suchecki 1996
No Association with CIEs
McNally 2003; Chalmers OVS 2010;
Sankaridurg 1999
No Conclusive Consensus
Characterization Of Bacteria From Contact Lens Storage
Cases Of Corneal Infiltrative Event Patients
Simon Kilvington1, Joseph P. Shovlin2, Marina Nikolic1.
1Corneal
R&D Microbiology, Abbott Medical Optics, Santa Ana, CA; 2Northeastern Eye Institute, Scranton, PA.
Of the 18 CLSC studied:
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.
  16/18 (89%) showed TVBC of ≥104 – 108 /mL.
Conclusions
  13/18 (72%) had TVBC of 106 – 108 /mL.
  2/18 were dry but yielded TVBC of 104 – 105 /mL when sterile
saline added.
 
Contact lens storage cases from CIE
patients can be grossly contaminated
with Gram negative bacteria.
 
Predominant bacteria such as
Achromobacter, Stenotrophomonas
and Delftia can be resistant to the
MPDS used by the patient and able
to proliferate to high numbers.
 
The resulting microbial bioburden
may initiate an immunological
response resulting in CIE, either
directly or from the presence of
endotoxins (e.g. lipopolysaccharides)
derived from the bacterial outer cell
membrane.
 
The significance of MPDS usage,
degree of contact lens storage case
contamination and bacterial species
present in the etiology of CIE
warrants further investigation.
 
Use of disinfection systems with
b r o a d a n t i m i c r o b i a l e f f i c a c y,
combined with good lens storage
case hygiene, may help prevent CIE
and also reduce the incidence of
microbial keratitis.4-5
Acanthamoeba was not isolated.
All bacterial isolates were Gram negative rods of which 10/18 cases
(56%) contained 13 strains of Achromobacter spp., 4/18
Stenotrophomonas
maltophilia (22%), 3/18 Serratia marcescens (17%), 2/18 Delftia spp.
(11%), and 6/18 (33%) Elizabethkingia spp. (3), Chryseobacterium sp.
(2) and Sphingobacterium sp. (1) (Table 1).
Bacteria log10 reduction
Achromobacte
r spp.
(10 strains)
S. maltophilia
(4 strains)
Delftia spp.
(2 strains)
Table 1. Bacteria identified from storage cases of CIE patients
Solution
CLSC +ve
Organism present
%
OPTI-FREE®
RepleniSH®
10
Achromobacter spp.
56
4
Stenotrophomonas maltophilia
22
RevitaLens
Ocutec™
3
Serratia marcescens
17
Biotrue™
6 hr
14 d
6 hr
14 d
<1
<1
<1 - 2
<1 >4a
6 hr
14 d
<1 - 2 <1b
Table 3. Efficacy of MPDS solutions against storage case bacteria
2 – >4c
≥4
>4
>4
≥4
≥4
<1 – >4d
≥4
>4
>4
≥4
≥4
a,b
2
Delftia spp.
11
6
Elizabethkingia sp.
Chryseobacterium sp.
Sphingobacterium sp.
33
Regrowth by 1-2 log for 2 strains of S. maltophilia and both Delftia spp.
C
90% strains ≥4 log kill. D50% strains ≥4 log kill
Contact: Simon Kilvington ([email protected])
2 7/28/13 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
3 7/28/13 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
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
LABORATORY WORKUP
Up to 50% of properly performed cultures will
reveal no growth in the setting of an actual
bacterial keratitis (false negative)
  Direct inoculation of solid and liquid media is best
method to increase the culture yield.
  Kimura spatula: culture the edge and base of the ulcer,
serves to debreed the lesion
  Gram stain: only 12-60% accurate at predicting organism
  Giemsa stain: provides better morphologic characteristics
of organisms and helps to distinguish bacteria from fungi
4 7/28/13 Termination of Therapy
RESISTANT BACTERIA
  Methicillin resistant Staphylococcus aureus
 Measures of improvement: blunting of the
perimeter of stromal suppuration, reduction in
density of suppuration, reduction in cellular
infiltrate and surrounding edema, reduction in
anterior chamber reaction, progressive reepithelialization
 Reducing anti-microbials and adjuvants: avoid
abrupt cessation, prolonged therapy needed for
Pseudomonas, Mycobacterium, Nocardia,
anaerobes
Newer Generation Fluoroquinolone
Resistance Trends
 Ocular Trust data found 3rd and 4th generation
fluoroquinolone effective against 30% of MRSA
isolates, while Polytrim effective against 95% of
the same isolates
 McDoanld & Blondeau Cat & Ref Surg 36(9):
2010
  Enterococcus Fecalis (group D
Streptococcus)
  Aminoglycoside resistant Pseudomonas
aeruginosa
  Beta lactamase producing Neisseria
  Atypical Mycobacteria
Gram positive: Vancomycin 20-30 mg/ml,
.28% Lysostaphin, IV Linezolid (Zyvos)
Gram negative: Amikacin 20 mg/ml
Causes of Antimicrobial Resistance
 Inappropriate use of antibiotics
 Tendency to use broader spectrum antibiotics
 Use of antimicrobials in an agricultural setting
 Spread of resistant organisms by increased
international travel
  Up to 85% MRSA strains resistant to moxifloxacin &
gatifloxacin
  Besifloxacin showed greater efficacy against multidrug resistant S. aureus
5 7/28/13 FLUOROQUINOLONE RESISTANCE
  UCSF Study (1996) Hwuang et al.: topical ciprofloxacin qid. S.
aureus resistance rose from 12%-50% with in-vitro testing
  Wills Eye Hospital Study (1996) Rodman:
  S. aureus resistance
- Strep. resistance
1992-4%
1992-20%
1996-13%
1996-26%
  LV Prasad Institute (1999) Kunimoto et al:
  30.7% corneal isolates not sensitive to ciprofloxacin
Bascom Palmer Eye Institute (1999) Chaudry et al: P.
aeruginosa resistance rose from .44% (1991-1994) to 4.1%
(1995-1998)
Ocular TRUST 2: Overview
 Methicillin resistance in staphylococci marker for
multi-drug resistance
 Fluoroquinolones most consistently active agents
across ocular pathogens
 Fluoroquinolone susceptibility profile
  Gatifloxacin = Levofloxacin = Moxifloxacin
  Modest diminution in S. pneumoniae
susceptibility to ciprofloxacin
 Polymixin B and penicillin most limited activity
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 hospitalnaive patients
CA-MRSA
MRSE
  S. epidermidis and MRSE are ubiquitous commensal organisms in
the human body.
  Among ophthalmic S. epidermidis isolates, MRSE rates may exceed
50%; MRSA rates approximately 30%.
  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.
  Most common cause of bacterial endophthalmitis.
  Additional therapies include quorem sensing and immunotherapy
against biofilm antigens and anti-biofilm activity.
6 7/28/13 New Antimicrobials
Collagen Cross-linking
  3rd and 4th Generation Fluoroquinolones and ITQs:
Trovofloxacin (Pfizer), Moxifloxacin (Bayer, Alcon), Gatifloxacin (Bristol-Myers/
Squibb, Allergan), Temafloxacin (Allergan), Gemifloxacin (Pharmacia)
  Peptide Antimicrobials and Inhibitors:
  deformylase, quorum sensing and efflux pump inhibitors
  Exazolidinones
  Pleuromutulins
  Oxazalidone linezolid
  Bacteriophages- new classes of viruses
  Aganocides
Guidelines: The Use of Topical
Steroids in Bacterial Keratitis
Steroids for Corneal Ulcers Trial
(SCUT)
  Risks vs. Benefit: - the rationale for and the case
against using topical steroids
 Topical steroids offer no significant benefit (or
risk) in treating bacterial keratitis.
  For: Steroids do not interfere with the ability of a
bactericidal antibiotic (in sufficient concentration) to
kill susceptible organisms.
 Adjunctive steroid therapy may improve visual
outcome in severe bacterial ulcers.
  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
Steroids in Ulcerative Keratitis
  Principles for successful use of corticosteroids: (1) scrapings
for stain and culture, (2) use of adequately dosed bactericidal
antibiotics, (3) delay initiation of steroids until a clearly
beneficial effect to antibiotic has been determined, (4)
continue concurrent use of antibiotic with steroids, and (5)
delay use of steroids if causative organism is not identified.
USE 2-5 days after appropriate antibiotic therapy.
  Avoid if fungal infection or atypical mycobacterium is
suspected, if there is severe thinning, enlarging epithelial
defect, poor wound healing (diabetes), or immunosuppression.
 Steroids should not be used in Nocardia
infections.
 MIC correlates with clinical results; antibiotics
with lower MIC are associated with better
outcomes.
 
Srinivarsan M, Mascarenhas J, Rajaraman R et al: Corticosteroids for bacterial keratitis: The
Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol (2012); 130(2):143-150.
Non-Bacterial Corneal Ulcers
  Bascom Palmer Series
(Alphonso et al.):
  1986: 3.1% of corneal ulcers treated were not bacterial
  2004-05: 64.7% of corneal ulcers treated were not bacterial
** some of the increase shift is due to 4th generation
fluoroquinolone usage
  In Acanthamoeba keratitis, steroids may increase potential for
pathogenicity and steroids likely cause an increase in the rate
of excystment and suppress macrophages.
7 7/28/13 FUNGAL INFECTION IN CONTACT
LENS WEAR
CLINICAL FEATURES OF FUNGAL
KERATITIS
CLASSIFICATION/MOST COMMON ORGANISMS
  MOLDS - epithelium can be intact or ulcerated, usually nonsuppurative with feathery infiltrates (focal or multi-focal /
satellite)
  Filamentous Fungi; Molds
  Septated: pigmented, non-pigmented
  Non -Septated
  Yeasts
  YEASTS - epithelium is usually ulcerated, generally suppurative
(focal or diffuse)
  Specific: infiltrates with gray/brown pigmentation,
elevated edges with rough texture
8 7/28/13 DIAGNOSIS OF KERATOMYCOSES
 Clinical Suspicion
 Corneal Scrapings
  Smears: gram, giemsa, acridine orange, calcofluor white
  Cultures: blood agar, Sabouraud s media
  Polymerase chain reaction
 Superficial Keratectomy/Biopsy
 Paracentesis
 Confocal Microscopy
Confocal Microscopy: Fungal
Keratitis
9 7/28/13 ANTIFUNGAL DRUGS AND
THEIR MECHANISM OF ACTION
  Sterol Binding
INITIAL THERAPY FOR FUNGAL
INFECTIONS
 HYPHAE -Natamycin 5 % suspension, topical
and oral Voriconazole, oral Ketoconazole,*
Fluconazole or Itraconazole
  Inhibition of Sterol Synthesis
  Interference of RNA Synthesis
  Inhibition of Mitosis
 YEAST OR PSEUDOHYPHAE - Amphotericin B,
Miconazole, Clotrimazole, Posaconazole or
Flucytosine
  Cationic Antiseptic
* Sub-conjunctival injection - Fluconazole
Medical Management of Fusarium Keratitis
  Topical: Natamycin 5%, Voriconazole 10mg/ml,
Chlorhexidine 0.2%
  Oral and IV: Voriconazole (Vfend/Pfizer) 200mg BID
  Surgical: debridement, full thickness grafting
*if unresponsive, systemic posaconazole or liposomal or lyophilized
Amphotericin B
** Natamycin may respond better than Voriconazole in monotherapy
especially in filamentous infections. (Mycotic Treatment Trial,
JAMA Ophthalmol. 131/4:422-29)
Surgical Therapy
 Biopsy
 Keratectomy
 Penetrating keratoplasty
 Conjunctival flaps
 Cryotherapy
 Excimer ablation
Unusual Outbreaks of Fusarium Keratitis
 Background: Fusarium keratitis is a relatively
rare infection around the world (except in humid
climates) and especially in contact lens wearers
(about 5%-Bascom Plamer)
 Disproportionate number of ReNu with Moisture
Loc users (Singapore, Hong Kong)
 Alphonso series: 2005-about 50% CL wear and
2006-over 70% CL wear
 Script trac experienced a 150% increase in
Natamycin prescriptions written in 2005.
10 7/28/13 CDC Case Control Study Results
Medical Management of Fusarium Keratitis
 Adjusted odds ratio:
 ReNu with MoistureLoc™-19 (2.4-944.9) p<.001
 ReNu®MultiPlus™-3.6 (0.3-189) p=0.5
  Topical: Natamycin 5%, Voriconazole 10mg/ml, Chlorhexidine
0.2%
Conclusion: ReNu®MultiPlus™ was not significantly
associated with the recent outbreak of Fusarium keratitis;
Cause of strong association with ReNu with MoistureLoc™ is
unclear .
On-going studies looking at environmental and formulation
under stress risks are continuing.
  Oral and IV: Voriconazole (Vfend/Pfizer) 200mg BID
  Surgical: debridement, full thickness grafting
*if
unresponsive, systemic posaconazole or
liposomal or lyophilized Amphotericin B
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 INFECTION IN
CONTACT LENS WEAR
Acanthamoeba polyphaga
  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
11 7/28/13 Acanthamoeba Morphology
Acanthamoeba
trophozoite
Acanthamoeba
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.
Acanthamoeba Keratitis can be an
Outbreak disease: History in the USA
Time period
Total
cases
1974-1983
Cases average Comments
Per year
31
3
(new infection hard
to diagnose)
1984-1991
Outbreak
1150
estimate
1994-2003
(June 03)
190
estimate
June 2004June 2007
485
Data
from
CDC
Outbreak
115
(6 x normal rate)
(1990=200 cases)
50% wore contact lenses but no
correlation made; this is the
beginning normal disease rate
85% soft contact lens wearers,
nearly all used non-Sterile
solutions to soak lenses due to
FDA approved salt tablets
19
excludes 137 cases in the
Iowa flooding outbreak 93- 96;
this is the normal disease rate
121
Outbreak cause? EPA
decrease of water disinfection
level and a constant small
number of patients using water
in their lens care regimen?
(2008 continues at
85 cases/yr or 4.5x
the normal rate)
Chicago-Gary-Kenosha 2000 Metropolitan Statistical Area
Annualized Incidence Rate of
Acanthamoeba Keratitis
Kenosha
McHenry
Lake
Incident AK Cases:
6/03 – 6/05
  One case/ 30,000-million contact lens wearers/ year
DeKalb
DuPage
  England incidence study: 17.53-21.42/mil.
  Chicago data-19/mil. (Joslin); 1/8-10,000 CMP users (Schein)
  Proctor increase: 1.8/yr (2000-2005) to 5/yr. (2005-2006)
nactual = 33
Nexpected* = 3.7 – 4.4
Kendall
Will
*Schaumberg DA et al, Cornea 1998
  Higher prevalence in Scotland and S. Korea
Seals D: Incidence of acanthamoeba keratitis in contact lens wearers. Eye, 2003; 17:893
Cook
Kane
  Mathers data following Iowa floods (1/10,000)
0
10
‐
20
Porter
Lake
Grundy
Kankakee
40 Miles
12 7/28/13 Insurgence of
Acanthamoeba Keratitis
Insurgence of Acanthamoeba
Keratitis in Contact Lens Wear
  40 confirmed cases from 6/03-11/05 in the Chicago area.*
  Clinical and demographic factors: chlorine levels in municipal
water supplies, change in pathogenicity, environmental shifts
in biofilms, attachment to new materials
 Background: Acanthamoeba keratitis remains
a relatively rare infection among contact lens
wearers with recent reports of outbreaks in
some geographic areas.
  88% hydrogel wearers, 12% RGP wearers
  Orthokeratolgy incidence: 30% of cases of microbial keratitis
  Kids may lack antibodies needed to ward off the infection
*Joslin CE, Tu EY, McMahon TT et al: Epidemiologic characteristics of a Chicago-area acanthamoeba keratitis outbreak. Am J
Ophthalmol, 142(2), 2006.
AMO Recall of Complete
Moisture®Plus™ Solutions
 Complete®Moisture Plus™ contains propylene
glycol, taurine and new surfactant and lower
concentration of EDTA
Acanthamoeba Keratitis Case
Control Studies: Relative Risk
June 25, 2007
 CDC interview of 79 soft lens wearers with AK:
45 (60%) reported at least some use of
Complete® MoisturePlus™ in the month prior to
symptom onset.
 Patients who used Complete® MoisturePlus™
had a relative risk of 16X or greater for
contracting acanthamoeba keratitis
 Complete®Moisture Plus™ contained propylene
glycol, taurine and surfactants with a lower
EDTA concentration.
Parallels with Fusarium Keratitis 2006 Outbreak
  Concurrent outbreaks of keratitis among CLU
  Multi-purpose solution implicated
  Fusarium: Bausch & Lomb ReNu with MoistureLoc
  No contamination
  Insufficient anti-microbial efficacy
  Topping off solution in case common risk factor
  Reduce anti-microbial efficacy
 CDC reports a disproportionate number of
Complete® MoisturePlus™ users in data set.
Complete® MoisturePlus™- 16.9, "top off"
solution 2.8, <5 years wear 2.8
  CDC:
 
Verani JR, Lorick SA, Yoder JS, et al. National outbreak of Acanthamoeba keratitis associated
with the use of a contact lens solution. Emerg. Infect. Dis. 2009;15(8):1236-1242.
Complete® MoisturePlus™- 18.51, Re-use
of solution (.5/mo.)- 3.17, "rub" (<10/mo.)9.05, showering with lenses (>5/mo.)- 9.07,
case replacement (>3 mos.)- 2.79
  Joslin:
 
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.
Epidemic Intelligence
Conference CDC, April, 2012
  Elevated Acanthamoeba Keratitis Incidence Despite a
2007 Outbreak-Associated Product Recall-A Multi-State
Investigation, 2008-2011 Brown AC, Ross J, Yoder J, Ayers
T, Roy S and Beach M.
  Multiple CL hygiene practices were associated with increased risk of
AK. The observed persistence of AK might be due to enhanced
disease awareness and clinical suspicion following the 2007
investigation.
  To prevent infection, CL wearers should observe recommended CL
care practices.
RISK FACTORS: topping off solutions 4.54X, recently starting CL use
3.22X, storing CL in water 5.37X, and handling CLs with wet hands
2.17X
  Concern about safety of multi-purpose solutions
13 7/28/13 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 negatve
bacteria)
Neil K. Acanthamoeba and its association with Legionellosis. Clin Infect
Dis, 14(9), 2000
Wheat and Rice Food Source
  Stenotrophomonas maltophilia and Delftia
acidovorans are bacteria commonly found in cases
where there is contamination with Acanthamoeba.
SYMPTOMATOLOGY IN
ACANTHAMOEBA KERATITIS
  Symptoms: Usually unilateral pain disparate to 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
doubled encystment rate with
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
ACANTHAMOEBA KERATITIS
  EPITHELIAL: patchy epithelial involvement (stellate,
irregular or pleomorphic epitheliopathy) bull s eye
lesion, white spots, persistent epithelial defect, elevated
corneal lines
  STROMAL: lack of vascularization, granulomatous or nonsuppurative inflammation, radial nerve infiltrates
( lightning flash ), ring infiltrate
  OTHERS: pseudoguttata, hyphema, hypopyon,
pseudomembrane, scleritis, episcleritis, adenopathy,
decreased corneal sensation (initial)
**poor response to therapy may suggest co-infection
14 7/28/13 DIAGNOSTIC CONFUSION WITH
DENDRIFORM LESIONS OF THE CORNEA
 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
15 7/28/13 DIAGNOSIS OF ACANTHAMOEBA
KERATITIS
  Clinical Suspicion
  Corneal Scrapings
  Superficial Keratectomy / Biopsy
  Paracentesis
  Confocal Microscopy
  Soft Lens Inspection
16 7/28/13 Higher resolu7on OCT can visualize pathogens Confocal Microscopy: Acanthamoeba
Keratitis
Acanthamoeba in 0.25% agar THERAPY FOR
ACANTHAMOEBA KERATITIS
  ANTIBIOTICS / Aminoglycosides**
  ANTI FUNGALS (anti-trophozoite agents)
  ANTIPARASITICS / Aromatic Diamidines
Clinical Outcome In Treating
Acanthamoeba Keratitis
  Propamidine and neomycin: 9/19 (47%) Meisler
  Propamidine and PHMB: 8/10 (80%) McCulley
105/111 (96%) Wilhelmus
  Propamidine and chlorhexidine: 40/42 (96%) Seals
  BIOCIDES / CATIONIC ANTISEPTICS
Intensive monotherapy with either PHMB or chlorhexidine may be equally as effective.
Note: No one case acts in the same manner
** Role of corticosteroid treatment is controversial
**aminoglycosides have now shown increased neomycin resistant strains with an
increased preponderance for trophozoite transformation
17 7/28/13 PREVENTION OF ACANTHAMOEBA KERATITIS
IN CONTACT LENS WEAR
 Avoid use of saliva, distilled and tap/well water
 Avoid swimming and hot tubs while wearing
contact lenses
 Precautions while showering with lenses in
place
 Hygiene related variables: proper maintenance
and care of lenses includes a rub and rinse ,
not topping off , and replacing lenses and
cases regularly.
ADDITIONAL PROTOZOAN
  Naegleria
  Hartmanella
  Vahlkampfiid
  Microsporidia
  Rhinosporidia
 Oxidative disinfection has reasonably good
cysticidal effects.
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 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
18 7/28/13 19 Un-invited Guests of the Cornea: Rare and Unusual Infections
Michael DePaolis, OD, FAAO
Joseph P. Shovlin, OD, FAAO
Several rare corneal pathogens causing infections in contact lens wearers have been
identified. What make these infections so difficult to manage are often the late
definitive diagnosis and the paucity of effective anti-microbial agents that impact a
clinical cure. A timely diagnosis including appropriate differentials in contact lens
wearers with ulcerative keratitis will be stressed along with a review of recent protocols
for managing rare bacterial, fungal and protozoan infections of the eye.
RISK FACTORS AND THE PATHOGENESIS OF ULCERATIVE
KERATITIS
RISK FACTORS FOR BACTERIAL CORNEAL ULCERS
EXOGENOUS: contact lenses, especially extended wear, contaminated cases and solutions, patching a
contact lens abrasion; trauma including foreign body, chemical and thermal injury; previous ocular
surgery including loose sutures; medicamentosa, contaminated medications and make-up.
OCULAR ADNEXAL DYSFUNCTION: misdirection of lashes; abnormal lid anatomy & function; tear
deficiencies, conjunctivitis; neuropathy involving cranial nerve(s) III, V and VII; blepharitis,
canaliculitis/dacryocystitis.
CORNEAL ABNORMALITIES: hypesthesia, bullous keratopathy, erosive disorders, viral keratitis.
SYSTEMIC DISEASE: diabetes mellitus; debilitating illness, especially malnutrition or respirator
dependence; collagen vascular disorders, substance abuse, mental illness; exfoliative skin disease;
immunocompromised patient; atopic dermatitis, vitamin A or B deficiency.
IMMUNOSUPPRESSIVE THERAPY: systemic corticosteroids; topical immunosuppressive agents;
systemic chemotherapy for malignancy, organ transplant or collagen vascular disease.
FUNGAL AND PROTOZOAN INFECTIONS
FUNGAL KERATITIS
Fungi are primitive non-motile plant-like organisms. Yeast are uni-cellular and
molds are multi-cellular filamentous structures. In the past 10 years there has been a
definite increase in the prevalence of fungal keratitis in certain geographic areas,
although nationwide there are probably only 300 cases per year. There are 40 different
genera that cause keratomycoses; most are saprophytic.
CLASSIFICATION/MOST COMMON ORGANISMS (Adapted from J. McCulley)
Filamentous fungi; Molds
Septate- most common cause of fungal keratitis, variable geographic
distribution, mostly in the southern and southwestern United
States,- Fusarium (most virulent due to complex enzymes + toxins),
Aspergillus, Curvularia, Paecilomyces, Phialophora
Non-septate- Mucoraceae (rare corneal pathogen)
Risk Factors: corneal injury (frequently a tree branch or vegetative matter
in an agricultural setting), soft contact lens wear (extended
wear/therapeutic), chronic topical medication, systemic steroids,
diabetes mellitus, radial keratotomy.
CLINICAL FEATURES
Epithelium
Type of stromal
inflammation
Site of inflammation*
Typical
Atypical, severe
intact or ulcerated
non-suppurative,
feathery infiltrate(s)
focal or multi-focal,
satellite infiltrates
ulcerated
suppurative
diffuse
*typically accompanied by a mild iritis, endothelial plaque and hypopyon in severe
infections; hypopyon is of no diagnostic value
Yeasts- worldwide distribution: Candida- C. albicans, C. parapsilosis,
C. tropicalis
Risk Factors- protracted ulceration of the epithelium, topical steroid
therapy, penetrating keratoplasty, bandage soft lenses
Epithelium
Type of stromal
inflammation
Site of inflammation
Typical, common
Atypical, rare
ulcerated
suppurative
intact
non-suppurative
focal or diffuse
multifocal
Note: ring infiltrates or abscess is possible with an intact epithelium
KERATOMYCOSES
DIAGNOSIS- clinical suspicion, corneal scraping, superficial keratectomy
(paracentesis)
Diagnostic stains- gram, Giemsa, GMS, PAS, KOH, acridine orange, Schwartzman’s,
calcofluor white
Culture media- Sabouraud dextrose agar (with gentamicin, without
Confocal
cyclohexamide), blood agar, brain-heart infusion agar
with gentamicin @ 25 + 37 C
microscopy- identifies hyphae, poor for Candida, a guide to therapeutic
response
ANTIFUNGAL DRUG MECHANISMS OF ACTION1.
Sterol Binding- Polyene drugs like Amphotericin B, Nystatin and Natamycin
2.
Inhibition of Sterol Synthesis- the Imidazoles including Miconazole, Ketoconazole,
Clotrimazole, Fluconazole
3.
Interference with RNA Synthesis- Flucytosine (fluorinated pyrimidine) and
Itraconazole (antimetabolites)
4.
Inhibition of Mitosis- Griseofulvin
5. Cationic Antiseptic- chlorhexidine
INITIAL THERAPY- drugs are generally not introduced until definitive
diagnosis is made.
Topical*-HYPHAE-Natamycin 5% (Natacyn) suspension (every hr. for 2448 hrs.) YEAST OR PSEUDOHYPHAE- Amphotericin B .1-.5%
(Fungizone) (every 15-20 minutes for 24-48 hrs.), Miconazole 1%
(Micatin, Monistat) (every hr., but very toxic) as an alternate therapy.
Clotrimazole (cream or powder) and Flucytosine (Ancobon tablets)
converted to a 1% solution have been effective against Candida
infection.
Oral- Ketoconazole (Nizoral) (200-400 mg/day) or Fluconazole (Diflucan)
(100-200 mg/day) [generally used for hyphae and endophthalmitis;
Candida generally responds to topicals alone]; Itraconazole
(Sporanox) is more effective against filamentous fungi especially
Aspergilli .Reserve systemic treatment for deep keratitis, impending
perforation, scleritis, endophthalmitis and post penetrating keratoplasty.
Sub-conjunctival injection-Fluconazole (Diflucan) .5ml = 1mg daily
pending initial response and identification of the organism.
Other agents- atropine 1% or hyoscine .25% 4x/day; glaucoma medication
as needed; role of collagen shield as a delivery device not well
defined. Avoid steroids in fungal keratitis since mold/yeast
replicate more freely and microbial agents are generally only
fungistatic.
*topicals are often continued for 6 wks. or longer; watch for toxicity
Note: excimer ablation may be of some value unless there is deep penetration.
PREVENTION-minimize extended wear, therapeutic lens application whenever
possible, avoid indiscriminate use of topical steroids.
ACANTHAMOEBA KERATITIS
Acanthamoeba keratitis remained a curiosity in the past; however recently
this pathogen affecting primarily the cornea and sclera is recognized with
increased frequency. Early detection will alter the course of therapy and
ultimately affect outcome, therefore early diagnosis is critical. The risks factors
that have been identified by epidemiologic studies, specifically as they relate to
contact lens wear will be examined.
THE ORGANISM- "a free living" protozoan (motile) with worldwide distribution;
isolated from fresh water, well water, sea and brackish water, sewage, hot tubs, air, soil,
wheat and barley; there may be high incidence areas following disasters (ie. Sacramento
floods and hurricane, "Hugo")
Acanthamoeba: >7 species show ocular parasitology [A. castellani, A. quina,
A. culbertsoni, A. lugdunesis, A. polyphaga, A. hatchetti, A. rysodes, A
griffini] Note: Sequence types are recommended as much less
ambiguous units of classification than currently used species names.
Forms: cyst (sessile)*and trophozoite (motile)
*makes the organism resistant to freezing, desiccation, standard chlorination and a
variety of antimicrobial agents
OCULAR INFECTION
Clinical features-initial signs are non-specific; they include: patchy epithelial
involvement (irregularity or pleomorphic focal or stellate epitheliopathy),
suppurative/granulomatous or non-suppurative stromal keratitis, “bull’s eye” lesions,
pseudo-guttata and iritis. More advanced signs include: a radial kerato-neuritis
("lightning flash"), ring infiltrate, nodular episcleritis, scleritis and hypopyon or
hyphema; there may be a pseudo-membrane or adenopathy present. A remarkable lack of
vascularization; is often the only feature to help differentiating this infection from herpes
simplex. Recently, early signs identified include a bull’s-eye lesion and the appearance
of randomly distributed white spots on the cornea. Persistent epithelial defects
immediately following penetrating keratoplasty may signal early amoebic infection.
Symptomatology-usually unilateral pain disparate to ocular findings, often history to
trauma +/or contact lens wear, symptoms generally wax and wane over time with
chronicity.
LABORATORY CONFIRMATION
Corneal scrapings*- examined with Giemsa or tri-chrome stains, also culture with
heated killed E. coli on non-nutrient agar or activated charcoal/yeast extract; other
valuable tests include immunofluorescent techniques which include: calcofluor white and
indirect immunofluorescent antibody testing. Standard culture negativity for bacteria,
fungi, and virus expected. Cysts can sometimes be seen on soft lenses with high
magnification. Confocal microscopy is an aid to early differential diagnosis, and the
infection produces a "lightning flash" appearance at the radial nerve infiltrates.
Polymerase chain reaction may be more sensitive than cultures as a diagnostic test. PCR
analysis of the tears and epithelium may prove a useful tool in confirming an early
diagnosis.
*biopsy with intact epithelium or graft histology
THERAPY
Reported improvement*Antibiotic/Aminoglycoside: paromomycin (Humatin), neomycin
Antifungal: clotrimazole, ketoconazole (Nizoral), itraconazole (Sporanox),
miconazole (Monistat, Micatin), fluconazole (Diflucon)
Antiparasitic/Aromatic Diamidine: propamidine isethionate (Brolene),
hydroxystilbamidine (Pentamidine),hexamidine di-isethionate (Desomedine)
Biocide/Cationic Antiseptic: polyhexamethylene biquanide (PHMB, Baquacil,
Cosmocil), chlorhexidine digluconate, povidone-iodine (Betadine)
*use one agent from the biocide/cationic antiseptic group plus one or more from
the above list, for recalcitrants with significant ocular toxicity use drops in a three
day cycle (hexamidine, paromomycin, and either PHMB or chlorhexidine
Supportive and adjunct therapy-debridement, conjunctival flaps, bandage lenses,
debulking procedures, cryotherapy and steroids with caution**; grafts show a high
recrudescence (NSAIDs seem to have little benefit in pain reduction when radial
keratoneuritis is present)
**inhibits metamorphogenesis and increases
pathogenicity by accelerating trophozoite proliferation
Success has been reported by Seals (1995) using .02% chlorhexidine digluconate & .1%
propamidine isethionate has been reported.
CONTACT LENS RELATED RISK FACTORS/ PREVENTION
Accouterment- use of distilled water, tap/well water*, or saliva;
bacterial contamination of case and care system a common factor
*recent concern especially with rigid lens wear
Disinfection- some resistance to chemical disinfection
Corneal trauma- hypoxia, mechanical trauma with lens wear
Note: should avoid swimming and using hot tubs with contact lens wear
ADDITIONAL PROTOZOAN
Other amoeba- A similar infection may be caused by another amoeba besides
Acanthamoeba, such as Naegleria, Hartmanella or Vahlkampfiid.
Microsporidia- an obligate intracellular protozoan recently found on corneal scrapings
of HIV infected patients from nasopharyngeal or urinary colonization. Generally it
presents as a superficial punctate, multifocal keratitis (may be confined to the superficial
cornea for months) in immuno-incompetent patients (genus-Encephalitozoon); a stromal
keratitis is possible following trauma especially in immunocompetent individuals (genusNosema). A slight improvement has been noted with trimethoprim/sulfisoxazole.
Recently itraconazole, propamidine isethionate, albendazole (benzimidazole), and
especially topical fumagillin bicyclohexylammonium salt (Fumadil B), a bacteriostatic
antibiotic secreted by Aspergillus, have shown some promise. Diagnosis is made by
Gram’s stain, cytology with chromotrope-based stain, or by using electron or confocal
microscopy.