Download Corneal Infections from A to Z - Heart of America Contact Lens Society

Corneal Infections From A (Acanthamoeba) to Z (Zoster)
Joseph P. Shovlin, OD, FAAO
This presentation begins with a review of the epidemiology and
pathogenesis of ulcerative keratitis due to many causes. Several recent
landmark studies will be analyzed in order to cite the risk factors
associated with the increased incidence of corneal infection. Preventive
measures in minimizing these occurrences will be stressed. The organisms
most likely to be encountered will be reviewed along with the key
measures used to make the important differential diagnosis between a
sterile versus an infectious keratitis.
TOPICS:
Risk Factors and Pathogenesis of Ulcerative Keratitis
The Differentials of Infiltrative Keratitis: Sterile v. Infectious
Diagnosis and Treatment of Bacterial Keratitis
Non-Bacterial (Fungal and Protozoan) Infections
The Herpes Group: Simplex and Zoster
Case Examples: Highlighting Differentials and Management
Risk Factors for Bacterial Keratitis
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.
Pathogenesis
Epithelial Compromise- hypoxic, mechanical, osmotic
Contact Lens Contamination- lens care products, case, cosmetics, skin
flora, adherence to lens
Cascade of Events- adherence of microorganism to surface of cornea,
invasion of the cornea, spread and multiplication, induction of the host
inflammatory response, encounter of microorganisms with host immune
factors, tissue damage, tissue repair and recovery
Epidemiology
Incidence in Contact Lens Wear
Daily Wear: approximately 1/2,500/year
Overnight wear of extended wear lenses: estimates range
from one case among 150-300 wearers/year
Population at risk- probably 12,000-15,000 cases /year in U.S
Clinical Features
Symptomotology- pain, photophobia, decreased acuity, foreign
body
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 the tear meniscus, and hypopyon
Laboratory Confirmation/Scrapings
Smears- Gram, Giemsa, acridine orange, acid fast, methenamine
silver, calcofluor white
Cultures- blood agar, chocolate agar (heated blood), thioglycolate
broth, Sabouraud’s, Lowenstein-Jensen, non-nutrient agar, and
others like Thayer-Martin medium for suspected Neisseria infection.
Reasons to culture before treatment- reveal sensitivities of organisms
to eliminate ineffective drugs to reduce toxicity, discriminate
between static and cidal properties of antibiotics and guide
modification in therapy, ineffectively treated organisms are often
difficult to isolate, medico-legal component of the patient’s record.
Corneal biopsy is indicated if there has been a poor response to
treatment or if cultures have been negative on more than one
occasion, and the clinical picture continues to suggest infection.
Also, used where a deep suppurration is not accessible by scraping.
The specimen should be sufficiently large to allow bisection; one
section for culture and the other for histopathology. Specimen
should be delivered to the technician without delay.
Treatment Protocols for Bacterial Keratitis
Assessment of Severity and Initial Plans
Objectives
To distinguish severe suppurative keratitis from non-severe
Implications of virulent versus lesser virulent organisms
Definition of latitudes of initial therapy
Guidelines [Adapted from J. McCulley]
Feature
Suppurative/Severe
Non-suppurative/Mild-Mod.
Onset/progression
acute/ rapid
sub-acute, chronic/slowly
progressive
Virulence
highly likely
uncertain, doubtful
Laboratory Studies
immediate, urgent
may delay
Laboratory Materials
standard
special
Initial Antibiotics
based on smears/broad
based on smears + biopsy/
antimicrobial agents
latitude for deferral
Broad spectrum of initial coverage: single agent (fluoroquinolones) vs.
multiple agents
Rapid, intensive topical therapy
Daily evaluation
Tailor antibiotic choice by culture results and clinical response
Design and Drug Penetration
Topical- every 15 min.- 1 hr. for initial 24-48 hrs. or altered
loading dose
Subconjunctival injections- once or twice daily for 1-2 days
Intravenous antibiotics- only for impending perforation or
scleral suppuration
Modification of Therapy
Objectives- eliminate replicating bacteria, avoid adverse reaction to the
medication, control the destructive components of the inflammatory
process
Guidelines- avoid abrupt changes in therapy until the response can
adequately be assessed and until the sensitivity tests are completed at
the lab
Expected response despite proper/ effective therapy:
Organism
Response
S. aureus, S. pneumoniae
may be relatively unchanged, then improve
rapidly after 24-48 hrs.; organisms generally
eliminated in 7-10 days
Pseudomonas aeruginosa
generally appears worse at 24 hrs.; organism
may persist for 14 days or longer
Bacteria of low virulence
(ie. S. epidermidis)
Mycobacterium, Filamentous fungi
generally improve rapidly in 24-48 hrs.;
organisms eliminated in 5-7 days
slow response; may persist for weeks
Resistant Bacteria
Methicillin resistant Staphylococcus aureus and epidermidis
Vancomycin resistant Enterococcus fecalis (group D
Streptococcus)
Aminoglycoside and Fluoroquinolone resistant Pseudomonas
aeruginosa
Beta lactamase producing Neisseria
Atypical Mycobacteria
Current antibiotic recommendation for suspected resistance:
Vancomycin 20-30 mg/ml (Vancocin) and Ceftazidine 50
mg/ml (Fortaz/Pentacef)
Gram positive organisms: Vancomycin 20-30 mg/ml
(Vancocin) or Cefazolin 50 mg/ml (Ancef), .28% Lysostaphin,
IV Linezolid (Zyvox)
Gram negative organisms: Amikacin 10-20 mg/ml (Amikin)
Adjuvant Therapy
Cycloplegia- for comfort and to prevent synechiae
Collagenase inhibitors (ie. EDTA, TCN, Galardin)- to minimize stromal
destruction
Heat (40 degrees C)
Steroids- hazardous early in treatment, safety and efficacy not well
established in most forms of microbial keratitis; helpful in reducing
harmful destruction due to host response
NSAIDs/ Analgesics- reduces inflammation and pain, may enhance
antimicrobial(s) efficacy (NSAIDs) *anecdotal reports suggest
very effective for pain in mycobacteria infections
Tissue adhesives- for impending and actual perforations if small/
bacteriostatic
Glaucoma medication- if needed, beta-blockers is drug of choice
Debridement/ Biopsy- may improve antibiotic penetration
Cryotherapy- possible role in sclerokeratitis
Bandage lens/ Collagen shield- may promote re-epithelialization and
allow for slow concentrated release of antibiotic
Continuous antibiotic infusion devices- possible benefit in extensive
sclerokeratitis
Therapeutic keratoplasty- for large perforations, central/deep
medically recalcitrant keratitis
Termination of Therapy
Elimination or substitute antibiotics only if directed by lab results
Elimination of the less effective agent if combined microbial
therapy initiated for monobacterial keratitis after lab results
Measures of improvement:
Blunting of the perimeter of stromal suppuration
Reduction in the density of suppuration
Reduction in cellular infiltrate and edema in surrounding stroma
Reduction in the anterior chamber reaction
Progressive re-epithelialization
Reducing antimicrobials and adjuvants:
Avoid abrupt cessation; prolonged therapy needed for
Pseudomonas, Mycobacterium, Nocardia, anaerobes
Reduce by “halving method”, substitute regular/commercial
strength for fortified antibiotics when possible
Penetrating Keratoplasty
Progressive suppuration despite appropriate therapy
Persistent infection
Corneal perforation not managed by other method
Non- Bacterial Infections (Protozoan and Fungal)
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 of Fungi (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,- Non-pigmented: Fusarium (most virulent due to
complex enzymes + toxins), Aspergillus, Pigmented: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 of Keratomycoses
Typical
Atypical, severe
Epithelium
intact or ulcerated
ulcerated
Type of stromal
non-suppurative,
inflammation
feathery infiltrate(s)
Site of inflammation*
focal or multi-focal,
suppurative
diffuse
satellite infiltrates
*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
Typical, common
Atypical, rare
Epithelium
ulcerated
intact
Type of stromal
suppurative
non-suppurative
focal or diffuse
multifocal
inflammation
Site of inflammation
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
cyclohexamide), blood agar, brain-heart infusion agar
with gentamicin @ 25 + 37 C
Confocal microscopy- identifies hyphae, poor for Candida, a guide
to therapeutic response
Antifungal Drugs and Mechanism of ActionSterol Binding- Polyene drugs like Amphotericin B, Nystatin and Natamycin
Inhibition of Sterol Synthesis- the Imidazoles including Miconazole, Ketoconazole,
Clotrimazole, Fluconazole
Interference with RNA Synthesis- Flucytosine (fluorinated pyrimidine) and Itraconazole
(antimetabolites)
Inhibition of Mitosis- Griseofulvin
Initial Therapy- drugs are generally not introduced until definitive
diagnosis is made.
Topical*-Hyphae-Natamycin 5% (Natacyn) suspension (every hr.
for 24-48 hrs.) Yeast or Pseudo-hyphae- 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 isoptohyoscine .25% 3x/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
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 Infections
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, ring infiltrate, nodular episcleritis,
scleritis and hypopyon or hyphema; there may be a pseudo-membrane
or adenopathy present. A remarkable lack of vascularization; 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. Diagnosis is easier in the earlier stages with superficial disease.
*biopsy with intact epithelium or graft histology
Medical Therapy
Reported improvement*- use one from the biocide/cationic antiseptic
group plus or more of the following:
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 diisethionate (Desomedine)
Biocide/Cationic Antiseptic: polyhexamethylene biquanide (PHMB,
Baquacil, Cosmocil), chlorhexidine digluconate, povidone-iodine
(Betadine)
*use one agent from at least two of the four categories above, plus
oral ketoconazole or fluconazole, apply topicals every 30-60
minutes; 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 suppresses macrophages; also
increases pathogenicity by accelerating trophozoite proliferation
Success has been reported by Seals (1995) using 0.02% chlorhexidine digluconate
& .1% propamidine isethionate has been reported.
Recent reports have shown success with intensive mono-therapy using PHMB
(0.02%) or chlorhexidine (0.02%) Initial dosing: given hourly around the clock for
the first few days then tapered for usually 3-6 months. Concentrations can be
increased with resistance to initial medical therapy (concern for increased
toxicity)
Related Risks and 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- resistance to most chemical disinfection
Corneal trauma- hypoxia, mechanical trauma with lens wear
Note: should avoid swimming and using hot tubs with contact lens
wear
Additional Protozoan
Additional 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 (genus-Nosema). 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 microscope.
The Herpes Group: Simplex and Zoster
Defining the Herpes Family: Epidemiology
 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. 25% of the population is seropositive by age 4 and nearly 100% by age 60.
 Neonates often infected with HSV-2.
Herpes Simplex Features
 Most are asymptomatic on primary infection; skin eruptions are not
common after primary infection.
 Recurrent HSV is commonly found along the oral or nasal mucosa.
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 infection.
Steroids will trigger infectious keratitis.
 Conjunctival dendrites may be present without corneal findings.
 In children, primary infection manifests with fever and cutaneous
outbreak around the lids. Outbreak is prolonged and less responsive
to therapy.
 Bilateral involvement or prolonged HSV suggests comorbid disease
(i.e. atopy, immunodeficiency or immunosuppression).
Viral Detection
 Cell Cultures
 ELVIS (enzyme-linked virus inducible system)**
 PCR (polymerase chain reaction/DNA detection)
HSV can be recovered by swabbing an untreated dendrite with a soft
tipped applicator inoculating it into viral transport media or a viral
culturette.
** high degree of sensitivity and specificity within 24 hrs.
Herpes Simplex Clinical Presentation
 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
 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
Treatment and Management of Herpes Simplex
 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.
 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.
Herpes Zoster
 HZV is the etiologic agent of both varicella (chickenpox) and
reactivation (shingles)
 Unlike HSV, HZV typically happens once in life (30% of adults).
 HZV established latency in the sensory root ganglia (maintained by
a T-cell immune response that wanes with advancing age)
 Exposure to cases of chickenpox may serve as a “booster vacciine”.
Herpes Zoster Kerato-uveitis
 Involves the ophthalmic division of the fifth cranial nerve.
 Without oral antivirals, 50% of HZV patients will experience ocular
involvement.
 Long list of ocular complications including: persistent keratitis, uveitis,
acute retinal necrosis, cranial nerve palsies and optic neuropathy.
 Complications are similar to HSV keratitis and include: punctate or
pseudo dendritic keratitis (mucous plaque), stromal infiltrates,
endotheliitis and neurotrophic keratopathy. Uveitis in severe cases is
not uncommon.
Recurrent Zoster
 Recurrent episodes (different locations) are somewhat atypical and
practitioners must consider a sinister etiology.
 Patients should be worked up for occult malignancy or other
reduced cell mediated immunity concerns (body scans, T4 and T8
subsets may be needed).
 HIV/CMV titers are suggested.
 4.5X greater risk of stroke the 1st yr.
Post-Herpetic Neuralgia
 Most frequent and debilitating complication of HZV regardless of
the dermatomal distribution.
 A neuropathic pain syndrome that persists or develops after shingles’
rash has resolved.
 Main PHN risks: advancing age, severity of acute zoster pain and
rash, a painful prodrome and ocular involvement.
Prevention Through Vaccination
 Controversies…..
 Should healthcare providers be vaccinated?
 When is vaccination appropriate after having the shingles?
 When should one stop antivirals before/after vaccination?
 Should patients with active kerato-uveitis or corneal
dendriform be vaccinated?
Anti-Viral Agents: Orals and Topicals
 Oral Agents
Acyclovir
Valacyclovir*
Famciclovir*
Penciclovir*
 Topical Agents
Trifluridine (Viroptic/non-selective)
Ganciclovir (Zirgan/selectivel)
*Better bioavailability and longer intracellular half-life than Acyclovir
Interferon has been used as an adjunct
Anti-Viral Resistance
 Rare event overall, but definitely more common in immunocompromised individuals. Any resistance does raise the concern for
immuno-compromised states (i.e CA).
 TK mutants (encodes for key enzyme) are responsible. Some
concern for prolonged prophylaxis and emerging resistance as in
bacterial disease.
 Acyclovir resistance are often resistant to valacyclovir and crossresistance to famciclovir; 45% of resistant strains are resistant to
ganciclovir. ACV efficacy may have reduced therapeutic effect in
lactose intolerant patients.
 In vitro resistance assays and molecular characterization of isolates
should be performed in refractory cases.