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Uninvited Guests of the Cornea: Rare
Corneal Infections
Michael D. 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 IN CONTACT LENS
WEARERS
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 IN CONTACT
LENS WEAR
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.
TRANSCRIPT QUALITY COURSE QUESTIONS- UN-INVITED GUESTS OF THE
CORNEA
1. Microsporidia are obligate parasites found on corneal scraping of some HIV infected
patients?
2. Chlorhexidine digluconate and propamidine isethionate used in combination have
shown a clinical cure in some patients with acanthamoeba keratitis?
3. Fusarium keratitis is considered the most virulent of the fungal infections of the
cornea due to the complex enzymes and toxins that are produced?
4. Although not an approved antifungal, Amphotericin B, is the suggested topical of
choice in the initial treatment of yeast related keratitis?
5. Corneal injury in an agricultural setting increases the risk of acquiring a
keratomycotic infection?
ANSWERS: 1. T 2. T 3. T 4. T 5. T