fungal keratitis

1. Done by
Maged Hemaid Mohamed Salem

2. Fungal Corneal Ulcer (FCU)
Fungal infection of the cornea is rare. It is usually seen only in the
context of trauma (including contact with organic material) or
where there is underlying susceptibility such as tissue
devitalization or immunosuppression (including topical
corticosteroid use). Candida, Fusarium, and Aspergillus spp. are
the most common infectious agents.
Epidemiology:
• Worldwide, fungal keratitis is a significant cause of ocular
morbidity and unilateral blindness.
• The incidence varies with climate and fungal keratitis is more
common in tropical regions.
• In the US, fungal keratitis remains rare, but fungi are a more
common cause of corneal ulcers in Southern states (35% in
South Florida) than in Northern ones (8.3% in New York).
• Contact lens wear increases the risk of fungal keratitis.
o In 2006, an outbreak of 130 cases of Fusarium keratitis
in the United States was linked to Bausch & Lomb
ReNu® contact solution.
• Topical steroid use is also associated with increased risk of
fungal keratitis, especially Candida keratitis, and carries a
poor prognosis in the resolution of fungal ulcers.
• Fungal keratitis is a common cause of corneal ulcers in
developing nations, accounting for 44% of corneal ulcers in
South India, 36% in Bangladesh, 37.6% in Ghana, and 17%
in Nepal.

3. • Fungal keratitis often occurs following ocular trauma from
vegetable matter; thus, agricultural workers are at greater
risk.
• Fungal keratitis is more common in males than in females.
Risk factors:
contact lens wear:
• When associated with poor lens hygiene or overnight lens wear,
is becoming increasingly important as a cause of corneal
infections in countries where rates of contact lens use are high.
• Recent increases in the rates of Acanthamoeba and Fusarium
species keratitis are being attributed to contact lenses.
corneal trauma:
• This remains the major cause of corneal infections in most
developing nations and agricultural settings.
• Corneal foreign bodies, especially those containing vegetable
matter, should raise suspicion of fungal pathogens.
corneal abrasion/erosion:
• A break in the corneal epithelium is a major breach in the
defense mechanisms of the cornea and leaves it vulnerable to
invasion by a range of pathogens.

4. recurrent corneal erosions:
• Recurrent epithelial breakdown may occur due to hereditary
corneal dystrophies or poor epithelial healing from previous
trauma.
Immunosuppression:
e.g. topical corticosteroids, alcoholism, diabetes, systemic
immunosuppression.
dry eye:
• Severe dry eye results in corneal surface irritation and epithelial
defects, whereas the lack of IgA and other immune mediators
(normally present in the tear film) compromises corneal defenses.
previous eye surgery:
e.g. Laser in situ keratomileusis (LASIK) surgery.
Pathogenesis:
Fungi are a group of microorganisms that have rigid walls and a
distinct nucleus with multiple chromosomes containing both DNA
and RNA. Fungal keratitis is rare in temperate countries but is a
major cause of visual loss in tropical and developing countries.
Though often evolving insidiously, fungal keratitis can elicit a
severe inflammatory response – corneal perforation is common
and the outlook for vision is frequently poor. Two main types of
fungi cause keratitis:

5. • Yeasts (e.g. genus Candida), ovoid unicellular organisms that
reproduce by budding, are responsible for most cases of fungal
keratitis in temperate climates
. • Filamentous fungi (e.g. genera Fusarium and Aspergillus),
multicellular organisms that produce tubular projections known as
hyphae. They are the most common pathogens in tropical
climates, but are not uncommon in cooler regions. The keratitis
frequently follows an aggressive course.
History:
A history of outdoor eye trauma often is reported.
In patients presenting with possible fungal keratitis, inquire about
possible risk factors.
Symptoms include the following:
• Foreign body sensation
• Increasing eye pain or discomfort
• Sudden blurry vision
• Unusual redness of the eye
• Excessive tearing and discharge from the eye
• Increased light sensitivity
Physical:
The clinical diagnosis of fungal keratitis is based on risk factor
analysis and characteristic corneal features.
The most common signs on slit lamp examination are nonspecific
and include the following:
• Conjunctival injection
• Epithelial defect

6. • Suppuration
• Stromal infiltration
• Anterior chamber reaction
• Hypopyon
Presenting clinical features that are specific to fungal keratitis
include an infiltrate with feathery margins, elevated edges, rough
texture, gray-brown pigmentation,
satellite lesions, hypopyon, and
endothelial plaque. The spread of
infection occurs through the
channel network of the cornea.
This mode of spread fully explains
the satellite lesions.
• Fine or coarse granular
infiltrate within the epithelium
and anterior stroma
• Gray-white color, dry, and rough corneal surface that may
appear elevated
• Typical irregular feathery-
edged infiltrate
• White ring in the cornea and
satellite lesions near the edge
of the primary focus of the
infection
• In advanced cases,
suppurative stromal keratitis
associated with conjunctival
hyperemia, anterior chamber
inflammation, hypopyon, iritis,
endothelial plaque, or possible corneal perforation.
Although these highly characteristic signs may be present,
obtaining a sample of the lesion by scraping or corneal biopsy is
Fungal corneal ulcer, with excessive vascularization
Marginal ulcer, fungus positive
Fungal corneal ulcer, with excessive vascularization

7. important before initiating treatment with antifungal therapy.
Several unfortunate cases have been reported in which antifungal
therapy had been initiated before fungi were seen or isolated, with
resultant misdiagnosis and progression of the process. In warm
developing countries, it is wise to start antifungal agents on mere
suspicion since hot weather promotes rapid fungal growth.
Mixed bacterial and fungal
infections are common in the
developing countries. The patients
may present after many days or
weeks. While antibacterial therapy
is started in most clinics in the
periphery, fungal infection may not
be considered. The most practical
approach in good clinics in
developing countries is to examine
a scraping from the ulcer, both for
bacteria and fungi. If hyphae and/or spores are found, the
treatment efforts are mainly directed toward the fungus, but
broad-spectrum antibiotics are also used to cover for bacteria.
Once a few fungal ulcers or fungal
keratitis cases have been carefully
examined, it becomes easy to
make a presumptive diagnosis of
fungus infection. In the developing
countries and tropics, fungal cases
are very common in the hot
summer months.
Advanced severe filamentous
fungal and yeast keratitis are
indistinguishable and resemble keratitis caused by virulent
bacteria, such as Staphylococcus aureus and Pseudomonas
aeruginosa.
Fungal infection
Fusarium keratitis with hypopyon

8. Investigations:
Samples for laboratory investigation should be acquired before
commencing antifungal therapy.
• Staining:
○ Potassium hydroxide (KOH) preparation with direct microscopic
evaluation is a rapid diagnostic tool that can be highly sensitive.
○ Gram and Giemsa staining are both about 50% sensitive.
○ Other stains include periodic acid–Schiff, calcofluor white and
methenamine silver.
• Culture. Corneal scrapes should be plated on Sabouraud
dextrose agar, although most fungi will also grow on blood agar or
in enrichment media. It is important to obtain an effective scrape
from the ulcer base. Sensitivity testing for antifungal agents can
be performed in reference laboratories but the relevance of these
results to clinical effectiveness is uncertain. If applicable, contact
lenses and cases should be sent for culture.
• Polymerase chain reaction (PCR) analysis of specimens is
rapid and highly sensitive (up to 90%) and may be the current
investigation of choice. Calcium-containing swabs can inhibit
polymerase activity and local collection protocols should be
ascertained prior to specimen collection.
• Corneal biopsy is indicated in suspected fungal keratitis in the
absence of clinical improvement after 3–4 days and if no growth
develops from scrapings after a week. A 2–3 mm block should be

9. taken, similar to scleral block excision during trabeculectomy.
Filamentous fungi tend to proliferate just anterior to Descemet
membrane and a deep stromal specimen may be required. The
excised block is sent for culture and histopathological analysis.
• Anterior chamber tap has been advocated in resistant cases
with endothelial exudate, because organisms may penetrate the
endothelium.
• Confocal microscopy frequently permits identification of
organisms in vivo, but is not widely available outside tertiary
centers.
Treatment:
Fungal keratitis treatment is generally prolonged and complicated,
especially because the correct treatment is often delayed as the
diagnosis is missed initially. A Cochrane review has found no
evidence that any particular antifungal, or combination of
antifungals, is more effective in the management of fungal
keratitis. Previous studies showed topical natamycin may be
superior compared with topical voriconazole. Oral voriconazole
has a high corneal penetration and may be used when associated
with severe inflammation or stromal infiltrate >2 mm, or when
topical antifungal medicines prove ineffective.
1st
: topical or oral antifungal therapy:
Primary options:
» natamycin ophthalmic: (5%) 1 drop into the affected eye(s)
every 1-2 hours until clinical and symptomatic improvement
(usually 1-3 weeks), then taper slowly.

10. Secondary options:
» voriconazole ophthalmic: (1%) 1 drop into the affected eye(s)
every 1-2 hours until clinical and symptomatic improvement
(usually 1-3 weeks), then taper dose slowly Consult pharmacist:
product needs to be specially compounded as it is not available
as a proprietary product.
OR
» amphotericin B ophthalmic: (1.5 mg/mL) 1 drop into the affected
eye(s) every 1-2 hours until clinical and symptomatic
improvement (usually 1-3 weeks), then taper dose slowly Chiefly
used in Candida infections. Consult pharmacist: product needs to
be specially compounded as it is not available as a proprietary
product.
Tertiary options:
» itraconazole: 400 mg orally once daily on day one, followed by
200 mg once daily for 2-6 weeks
OR
» neomycin/polymyxin B/gramicidin ophthalmic: 1 drop into the
affected eye(s) every 30 minutes to 2 hours until clinical and
symptomatic improvement (usually 2-3 weeks), then taper dose
slowly
OR
» clotrimazole ophthalmic: (1%) 1 drop into the affected eye(s)
every 30 minutes to 2 hours until clinical and symptomatic
improvement (usually 2-3 weeks), then taper dose slowly Consult
pharmacist: product needs to be specially compounded as it is not
available as a proprietary product.
OR

11. » voriconazole: weight <40 kg: 100 mg orally twice daily for 2-6
weeks; weight >40 kg: 200 mg orally twice daily for 2-6 weeks
» Treatment is generally prolonged and complicated, especially
because the diagnosis is often missed initially.
» If corneal ulcer has re-epithelialized but infiltrate appears active,
epithelial debridement may improve drug penetration.
» Contact lens wear should be discontinued during therapy. If
corneal thinning >50% is present, an eye shield should be placed
without an eye patch over the involved eye.
» If a large epithelial defect is present, a broad-spectrum topical
antibiotic such sulfacetamide, polymyxin-B/trimethoprim, or
bacitracin should be added.
» Fungal keratitis with severe inflammation or stromal infiltrate >2
mm or poor response to topical therapy is recommended to be
treated with oral itraconazole.
» A Cochrane review has found no evidence that any particular
antifungal, or combination of antifungals, is more effective in the
management of fungal keratitis. Previous studies showed topical
natamycin may be superior compared with topical voriconazole
Adjunct: symptom relief (for photophobia and
anterior chamber reaction):
Treatment recommended for SOME patients in selected patient
group
Primary options:
» atropine ophthalmic: (1%) 1 drop into the affected eye(s) up to
three times daily
OR

12. » homatropine ophthalmic: (1%, 2%, or 5%) 1 drop into the
affected eye(s) up to four times daily
OR
» hyoscine ophthalmic: (0.25%) 1 drop into the affected eye(s) up
to four times daily
OR
» cyclopentolate ophthalmic: (1%) 1 drop into the affected eye(s)
up to four times daily
» Cycloplegic drops paralyse the ciliary muscles thus, dilating the
eye, provide pain relief by preventing ciliary spasm and prevent
posterior synechiae in cases of severe anterior chamber reaction.
Adjunct: pain relief
Treatment recommended for SOME patients in selected patient
group.
Primary options:
» paracetamol: 500-1000 mg orally every 4-6 hours when
required, maximum 4000 mg/day
Secondary options:
» ibuprofen: 400-800 mg orally every 4-6 hours when required,
maximum 2400 mg/day
OR
» naproxen: 500 mg orally initially, followed by 250 mg every 6-8
hours when required, maximum 1250 mg/day
Tertiary options:
» codeine phosphate: 15-60 mg orally every 4-6 hours when
required, maximum 240 mg/day

13. OR
» oxycodone: 5-30 mg orally (immediate release) every 4 hours
when required
» Fungal keratitis can result in severe pain that needs to be
adequately addressed. Pain medications consist of oral
paracetamol, nonsteroidal anti-inflammatory drugs, or opiates.
Ongoing treatment:
• Taper treatment, according to clinical improvement. Relapse is
common and may signify incomplete sterilization or reactivation.
Treatment is prolonged (12wk). In the healing phase, topical
corticosteroids (e.g. preservative-free dexamethasone 0.1% 1×/d)
are sometimes used; this should be at the direction of a corneal
specialist and carefully monitored.
• Consider PK for progressive disease (to remove fungus/prevent
perforation) or in the quiet, but visually compromised, eye.
Complications:
• Fungal keratitis can lead to
severe ocular infections
involving any intraocular
structure and can result in
severe visual loss or even loss
of the eye.
Fungal abscess

14. • Corneal perforation is not unusual, and secondary
endophthalmitis has been reported.
Prognosis:
Fungal keratitis can cause significant morbidity due to delayed
diagnosis, fewer effective medications, and aggressive
pathogens. A study from Florida (where ophthalmologists
generally have a high degree of familiarity with fungal keratitis),
found that final visual acuity was 20/40 or better in 70% of
patients treated with medication alone and 16% of patients
requiring keratoplasty. Surgical intervention in the acute phase
was necessary in 23% of patients.
Differential diagnosis:
• Bacterial keratitis.
• Acanthamoeba keratitis.
• Herpes simplex virus (HSV) keratitis.
• Atypical mycobacterial infection.
• Sterile corneal ulcer.
• Retained foreign body.
Perforated fungal ulcer

15. Microsporidial keratitis
Introduction
Microsporidia (phylum Microspora) are obligate intracellular
single-celled parasites previously thought to be protozoa but now
reclassified as fungi. They rarely cause disease in the
immunocompetent and until the advent of acquired
immunodeficiency syndrome (AIDS) were rarely pathogenic for
humans. The most common general infection is enteritis and the
most common ocular manifestation is keratoconjunctivitis.
Diagnosis
• Signs
○ Bilateral chronic diffuse PEK (Fig. A).
○ Unilateral slowly progressive deep stromal keratitis (Fig. B) may
rarely affect immunocompetent patients.
○ Sclerokeratitis and endophthalmitis are rare.
• Biopsy shows characteristic spores and intracellular parasites.
• PCR of scrapings may have relatively low sensitivity.
Diffuse punctate epithelial keratitis deep stromal infiltrates

16. Treatment
• Medical therapy of epithelial disease is with topical fumagillin.
Highly active antiretroviral therapy (HAART) for associated AIDS
may also help resolution. Stromal disease is treated with a
combination of topical fumagillin and oral albendazole 400 mg
once daily for 2 weeks, repeated 2 weeks later with a second
course. Patients should be closely monitored for hepatic toxicity.
Long-term fumagillin treatment may be required and it is difficult
to eradicate the parasites in immunocompromised patients.
• Keratoplasty may be indicated although recurrence of disease
can occur in the graft periphery. Cryotherapy to the residual tissue
may reduce this risk.

17. References:
Oxford handbook of ophthalmology third edition.
Kanski’s clinical ophthalmology ninth edition.
https://bestpractice.bmj.com/topics/en-gb/561?q=Keratitis
https://www.aao.org/topic-detail/fungal-keratitis-europe
https://emedicine.medscape.com/article/1194167-clinical#b1