Fungal Keratitis.pdf

Fungal Keratitis
chalky white infiltrates
Ring infiltrate
Stromal necrosis and
central thinning
Tukezban Huseynova, MD

Dr. Tukezban Huseynova
Introduction

Introduction
v Fungal or mycotic keratitis (MC) is a leading cause of ocular morbidity, opacification
and preventable blindness
v Fungal keratitis represents one of the most difficult forms of microbial keratitis to
diagnose and to manage
v Failure with medical management alone is common. Both medical and surgical
success may be limited
v MK is mostly observed in male outdoor workers and it was for the first time described
in Germany by Leber in 1879 in a 54-year-old farmer, who had a mild corneal injury
due to oat chaff while working with a shredder (Dreschmaschine) (Leber 1879)
v It is proposed that the frequency of MK is more in developing countries as compared
to developed countries
„Fungal corneal ulcers: clinical features and laboratory identification methods“, Lalitha Prajna, Vijakumar N Venkatesch Prajna, M Srinivasan (2008)
„Mycotic Keratitis“, Mahendra Rai, Marcelo Luis Occhiutto (2019)

Introduction
Morphology and Classification of Fungi
v Elongation of the cell produces a tubular, thread
like structure called Hypha. Hypha means the
web
v The simplest type of fungus is the unicellular
yeast
v Mycelium is a network of hyphae
v From mycelium extend fungi
https://preparmy.com/life-science/biology/agriculture/general-characteristics-fungi/

Introduction
Morphology and Classification of Fungi
1. Filamentous Fungi or Molds: Its subtypes are:
a. Septate (Hyphae): They are further divided into:
- Nonpigmented (Moniliacea), such as Aspergillus or Fusarium.
- Pigmented (Dematiaceae), such as Alternaria or Curvularia.
b. Nonseptate organisms: They do not form cross-walls, such as Mucor
2. Yeasts: They produce opaque, pasty, creamy colonies on the surface of culture or media,
such as Candida
3. Dimorphic Fungi: They exhibit properties of yeasts when cultivated at 37°C and molds
when grown at 25–30°C. Examples include Blastomyces, Cryptococcus and Sporothrix

Introduction
Risk and Predisposing Factors
ØContact lens wear (therapeutic)
ØChronic ocular surface desease
ØChronic Keratitis
ØChronic trauma
ØImmunosuppression
ØCorneal anesthetic abuse
ØChronic use of broad-spectrum antibiotics
ØPrior corneal surgery
ØCorneal trauma with soil/organic matter
Ocular factors Systemic factors
ØDiabetis mellitus
ØHIV
ØLeprosy

Pathogenesis

Fungi
Release of protease
and mycotoxins
Epithelium Defect
A defect in the epithelium
Fungi enter into the corneal stroma
Fungi multiply and proliferate
Severe tissue necrosis and inflammation
D.M penetration to the anterior chamber
Pathogenesis

Clinical presentation

Manifestation of Fungal Keratitis
v Foreign body sensation
v Gradually increasing pain
v Diminution of vision
Nonspecific
Symptoms
Signs
Specific
v Feathery margins
v Elevated edges
v Rough texture
v Satellite lessions
v Gray/Brown pigmentation
v Collar button configuration
v Fixed Hypopion
v Lack of corneal sensation
v Conjunctival injection
v Epithelial defect
(5 to 10 days)

Branching vesicular
lesion
Fusarium Keratitis
v Fusarium solani keratitis has a more severe course so that deep extension and perforation
may occur in few weeks
v Aspergillus species on the other hand, causes a less severe and not so rapidly progressive
keratitis, which is amenable to therapy
Clinical Features
o May involve any area of the cornea
o White, yellow or grey ulcer
o Raised edges
o Growth in extension and depth
o Satellite lesions with corneal opacity
o Feathery margins
Note: Fusarium keratitis can
completely destroy the eye in a
couple of weeks

Branching
vesicular
lesion
q Fussarium Keratitis
Feathery margin
Feathery margin
Feathery margin
Note feathering margins
„Principle and Practice of cornea, Robert A Copelnd Jr, Natalie A Afshari, 2013
„Cornea: Fundamentals, Diagnosis and Management“, Mark J. Mannis, Edward J. Holland, 2017

Note Satellite lesions

Branching vesicular
lesion
Double layered hypopion Double layered hypopion
Thick plaque

Branching vesicular
lesion
Dematiaceous Keratitis
vDematiaceous fungi are melanized fungi that produce pigments
vThe most reported etiologic agent is Curvularia spp
Clinical Features
o Ulcers with whitish to white yellowish corneal pitting
o Corneal edema and infiltration in the peripheral part of the ulcer
o Immune ring
o Hypopion
o Iritis
o Endophthalmitis

q Dematiacious Keratitis
Brown pigmentation
Brown
pigmentation
Brown
pigmentation
Note brown pigmentation

q Dematiacious Keratitis
Note brown pigmentation

Branching vesicular
lesion
Greyish infiltrates
Creamy
exudates
Irregular
feathery
margins and
dry texture
Endothelial plaque
with perforation
q Different clinical samples of FK
„Corneal ulcers diagnosis and management“, Hugh R Taylor, Peter R Laibson (2008)

A “collar button”
configuration
Candida keratitis with overlying
intact epithelium.
Elevated corneal lesion (1), gray/dirty
white surface, a ring infiltrate (2), and a
hypopyon (3).

A. FK with active infiltrate B. Same ulcer showing signs of healing
after topical natamycin therapy
A B

1 year after penetrating
keratoplasty
deep infiltrate
„Cornea Atlas, Third Edition“, Jay H Krachmer, David A Palay (2014)

Deposits
Deposits
Natamycin (eye drops) deposits

Laboratory Investigations

Laboratory investigations
ØProvides diagnostic clue
ØMay be therapeutic by the debulking of the
organism
ØBreaches the epithelium for better penetration
of the anti-fungal agents
Corneal scraping provides:
Laboratory diagnosis includes:
ØDirect microscopy
ØPolymerase chain reaction (PCR)
ØConfocal microscopy
Culture media showing growth of various
fungi

Medical Therapy

General information
Medical Therapy
v Medical management of fungal keratitis is problematic
v There are no standard guidelines for selecting current antifungals
v Topical antifungal therapy is the current standard for the medical management of
fungal keratitis
v One or more topical antifungals are usually administered with systemic
support of oral antifungals
v The most common classes of antifungal used for medical therapy include the polyenes and
azoles
v Among the polyenes, the most used compounds have been Amphotericin B and natamycin

Pharmacological Treatment options

Amfotericin B
o First line therapy for Candida species
o Good to moderate activity against Aspergillus, Fusarium species
o In order to prepare the topical form, the compound has to be diluted with dextrose
or distilled water to obtain a concentration of 0.15 % Topical administration 0.05 – 0.3%
o Intravenous administration 0.25 – 1mg/kg
o Intracameral administration 0.8 – 1.0 mg
o Intrastromal 0.5 μg–5 mg
o It is used mainly for the management of superficial fungal keratitis
o Its effectiveness is dose dependent
Polyenes bind directly to cell membrane sterols leading to cell death
Do not penetrate intact epithelial barrier
Characteristics
Toxicity
o Presents low potential for hypersensitivity/toxicity when used topically at 0.15%
o Desocycholate formulation is less soluble and more toxic than the water-soluble formula
Medical Therapy

Natamycin (or Piramicin)
Polyenes
Characteristics
o Good activity against most Fusarium, Aspergillus, less
effective against Candida species
o Topical administration 2.5 – 5%
o Intravenous/Intracameral administration – Not available
o First antifungal FDA approved
o It is used as monotherapy for the superficial infection's treatment
o Combined with an azole antifungal-oral-treatment for severe infections (1)
Kalavathy, C.M., Parmar, P., Kaliamurthy, J., Philip, V.R., Ramalingam, M.D.K., Jesudasan, C.A.N., Thomas, P.A. 2005. Comparison of topical itraconazole 1% with topical natamycin
5% for the treatment of filamentous fungal keratitis. Cornea 24(4): 449–452.
Medical Therapy

Azoles Inhibit cytochrome P450 enzyme
v Azoles were developed as a less toxic alternative than amphotericin
v In 1981, the FDA approved the use of oral ketoconazole as the first compound available for the
treatment of systemic fungal infections
v All are prepared extemporaneously, except for clotrimazole which exists as a 1% cream or
suspension for dermatological use
General information
Toxicity
v Burning sensation and contact dermatitis (clotrimazole)
v Irritation (econazole, fluconazole)
v No significant corneal toxicity (ketoconazole)
v Blurred vision on instillation
v Ocular discomfort
v Hyperemia and dry eye (itraconazole)
v Photophobia and changes in color vision (transient) (posaconazole and voriconazole)
Medical Therapy

Azoles
Voriconazole
v Broad spectrum with good activity against Candida and Aspergillus and good to moderate
activity against Fusarium species
v It is less effective against Fusarium solani isolates
v 1% eye drops were found to have strong tissue penetration
v Unlike some triazole antifungals (e.g., itraconazole and ketoconazole), it is orally available
v Topical 1-2%
v Oral administration 200 – 400 mg/day
v Intrastromal administration 5mg/ml
v Intracameral administration 50mg/0.1ml
Toxicity
Characteristics
v Nausea
v Photosensitivity
v Hallucinations
v Headache
v Visual disturbances
v Rash
Medical Therapy
„Cornea. Fundamentals, Diagnosis and management – Fourth Edition“, Mark J. Mannis, Edward J. Holland (2017)

Azoles
Fluconazole
v Oral administration presents a good ocular penetration.
v It is less effective against Fusarium solani isolates
v Topical administration (0.2 -2%) presents a good corneal penetration
v Broad spectrum with activity against Candida species
v It has limited or no activity against Fusarium or Aspergillus species
Toxicity
Characteristics
v Headache
v Hives
v Itching or skinrash
v Abdominal pain
v Hematemesis
Medical Therapy

Azoles
Ketoconazole
v Good to moderate activity against Candida species, but has limited activity against
Aspergillus or Fusarium species
v Topical administration 1-2%
Itraconazol
v Moderate activity against Candida and Aspergillus species
v Can be used for long-term maintenance treatment of chronic fungal infections
v Has poor ocular penetration
Medical Therapy

Pyrimidines
Flucytosine (5-fluorocytosine)
affect the fungal DNA preventing cellular replication
v It has a great activity against yeasts such as Candida spp., Cryptococcus spp. and a variable
susceptibility against Aspergillus spp. (1)
v It shows resistance to many other etiological agents that cause fungal keratitis such as Fusarium
spp., where it is topically applied (10–15 mg/ml) in combination with amphotericin due to their
synergistic effects (2,3)
1. Gubert Müller, G., Kara-José, N., Silvestre de Castro, R. 2013. Antifungals in eye infections: Drugs and routes of administration. Rev. Bras Oftalmol. 72: 132–141
2. Ganegoda, N., Rao, S.K. 2004. Antifungal therapy for keratomycoses. Expert. Opin. Pharmaco. 5(4): 865–874
3. Thomas, P.A., Kaliamurthy, J. 2013a. Mycotic keratitis: epidemiology, diagnosis and management. Clin. Microbiol. Infec. 19(3): 210–220
Medical Therapy

Other antifungals
Povidone - Iodine
v In several cases, 2.3% povidone-iodine solution was successfully used on the fungal keratitis
treatment caused by Candida albicans and Acremonium strictum (1)
v Nevertheless, a comparative study by using 0.5% povidone-iodine solution showed no benefit
compared to 5% natamycin suspension in the Fusarium solani keratitis treatment (2)
Polyhexamethylene Biguanide (PHMB)
v Antimicrobial efficacy has been demonstrated on Acanthamoeba polyphaga, A. castellanii, and A.
hatchetti by using 0.02 to 0.053% solutions without causing side effects (3)
1. Ndoye Roth, P.A., Ba, E.A., Wane, A.M., De Meideros, M., Dieng, M., Ka, A., Sow, M.N., Ndiaye, M.R., Wade, A. 2006. Fungal keratitis in an intertropical area: diagnosis and treatment problems. Advantage of local use of polyvidone
iodine. J. Fr. Ophthalmol. 29(8
2. Gubert Müller, G., Kara-José, N., Silvestre de Castro, R. 2013. Antifungals in eye infections: Drugs and routes of administration. Rev. Bras Oftalmol. 72: 132–141
3. Asiedu-Gyekye, I.J., Mahmood, A.S., Awortwe, C., Nyarko, A.K. 2015. Toxicological assessment of polyhexamethylene biguanide for water treatment. Interdiscip. Toxicol. 8(4): 193–202
Medical Therapy

Medical Therapy
Suppress the inflammation by interfering with the normal immunologic response to various stimuli
Corticosteroids
Ø Advantages of steroid use in ocular disease include inhibition of
- cellular infiltration
- opacification
- scarring
- release of toxic enzymes
- neovascularization
- can be beneficial in patients after keratoplasty (as a prevent in graft rejection)
Ø Disadvantages include
- penetration to deeper layers
- reduce antifungal agents' effectiveness (natamycin, flucytosine and miconazole)

Medical Therapy
Systemic antifungals
v Indications
- very large ulcers
- severe deep keratitis
- scleritis
- endophthalmitis
- prophylactic after penetrating
keratoplasty for fungal keratitis
Note:
o The most frequently used oral anti-fungal is
ketoconazole, which is given in the dose of
600 mg per day
o It is mandatory to assess liver function
tests every 2 weeks after starting
ketoconazole.
o Systemic therapy is given for a period of 6
to 8 weeks

Medical Therapy
Presence of Hyphae
Epithelial Debridement
+
1st Choice
– Natamycin 5%
2nd Choice
– Voriconazole 1%
– Chlorhexidine 0.2%
Presence of yeast-like Fungi
+
1st Choice
– Amphotericin B 0.15 – 0.25%
2nd Choice
– Voriconazole 1%
Good Response
o Continue treatment during
6-12 weeks
Poor Response
o Check antifungigram
o Combined treatment
– Natamycin 5% + Chlorhexidine 0.2%
o Intrastromal/intracameral injection
o Systemic treatment
Poor Response
o Check antifungigram
o Intrastromal/intracameral injection
o Systemic treatment
Algorithm to therapeutic management of fungal keratitis

Medical Therapy
Response to therapy
Clinical signs of improvement
v Diminution of pain
v Decrease in size of infiltrate
v Desappearance of satellite lesions
v Rounding out of the feathery margins of the ulcers and hyperplastic masses/fibrosis sheets

Medical Therapy
Resolution of fungal keratitis on topical (Natamycin) therapy

Surgical Therapy

Surgical Therapy
v Improves drug penetration
v May be repeated within 24-48 hours in some cases
v Is an excellent procedure for removing necrotic tissue from the cornea
v Increases drug topical efficacy
Amniotic membrane transplant
v Reduces pain/inflammation/neovascularization
v Stimulates re-epithelialization
v Minimizes scaring

Surgical Therapy
Conjunctival Flap transposition
v Corneal thinning with risk of perforation
v Peripheral ulceration refractory to drug
treatment
v Unavailability of donor corneal tissue or
antifungal medication
Indications
Gundersen Technique
v Conjunctival flap covers the entire cornea
Conjunctival flap transposition in mycotic
keratitis treatment.

Surgical Therapy
Keratoplasty
ØIndications
- Infection spreading to the limbus and sclera
- Risk of endophthalmitis
- Worsening the prognosis (perforation or deep keratitis)
- To preserve the eyeball integrity
ØKey points
- Trepanation at 1–1.5 mm from the affected area
- The risk of rejection is higher when grafts larger than 8 mm are needed
- Interrupted sutures should be used
- Topical antifungal treatment should be maintained during the post-operative period
- Systemic treatment is also recommended
- Steroids use in these patients is controversial

Surgical Therapy

Surgical Therapy
Cross – linking, CXL
v CXL has been proposed as an adjutant treatment for infectious keratitis with poor response and has
been named as Photo Activated Chromophore for keratitis: ‘PACK-CXL’
v This procedure aims to reduce the infective load by destroying microorganism's DNA and RNA through
photo-oxidation
v In other studies, the response to CXL in fungal keratitis was variable
v It should be considered as an adjutant treatment in the early stages of infection
v The depth of the infiltrate should not be deeper than 250 µm depth

Surgical Therapy
Targeted drug delivery (TDD)
v TDD achieves better drug concentration at the affected site and can achieve better outcomes
Advantages
o Easy to reconstitute, administer and has minimum learning curve
o Provide optimum concentration of drug in the anterior chamber and deep stromal layers in a short
time and can be repeated safely
o Intracameral agents as compared with topical medication have better fungicidal action
Disadvantages
o Intracameral agents can be a potential cause of toxic reactions in anterior chamber, if reconstitution is
not proper
o Intrastromal injections which are given through clear corneal site, predisposes them to seeding
of microbes elsewhere resulting in a new satellite lesion
o Chances of perforation in the anterior chamber remains high if injections are done through a hazy
cornea and deep stroma

Surgical Therapy
Targeted drug delivery
Intrastromal injection
v The drug is injected in 4–5 divided doses around
the abscess to form a deposit of the drug around
the circumference of the lesion to barrage the
entire abscess
v Corneal scrapings should be performed for
standard microbiological investigations prior to
administration of intrastromal antifungal

Surgical Therapy
Targeted drug delivery
Intracameral injection
v Administration should be done in strict aseptic
conditions
v Anterior chamber entry should preferably be done
from infero-temporal site (being most accessible)
v In cases of overlying corneal opacity, AC
entry should be made from other accessible
sites
v AC is entered with a 22–23G needle to facilitate
extrusion of exudates/hypopyon from AC

Therapy
Mycotic Ulcer Treatment Trial I
(MUTT I)
Conclusion: In fungal corneal ulcer cases with filamentous fungal keratitis,
particularly the Fusarium species, patients treated with natamycin had a
better outcome than those treated with voriconazole. The difference in
outcome in other species were not significant. Voriconazole should not be
used as monotherapy in the treatment of Fusarium keratitis

Therapy
Mycotic Ulcer Treatment Trial II
(MUTT II)
Conclusion: The addition of oral voriconazole to topical antifungals does not
provide any therapeutic benefit for advanced filamentous fungal ulcer cases

Fungal Keratitis.pdf

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