A corneal ulcer , or ulcerative/microbial keratitis , is an inflammatory or more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma.

Corneal ulcers occur after corneal trauma with a foreign body (including contact lenses), and with dry eyes or lid disease, which allow microbes to enter the cornea, causing a deep infection and inflammation.

Corneal ulcer is a severe infection of the cornea which, after treatment, can often result in a scar in the region where it was located. If infection is located at or near the center of the cornea, this scar can result in reduced vision.

Corneal ulceration is major cause of monocular blindness in developing countries . A report on the causes of worldwide blindness lists corneal scarring second to cataract as a major cause of blindness and visual disability.

The cornea is an avascular structure continuously washed by a tear film containing microorganisms; normally the tear film and lids are barriers to infection. The lids provide a physical defense against microorganisms, and tears provide lubrication to wash away organisms. Tears also contain antimicrobial agents including lymphocytes, immunoglobulins, lysozyme, lactoferrin, betalysins, ceruloplasmin, and complement components.

The intact corneal epithelium is normally an effective barrier against microbial invasion; thus, the majority of infectious ulcers require a mechanical or chemical disruption of this barrier.

The most common causative agents in the etiology of corneal ulcers can be listed as

• Bacteria
• Nocardia
• Protozoa ( Acanthamoeba )
• Fungi
• Virus

In this article we concentrate on the keratitis and corneal ulcerations of fungal origin .

Infective keratitis is an important cause of corneal blindness and fungal keratitis is a major subgroup accounting for around 30% of all cases. Fungal keratitis remains a diagnostic and therapeutic challenge to the ophthalmologist and is associated with significant ocular morbidity.

Fungi are opportunistic in the eye, since they rarely infect healthy, intact ocular tissues. Even the trivial trauma of a dust particle falling on the cornea may disrupt the integrity of the corneal epithelium, predisposing to mycotic infection. In a com-promised or immunosuppressed individual, serious sight-threatening ulceration of the cornea or keratitis may be mostly of fungal origin.

Ulceration can be defined as a loss of corneal epithelium with underlying stromal infiltration and suppuration associated with or without hypopyon.

Fungal organisms can extend from the cornea into the sclera and intraocular structures. Fungi can cause severe infections, such as scleritis, endophthalmitis, or panophthalmitis. These infections are usually very difficult to treat and may result in severe visual loss or even loss of the eye

• Filamentous fungi form the major etiologic agents of fungal keratitis. Fusarium species (37–62%) and Aspergillus species (24–30%) have been implicated as main pathogens.
• Dematiaceous fungi are the cause of 8 to 16.7% of cases of fungal keratitis. Most filamentous fungi associated with corneal ulceration in the tropics are found widely within the environment.
• Chang et al. [from Taiwan have reported that Fusarium species are common plant pathogens, particularly in corn crops or onion fields.
• Yeast can also cause keratitis. Gopinathan et al from India have reported Candida as a rare fungal corneal pathogen (0.7%).
• In a series of 24 patients from Wills Eye Hospital , Philadelphia , Candida was identified in 45.8% of cases of fungal keratitis; this probably represents
• the only study reporting Candida as the commonest etiologic agent of fungal keratitis
• Unlike the experience of bacterial keratitis, for the past two decades the spectrum of fungal pathogens causing fungal keratitis has not changed significantly

Fungal keratitis is a leading cause of ocular morbidity; one report from South India found that 44% of all central corneal ulcers are caused by fungi.An overwhelming number of fungal genera and species have been implicated as causes of corneal ulcers, and this number is steadily increasing.

According to a study carried out at Aravind Eye Hospital ( South India) , it was observed that 47% of fungal corneal ulcers were caused by Fusarium spp, followed by 16% Aspergillus spp., while north India the prevalence of Aspergillus spp was in 40.8% of the cases while that of Fusarium spp was 12.5% , with the incidence being greater in men 68% , than in women.

Keratitis caused by Candida is extremely rare in India .

(1) Fusarium

Species of Fusarium are widespread saprobic fungi that cause important diseases of plants, particularly major crop plants , and of humans, particularly immunocompromised patients. They have long been regarded as important pathogens in eye infections, especially corneal ulcers.

(2) Aspergillus

Aspergillu s spp. abounds in the environment worldwide, thriving on a variety of substrates such as corn, decaying vegetation, and soil. These fungi are also common contaminants in hospital air and have been implicated in a recent outbreak of endophthalmitis following cataract

(3) Candida

Most episodes of yeast infections in corneal ulcers and other ocular infections are due to various Candida species , predominantly Candida albicans , and usually occur in the presence of systemic illness (diabetes mellitus or immunocompromise) or ocular disease (lid abnormalities or dry eyes) or in patients receiving prolonged topical medications or topical corticosteroids

Bharathi et al. reported a large series of fungal ulcers (1095) occurring in South India.In this study, male patients were affected more commonly than female patients. Approximately 65% of patients were in the age group of 21 to 50 years.

Risk factors for fungal keratitis include:

(a) Farming: Occupational risk factor :

Corneal ulceration was seen more in males than females, predominantly in farmers (55-65%) and trauma was the commonest predisposing factor, the agents being mainly organic agricultural materials. The incidence of fungal keratitis was higher during paddy harvesting and also during the time of year when agriculture activity was greater. In our study it was more prevalent during June through September. The peak incidence correlates with windy and dry weather during the month of June through September. In coastal Karnataka, higher incidence is reported in October, June and January and in Hyderabad , higher incidence of fungal keratitis is reported during the winter (October to January) and monsoon (June to September) seasons. A hot, humid, windy climate and an agriculture-based occupation of a large population make fungal keratitis more frequent in tropical zones.

(b) Previous history of microtrauma to the corneal epithelium

(c) Antecedent topical corticosteroid therapy.

Incidence of fungal keratitis has increased over the past 30 years. This increased occurrence of fungal keratitis is a result of the frequent use of topical corticosteroids and antibacterial agents in treating patients with keratitis, the rise in the number of patients who are immunocompromised, and better laboratory diagnostic techniques that aid in its diagnosis.

Polymorphonuclear leukocytes are known to be pivotal in preventing fungal infections since they phagocytize and subsequently destroy fungal structures by oxygen-dependent mechanisms; the presence of disease or the use of corticosteroids, tetracycline, doxycycline, or certain other drugs may interfere with these mechanisms and hence lower the host resistance to fungal infection or predispose the individual to fungal corneal ulcers

Polymorphonuclear leukocytes are known to be pivotal in preventing fungal infections since they phagocytize and subsequently destroy fungal structures by oxygen-dependent mechanisms; the presence of disease or the use of corticosteroids, tetracycline, doxycycline, or certain other drugs may interfere with these mechanisms and hence lower the host resistance to fungal infection or predispose the individual to fungal corneal ulcers

(d) Pre-existing ocular or systemic immunosuppressive diseases . Diabetes has also been associated with increased risk of fungal keratitis.

Fungal keratitis also has been described to occur secondary to fungal endophthalmitis. In these cases, fungal organisms extend from the posterior segment through the Descemet membrane and into the corneal stroma.

(e) Contact lenses wearers: Contact lenses are a major risk factor for fungal keratitis . Approximately 29% of those individuals wearing any type of contact lens can get fungal keratitis.

Risk factors to which contact lens wearers are exposed:

• Overnight wear
• Poor lens hy­giene/non-com­pliance
• Smoking;
• Male sex
• Lower socioeconomic status.

It has been reported that upwards of 46 to 57 percent of pa­tients are non-complaint with recommended lens care guidelines.

Contact lens wearers and keratitis: Use of soft contact lenses has been associated with the potential risk of developing microbial keratitis. Common organisms associated in these infections are bacteria, such as Pseudomonas aeruginosa and Staphylococci aureus . Previous reports on microbial keratitis have reported low prevalence of fungal keratitis associated with soft contact lens wear .

Given that the popularity of contact lens wear has exploded in the last 30 years—from approximately 5 million wearers in the United States in 1970 to 33 million wearers in 2000—it is not surprising that the frequency of contact lens-related corneal ulceration has been increasing

The responsible organism in these cases has been Fusarium solani and most of the cases have involved individuals wearing their lenses extended wear.

Thus, there has been a changing trend in the number of non-therapeutic soft contact lens–related ulcerative keratitis due to fungi.  

As of February, 2006, 39 cases of fungal keratitis (all Fusarium ) were reported with contact lens wearers in Singapore over a 10 month period. As of April 27th, 2006, the Center for Disease Control (CDC) in Atlanta is investigating 228 reports of possible Fusarium keratitis in 29 states. Of these reports, CDC and state/local health departments have identified 84 confirmed and possible cases; 98 remain under investigation and 46 have been excluded. The majority of these patients have not yet been interviewed; however, of the first 58 patients who have been contacted, 56 were contact lens wearers

Ocular fungal infections probably occur due to an interaction between various agent (fungus), host (tissue and immunological mechanisms), and other factors.

The key agent factors thought to be involved in pathogenesis of mycotic infections include adherence, invasiveness, morphogenesis, and toxigenicity which are described as below

Invasiveness: Fungi causing keratitis, in particular Fusarium spp., sometimes invade the anterior chamber and form a lens-iris- fungus mass at the pupillary area, thereby interfering with the normal drainage of the aqueous humor and leading to a rise in the intraocular pressure.

Once fungi begin colonization, their virulence determines their ability to proliferate within the stroma and to penetrate into deeper layers beyond the reach of typical diagnostic and therapeutic measures. The hyphae make the organisms large enough to preclude their complete ingestion by the host's inflammatory cells.

Morphogenesis and phenotypic switching permit fungi to adapt to live in different microenvironments and to survive in the infected host This requires the demonstration of fungal toxins and enzymes in situ in fungus infected tissues in humans. Morphological alterations may constitute a barrier against antifungal drugs or host defenses or may be a virulence factor for fungi in corneas where the defense mechanisms have been compromised by the application of corticosteroids.

Toxigenicity: Fusarium spp. are known to cause myelosuppression through toxin production but little is known about whether Fusarium toxins such as nivalenol, and fusaric acid contribute to the pathogenesis of mycotic keratitis

The most common signs on slit lamp examination are nonspecific and include the following:

• Conjunctival injection
• Epithelial defect
• Suppuration
• Stromal infiltration
• Anterior chamber reaction
• Hypopyon is present in almost 60% of cases.

Fungi initially produce a feathery, branching pattern in the cornea. The cornea will appear a dull gray with possible heaping of epithelium and a dry, rough texture. There will typically be a plasmoid aqueous with hypopyon. Later, these features are lost and fungal keratitis begins to resemble advanced bacterial keratitis. Subsequent misdiagnosis is likely. Candida infection is more localized with a "button appearance," an expanding stromal infiltrate and a relatively small epithelial ulceration.

Fungal Keratitis: Clinical Features

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.

• 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 i.e corneal ulceration

Clinical Features of Fungal Ulcers

For several decades, the fungal ulcer has been described as indolent and dry, with a leathery, tough, raised surface .In this author's experience in treating several hundred fungal ulcers, the clinical features do not always correlate with classic textbook descriptions.

• Presenting clinical features that are specific to fungal keratitis include an infiltrate with feathery margins, rough texture, raised borders, brown pigmentation, associated endothelial plaque, and satellite lesions.
• A deep stromal infiltrate with an intact epithelium also may be present.

The early fungal ulcer will appear like a dendritic ulcer of herpes simplex virus origin as shown in figure (a)

Figure (a)

The signs of inflammation will be minimal in comparison with bacterial keratitis. The absence of lid edema is a common feature.

The infiltrates appear grayish-white or yellowishwhite, and the base of the ulcer is often filled with soft,creamy, raised exudates, making it very easy to scrape the material even with a Kimura spatula. Feathery borders or hyphate edges are seen in 70% of patients, and satellite lesions in 10% of patients with fungal keratitis.

Figure (b)

 

Fungal keratitis due to dematiaceous fungi is characterized by : Brown or black pigmentation on the surface of the ulcer , which appears dry, rough, and leathery. It can be difficult to obtain scrapings for culture using a spatula.

Figure (c)

An immune ring with raised surface and hyphate edges ( fig d) and satellite lesions, and posterior corneal abscess( fig e) are seen infrequently as shown below .

Figure. (d)

Figure.(e)

• The laboratory diagnosis of fungal keratitis may be problematic because of the very small sample obtained by scraping the corneal ulcer. Therefore, recent methods for the identification of fungi have been under study and include the following:
• Smears are used to obtain rapid information about the pathogen.

•  Gram stain identifies yeast and

•  Giemsa Staining: Useful in detecting fungal elements.

The routinely used Gram's and Giemsa stains, KOH, and CFW preparation for fungal filaments give reliable and rapid results with a sensitivity of 35-95%.

•  Silver impregnation technique of detecting fungus, which is routinely used in cytology and histopathology practice called as Grocott's Methenamine (GMS).

By using the domestic microwave model, staining time was reduced from the routine 3 hours to 20 minutes without compromising the quality of the staining. The fungal filaments appeared black against the green background facilitating rapid identification under low magnification , in contrast to the variable staining of Gram's or Giemsa stained smears

•  Immunofluorescence staining : if fluorescein microscopy is available, acridine orange and calcofluor white are the stains of choice.

•  Electron microscopy .

•  Confocal microscopy : It is a relatively new, noninvasive technique for imaging the cornea in normal and diseased states

•  The polymerase chain reaction (PCR) technique holds promise as an effective method of diagnosing fungal keratitis because it offers increased sensitivity and significant reduction in the time required to establish a diagnosis.

Although polymerase chain reaction (PCR) and confocal microscopy are being used as new rapid diagnostic methods; they are not available in areas where fungal keratitis is highly prevalent.

•  KOH microscopy

POTASSIUM HYDROXIDE (KOH) WET PREPARATION: A10 % solution of potassium hydroxide is used to visualize fungal elements in corneal scrapes, in a homogenous background of corneal tissue digested by KOH

Clinical Differentiation between most commonly seen bacterial ulcers as compared with fungal corneal ulcers which have been already discussed.

•  Streptococcus pneumoniae , one of the most common causes of microbial keratitis classically forms a deep central ulcer and is associated with a hypopyon. •  Staphylococcus aureus produces an oval, yellow-white and opaque stromal suppuration surrounded by clear stroma. •  Pseudomonas aeruginosa keratitis is often very aggressive and associated with a thick mucopurulent exudate and edema surrounding the ulcer. Perforation (within 48 - 72 hours) is a threat in this infection due to the multitude of enzymes and toxins produced by the organism Moraxella are most commonly found in alcoholic or immune-suppressed patients, these ulcers are found centrally or inferiorly in areas of exposure. The ulcers are often painless but can cause a large hypopyon if allowed to progress.

The symptoms of infectious bacterial ulceration include severe pain, redness, decreased vision, and photophobia. Signs include significant lid edema and reactive ptosis, conjunctival and ciliary injection, discharge, papillary response, stromal infiltration, surrounding tissue edema, epithelial defect, anterior chamber reaction, cellular debris in the tear meniscus, and even hypopyon.

These signs and symptoms are influenced by prior corneal status and therapy, the virulence and pathogenicity of the organisms, the length of the infection, and the host immune response to the infection

Epithelial defects with mucopurulent exudates adherent to the ulcer, focal stromal suppuration, diffuse stromal infiltrates, radiating folds in Descemet's membrane and an anterior chamber reaction with or without a hypopyon are strongly suggestive of bacterial infection

Currently, the commercially available therapy of fungal disease of the eye is unsatisfactory. The antifungal agents available today are mostly fungistatic, requiring a prolonged course of therapy.

Although models of Aspergillus and Candida have been established, there are no reliable animal models of Fusarium keratitis.

Fungi considered to be ocular pathogens are rarely encountered among the systemic mycoses. Thus, the therapeutic principles valid for systemic fungal infections may not apply to the cornea

In treating ophthalmic mycoses, the ultimate aim is to preserve vision, and this depends on rapid diagnosis and efficient administration of appropriate antifungal therapy . There are three main chemical groups of drugs with antifungal activity for use in therapy of ophthalmic mycoses, namely, the polyenes, azoles (imidazoles and triazoles), and flucytosine (5-fluorocytosine).

(a) Polyenes

Polyenes disrupt the cell by binding to fungal cell wall ergosterol and are effective against both filamentous and yeast forms . Polyenes include natamycin and amphotericin B.

(1) Natamycin: It is c onsidered the drug of choice for filamentous fungi

Advantages and features

• Belongs to the Polyene group of antibiotics
• Commercially available as topical 5% suspension for ophthalmic use, where it constitutes the first-line therapy for mycotic keratitis
• Ophthalmic preparation is well tolerated and stable and can be sterilized by heat Relatively high levels reportedly achieved in cornea after topical application

Disadvantages

• Not commercially available as an ophthalmic preparation in many regions.
• Effective only when applied topically. Because of poor penetration, it is effective only in nonsevere superficial keratitis. May not be effective when keratitis is associated with deep stromal lesions
• Only about 2% of the total drug in corneal tissue is bioavailable.
• Natamycin is very costly; the supply is erratic, and it is difficult to obtain in the third world.

(2) Amphotericin B:

• Available as a systemic preparation. To prepare the topical form, the compound is diluted with dextrose or distilled water to arrive at a 0.15 to 0.5% concentration.
• Can also be used through the subconjunctival (10 µg), intracameral (5–7.5 µg), intravitreal (10 µg) and intravenous routes (0.1 mg/kg body weight).
• The penetration of topically applied amphotericin B is poor in cornea with intact epithelium.
• Collagen shields soaked in 0.5% amphotericin B have been found useful in experimental mycotic keratitis Penetrates deep corneal stroma after topical application; bioavailability sufficient for susceptible fungi Exerts direct fungicidal effect and exhibits immunoadjuvant properties
• Good in vitro activity against Aspergillus spp. and Candida spp.; emergence of resistant mutants rare .

Amphotericin B is the drug of choice to treat patients with fungal keratitis caused by yeasts.

Disadvantages

• Subconjunctival injection causes marked tissue necrosis at the site of injection Topical application of concn >5.0 mg/ml may cause ocular irritation (solutions of 1.5-3.0 mg/ml are better tolerated)
• Not commercially available as topical ophthalmic preparation; needs to be reconstituted from powder or intravenous preparation.
• Poor intraocular penetration after intravenous administration.
• It is not effective against Fusarium species

(b) Azoles: The azole compounds include amidazoles and triazoles .

e.g ketoconazole, miconazole, fluconazole, itraconazole, econazole, and clotrimazole and voriconazole , posoconazole.

Azoles inhibit ergosterol synthesis at low concentrations, and, at higher concentrations, they appear to cause direct damage to cell walls.

Triazole :

(1) Econazole

Econazole 1% in arachis oil is available as an ophthalmic preparation . Prajna et al h ave found that the effect of this drug is equal to that of natamycin against filamentous fungi.

(2) Clotrimazole

Clotrimazole is also available as a 1% topical preparation as drops and in ointment form. Mselle treated 12 patients with proven fungal keratitis with clotrimazole but suggested that clotrimazole as monotherapy is not an ideal choice.

(3) Posoconazole

Posaconazole is a triazole antifungal agent available as a suspension for oral administration. Fungistatic against Candida and fungicidal against Asperigillus species. Similar structure to Itraconazole, absorbtion greatly affected by food.

(c) Imidazoles

Whereas the imidazoles, miconazole and ketoconazole,have less systemic toxicity, they are inferior to amphotericin B.Because of relatively reduced systemic toxicity and better corneal penetration, these compounds can be used systemically for keratomycosis.

Thomas et al. over a period of 10 years (1984–1994) treated 330 cultured-proved fungal keratitis cases with ketoconazole, itraconazole, amphotericin B, and natamycin and found that

• 69% of patients responded to ketoconazole,
• 66% to itraconazole,
• 53% to amphotericin B,
• 56% to natamycin.

(1) Flucanazole

Fluconazole has been shown to penetrate better into the cornea after systemic administration compared to other azoles and may be associated with fewer adverse effects.

Oral fluconazole and ketoconazole are absorbed systemically with good levels in the anterior chamber and the cornea; therefore, they should be considered in the management of deep fungal keratitis..

An oral antifungal (eg, ketoconazole, fluconazole) should be considered for patients with deep stromal infection. Antifungal therapy usually is maintained for 12 weeks, and patients are monitored closely.

(2) Voriconazole: Newest agent on the horizon with broadest spectrum of activity

A new azole antifungal agent, voriconazole, is a second-generation synthetic derivative of fluconazole which shows a broader spectrum of activity against Candida, Aspergillus , Scedosporium, Fusarium and Paecilomyces.

Reports of topical and oral voriconazole have illustrated its efficacy in the management of fungal keratitis caused by Candida.

Jeu et al. described the mechanism of action. As with other triazole antifungal agents, voriconazole exerts its effect primarily through inhibition of cytochrome P450–dependent 14-alpha demethylase, an enzyme responsible for the conversion of lanosterol to 14 alpha emethyl lanosterol in the ergosterol biosynthetic pathway .

80% of this drug is hepatically eliminated.

Reports of topical and oral voriconazole have illustrated its efficacy in the management of fungal keratitis caused by Candida, Fusarium, Alternaria, Scedosporium that was refractory to standard antifungal agents but responded to voriconazole treatment.

It has also been effective for the treatment of Aspergillus fumigatus scleritis and epibulbar abscess resulting from scleral buckle infection.

Intravitreal voriconazole has been used for drug-resistant fungal endophthalmitis.

A recent report has compared the minimum inhibitory concentration (MIC) of natamycin, amphotericin, and voriconazole against Aspergillus species isolated from keratitis.

MIC of natamycin was 32 µg/ml, MIC of amphotericin B was 2-4 µg/ml, and that of voriconazole was the lowest 0.25-0.5 µg/ml. It is to be noted that effectiveness of antifungal agents depends on the concentration of drug achieved locally; in practice, the topical antifungals are given at different concentrations - amphotericin B because of toxicity is prescribed at 0.15%, voriconazole at 1% and natamycin at 5%.

The minimal inhibitory concentration of voriconazole for Scedosporium apiospermum is 0.5 µg/mL, a concentration lower than that of the other imidazoles

For optimum intraocular drug concentration, both oral and topical administration of voriconazole is recommended.

Preparation of Voriconazole Eye Drops: In house pharmacy

Voriconazole eye drops are prepared by reconstituting lyophilized powder used for parenteral administration (Vfend 200 mg, Pfizer) with 19-ml sterile water for injection to obtain 20 ml of 1% solution and are administered every hour round the clock initially, they were then gradually tapered as the infection resolves Voriconazole eye drops are required to be prepared every alternate day, stability of the solution could be extended up to 48 h between 2°C and 8°C, according to the manufacturer.

Epithelial debridement may not be necessary for voriconazole penetration, because voriconazole is a small, lipophilic molecule.

Adverse effects of systemic use include visual disturbances such as enhanced light perception, color vision changes, visual blurring, skin rash, and hepatotoxicity, which are all transient in nature; on topical application, ocular burning has been reported.

The duration of treatment depends on severity of keratitis and individual clinical response; it has been used for upto 4 months.
Because of its broad spectrum of coverage, good tolerability, and excellent bioavailability with oral administration, voriconazole may be a good alternative against fungi-resistant to standard antifungal agents; however, the expenditure involved in voriconazole treatment will pose a constraint in its more frequent usage.

Other management modalities

Fluorinated pyrimidines, such as flucytosine , are other antifungal agents. Flucytosine is converted into a thymidine analog that blocks fungal thymidine synthesis. It usually is administered in combination with an azole or amphotericin B.

Treatment should be instituted promptly with topical fortified antifungal drops, initially every hour during the day and every 2 hours over night.

Subconjunctival injections may be used in patients with severe keratitis or keratoscleritis. They also can be used when poor patient compliance exists.

In vitro antifungal sensitivities often are performed to assess resistance patterns of the fungal isolate. However, in vitro susceptibility testing may not correspond with in vivo clinical response because of host factors, corneal penetration of the antifungal, and difficulty in standardization of antifungal sensitivities. Therefore, they should be performed in a standardized method at a reference laboratory.

Note:

Frequent topical application of drops is a useful means of achieving therapeutic levels in the eye, but this is laborious and may cause irritation. Ointments and subconjunctival injections may prolong the contact time between the antifungal and the corneal and conjunctival tissue. Only amphotericin B and miconazole are available as ophthalmic ointments. Subconjunctival injections can be painful for the patient and inconvenient for the physician.

Surgical therapy

The use of N -butyl cyanoacrylate tissue adhesive in the management of corneal thinning or perforation associated with active fungal keratitis has been reported In a study of 73 patients, 63% showed resolution of infiltration with scar formation. •  Xie et al. ] have tried lamellar keratoplasty. •  Amniotic membrane transplantation (AMT) promotes healing and reduces inflammation in suppurative keratitis. •  AMT is effective in promoting epithelialization and preventing corneal perforations in acute fungal keratitis, and there is no risk of rejection. However, the risk of persistent or recurrent infection necessitates continued antifungal treatment and patient monitoring. •  Structural integrity and eradication of sepsis is achieved in 80 to 90% of eyes and graft clarity in 36 to 89%

Surgical therapy may be required not only for complications of acute infectious processes, but also because medical management may fail.

Debridement

Debridement is the simplest form of surgical intervention. The organisms and necrotizing material is removed and the penetration of antifungal medications is enhanced by the removal of the epithelium, which is a barrier for the topical anti-fungals. Debridement should be performed every 24 to 48 hours.

Biopsy

A biopsy is indicated for the direction of diagnostic and/or therapeutic treatment.

Conjuntival Flaps

Conjunctival flaps have been advocated for non-healing ulcers and are often effective, although fungal organisms have been found to persist under a conjunctival flap.

Lamellar keratoplasty

Lamellar keratoplasty may be ineffective in treating fungal keratitis. Because of the inability to remove the infectious agent. If the area of infection can be completely encompassed by the penetrating graft, and if there has been an inadequate response to medical treatment, the corneal graft may be an effective cure.

Penetrating keratoplasty

An Ideal method to treat non-healing fungal keratitis threatening perforation.

Because of the difficulty of accurately diagnosing fungal keratitis, many patients from rural areas had a long duration of disease and severe corneal infection including corneal perforation by the time that they were referred to our hospital.

Very little information has been published regarding the treatment of advanced fungal infection of the cornea in such patients and some ophthalmologists only perform penetrating keratoplasty (PKP) as a last resort

A study published described the following procedure for penetrating keratoplasty.

For routine PKP donor tissue should have a diameter of 0.25 mm larger than the diameter of the recipient graft site. In general, if the recipient site is greater than 8 mm, the donor graft should be 0.50 mm larger.

For removal of the diseased cornea, the trephine should be 0.25 mm larger in diameter than the area of infection. After removal of the diseased cornea, the anterior chamber angle and iris surface were carefully irrigated with 0.2% fluconazole and the hypopyon and fibrous membrane was carefully removed.

If bleeding occurred, Healon was used to coat the injury and cautery can be used to close ruptured blood vessels if necessary. Peripheral iridectomies were not performed in these patients because in our past experience we have encountered bleeding into the anterior chamber caused by irises with vascularisation and, on occasion, the development of an infiltrative membrane to cover the iridectomy's hole, leading to glaucoma. When necessary, 250 ml of 20% mannitol containing 10 mg of dexamethasone was given intravenously once or twice after PKP to lower intraocular pressure and suppress the development of intraocular inflammation.

Thirty patients were treated with this corticosteroid regimen postoperatively in this study. Corneal grafts were secured in place with 16 interrupted 10–0 nylon sutures. Immediately after surgery 2x10 4 units of gentamicin and 1mg of fluconazole were injected subconjunctivally. Fluconazole was given orally beginning the day before surgery and for 21 days thereafter. Liver function was monitored by serum liver enzyme analysis. Fluconazole was given subconjunctivally once daily for 3 days after surgery. In addition, fluconazole or amphotericin B ointment was applied to the grafts immediately before sleep.

Five days after corneal grafting 1% fluconazole eye drops were used four times daily. All antifungal agents were tapered so that treatment was discontinued between 20 and 30 days after surgery. Atropine ointment was used in all cases with hypopyon. Corticosteroid was not used in the immediate postoperative period unless there was significant inflammation before surgery.

Systemic and topical steroids and topical 1% cyclosporine A were given beginning 2 weeks after PKP if the fungal infection did not recur.

Recurrent fungal infection can be particularly difficult to treat. Following PKP both systemic and topical antifungal agents must be used.

Conclusion

If the infection does not respond to chemotherapy PKP should be considered as an alternative. The results of this study suggest that PKP is an effective method not only to cure fungal keratitis, but also to rehabilitate useful vision if the surgery is performed soon enough to preserve the eye.

Precautions to be taken post surgery

Corticosteroid drops should not be used until after 2 weeks of antifungal treatment and clear clinical evidence of infection control. Steroids should only be used when the active inflammation is believed to be causing significant damage to the structure of the cornea and/or vision. The steroid is always used in conjunction with the topical antifungal.

Table 1: Differential Medical Therapy for Fungal Keratitis

YEASTS	FUNGI
First Choice:	First Choice:
Amphotericin B 0.15% &  Flucytosine (1% + 150 mg/kg PO )	Natamycin 5%
Alternative Choice:	Alternative Choice:
Fluconazole (0.5% = 200 mg PO ) & Miconazole 1%	Amphotericin B 0.15% & Flucytosine Itraconazole (1% cream + 200-400 mg PO ) & silver sulfadiazine
Voriconazole 1%	Voriconazole 1%

All topical medications are delivered hourly around the clock.
(Adapted from Abad JC, Foster CS. Fungal keratitis. Int Ophthalmol Clin 1996;36(3):1-15.)

Fungal keratitis is responsible for a significant burden of blinding disease in the developing world. Current treatment methods frequently fail to preserve or restore vision after fungal keratitis. Although emerging antifungal agents show promise, therapeutic gaps will probably persist, and further development is necessary. Priorities should be given to develop and undertake drug trials against filamentous fungal keratitis.

1. Always wash your hands before handling contact lenses.
2. Carefully and regularly clean contact lenses.
3. Store lenses in clean and proper case. Replace case every 3 months.
4. Use only cleaning products recommended by your optometrist.
5. Never re-use old solution.
6. Replace contact lenses as prescribed by

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