Fungal Keratitis

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Background

Fungal keratitis was first described by Leber in 1879. This entity is a very common cause of corneal infection in developing countries, although it is not common in Western countries. If not diagnosed and treated promptly and effectively, significant damage can occur.



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Fungal corneal ulcer.



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Fungal ulcer in an elderly woman.



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Fungal keratitis.



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Fungal infection.



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Fungal infection.



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Fungal ulcer.



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Fungal corneal ulcer, with excessive vascularization.

Keratitis is a general term meaning any inflammation of the cornea. The term fungal keratitis refers to a corneal infection caused by fungi. One type of fungus that can infect the cornea is Fusarium. When Fusarium infects the cornea, the eye disease is referred to as Fusarium keratitis.

The early stage of fungal keratitis remains a diagnostic and therapeutic challenge to the ophthalmologist. There is difficulty in establishing the clinical diagnosis, isolating the etiologic fungal organism in the laboratory, and treating the keratitis effectively with topical antifungal agents. Unfortunately, delayed diagnosis is common, primarily because of lack of suspicion. When a diagnosis has been made, management remains a challenge because of the poor corneal penetration of antifungal agents.

The 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 along with antibacterial agents in treating patients with keratitis. With better laboratory facilities, the awareness about fungal keratitis has increased.

Classification

Of the 70 different fungi that have been implicated as causing fungal keratitis, the 2 medically important groups responsible for corneal infection are yeast and filamentous fungi (septate and nonseptate).

Yeast produces characteristic creamy, opaque, pasty colonies on the surface of culture media. Candida is the most representative pathogen in this group, primarily affecting those corneas already compromised by topical steroids, surface pathology, or both.

A feathery or powdery growth on the surface of culture media is produced by septate filamentary fungi, which are the most common cause of fungal keratitis.

Fluid movement in the cornea

For the past 15 years, the author (Singh) has been studying the possibility of fluid channels existing in the cornea. Some of the observations are summarized below.

The channels in the cornea are normally invisible. However, if it becomes semiopaque for some reason, the channels tend to stand out.

The question arises as to where the corneal network of channels ends. It joins a peripheral circular corneal channel, which is present in every eye, but becomes visible as a transparent line in all cases of arcus senilis. It is the “lucid interval,” which actually is a canal, the canal of Singh. The corneal network joins canal of Singh in multiple layers all around the limbus.

If cases of arcus senilis are studied regularly with optical coherence tomography, the Singh canal and Schlemm canal will be visualized as being connected through ”aqueducts.” The corneal channel structure helps to understand and explain many observations in corneal infections.

Pathophysiology

Many fungal organisms associated with ocular infections are ubiquitous, saprophytic organisms and have been reported as causes of infection only in the ophthalmic literature. Fungal isolates have been classified into the following groups: Moniliaceae (nonpigmented filamentary fungi, including Fusarium and Aspergillus species), Dematiaceae (pigmented filamentary fungi, including Curvularia and Lasiodiplodia species), and yeasts (including Candida species).

Fungi gain access into the corneal stroma through a defect in the epithelium, then multiply and cause tissue necrosis and an inflammatory reaction. The epithelial defect usually results from trauma (eg, contact lens wear, foreign material, prior corneal surgery). The organisms can penetrate an intact Descemet membrane and gain access into the anterior chamber or the posterior segment. Mycotoxins and proteolytic enzymes augment the tissue damage.

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. Another possibility is entry through corneoscleral trabeculae in to the many channels in the cornea that exist as a network.

In the advanced countries of the West, fungi are not a common cause of microbial keratitis. However, in the developing countries, fungal infections are extremely common. Farm injuries are the most important cause. Fungi cannot penetrate the intact corneal epithelium. They need a penetrating injury or a previous epithelial defect to enter the cornea. Once within the cornea, however, they are able to proliferate and spread through the corneal channels.

Organisms that infect preexisting epithelial defects belong to the normal microflora of the conjunctiva and adnexa. The most common pathogen that invades a preexisting epithelial defect is Candida. Filamentous fungi are the principal causes of posttraumatic infection. The intrinsic virulence of fungi depends on the fungal substances produced and the host response generated.

Filamentous fungi proliferate within the corneal stroma without release of chemotactic substances, thereby delaying the host immune/inflammatory response. In contrast, Candidaalbicans produces phospholipase A and lysophospholipase on the surface of blastospores, facilitating the entrance to the tissue. Fusariumsolani, which is a virulent fungus, is able (as are other filamentous fungi), to spread within the corneal stroma and penetrate the Descemet membrane.

Corneal trauma is the most frequent and major risk factor for fungal keratitis. In fact, the physician should have a high level of suspicion in a patient with a history of corneal trauma, particularly with plant or soil matter.

The trauma that accompanies contact lens wear is miniscule; contact lenses are not a common risk factor of fungal keratitis. Candida is the principal cause of keratitis associated with therapeutic contact lenses, and filamentous fungi are associated with refractive contact lens wear. Photorefractive keratectomy and laser in-situ keratomileusis (LASIK) cases, on a rare occasion, can develop fungal infection, which may result in severe damage to the cornea, even loss of an eye. Infections may develop in a series of patients if an infected fluid is used in a number of patients at one session.

Topical steroid use has definitively been implicated as a cause of increased incidence, development, and worsening of fungal keratitis. Other risk factors to consider are foreign bodies, and immunosuppressive diseases.

Epidemiology

Frequency

United States

The incidence of fungal keratitis varies according to geographical location and ranges from 2% of keratitis cases in New York to 35% in warm weather Florida. Fusarium species are the most common cause of fungal corneal infection in the southern United States (45-76% of fungal keratitis), while Candida and Aspergillus species are more common in northern states.

In a large series of fungal keratitis from south Florida, Rosa et al reported that Fusarium oxysporum was the most common isolate (37%), followed by, in order of decreasing frequency, Fusarium solani (24%), Candida, Curvularia, and Aspergillus species.[1]

Fusarium species are commonly found in soil, in water, and on plants throughout the world, particularly in warmer climates. Past studies of Fusarium keratitis have found that most incidences of Fusarium keratitis have been caused by an eye injury with vegetative matter (eg, being hit in the eye with a palm branch).

An estimated 30 million persons in the United States wear soft contact lenses. The annual incidence of microbial keratitis is estimated to be 4-21 per 10,000 soft contact lens users, depending on whether users wear lenses overnight.

A number of individuals have contracted Fusarium keratitis from contact lens wear, especially through the use of the Bausch & Lomb ReNu with Moisture Lock contact lens solution. This number is generally very small, particularly in the northern part of the United States.

On March 8, 2006, the Centers for Disease Control and Prevention (CDC) received a report from an ophthalmologist in New Jersey regarding 3 patients with contact lens-associated Fusarium keratitis during recent months. Initial contact with several corneal disease specialty centers in the United States revealed that other centers also had seen recent increases in Fusarium keratitis.

The CDC began an investigation of the Fusarium keratitis outbreak. There were 130 confirmed cases of Fusarium keratitis. Over 60% of people with confirmed Fusarium keratitis had used Bausch & Lomb ReNu with Moisture Lock contact lens solution, and 37 of these cases resulted in cornea transplant surgery.

The US Food and Drug Administration (FDA) recalled Bausch & Lomb ReNu with Moisture Lock contact lens solution.

According to Bausch & Lomb, "unique characteristics of the formulation of the ReNu with Moisture Lock product in certain unusual circumstances can increase the risk of Fusarium infection."

International

Aspergillus species is the most common isolate in fungal keratitis worldwide. Large series of fungal keratitis from India report that Aspergillus species is the most common isolate (27-64%), followed by Fusarium (6-32%) and Penicillium (2-29%) species.

Mortality/Morbidity

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.

Sex

Fungal keratitis is more common in males than in females and often occurs in patients with a history of outdoor ocular trauma.

Prognosis

Prognosis depends on several factors, including the extent of corneal involvement upon presentation, the patient's health status (eg, immunocompromised), and the timing of establishing a clinical diagnosis confirmed by culture in the laboratory.

Patients with mild infections and an early microbiologic diagnosis have a good prognosis; however, controlling or eradicating an infection that spreads into the sclera or the intraocular structures is very difficult.

Approximately one third of fungal infections result in either medical treatment failure or corneal perforation.

Patient Education

Patients who wear contact lenses should consult their eye care professional concerning use of an appropriate cleaning/disinfecting product. (Patients should discontinue use of Bausch & Lomb ReNu with Moisture Lock contact lens solution.)

Patients should consider performing a “rub and rinse” lens cleaning method, rather than a no rub method, regardless of which cleaning/disinfecting solution used, in order to minimize the number of germs and to reduce the chances of infection.

Patients should continue to follow proper lens care practices. Wash their hands with soap and water and dry (lint-free method) them before handling lenses. Wear and replace lenses according to the schedule prescribed by their eye care professional. Follow the specific lens cleaning and storage guidelines from their eye care professional and the solution manufacturer. Keep the contact lens case clean and replace every 3-6 months.

Patients should remove the lenses and consult their eye care professional immediately if they experience symptoms, such as redness, pain, tearing, increased light sensitivity, blurry vision, discharge, or swelling.

History

A history of outdoor eye trauma often is reported.

In patients presenting with possible fungal keratitis, inquire about possible risk factors (see Causes).

Symptoms include the following:

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:

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.

Although these highly characteristic signs may be present, obtaining a sample of the lesion by scraping or corneal biopsy is important before initiating treatment with antifungal therapy (see Procedures). 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.

Causes

Aspergillus is the most common cause of fungal keratitis worldwide. However, the epidemiology of fungal keratitis is climate specific. In the southern United States, Fusarium species are the most common cause of fungal keratitis, with an especially high incidence in Florida. In contrast, Candida and Aspergillus species are the most common pathogens in the northern United States.

Common risk factors for the development of fungal keratitis include the following:

Risk factors for Candida keratitis are as follows:

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.

Corneal perforation is not unusual, and secondary endophthalmitis has been reported.



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Perforated fungal ulcer.



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Perforated fungal corneal ulcer.



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Corneal perforation, blocked by a crystalline lens and being covered by epithelium.

Laboratory Studies

The diagnosis of fungal keratitis continues to be problematic. Many clinical characteristics are not specific to fungal ulcers; therefore, antifungal therapy should be withheld until a diagnosis is confirmed by laboratory studies.

The most important step in the initial management of suspected fungal keratitis is to obtain corneal material for directed smears and inoculation of media. Smears are used to obtain rapid information about the pathogen. Gram stain identifies yeast, and Giemsa stain is useful in detecting fungal elements. However, if fluorescein microscopy is available, acridine orange and calcofluor white are the stains of choice. The primary isolation cultures for fungus are Sabouraud and blood agar at room temperature.

In all patients with suspected fungal keratitis, initial corneal smears and cultures should be performed. Culture media for suspected fungal keratitis should include the same media used for a general infectious-keratitis workup.

When confronted with a likely fungal ulcer of days or weeks duration, a clinician in a developing country must urgently institute an antifungal treatment regimen; however, the choice of treatment is limited based on the antifungal agents available in that particular market.

Imaging Studies

If clinical evidence or suspicion of posterior segment involvement exists, ophthalmic B-scan ultrasound may be necessary to rule out concurrent fungal endophthalmitis.

Other Tests

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 immunofluorescence staining, electron microscopy, and confocal microscopy. Confocal microscopy may help in correctly diagnosing early stages of fungal keratitis and in monitoring disease progress at the edges and depth. It may also help guide timely decision for keratoplasty and may be helpful in determining when to stop medication.[2]

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.

Procedures

If corneal smears and cultures are negative at 48-72 hours in a patient who is strongly suspected of having a fungal infection and who is not improving on the initial, broad-spectrum antibacterial therapy, the authors recommend proceeding to a corneal biopsy to establish a diagnosis.

The corneal biopsy specimen should be submitted to the laboratory. A substantial portion also should be submitted for histopathologic examination. The pathologist should be alerted regarding the suspected diagnosis and especially that the specimen is a small piece of cornea.

A negative biopsy result indicates that the destructive corneal process is progressing, and hypopyon exists; therefore, anterior chamber paracentesis or excisional biopsy (keratoplasty) should be performed.

Histologic Findings

Histopathologic examination of corneal buttons can reveal the presence of fungal elements in 75% of patients. Fungal hyphae usually lie parallel to the corneal surface and lamellae. The presence of vertical oriented fungal elements in regard to stromal lamellae depicts high virulence of the organism and usually is associated with more aggressive infection. The Descemet membrane may serve as a partial barrier for invasion of fungal organisms. Penetration of the Descemet membrane by the fungal elements depicts an aggressive organism and a higher risk for contamination of the globe.

Medical Care

Antifungal agents are classified into the groups below.

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

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

Although polyenes penetrate ocular tissue poorly, amphotericin B is the drug of choice for treatment of fungal keratitis caused by Candida. In addition, it has efficacy against many filamentous fungi. Administration is every 30 minutes for the first 24 hours, every hour for the second 24 hours, and then is slowly tapered according to the clinical response.

Natamycin has a broad-spectrum of activity against filamentous organisms. The penetration of topically applied amphotericin B is found to be less than that of topically applied natamycin through the intact corneal epithelium.

Natamycin is the only commercially available topical ophthalmic antifungal preparation. It is effective against filamentous fungi, particularly for infections caused by Fusarium. However, because of poor ocular penetration, it has primarily been useful in cases with superficial corneal infection.

Azoles (imidazoles and triazoles) include ketoconazole, miconazole, fluconazole, itraconazole, econazole, and clotrimazole. Azoles inhibit ergosterol synthesis at low concentrations, and, at higher concentrations, they appear to cause direct damage to cell walls.

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.

Imidazoles and triazoles are synthetic chemical antifungal agents. High cornea levels of ketoconazole and fluconazole have been demonstrated in animal studies. Because of excellent penetration in ocular tissue, these medications, given systemically, are the preferred treatment of keratitis caused by filamentous fungi and yeast.

The adult dose of ketoconazole is 200-400 mg/d, which can be increased to 800 mg/d. However, because of the secondary effects, increasing the dose should be done carefully. Gynecomastia, oligospermia, and decreased libido have been reported in 5-15% of patients who have been taking 400 mg/d for a long period.

The potential role of itraconazole in treatment of fungal keratitis is still unclear. However, it may be a helpful adjunctive agent in fungal keratitis.

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; it is synergistic with these medications. Otherwise, if flucytosine is the only drug used in therapy for candidal infections, emergence of resistance rapidly develops. Therefore, flucytosine should never be used alone.

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.

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.

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.

A study by Matsumoto et al has shown that topical 0.1% micafungin eye drops are comparable to 0.2% fluconazole in the treatment of fungal keratitis no matter patient’s age, gender, or ulcer size.[3]

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.

The promotion of fungal growth by corticosteroid treatment is well recognized; therefore, corticosteroid drops should not be used in the treatment of fungal keratitis 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.

Therapy may be modified.

Decisions about alternate therapy must be based on the biomicroscopic signs and on the tolerance of the topical medications. Improvement in clinical signs may be difficult to detect during the initial days of antifungal therapy. However, some of the biomicroscopic signs that may be helpful to evaluate efficacy are as follows:

Successful antifungal therapy for fungal keratitis requires frequent drug administration for prolonged periods (ie, at least 12 wk). Some corneal manifestations of toxicity are as follows:

In the developing countries, owing to the paucity of medications and good laboratory facilities, it is highly practical to start treatment by using an antiseptic. The author routinely uses silver nitrate 0.75%, followed by Lugol iodine. The ulcer is first dried, followed by silver nitrate application with a swab stick. This is immediately followed by Lugol solution application with a swab stick. With this treatment, the surface of the ulcer is coated with a thin layer of silver iodide. It is expected that silver nitrate shall start ionizing, thus releasing nascent oxygen that has the capacity to destroy the fungal wall. This is followed by whatever antifungal medication is available. The author has been using this initial treatment for more than 20 years and treats more than 200 corneal ulcer cases (most of them fungal) every year.

Surgical Care

Patients who do not respond to medical treatment of topical and oral antifungal medications usually require surgical intervention, including corneal transplantation. Approximately 15-27% of patients require surgical intervention. In some cases, though, even corneal surgery will not restore vision, and patients will be blind or otherwise visually impaired. Therefore, early diagnosis coupled with appropriate treatment is critical to recovery from keratitis.

Frequent corneal debridement with a spatula is helpful; it debulks fungal organisms and epithelium and enhances penetration of the topical antifungal agent.

Approximately one third of fungal infections fail to respond to medical treatment and may result in corneal perforation. In these cases, a therapeutic penetrating keratoplasty is necessary.

Penetrating keratoplasty generally should be performed within 4 weeks of presentation. A small number of patients have been treated successfully with a conjunctival flap. The main goals of surgery are to control the infection and to maintain the integrity of the globe. Topical antifungal therapy, in addition to systemic fluconazole or ketoconazole, should be continued following penetrating keratoplasty. The use of topical corticosteroids in the postoperative period remains controversial.

Further Outpatient Care

Most patients with fungal keratitis are treated on an outpatient basis.

Antifungal therapy generally should be maintained for 12 weeks with routine follow-up examinations.

Further Inpatient Care

Indications for inpatient care include clinical evidence of an impending corneal perforation or if the patient is unable to administer frequent eye drops. In such cases, inpatient care includes topical fortified antifungal therapy administered every hour around the clock with frequent monitoring for any signs of corneal perforation.

Inpatient & Outpatient Medications

The medications prescribed depend on the specific etiologic agent identified in cultures.

In general, amphotericin B should be prescribed to a patient presenting with a fungal ulcer suggestive of yeast infection (Candida species), and natamycin should be prescribed when a high suspicion exists for a filamentous fungus (eg, Fusarium species). Candida species are frequently more common in sick corneas, while Fusarium species are often more common after trauma.

Fluconazole or ketoconazole should be used in patients with deep stromal infection.

Medication Summary

The antifungal agents used include polyenes (eg, natamycin, amphotericin B), azoles (eg, ketoconazole, miconazole, fluconazole, itraconazole), and fluorinated pyrimidines (eg, flucytosine). Amphotericin B is the drug of choice in fungal keratitis caused by yeasts. Natamycin has a broad-spectrum of activity against filamentous organisms. Oral fluconazole and ketoconazole should be considered in the management of deep fungal keratitis.

Natamycin (Natacyn)

Clinical Context:  Initial drug of choice in Fusarium keratitis. Predominantly fungicidal tetraene polyene antibiotic, derived from Streptomyces natalensis that possesses in vitro activity against a variety of yeast and filamentous fungi, including Candida, Aspergillus, Cephalosporium, Fusarium, and Penicillium species. Binds fungal cell membrane forming a polyenesterol complex that alters membrane permeability, depleting essential cellular constituents. Activity against fungi is dose-related but not effective, in vitro, against gram-negative or gram-positive bacteria.

Generally, therapy should be continued for 14-21 d or until the fungal keratitis has resolved. In many cases, may help to reduce dosage gradually at 4- to 7-day intervals to ensure elimination of the organism.

Amphotericin B 0.1-0.25% (Amphocin, Fungizone)

Clinical Context:  Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. First agent of choice in corneal infections due to yeasts, such as Candida species.

Ketoconazole (Nizoral)

Clinical Context:  Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

Often used systemically in the treatment of deep fungal infections. Studies have confirmed intraocular penetration in keratitis due to Fusarium, Aspergillus, Curvularia, and Candida species.

Fluconazole (Diflucan)

Clinical Context:  Alternative drug to ketoconazole in the treatment of deep fungal keratitis caused by a variety of fungi. Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Flucytosine 1% (Ancobon)

Clinical Context:  Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus and generally used in combination with amphotericin B. High incidence of acquired resistance has occurred; therefore, combined treatment with other agents is recommended.

In the treatment of fungal keratitis, polyenes and imidazoles have mostly replaced flucytosine.

Voriconazole (Vfend)

Clinical Context:  Voriconazole is the drug of choice for Aspergillus fumigatus, Aspergillus flavus, Fusarium species, Blastomyces dermatitidis, Coccidioides immitis, Curvularia species, Candida albicans, and Cryptococcus neoformans.

The mode of action is the inhibition of fungal cytochrome P-450, preventing fungal ergosterol biosynthesis, thus damaging the fungal cell wall. A 1% solution is used for local instillation, every hour during the day and every 2 hours during the night.

Class Summary

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Author

Michael Ross, MD, Clinical Instructor, University of British Columbia Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Coauthor(s)

Jean Deschênes, MD, FRCSC, Professor, Research Associate, Director, Uveitis Program, Department of Ophthalmology, McGill University Faculty of Medicine; Senior Ophthalmologist, Clinical Director, Department of Ophthalmology, Royal Victoria Hospital, Canada

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire<br/>Received income in an amount equal to or greater than $250 from: AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab.

Chief Editor

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Arun Verma, MD, Senior Consultant, Department of Ophthalmology, Dr Daljit Singh Eye Hospital, India

Disclosure: Nothing to disclose.

Daljit Singh, MBBS, MS, DSc, † Professor Emeritus, Department of Ophthalmology, Guru Nanak Dev University; Director, Daljit Singh Eye Hospital, India

Disclosure: Nothing to disclose.

Acknowledgements

George Alexandrakis, MD Consulting Staff and Surgeon, Department of Ophthalmology, Southern California Permanente Medical Group

George Alexandrakis is a member of the following medical societies: American Academy of Ophthalmology

Disclosure: Nothing to disclose.

Anastasios J Kanellopoulos, MD Assistant Program Director, Clinical Associate Professor, Department of Ophthalmology, Manhattan Eye, Ear, and Throat Hospital, New York University

Anastasios J Kanellopoulos, MD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, Eye Bank Association of America, and International Society of Refractive Surgery

Disclosure: Nothing to disclose.

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Fungal corneal ulcer.

Fungal ulcer in an elderly woman.

Fungal keratitis.

Fungal infection.

Fungal infection.

Fungal ulcer.

Fungal corneal ulcer, with excessive vascularization.

Fungal corneal ulcer, with excessive vascularization.

Marginal ulcer, fungus positive.

Fungal abscess.

Fungal corneal abscess/ulcer. A proven case of fungal infection, 5 days' duration. Intense infiltration around the abscess.

Perforated fungal ulcer.

Perforated fungal corneal ulcer.

Corneal perforation, blocked by a crystalline lens and being covered by epithelium.

Fungal corneal ulcer.

Perforated fungal ulcer.

Fungal infection under treatment.

Perforated fungal corneal ulcer.

Fungal ulcer in an elderly woman.

Fungal ulcer.

Fungal corneal ulcer, with excessive vascularization.

Marginal ulcer, fungus positive.

Healed fungal ulcer.

Fungal keratitis.

Corneal perforation, blocked by a crystalline lens and being covered by epithelium.

Fungal keratitis, being controlled.

Fungal infection.

Fungal infection.

Fungal abscess.

Fungal corneal abscess/ulcer. A proven case of fungal infection, 5 days' duration. Intense infiltration around the abscess.

Surgical trauma producing edema and striate keratitis. The corneal channels stand out in semiopaque corneal tissue, since they themselves are no-tissue spaces.

Surgical trauma producing edema and striate keratitis. The corneal channels stand out in semiopaque corneal tissue, since they themselves are no-tissue spaces.

A network of channels is visible in a case of megalocornea with faint opacification of stroma. The channels stand out as nonstructures.

This kind of opacification is termed keratitis. Anatomically, it appears to be a microchannel structure.

A network of corneal channels stands out inside the arcus senilis of an old patient. Whatever causes the opacification in the corneal tissue is not able to opacify the emptiness of corneal channels.

Network of corneal channels in a 92-year-old patient.

The corneal channels open in the lucid interval channel of Singh.

Peripheral corneal channel network and canal of Singh in 3 dimensions.

Optical section of corneal channels in a case of arcus senilis.

The lucid interval in optical section clearly shows its triangular configuration and an anterior and posterior wall. The apex continues towards corneal channels in the stroma. The lucid interval channel is connected to limbal lymphatics.

The lucid interval channel is connected to the lymphatics at the limbus and the corneal channels centrally.

A blunt wire of 100 micrometers diameter has been pushed into the canal of Singh.

A 230-micrometer blunt cannula in the canal of Singh.

This networklike pattern of fungal corneal infection is explained only by the preferential path of spread through the corneal channel network.

The fungal infection travels in various directions. Also seen are satellite lesions. Satellite lesions and other appearances are explained by the presence of channels in the cornea.

Notice centrifugal, linear, circular, and satellitelike spread of fungal infection through the corneal channels.

This patient presented with infection of the lucid interval of Singh without any evidence of corneal ulceration as a starting point, suggesting systemic spread. A satellite of infection is seen near the 6-o'clock position.

Same patient with infection of the lucid interval of Singh without any evidence of corneal ulceration as a starting point, suggesting systemic spread. A big and a small satellite at the 6-o'clock position.

The same eye showing the spread of fungal infection on the nasal side of the Singh canal. This patient showed no evidence of corneal injury, thus a systemic origin of infection is a distinct possibility.

The whole of the infected lucid interval canal of Singh was opened. The scraping showed the presence of hyphae. The patient was treated by oral medication, local drops, and intracorneal antifungal voriconazole injections. Final vision was 6/6 uncorrected. There was no recurrence.

Optical coherence tomography scans clearly showing the canal of Singh connected to the Schlemm canal.

Optical coherence tomography scans clearly showing the canal of Singh connected to the Schlemm canal.

Fungal keratitis under treatment. The infection has spread into the nearby lucid interval canal of Singh.

The same case as in the previous photo. Optical coherence tomography scans shows the presence of exudates in the lucid interval canal of Singh and the adjoining trabecular meshwork.