Bacteria, viruses, and fungi can cause infectious keratitis. Fungal keratitis (FK) was first documented in 1879, and incidence has been increasing for the past 30 years. It is accountable for 40% to 50% of all isolated keratitis cases. FK develops rapidly and can lead to corneal ulcers and vision loss, so early diagnosis and prompt treatment are essential to prevent long-term complications.
Around 70 different fungi have been implicated in the causation of fungal keratitis; yeast and filamentous fungi (septate and non-septate) are the most relevant.
Trauma and immunocompromised state are the most prevalent risk factors associated with fungal keratitis. It is also believed that fluid transport across the endothelium plays an important role in the spread of the infection.
The early stage of fungal keratitis is not always easy to detect, and diagnostic delays are common. Even if the diagnosis is made, treatment is challenging as many antifungal agents have poor penetration into the cornea.
Worldwide, Aspergillus species are the most frequent isolate in FK. An Indian study on FK reports that Aspergillus species are the most common isolate (27% to 64%), followed by Fusarium (6% to 32%) and Penicillium (2% to 29%).
Another common fungal organism causing keratitis is Fusarium. Fusarium species are found in soil, water, and on plants throughout the world, especially in warmer climates. Past studies on FK have found that eye injuries caused by vegetative matter account for most reported cases; for example, being hit in the eye with a palm branch.
In one study, 275 patients were confirmed with FK. Of those, 198 patients were diagnosed by positive fungal cultures. They reported that the sensitivity of fungal culture was 72.0%. Among these patients, 210 fungal isolates belonging to 17 genera and 29 species were isolated. The isolates of Fusarium were the most common (49.5 %), followed by Aspergillus (18.6 %), Candida (12.4 %), and other genera (19.5 %), such as Alternaria, Acremonium, Cladosporium, and Beauveria. Among these isolates, the predominant species were with Fusarium solani, Aspergillus fumigatus, and Candida glabrata, accounting for 56.6% of the isolated fungi.
Trauma to the cornea is the most common risk factor for fungal keratitis. It is vital to obtain a history of exposure to soil or plant matter when encountering a patient with suspected fungal keratitis. Among contact lens wearers, Candida is a common cause of keratitis. Besides topical corticosteroid use, other risk factors include immunosuppression and the presence of a foreign body.
Like most infectious diseases, geographical location, and socioeconomic status influence prevalence. In the United States, warm places like Florida have an incidence of 35%, while colder places like New York can be as low as 2%. In the United States, Candida and Aspergillus are most frequently isolated in fungal keratitis. Aspergillus is most common in northwestern states. Fusarium is the most common cause of fungal keratitis in warmer climates.
An estimated 30 million persons in the United States use soft contact lenses. Contact use can lead to microbial keratitis, which has an incidence of approximately 4 to 21 per 10,000 users. Wearing the lenses overnight is an aggravating factor. A CDC investigation of 130 reported FK cases from 2005 to 2006, reported more than 60% had used a contact lens solution, and 37 of these cases resulted in cornea transplant surgery.
Studies have shown a higher incidence in males, with the majority of the patients between the ages of 16 and 49. It occurs more often in patients with a history of trauma, and those frequently outdoors.
Usually, FK results from fungi access into the corneal stroma through a defect in the epithelium; this is the reason the disease is associated with trauma. Once in the tissue, the fungi start to replicate in the anterior chamber, a space protected by the cornea, and posteriorly, by the iris diaphragm and pupil. The cornea and conjunctiva create a protective anatomic barrier against pathogens. That is the reason when penetrated by trauma, it is no longer impermeable. 
The cornea is avascular, and on top of its barrier capacity, has restricted defense mechanism, dendritic cells, and immunoglobulins, making it easy to be colonized by fungi. The fungal organisms can spread from into the sclera and intraocular structures, causing severe infections such as endophthalmitis, panophthalmitis, or scleritis. These have difficult treatments and may lead to vision or eye loss.
Zygomycetes are known to cause the rapid and severe destruction of the extraocular and rhinocerebral soft tissues; however, due to the avascular nature of the corneal tissue, it behaves less aggressively in keratitis.
Coarse granular infiltration of the corneal epithelium and the anterior stroma is the main finding in FK, and having low neutrophils is a positive finding as they are the ones that contribute to the destruction of the cornea with intent to control the causative agent. The union of the fungi and the host antibodies is usually surrounded by a ring (showing infiltration); the fungal hyphae normally are parallel to the corneal surface and lamellae.
Most patients present with pain, redness, blurred vision, sensitivity to light, excessive tearing, or discharge within 24 to 36 hours after the trauma. Elevated edges, branching ulcers, feathery margins, rough texture, and satellite lesions are specific for FK.
It is important to obtain a sample of the lesion by scraping before starting antifungal therapy.
Approaches for patient evaluation vary, but the smear must be done as soon as it is suspected. Because fungi have the predilection to penetrate deeper layers of the cornea, tissue swabbing is usually inadequate in confirming a fungal agent. Corneal scrapings are recommended. Ideally, every sample should be sent for polymerase chain reaction (PCR) and culture. Cultures usually take 1 to 35 days. Another major disadvantage of the fungal cultures is low sensitivity, especially for cases that have been treated with antifungal agents. PCR testing has been established as a better way to get an FK diagnosis and takes 2 to 3 hours. The obstacle to using PCR is that it requires very specialized equipment that might not be available. Therefore, Kue et al. suggested implementing a dot essay, which is highly sensitive and can detect a wide variety of fungus. Confocal microscopy is a noninvasive technique and another method for FK diagnosis.
Ophthalmologists perform an ophthalmic B-scan ultrasound if there is a suspicion of posterior segment involvement or endophthalmitis. Biopsy of the corneal body is a procedure that can be done if previous studies are negative. There has not been an improvement with broad-spectrum antibiotics, but this is not routinely done.
In patients with negative cultures and smears after 48-72 hours who are suspected of having a fungal infection, a corneal biopsy is recommended. Besides microbiological evaluation, the corneal biopsy should be examined for histopathology to determine the presence of a fungus.
Natamycin eye drops are frequently used for FK. They inhibit the growth of fungi by inhibiting transport of amino acids and glucose across the plasma membrane by binding to ergosterol and inhibiting membrane transport proteins. It has negligible absorption when taken orally, so it is not useful for systemic infections. 
Other agents used in FK are amphotericin B, voriconazole. Voriconazole has better penetration into the eye and is purported to be a superior alternative to natamycin.
Subconjunctival injections may be used in patients with poor compliance and those with severe keratitis.
Decisions to continue therapy as based on the following biomicroscopic signs:
However, recently published clinical trials have reported equal or inferior efficacy of 1% voriconazole (reconstituted from injection vial) compared with 5% natamycin eye drops in FK. These results are contradictory to experimental and in vitro data. Sharma conducted a study of 118 patients where 58 patients were treated with voriconazole and 60 patients with natamycin. Despite the frequency of healed or resolving ulcers being similar on day 7 (natamycin 35/54, 65%; voriconazole 34/50, 68%), at the final visit the percentage of patients who had healed corneal ulcer were significantly higher in the group treated with natamycin (50/56, 89.2% versus 34/51, 66.6%; p=0.005).
In a 10-year retrospective study, Gina analyzed 73 cases of fungal keratitis and reported a microbiological cure was achieved in 72 corneas (98.6%). Forty-one (56.2%) were cured with medical therapy alone, and 32 (43.8%) required therapeutic keratoplasty (TKP) only once. Among the 32 that were treated with TKP, 17 (53.1%) maintained a clear graft.
Patients who fail to respond to drug therapy need surgical intervention, including a corneal transplant. Unfortunately, surgery does not guarantee restoration of vision in almost 20% of patients. If a corneal perforation occurs, a keratoplasty is required.
The prognosis depends on the depth, extension of infection, and timing of treatment initiation. Some patients can be cured microbiologically by topical antifungals alone, and in some patients, keratoplasty is needed. The Descemet membrane, an interior basement membrane near the aqueous humor, is impermeable to bacteria but can be breached by fungal hyphae, leading to endophthalmitis; endophthalmitis is a rare consequence of fungal keratitis that causes a poor prognosis. About 30% of fungal infections fail to respond to drug therapy and/or result in corneal perforation.
The majority of patients with fungal keratitis present to the emergency department or their primary care provider; in order to expedite the referral process to an ophthalmologist, an interprofessional approach in diagnosis and care is vital. Any delay can lead to vision loss and permanent blindness. The majority of patients with fungal keratitis are managed as outpatients and treated with antifungal therapy for at least 12-16 weeks.
Patient education is vital in the prevention of fungal keratitis. Contact lens wearers need to be educated about hand washing, use of appropriate cleaning solution, and avoiding sleep and swimming while wearing contact lenses. Contact lens wearers should also regularly follow up with the optician or ophthalmologist and get the eyes checked. All contact lens wearers should be told to immediately see an ophthalmologist if they experience pain, redness, and loss of vision. Ophthalmology nurses educate patients, arrange follow up, and ensure communication between team members. Pharmacists review medication dosage, check for drug interactions, and review administration with patients. [Level 5]
Close follow up is required to ensure that the symptoms are not worsening. The eventual outcome depends on factors like overall patient health, the status of the immune system, and other comorbidity. Patients with a mild infection who are promptly treated have a good outcome, but in patients with an infection that has spread into the sclera, the prognosis is guarded. Data indicate that at least 30% of patients with fungal keratitis develop corneal perforation or fail to respond to drug therapy.
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