Fungal Keratitis Treatment & Management

Updated: Sep 08, 2017
  • Author: Michael Ross, MD; Chief Editor: Hampton Roy, Sr, MD  more...
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Treatment

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:

  • Blunting of the perimeters of the infiltrate

  • Reduction of the density of the suppuration

  • Reduction in cellular infiltrate and edema in the surrounding stroma

  • Reduction in anterior chamber inflammation

  • Progressive reepithelization

  • Loss of the feathery perimeter of the stromal inflammation

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:

  • Protracted epithelial ulceration

  • Punctuate corneal epithelial erosion

  • Diffuse stromal haze

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.

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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.

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