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 (NTM) is the only commercially available topical ophthalmic antifungal preparation and it is approved by the FDA. It has a broad spectrum of antifungal activity, and works well against various fungal species such as Fusarium, Aspergillus, Alternaria, Candida, Cephalosporium, Colletotrichum, Curvularia, Lasiodiplodia, Scedosporium, Trichophyton, and Penicillium [4] . The Mycotic Ulcer Treatment Trial-1 (MUTT-1) compared topical NTM with Voriconzale (VCZ) in a multi-centric randomized clinical trial, the authors found patients recieving NTM had better BCVA and lower perforation rate than patients treated with VCZ at 3 months FU. [8]
Few authors recommend concurrent corneal epithelial debridement to increase the penetration of Natamycin. Nonetheless, Prajna et al performed a multicentric double-masked clinical trial comparing topical Natamycin and topical Voriconazole and they did not find any difference in the healing time, when epithelial debridement was performed additional to topical therapy. [9]
Azoles (imidazoles and triazoles) include Voriconazole 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. Voriconazole (VCZ) is the second-best topical drug available for the treatment of fungal keratitis. Similar to NTM, VCZ displays a broad spectrum of activity against various species of Aspergillus, Candida, Cryptococcus, Fusarium, and Scedosporium.
The role of oral VCZ in fungal keratitis is controversial. Some case reports suggest its usefulness as an adjuvant to topical treatment, but others like the MUTT-2 trial did not show significant difference. [10] Oral azoles are absorbed systemically with good levels in the anterior chamber and the cornea, so the pharmacokinetics of the drug support its use. The major study that suggests the usefulness of oral VCZ is the TST (Topical, Systemic, and Targeted Therapy) protocol by Sharma et al. They reported a success rate of 79,8% using the following protocol. First line therapy was NTM 5% with adjuvant therapy of oral VCZ or Ketoconazole (KTZ) only in cases with ulcer >5 mm or ulcer depth >50%. If they had good response, they would continue same treatment, if not, additional VCZ topical was given. If poor response they would consider intracameral or intrastromal injection with both antifungals. [11]
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.
Subconjunctival injections may be used in patients with severe keratitis or keratoscleritis. They also can be used when poor patient compliance exists.
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 the patient’s age, gender, or ulcer size.6
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.
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.
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, whereas Fusarium species often are more common after trauma.
Fluconazole or ketoconazole should be used in patients with deep stromal infection.
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Fungal corneal ulcer.
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Perforated fungal ulcer.
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Fungal infection under treatment.
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Perforated fungal corneal ulcer.
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Fungal ulcer in an elderly woman.
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Fungal ulcer.
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Fungal corneal ulcer, with excessive vascularization.
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Marginal ulcer, fungus positive.
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Healed fungal ulcer.
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Fungal keratitis.
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Corneal perforation, blocked by a crystalline lens and being covered by epithelium.
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Fungal keratitis, being controlled.
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Fungal infection.
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Fungal infection.
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Fungal abscess.
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Fungal corneal abscess/ulcer. A proven case of fungal infection, 5 days' duration. Intense infiltration around the abscess.
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Surgical trauma producing edema and striate keratitis. The corneal channels stand out in semiopaque corneal tissue, since they themselves are no-tissue spaces.
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Surgical trauma producing edema and striate keratitis. The corneal channels stand out in semiopaque corneal tissue, since they themselves are no-tissue spaces.
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A network of channels is visible in a case of megalocornea with faint opacification of stroma. The channels stand out as nonstructures.
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This kind of opacification is termed keratitis. Anatomically, it appears to be a microchannel structure.
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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.
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Network of corneal channels in a 92-year-old patient.
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The corneal channels open in the lucid interval channel of Singh.
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Peripheral corneal channel network and canal of Singh in 3 dimensions.
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Optical section of corneal channels in a case of arcus senilis.
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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.
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The lucid interval channel is connected to the lymphatics at the limbus and the corneal channels centrally.
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A blunt wire of 100 micrometers diameter has been pushed into the canal of Singh.
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A 230-micrometer blunt cannula in the canal of Singh.
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This networklike pattern of fungal corneal infection is explained only by the preferential path of spread through the corneal channel network.
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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.
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Notice centrifugal, linear, circular, and satellitelike spread of fungal infection through the corneal channels.
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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.
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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.
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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.
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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.
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Optical coherence tomography scans clearly showing the canal of Singh connected to the Schlemm canal.
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Optical coherence tomography scans clearly showing the canal of Singh connected to the Schlemm canal.
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Fungal keratitis under treatment. The infection has spread into the nearby lucid interval canal of Singh.
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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.
