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Fortified Fluconazole Eyedrops for Treatment of Culvularia Corneal Ulcer

Introduction. Fungal keratitis is less common than bacterial keratitis, generally representing less than 5%–10% of corneal infections in reported clinical series in the United States. But in developing countries (Ghana, India, China) it accounts for more than 90% of the cases. Corneal trauma by plant or vegetative material is the leading risk factor for fungal keratitis. One or more topical antifungals are usually administered with systemic support of oral antifungals. The most common classes of antifungal used for medical therapy include the polyenes, azoles, and the echinocandins. Case presentation. A 47-year-old male presented with a widening white patch on his left eye since 4 days before coming to our hospital. The left eye was injured by wood flakes 3 weeks ago. He felt a sore, red, watery left eye and blurred vision. He washed his eyes with betel leaf water. His left eye visual acuity was 1/60 and not improved with pinhole. There were blepharospasm, ciliary and conjunctival injection. Corneal examination showed a cloudy cornea, a central corneal defect sized 8x6 mm with an irregular margin, 2/3 to stromal depth, infiltrate, satellite lesion, and positive fluorescein staining at the defect margin. KOH examination demonstrated hyphae. The culture test of left corneal discharge identified a fungi species (Curvularia sp). We prescribed fortified fluconazole eye drops in combination with supportive therapy for 2.5 months. This regimen showed a significant increase in visual acuity to 6/30 with pinhole improvement of 6/21


Introduction
Fungal keratitis is less common than bacterial keratitis, representing less than 5% -10% of corneal infections in clinical reports reported in the United States. 1 But in developing countries (Ghana, India, China) it accounts for more than 90%. 2 In corneal ulcers, some of the causes including bacteria, viruses, fungi, protozoa, and autoimmune diseases. The most common etiology of corneal ulcers is bacterial infection in the majority of cases. [3][4][5] Fungal corneal ulcers is more common in young male outdoor workers. It is also more common in developing countries and its incidence varies widely with climate. In the UK a study found the incidence of mycotic keratitis to be 0.32 cases per million person/year. However, in tropical and subtropical environments fungal keratitis can account for up to 50% of all infectious keratitis cases. 4 Corneal trauma by plants or vegetative material is a major risk factor for fungal keratitis. 1 One or more topical antifungals are usually administered with oral antifungal systemic support.
The classes of antifungals most commonly used for medical therapy include polyenes, azoles, and echinocandins. 6 Corneal ulcer management aims to eradicate the cause of the corneal ulcer, suppress the inflammatory reaction so that it does not aggravate the destruction of the cornea, accelerate the healing of epithelial defects, resolve complications and improve visual acuity.

Case report
A 47-year-old male presented with a widening white patch on his left eye since 4 days before coming to our hospital. The left eye was injured by wood flakes 3 weeks ago. He felt a sore, red, watery left eye and blurred vision. He washed his eyes with betel leaf water, but there's no improvement. The patient complained that the left eye was still red, the vision was getting blurry, there's more eye discharge, watery eyes, difficulty in the eyelid's opening, and white spots on the black part of the left eye after two weeks. Patient went to the hospital and prescribed three eye  When the patient returned on day 90 th after receiving therapy, the complaints has been improved. The patient only complained of blurred vision and glare. On ophthalmological examination, the visual acuity was still the same as before, and the treatment has been stopped because there were no signs of infection. In ophthalmology examination, visual acuity was 1/60. There were blepharospasm and cloudy cornea, a central corneal defect sized 8x6 mm with an irregular margin, 2/3 to stromal depth, infiltrate, satellite lesion, and positive fluorescein staining at the defect margin. The corneal defect showed discontinuity of corneal tissue that can occur from the epithelium to the stroma, thus corneal ulcers has been confirmed as a diagnosis. Defects in the central part caused interference with the entry of light in the optic zone, as a result the patient experienced a decrease in visual acuity to 1/60. Irregular, feathery edges, which is a fibrous or hairy edge, is typical for fungal infections.
The main goal of treatments in patients with corneal ulcers is to eradicate the causal microorganisms thus the invasion of these pathogenic microorganisms will not cause damage to the deeper corneal structure and to keep the corneal repair process to a maximum and the resulting cyclic to be minimal. It can be a primary factor in the patient's visual acuity improvement after hours. The use of Natamycin 5% is recommended for the treatment of most cases of filamentous fungal keratitis. 5,10-13 The use of fluconazole was continued topically after we observed wellresponse to subconjunctival administration. This fortified fluconazole was given at a dose of 1 drop every 1 hour with a concentration of 2 mg/ml. This dose is maintained to achieve therapeutic concentration in the cornea. The patient was also prescribed with Sulfas Atropine 1%, a cycloplegic drug administered 1 drop every 8 hours a day to dilate the pupil. This can help to prevent synechiae and relieve pain.
The initial prognosis quo ad Vitam is Bonam because vital signs are within normal values while quo ad Functionam is Dubia ad Malam due to the success of therapy depends on the timing and the accuracy of drugs administration. Structural damage to the cornea due to corneal ulcers will also determine the prognosis quo ad Functionam, if the depth of the corneal ulcer has reached deeper structure, the improvement in visual acuity will not likely to be achieved because the corneal transparency has been changed. It occurred to this patient where the corneal damage involved 2/3 of the stromal depth. In the stroma, the wound repair process will form a network of fibroblasts that are arranged irregularly so that a cyclone is formed which makes the cloudy cornea. This turbidity makes the rays that enter through the optical zone cannot be transmitted optimally. After the eradication of the etiological microorganisms has been successful, the visual function remains difficult to achieve the initial baseline vision before the corneal ulcer occurred.
When the patient returned on day 75 th after receiving therapy, there was a significant examination result where the clinical symptoms began to decrease and accompanied by an increase in vision. On corneal examination, a negative fluorescent test was also obtained. This indicates that the corneal epithelialization process has been complete and left a corneal scar. Afterwards, we tapered the dose of the previous therapy and continued the administration of fortified fluconazole.
The reduced doses were given to keep the infection process from reappearing.
When the patient returned on day 90th after receiving therapy, there has been some improvement. The patient only complained of blurred vision and glare. On ophthalmological examination, the visual acuity was still the same as the previous month. This is due to the formation of cicatrix on the cornea covering the visual axis. On corneal examination, a negative fluorescent test and cicatrix measured 6x6 mm in size in the center cornea were found. The process of corneal reepithelialization remodelling has occurred optimally and the treatment can be stopped.
Imidazoles work by inhibiting the biosynthesis of ergosterol from fungal cell walls, through action on enzymes that depend on cytochrome P450. It results in destabilization and leakage of the cell membrane. Curvularia sp belongs to the dematiaceous fungi family. Clinical manifestations include raised lesions and hairy margins; hypopyon is rare, and the prognosis is favorable.
Fluconazole (2 mg/ml) is available for injection and is a well-tolerated eye drop. Intravenous fluconazole can be used as a topical treatment and can be administered subconjunctivally at the same concentration. 3,9,14

Conclusion
Fortified fluconazole eye drops (2 mg/ml) can be an alternative and additional therapy for deep fungal keratitis, especially for Curvularia sp.