Subconjunctival Injection of Fluconazole in the Treatment of Fungal Alternaria Keratitis

Abstract

Purpose: We report two cases of Alternaria keratitis refractory to the conventional antifungal medical treatment successfully treated with subconjunctival fluconazole injection.

Methods: Report of two cases.

Results: After subconjunctival injection of fluconazole (2 mg/mL) 0.5 mL twice a day for 5 days then once a day till 14 days, two cases of Alternaria keratitis refractory to the conventional antifungal medical treatment were successfully treated. No severe local and systemic side effects were found in these two patients.

Conclusions: Alternaria keratitis has a varied clinical presentation and suspicion must be maintained for unusual causes of infectious keratitis. Alternaria keratitis can be difficult to eradicate even with traditional antifungals such as amphotericin B and natamycin. Subconjunctival injection of fluconazole could be effective for Alternaria keratitis unresponsive to conventional antifungal medical treatment.

Fungal keratitis is an insidious and potentially sight-threatening infection, and usually requires a long course of medical therapy.1^,2 The treatment of fungal keratitis is a challenge for ophthalmologists, and sometimes surgical intervention is indicated in the management of recalcitrant cases that are unresponsive to medical therapy.2 The majority of the pathogens isolated from human cornea with keratomycosis are hyaline fungi; the dematiaceous fungi are a relatively less common cause of keratomycosis.3 Alternaria species have been previously associated with keratitis. They are filamentous fungi from the dematiaceous family commonly isolated from plants, soil, food, and indoor air environments.4^,5 Previous studies suggest that dematiaceous fungi are more susceptible to the newer triazoles, voriconazole and posaconazole.4–6 However, the expenditure involved in voriconazole treatment poses a constraint on its more frequent usage. Here we report two cases of keratitis caused by an Alternaria species refractory to the conventional antifungal medical treatment successfully treated with subconjunctival injection of fluconazole. The treatment adhered to the tenets of the Declaration of Helsinki and the patients were informed regarding the advantages, disadvantages, and potential side effects of this modality, and also the possible risks of the procedure. Written informed consent was obtained prior to treatment.

The first case was a 69-year-old woman who was referred from her general ophthalmologist due to declined visual acuity, severe pain, and redness of her right eye with a history of agricultural trauma; the condition did not improve despite topical antibiotics use for 2 weeks. At referral, her best corrected visual acuity (BCVA) of the right eye was 20/400, and she had moderate conjunctival hyperemia, mild chemosis, and a dense, whitish, elevated inferior paracentral corneal ulcer (2 × 2 mm) associated with marked corneal edema and localized necrosis at its periphery (Figure 1A). Corneal scrapings and cultures were obtained and submitted for bacterial and fungal investigation. A Gram stain of the ulcer was performed, which showed only a few polymorphonuclear cells with no organisms seen.

Figure 1. Case 1 presentation. (A) Slit-lamp microscopic images showing a dense, whitish, elevated inferior paracentral corneal ulcer, associated with corneal edema and localized necrosis at its periphery of the right eye cornea. (B) Fourteen days after therapy, slit-lamp microscopic images showing a quiet stromal scar with resolved corneal lesion. Case 2 presentation. (C) Slit-lamp microscopic images showing a paracentral corneal ulcer (2 × 2 mm), associated with “fluffy”-appearing infiltrates and feathered borders. (D) Fourteen days after therapy, slit-lamp microscopic images showing a faint stromal scar with corneal ulcer subsided.

The patient was hospitalized and hourly empiric antibiotic eyedrops with atropine 1% twice daily were given initially. On the seventh day of hospital admission, the cultures showed growth of fungus but not bacteria. An Alternaria species was identified in the culture. The treatment was then changed to hourly topical amphotericin B 0.15% and natamycin 5% drops but no improvement was noted.

Increased inflammation with a 2-mm hypopyon developed 1 week later. The topical antifungals were stopped and a trial of 0.5 mL subconjunctival fluconazole (2 mg/mL) injection twice a day for 5 days then once a day for 14 days was used. The subconjunctival fluconazole injections were performed by one doctor (YMC). After skin disinfection with topical anesthesia, the intravenous form of fluconazole (2 mg/mL) solution, up to 0.5 mL, was injected into the inferior nasal or temporal bulbar conjunctiva of the patient with a tuberculin syringe on a 27-gauge needle. After the fifth day of treatment, the patient showed clinical improvement. The patient responded well to the treatment and the infection subsided with a faint corneal scar developed with the BCVA of the right eye increased to 20/100 14 days later (Figure 1B).

The second case was a 58-year-old man who was referred with 10 days of right eye pain and redness with a history of right eye trauma on a chicken farm that did not improve despite topical moxifloxacin (Vigamox, Alcon, Fort Worth, TX) used for 1 week. At referral, his BCVA of the right eye was 20/200 and he had severe conjunctival hyperemia and a paracentral corneal ulcer (2 × 2 mm) associated with “fluffy”-appearing infiltrates and feathered borders (Figure 1C). Corneal scrapings and cultures were obtained and submitted for bacterial and fungal investigation. A Gram stain of the ulcer was performed, which showed some polymorphonuclear cells with no obvious organisms found.

The patient was then hospitalized and topical natamycin 5% eyedrops hourly with atropine 1% twice daily were given along with empiric antibiotics eyedrops initially. The cultures showed growth of an Alternaria species few days later and the treatment was then changed to hourly topical amphotericin B 0.15% and natamycin 5% eyedrops. However, the condition did not improve, with marked pain and increased corneal melting noted 1 week later. The topical antifungals were stopped and the treatment was then changed to 0.5 mL subconjunctival fluconazole (2 mg/mL) injection twice a day for 5 days then once a day till 14 days and the patient showed clinical improvement. The patient responded well to the treatment and a faint corneal scar developed with the BCVA of the right eye increased to 20/50 14 days later (Figure 1D). During the treatment period, no severe local and systemic side effects were found in these 2 patients.

Over the past few decades, Alternaria species have been emerging as opportunistic pathogens, mainly in bone marrow transplant patients and also immunocompromised patients.5 However, they generally do not invade the eye except after trauma.5 Although Alternaria keratitis has been reported in several articles from other parts of the world,4–7 it was less commonly reported in East Asia.8^,9 To our knowledge, these are the rare reports showing human keratitis infected by Alternaria species refractory to the conventional antifungal medical treatment treated successfully by subconjunctival fluconazole injection. A review of the literature indicates that several different antifungal agents have been used for the therapy of Alternaria keratitis, but no clear standard therapeutic approach has been established.4–7 First-line therapy with natamycin and amphotericin B are frequently used in the treatment of fungal keratitis. However, previous reports have also shown clinical resistance of Alternaria to natamycin and amphotericin B.4–6 In these previous reports, there might be some reporting bias, but they may also reflect that natamycin or amphotericin B is not a reliable first-line therapy for this pathogen.

In our cases, we chose to combine topical natamycin and amphotericin B use for this unusual organism initially for the reason that the combination therapy may shorten therapy and that the increased toxicity of amphotericin B may cause corneal epithelium breakdown and allow better penetration of topical natamycin.10 However, the result was not satisfactory.

The newer triazole, voriconazole, has been advocated for the treatment of fungal keratitis resistant to standard antifungal agents.5 However, the expenditure involved in voriconazole treatment poses a constraint in its more frequent usage in many countries where fungal keratitis is not uncommon. While voriconazole is too expensive for many patients to use, fluconazole is a relatively less expensive, stable, water-soluble, low-molecular-weight bis-triazole antifungal with high bioavailability and low toxicity.11 Although several in vitro antifungal sensitivity analyses showed fluconazole to be less effective to filamentous fungi,12 clinical response to topical fluconazole was reported anecdotally.4^,8 Good response to systemic fluconazole in systemic Alternaria infections was also reported.13 In our opinion, this agent may merit further investigation for its antifungal effects.

Topical antifungal eyedrops usually cause irritation, eye redness, and even severe eye pain due to their toxicity to normal ocular surface cells when used hourly. When external eye disease specialists deal with fungal keratitis, other methods of administering, i.e. intrastromal and subconjunctival injection, are used sometimes.14^,15 Subconjunctival use of fluconazole may not only potentiate the efficacy of the drug in the treatment of fungal keratitis but also decrease the chance of side effects and hazards for the corneal and conjunctival tissues.15 Yilmaz et al. used subconjunctival fluconazole treatment therapy for severe fungal keratitis refractory to the conventional antifungal medical treatment and found that it could be effective for treatment of severe fungal keratitis and also very useful to avoid surgical intervention at an acute stage of infection.14 Mahdy et al. reported that combination therapy of topical amphotericin B eyedrops with subconjunctival injection of fluconazole (2 mg/mL) was more efficient than the use of topical amphotericin B eyedrops alone in dealing with fungal keratitis.15 However, in their studies, the positive cultures showed only Fusarium species, Aspergillus species, Penicillium, and Candida albicans.14^,15

Although the effect of subconjunctival fluconazole monotherapy for Alternaria keratitis is still not quite clear, good response of subconjunctival fluconazole injections for deep keratomycosis with hypopyon resistant to topical fluconazole of the same concentration to avoid keratoplasty had been reported.14 It is possible that a subconjunctival injection of fluconazole will increase the penetration of the drug and that could be the reason for the better outcome. In these 2 cases, we chose to use only subconjunctival injection of fluconazole for the treatment of Alternaria keratitis resistant to topical amphotericin B and natamycin, and the clinical results showed that the corneal infiltrates responded well to the treatment in these 2 patients.

With this report, we aim to draw attention to the increase in infectious keratitis caused by unusual fungal agents such as Alternaria. Fungal keratitis caused by Alternaria species resistant to conventional topical antifungal treatment can be difficult to treat. Subconjunctival injection of fluconazole (2 mg/mL) seemed to be efficacious and well tolerated and may be considered as an alternative for the treatment of Alternaria keratitis.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.