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The Official Scientific Journal of Delhi Ophthalmological Society
Recalcitrant Candidal Corneal Ulcer- A Therapeutic Challenge
Bibek Kumar, N. Z. Farooqui 
Department of Ophthalmology, Deen Dayal Upadhaya Hospital, New Delhi, India

Corresponding Author:
Bibek Kumar MBBS, DNB
Post Graduate
Department of Ophthalmology, 
Deen Dayal Upadhaya Hospital, New Delhi, India
Email Id: drbibekkumar@gmail.com
Received: 26-AUG-2017 Accepted: 27-OCT-2017 Published Online: 03-MAR-2018
DOI: http://dx.doi.org/10.7869/djo.335
Abstract
We are hereby presenting a case of recalcitrant fungal corneal ulcer caused by Candida Albicans which did not respond to conventional treatment methods of fungal corneal ulcer ie oral and topical antifungals. The fungal keratitis responded to intrastromal Amphotericin B; thereby highlighting the importance of newer treatment modalities in management of recalcitrant fungal keratitis, e.g. intrastromal and intracameral antifungals. The keratitis started to heal rapidly after the first intrastromal injection of Amphotericin B, and healed completely after three intrastromal injections administered at fortnightly intervals; with residual corneal scarring and vascularization.
Keywords : fungal keratitis, Candida albicans, intrastromal Amphotericin B

Case History
A 60 year old female home maker, who was a non-diabetic, non-hypertensive, non alcoholic, non smoker presented to OPD with complaints of gradually increasing pain , photophobia, blurred vision and mucopurulent discharge in her right eye since fifteen days. There was no preceding history of trauma, fever, treatment for any systemic illness, ocular surgery, topical or systemic drug use, contact lens use. She gave history of putting some eyedrop obtain from a local chemist shop one week back which did not obtained any relief.

Ocular findings in the right eye was as follows: vision PL+, PR accurate, there a 7*8 mm yellow white stromal corneal infiltrate (Figure 1), with fluffy margins and a 5*5 mm epithelial defect, associated with a 3mm hypopyon. The IOP was 12 mm Hg and B scan ultrasound showed no evidence of endophthalmitis.



The left eye examination was within normal limits. All routine blood and urine investigations were reported to be normal, including chest radiology. Corneal ulcer scrapings were negative on Gram’s,Giemsa stain and 10% KOH mount. The patient was started empirically on fortified cefazoline 5% eyedrops, fortified tobramycin 1.3 % eyedrops, homatropine 2% and oral amoxicillin plus clavulinic acid. Bandage contact lens was applied. Scrapings sent for culture on 10% sheep blood agar, nutrient agar,chocolate agar and Sabourand’s Dextrose agar showed no growth after 48 hours and 7 days of incubation. After one week of starting empirical treatment, she was followed up and showed further deterioration of keratitis. The infiltrate size increased to 8*9 mm. Based on the clinical picture and poor response to antibacterials, it was suspected to be a case of fungal keratitis and thus Natamycin 5% eyedrops 1 hourly was added to treatment. Two weeks post incubation, Sabourauds agar showed growth of creamy white opaque colonies. Grams stain and 10% KOH wet mount of growth showed oval budding yeast cells 2-10 microns in diameter with pseudohyphae formation, which was later confirmed on microbiology report by germ tube test to be Candida Albicans. There was no improvement in the infiltrate size with natamycin eyedrops, so the patient was started on topical Amphotericin 0.15% eyedrops and oral fluconazole 100mg OD for 14 days. Even with topical Amphotericin B, there was no change in the size of infiltrate, implying poor penetration of Amphotericin eyedrops.1,2 To overcome this problem, it was proposed to use alternate routes such as intracameral or intrastromal Amphotericin B (AMB) injections to treat candidal keratitis.3-6 

Injection Amphotericin B was reconstituted in 5% dextrose to make concentrations of 25 ??g/mL (for intrastromal corneal injection) and 50 ??g/mL (for intracameral injection).7 Peribulbar and topical anaesthesia was given (because intrastromal injections are painful). 0.5 ml of Amphotericin B was injected intrastromally using a 27-gauge needle bevel down (to avoid iatrogenic corneal perforation) inserted obliquely from the uninvolved,clear area to reach just flush with the corneal infiltrate at the midstromal level (intended level for drug deposit) in the circumference around the ulcer to form a drug deposit around the circumference of the lesion.

For intracameral injection, 0.5??g Amphotericin B (50 ??g/mL) in 0.1mLwas injected using a 30-gauge needle in the anterior chamber after washing the hypopyon. Topical Amphotericin B eyedrop 0.15% was continued 1 hourly along with oral fluconazole. One week following the first intrastromal injection of amphotericin B, there was marked improvement in the size of stromal infiltrate to 5*4 mm (Figure 2). The patient needed two more injections of intrastromal Amphotericin B at two week intervals. Thereafter the ulcer healed with subsequent scarring and vascularization (Figure 3). She was advised penetrating keratoplasty for visual rehabilitation but the patient refused as she was satisfied with healing of her ailment. The only ocular complications manifested after intrastromal injection of Amphotericin B was pain lasting 2 -3 days.



Discussion
Fungal keratitis was first described by Leber in 1879. This entity is a very common cause of corneal infection in developing countries. The term fungal keratitis refers to a corneal infection caused by fungi. The early stage of fungal keratitis remains a diagnostic and therapeutic challenge to the ophthalmologist. There is difficulty in establishing the clinical diagnosis, isolating the etiologic fungal organism in the laboratory, and treating the keratitis effectively with topical antifungal agents. Unfortunately, delayed diagnosis is common, primarily because of lack of suspicion. When a diagnosis has been made, management remains a challenge because of the poor corneal penetration of antifungal agents. The common etiology of fungal keratitis is a result of the frequent use of topical corticosteroids along with antibacterial agents in treating patients with keratitis, trauma with vegetable matter, contact lens use, ocular surface disease, following ocular surgery like penetrating keratoplasty. A total of 70 different fungi have been implicated as causing fungal keratitis. Medically, the most important groups responsible for corneal infection along with their frequency of isolation in northern India are as follows: 
  1. Aspergillus sp. 40%
  2. Fusarium sp 16%
  3. Candida albicans 8%
  4. Curvularia sp 8%
  5. Acremonium sp 6 %
  6. Paecilomyces sp. 5%
  7. Penicillium sp 3% 

In India, the incidence of fungal keratitis varies according to the geographical location and ranges from 44% to 47%. Fungal keratitis is more common in males than in females and often occurs in patients with a history of outdoor ocular trauma.

Fungi gain access into the corneal stroma through a defect in the epithelium, then multiply and cause tissue necrosis and an inflammatory reaction. The epithelial defect usually results from trauma (eg, contact lens wear, foreign material, prior corneal surgery). The organisms can penetrate an intact Descemet membrane and gain access into the anterior chamber or the posterior segment. Mycotoxins and proteolytic enzymes augment the tissue damage. Fungal keratitis also has been described to occur secondary to fungal endophthalmitis. In these cases, fungal organisms extend from the posterior segment through the Descemet membrane and into the corneal stroma. Another possibility is entry through the corneoscleral trabeculae in to the many channels in the cornea that exist as a network.

Fungi cannot penetrate the intact corneal epithelium. They need a penetrating injury or a previous epithelial defect to enter the cornea. Once within the cornea, however, they are able to proliferate and spread through the corneal channels. Filamentous fungi proliferate within the corneal stroma without release of chemotactic substances, thereby delaying the host immune/inflammatory response. In contrast, Candida albicans produces phospholipase A and lysophospholipase on the surface of blastospores, facilitating the entrance to the tissue. Fusarium solani, which is a virulent fungus, is able (as are other filamentous fungi), to spread within the corneal stroma and penetrate the Descemet membrane. The trauma that accompanies contact lens wear is miniscule; contact lenses are not a common risk factor of fungal keratitis. Candida is the principal cause of keratitis associated with therapeutic contact lenses, and filamentous fungi are associated with refractive contact lens wear. Photorefractive keratectomy and laser in-situ keratomileusis (LASIK) cases, on a rare occasion, can develop fungal infection, which may result in severe damage to the cornea, even loss of an eye. Infections may develop in a series of patients if an infected fluid is used in a number of patients at one session. Topical steroid use has definitively been implicated as a cause of increased incidence, development, and worsening of fungal keratitis. Other risk factors to consider are foreign bodies, and immunosuppressive diseases.

Routinely used investigations for diagnosis are Grams stain, Giemsa stain and 10% KOH mount to identify fungal elements in corneal scrapings. Calcoflour white stain and acridine orange are used when fluorescence microscope is available. Other microscopic methods are Immunofluorescense staining, Electron microscopy and Confocal microscopy. Culture media include Sabourauds dextrose agar, blood agar, brain heart infusion broth. Culture is positive in 83% cases in 72 hours and 93% cases in the 1st week. Usually two weeks are needed to declare a culture to be negative for fungal growth. Corneal biopsy can be performed in culture negative cases. Histopathologic examination of corneal buttons can reveal the presence of fungal elements in 75% of patients. Fungal hyphae usually lie parallel to the corneal surface and lamellae. The presence of vertical oriented fungal elements in regard to stromal lamellae depicts high virulence of the organism and usually is associated with more aggressive infection. The Descemet membrane may serve as a partial barrier for invasion of fungal organisms. 

Penetration of the Descemet membrane by the fungal elements depicts an aggressive organism and a higher risk for contamination of the globe. 
Polymerase chain reaction or PCR is another newer investigation modality with highest positive detection rate; used in culture and smear negative cases, the only drawback being that it is very expensive.

Antifungal Agents In Common Use
1. Amphotericin B
Used as topical eyedrops 1.5-5mg/ml and intrastromal and intracameral injection 3-10mcg/0.1ml.
Mainly used in candida and aspegillus keratitis.
2. Natamycin
Used as 5% eyedrops primarily in filamentous fungal keratitis.
3. Voriconazole
Used as oral dose 200mg bd, topical eyedrops 1mg/ml and intrastromal and intracameral injection 50mcg/0.1ml. Good efficacy against fusarium species.
4. Ketoconazole 
Oral tablet 100-400 mg bd dose in deep fungal keratitis, scleritis and endophthalmitis.
5. Fluconazole
Oral dose 200-400 mg/day, eyedrops 2mg/ml, subconjunctival injection 2mg/ml. indications are similar to ketoconazole.
6. Other antifungals
Miconazole subconjunctival injection
Econazole topical eyedrops
Itraconazole topical and oral form
Flucytosine eyedrops
Caspofungin and micafungin eyedrops
Posaconazole topical and systemic use

Antimicrobial peptides, collagen crosslinking and Rose Bengal aided photodynamic therapy still need to be evaluated in terms of safety, feasibility and efficacy.
AMB acts on both yeasts and filamentous fungi. It has an excellent spectrum, being effective against Candida spp., Aspergillus spp, Penicillium marneffei, Cryptococcus spp. and the causative agents of mucormycosis. It is also effective, to a lesser extent, against the main Fusarium sp.8

When used as a topical antifungal agent, Amphotericin B has broad spectrum antifungal activity but strong cytotoxicity at high concentrations and poor corneal penetration. Intracameral injections of Amphotericin B are not very effective at inhibiting thehypha growth in the stroma and usually cause some complications, including immediate anterior chamber reactions, secondary glaucoma, and cataract. Subconjunctival injections can produce long-standing periocular inflammation and can lead to epithelial ulcerations, with little penetration into the aqueous.9 Combined intrastromal and intracameral injection of Amphotericin B is recommended, if the infection is not controlled with 1 week of the intracameral x`injection, shows a tendency to aggravation, and presents with serious corneal damage and intraocular extension such as severe corneal inflammation, diffuse edema and opacity, local staphyloma and descemetocele, increasing endothelial plaque and hypopyon, or visible fungal mass in the anterior chamber and pupillary space. The clinical signs of a healing fungal kerataitis are 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 re-epithelization and loss of the feathery perimeter of the stromal inflammation.

Some corneal manifestations of toxicity after intrastromal injections are protracted epithelial ulceration, punctate corneal epithelial erosion and diffuse stromal haze.
To summarise, fungal keratitis should be kept in mind in the differential diagnosis of keratitis, especially if there is a risk factor; because devastating ocular consequences that can occur if the diagnosis and treatment is not made promptly.

References
  1. Qu L, Li L, Xie H. Corneal and aqueous humor concentrationsof amphotericin B using three different routes ofadministration in a rabbitmodel. Ophthalmic Research 2013; 43:153–8.
  2. Schwartz SD, Harrison SA, Engstrom RE Jr, Bawdon RE, Lee DA,. et al. Collagen shield delivery of amphotericin B. Am J Ophthalmol 1990; 109:701-4.
  3. Garcia-Valenzuela E, Song CD. Intracorneal injection of amphothericin B for recurrent fungal keratitis and endophthalmitis. Arch Ophthalmol. 2005; 123:1721-3.
  4. Yilmaz S, Ture M, Maden A. Efficacy of intracameral amphotericin B injection in the management of refractory keratomycosis and endophthalmitis. Cornea 2007; 26:398–402.
  5. Kaushik S, Ram J, Brar GS, Jain AK, Chakraborti A, Gupta A. Intracameral amphotericin B: initial experience in severe keratomycosis. Cornea 2001; 20:715-9.
  6. Kuriakose T, Kothari M, Paul P, Jacob P, Thomas R. Intracameral amphotericin B injection in the management of deep keratomycosis. Cornea 2002; 21:653-6.
  7. Hu J, Zhang J, Li Y, Han X, Zheng W, Yang J, et al. A combination of Intrastromal and Intracameral Injections of Amphotericin B in the Treatment of Severe Fungal Keratitis. J Ophthalmol 2016; 2016:3436415. 
  8. Müller, Kara-José N, Silvestre de Castro R. Antifungals in eye infections: drugs and routes of administration. Rev Bras Oftalmol 2013; 72:132-41.
  9. O’Day DM, Pepose JS, Holland GN, Wilhelmus KR. Fungal keratitis, in Ocular Infection and Immunity. Mosby Year-Book 1996:1048–61.


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Bibek Kumar, N. Z. FarooquiRecalcitrant Candidal Corneal Ulcer- A Therapeutic Challenge.DJO 2018;28:44-47
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Bibek Kumar, N. Z. FarooquiRecalcitrant Candidal Corneal Ulcer- A Therapeutic Challenge.DJO [serial online] 2018[cited 2018 May 21];28:44-47. Available from: http://www.djo.org.in/articles/28/3/RecalcitrantCandidalCornealUlcerATherapeuticChallenge.html
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