Treatment of dematiaceous fungal keratitis in a dog

Jonathan D. Pucket Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Rachel A. Allbaugh Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Amy J. Rankin Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Abstract

Case Description—A 9-year-old castrated male Bichon Frise was evaluated because of a 3-week history of a nonhealing corneal ulcer and corneal pigmentation of the left eye.

Clinical Findings—Ophthalmic examination of the left eye revealed conjunctival hyperemia, corneal neovascularization, corneal edema, corneal ulceration, and central corneal pigmentation. Intraocular structures of the left eye could not be visually examined because of the diffuse nature of the corneal lesions. The right eye had anterior cortical incipient cataracts, nuclear sclerosis, and an inactive chorioretinal scar.

Treatment and Outcome—Superficial lamellar keratectomy of the left eye was performed for both therapeutic and diagnostic purposes. Histologic evaluation of corneal biopsy specimens revealed dematiaceous fungal keratitis of the left eye, and topical administration of voriconazole was used to successfully resolve the keratitis. Seven months after diagnosis of dematiaceous fungal keratitis, the dog had no clinical signs or history of recurrence of the keratitis.

Clinical Relevance—Dematiaceous fungal keratitis should be considered as a possible cause of nonhealing corneal ulceration with heavy pigment deposition in dogs. Results suggested that lamellar keratectomy along with topical administration of voriconazole can be used successfully to treat dematiaceous fungal keratitis in dogs.

Abstract

Case Description—A 9-year-old castrated male Bichon Frise was evaluated because of a 3-week history of a nonhealing corneal ulcer and corneal pigmentation of the left eye.

Clinical Findings—Ophthalmic examination of the left eye revealed conjunctival hyperemia, corneal neovascularization, corneal edema, corneal ulceration, and central corneal pigmentation. Intraocular structures of the left eye could not be visually examined because of the diffuse nature of the corneal lesions. The right eye had anterior cortical incipient cataracts, nuclear sclerosis, and an inactive chorioretinal scar.

Treatment and Outcome—Superficial lamellar keratectomy of the left eye was performed for both therapeutic and diagnostic purposes. Histologic evaluation of corneal biopsy specimens revealed dematiaceous fungal keratitis of the left eye, and topical administration of voriconazole was used to successfully resolve the keratitis. Seven months after diagnosis of dematiaceous fungal keratitis, the dog had no clinical signs or history of recurrence of the keratitis.

Clinical Relevance—Dematiaceous fungal keratitis should be considered as a possible cause of nonhealing corneal ulceration with heavy pigment deposition in dogs. Results suggested that lamellar keratectomy along with topical administration of voriconazole can be used successfully to treat dematiaceous fungal keratitis in dogs.

A 9-year-old castrated male Bichon Frise was referred to the Kansas State University Veterinary Medical Teaching Hospital for evaluation of a nonhealing corneal ulcer of the left eye. The ulcer had been detected 3 weeks previously and had recently developed axial corneal pigmentation. Initially, the referring veterinarian had treated the dog with topical administration of neomycin-polymixin-bacitracin ophthalmic ointment every 6 hours and 1% atropine sulfate ophthalmic solution every 12 hours in the left eye, and carprofen (2.2 mg/kg [1 mg/lb], PO, q 12 h) to alleviate pain and inflammation. After 1 week of treatment, the ulcer was not healing as expected; therefore, the loose epithelial edges were debrided with a swab, and a grid keratotomy and third eyelid flap surgery were performed to assist in healing. One week later, the third eyelid flap was removed and axial corneal pigmentation was detected. Administration of neomycin-polymixin-bacitracin was discontinued, topical administration of 0.3% gentamicin sulfate ophthalmic solution every 6 hours in the left eye was initiated, and administration of the 1% atropine ophthalmic solution and carprofen was continued. The dog was referred to the teaching hospital 1 week later because of lack of improvement in corneal ulceration and the deposition of an unknown pigment in the cornea.

At the teaching hospital, a complete physical examination revealed mild dental tartar and bilateral medially luxating patellas (grade II/IV). A CBC and serum biochemical analysis revealed no clinically relevant abnormalities. Ophthalmic examination revealed menace and palpebral reflexes within expected limits in both eyes. Direct and indirect pupillary light reflexes (left to right) were positive in the right eye but were not detected in the left eye because of the diffuse corneal lesions. Diffuse transillumination was used to examine both eyes; abnormalities were detected only in the left eye and included mild blepharospasm, a small amount of mucoid discharge, moderate conjunctival hyperemia, substantial peripheral corneal neovascularization, corneal edema, loose corneal epithelial edges surrounding the ulcerated region, and superficial axial corneal pigmentation. Examination of the left eye with slit-lamp biomicroscopya revealed that the pigmented area was avascular and had a plaque-like appearance (Figure 1). Intraocular structures could not be visually examined because of the corneal lesions. Slit-lamp examination of the right eye revealed nuclear sclerosis and anterior cortical incipient cataracts. Indirect ophthalmoscopyb following complete pupillary dilation with 1% tropicamide solutionc revealed an inactive chorioretinal scar in the inferiomedial nontapetal fundus of the right eye. The chorioretinal scar was 3 optic nerve heads in diameter, and its cause or importance was not determined. Schirmer tear test Id values were found to be within reference limits (right eye, 17 mm/min; left eye, 15 mm/min; reference range, 15 to 30 mm/min). Intraocular pressures obtained via rebound tonometrye were 14 and 9 mm Hg (reference range, 10 to 20 mm Hg) in the right and left eyes, respectively. Prior to application of topical anesthetic, sterile swabs were used to obtain samples from the ulcerated area of the left cornea. The swab specimens then were submitted for aerobic and anaerobic bacterial cultures and susceptibility testing; no bacterial growth was obtained on culture. After instillation of a topical anestheticf in the left eye, a microbrushg was used to obtain cells from the ulcerated area of the cornea for cytologic evaluation. The cells were transferred to slides and stained with Wright-Giemsa stain. Cytologic evaluation revealed epithelial cells and neutrophilic inflammation but no infectious organisms. Fluorescein stainingh of the left eye resulted in positive uptake of the stain around the loose edges of epithelium surrounding the pigmented region.

Figure 1—
Figure 1—

Photographs of the clinical progression of a corneal lesion in the left eye of a 9-year old castrated male Bichon Frise that was referred to a teaching hospital because of a nonhealing corneal ulcer of 3-weeks' duration. Histologic evaluation of a corneal biopsy specimen obtained by superficial lamellar keratectomy led to a diagnosis of dematiaceous fungal keratitis, and the dog was successfully treated with topical administration of voriconazole. A—In the left eye during initial ophthalmic examination at the teaching hospital prior to keratectomy and treatment with voriconazole, notice the brown superficial avascular pigmentation of the cornea that prevented visual examination of intraocular structures. B—In the left eye 1 week after keratectomy, the corneal lesions are sufficiently improved to allow evaluation of intraocular structures. C—In the left eye 8 weeks after keratectomy (1 week after stopping topical voriconazole treatment), notice the complete resolution of the keratitis with minimal scarring.

Citation: Journal of the American Veterinary Medical Association 240, 9; 10.2460/javma.240.9.1104

Anesthesia was induced with propofol (5 mg/kg [2.3 mg/lb], IV, to effect) and maintained with isoflurane mixed with oxygen. Lamellar keratectomy was performed to excise the area of abnormal corneal pigmentation of the left eye. Excision of the lesion extended into the rostral 20% of the corneal stroma, and care was taken to remove all pigmented portions of the cornea. The excised tissue was immersion-fixed in neutral-buffered 10% formalin and submitted to the Comparative Ocular Pathology Laboratory of Wisconsin for histologic examination. Because of the superficial depth of the resulting corneal defect, a grafting procedure was not necessary. Medical treatment was continued after surgery and included topical administration of tobramycin ophthalmic solutioni every 6 hours, 1% atropine ophthalmic solutionj every 24 hours, and artificial ophthalmic lubricant gelk every 6 to 8 hours in the left eye and deracoxibl (1 mg/kg [0.45 mg/lb] PO, q 24 h). An Elizabethan collar was prescribed to be on the dog at all times until the follow-up examination 1 week after surgery.

At the examination 1 week after surgery, the left eye had no blepharospasm or discharge. The conjunctival hyperemia had resolved, and there was no evidence of corneal pigmentation. The corneal neovascularization and edema had decreased considerably, and the ulcer had epithelialized (Figure 1). However, there was a white central corneal opacity deep to the keratectomy site.

At this time, results of the histologic evaluation of the corneal biopsy specimens became available and revealed severe neutrophilic, collagenolytic keratitis with a myriad of intralesional hyperpigmented dematiaceous fungi. Incomplete excision of the fungal infection was also detected; nonbranching chains of fungi were seen extending into the deeper layers of the corneal stroma (Figure 2). On the basis of the histologic diagnosis and the white central opacity at the keratectomy site, topical administration of voriconazole,m an antifungal medication, was initiated in the left eye every 6 hours. All other medications remained the same until the next examination.

Figure 2—
Figure 2—

Photomicrograph of a tissue section from the superficial corneal stroma of the left eye of the dog in Figure 1. Notice the dematiaceous fungal organisms (asterisk) throughout the section. H&E stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 240, 9; 10.2460/javma.240.9.1104

At the examination 3 weeks after surgery, the corneal neovascularization and edema had resolved and only a faint corneal haze remained in the region of the lamellar keratectomy. Resolution of the corneal lesions allowed visual inspection of intraocular structures in the left eye, and incipient anterior cortical cataracts with nuclear sclerosis were detected. On the basis of the clinical response to treatment, administration of voriconazole was continued topically every 6 hours in the left eye, and all other medications were discontinued. Four weeks after initiation of topical voriconazole treatment, administration was decreased to every 8 hours for 2 weeks; voriconazole treatment was then discontinued. One week after discontinuation of topical voriconazole treatment, the dog was reexamined and had no clinical signs or corneal lesions (Figure 1). The dog's owner was contacted via telephone 5 months after discontinuation of medications and reported that the dog had had no recurrence of clinical signs or pigmentation in the left eye.

Discussion

Fungal keratitis is an uncommon disease in small animal patients. This type of corneal disease is more frequently reported in equine and human patients, with few reports1–4 in small animal patients. Most cases of fungal keratitis are thought to be initiated by corneal damage, usually of traumatic origin.4,5 Once fungal organisms adhere to the exposed stroma of the cornea, they can penetrate more deeply and lead to corneal perforation.6 There may also be concurrent bacterial infections caused by commensal or pathogenic bacteria. A superficial fungal infection of the eyes caused by dematiaceous fungi is referred to as corneal phaeohyphomycosis.7

Dematiaceous fungi are a group of darkly pigmented, saprophytic fungal organisms that can be found worldwide but are most commonly found in tropical and subtropical climates.8 They are named for the characteristic production of melanin in their cell walls, which is easily detected via microscopic examination. The production of melanin by the fungi is generally downregulated at core body temperatures, but when the organisms are exposed to cooler temperatures, such as those on the surface of the cornea or skin, melanin production and pigmentation can develop.9 Melanin in the cell walls of these dematiaceous fungi increases the resistance of the fugal cells to death and may contribute to their pathogenicity.9 Melanin may also provide a protective advantage by scavenging free radicals and hypochlorite produced by phagocytic cells.10 Melanin can also bind to hydrolytic enzymes, thereby preventing lysis of the fungal cell membrane. These protective mechanisms help these pathogenic fungi cause infections in immunocompetent individuals.10

A swab specimen for fungal culture was obtained from the left eye of the dog of the present report but was not submitted, so it is unknown whether a fungal culture would have accurately identified the organism, especially given that corneal fungal cultures often yield false-negative results.11,12 Antifungal susceptibility testing is generally not performed because it is extremely expensive and time-consuming.13 The lack of submission of the specimen for fungal culture was not discovered until after the results of the histologic examination were obtained and the ulcer had epithelialized. Because the dog appeared comfortable and was improving clinically by the time the histologic results became available, the ulcer was not denuded of epithelium to obtain another sample for fungal culture in an attempt to identify the causative agent. Fungal organisms reported to cause corneal disease in dogs include Acremonium spp, Alternaria spp, Aspergillus spp, Candida spp, Cephalosporium spp, Curvularia spp, Fusarium spp, Pseudallescheria spp, and Scedosporium spp.1,2,4 Of these, Alternaria spp and Curvularia spp are dematiaceous fungi, with Curvularia spp being the fungal organisms most commonly associated with keratitis in both humans and species of veterinary interest.1,9,14

Predisposing factors for the development of fungal keratitis include trauma, immunocompromise, previous corneal surgery, and topical treatment with corticosteroids or antimicrobials.13,15 In the dog of the present report, it was suspected that the superficial, nonhealing corneal ulcer resulted in a breach in the ocular surface barriers that enabled the fungal organisms to infect the cornea. The exact source of the organisms was unknown, but most cases of dematiaceous fungal keratitis originate from contaminated soil or plant material.2,9 Although it is possible that the grid keratotomy caused the ocular trauma that allowed the fungal organisms to gain access to the corneal stroma and establish an infection, it was considered unlikely because there was a visible grid pattern on the plaque-like pigmented area (ie, fungal plaque) detected during the initial ophthalmic evaluation at the teaching hospital, which suggested that the ulcer was already infected at the time of keratotomy. The third eyelid flap surgery performed immediately after the keratotomy may have contributed to the establishment of the fungal infection by causing a disruption of the ocular defenses and allowed the organisms the opportunity for prolonged contact with the corneal stroma.

The surface of the cornea is cooler than a dog's core body temperature, which likely resulted in the production of melanin in the cell walls of the dematiaceous fungi as they replicated. This was visually evident as a superficial brown pigmentation of the central cornea detected during the initial ophthalmic examination at the teaching hospital. Pigmented lesions on the corneas of small animals with dematiaceous fungal keratitis have been infrequently reported.2

Despite the fact the ulcer had been existent for at least 3 weeks prior to initial examination at the teaching hospital, the ulcer remained shallow and most of the fungal organisms were confined in the anterior corneal stroma. The reason the fungi did not extend into the deeper structures of the cornea is unknown, but this finding was consistent with other reports1,16 of dematiaceous fungal keratitis in that chronic ulcerations were confined to the superficial corneal stroma. These ulcerations can progress into infections involving deeper structures of the cornea if they are not appropriately treated.16 The reason the infection did not extend into deeper structures of the eye in the dog of the present report may have been the topical use of antimicrobials because topical ophthalmic antimicrobials have been reported to have some inhibitory effects on fungal organisms.17 The antimicrobials evaluated in that report17 (amoxicillin, cefazolin, chloramphenicol, moxifloxacin, tobramycin, and benzalkonium chloride) were not the same as those used in the dog of the present report. However, gentamicin was used in the dog of the present report and is in the same drug class (aminoglycoside) as tobramycin, so it may have a similar spectrum of activity against fungal organisms.

Treatment for fungal keratitis in small animal patients can include both medical and surgical management, but medical management is used most frequently. Superficial lamellar keratectomy can be an effective treatment for noninvasive and noninfectious corneal disease18,19 and may be beneficial for the treatment of superficial infectious disease. In the dog of the present report, superficial lamellar keratectomy was performed for both diagnostic and therapeutic purposes, and although it aided the resolution of the corneal ulcer, it did not cure the infection, as evidenced by the penetration of the fungal organisms into the deeper tissues of the cornea detected during histologic evaluation. Because the fungal infection extended beyond the surgical margins of the lamellar keratectomy, topical antifungal treatment was used to eradicate the remaining fungal organisms.

Several systemically and topically administered antifungal drugs have been used with variable success to treat fungal disease in veterinary patients; these drugs include polyenes, azoles, allylamines, lipopeptides, and pyrimidines.20 Antifungal treatment of fungal keratitis in small animal patients is best achieved with topical ophthalmic antifungals. Benefits of topical ophthalmic antifungal treatment include higher drug concentrations at the site of infection, no necessity for hepatic metabolism, and fewer adverse systemic effects.20 The most commonly prescribed antifungals for topical ophthalmic use include natamycin, amphotericin B, miconazole, and voriconazole.1,20,21 Although natamycin is the only commercially available and approved antifungal for topical ophthalmic use, it does not penetrate intact corneal epithelium well, and investigators of another study22 reported no benefit for its use, compared with that for the use of voriconazole. For the dog of the present report, natamycin was not used because the corneal epithelium was intact (as evidenced by the lack of fluorescein stain uptake) at the time fungal keratitis was diagnosed. Of the remaining options for topical ophthalmic treatment, voriconazole was chosen because of its ability to penetrate both intact and damaged corneal epithelium,23,24 in vivo and vitro activity against dematiaceous fungal organisms,25 and superior efficacy, compared with that of other commonly used antifungals, for treatment of a variety of fungal isolates.26,27 The dog of the present report tolerated the topical ophthalmic application of voriconazole well throughout the treatment period, and no adverse effects were reported.

Voriconazole is a second-generation triazole antifungal. It is a derivative of fluconazole but has enhanced potency and a greater spectrum of activity than fluconazole.28 Similar to other azoles, voriconazole inhibits the synthesis of ergosterol, a sterol unique to fungal hyphal membranes; this blockage of ergosterol synthesis inhibits the growth of fungi.24 Voriconazole also binds to the active site of the cytochrome P450—dependent enzyme lanosterol 14-demethylase and li-gates the iron heme cofactor via a nitrogen atom, which results in the accumulation of toxic intermediate sterols that compromise the integrity and function of the fungal membrane and lead to the death of the organism.24

Currently, there is no commercially available formulation of voriconazole for topical ophthalmic use; however, authors of other reports20,22,23 have described the successful use of a diluted IV solution of voriconazole as a topical ophthalmic solution. For the dog of the present report, voriconazole powder (200 mg) was aseptically reconstituted with 19 mL of sterile water to obtain 20 mL of a 10 mg/mL (1%) solution. After reconstitution, the contents were carefully transferred into a sterile ophthalmic dropper bottle for administration. Voriconazole is a lipophilic compound with low solubility in water, so the manufacturer had to encapsulate the drug with a β-cyclodextrin derivative to create a lyophilized powder of cyclodextrin-voriconazole that would remain suspended in an aqueous solution for IV administration.29 This alteration maintains the lipophilicity of voriconazole, which allows for high corneal permeability when it is applied topically.30 Mean recovery of voriconazole after this preparation is > 99%, providing evidence that little of the drug is lost during preparation.31 Once prepared, the preservative-free voriconazole solution is stable and can remain sterile for at least 30 days at room temperature (24°C [75.2°F]) to 4°C (39.2°F).31 However, if prepared with sterile 0.01% benzalkonium chloride solution and kept refrigerated at 2°C (35.6°F) to 8°C (46.4°F), the voriconazole solution will be stable for at least 14 weeks.32

Fungal keratitis is rarely reported in small animal patients, and the finding of a dematiaceous fungal organism in a patient from a nontropical and nonsubtropical region with no history of the patient having traveled outside the region is also uncommon. However, dematiaceous fungal keratitis should be considered whenever a pigmented corneal plaque is associated with corneal ulceration. Bacterial as well as fungal culturing should be performed for any suspicious corneal lesions. It is unknown whether a fungal culture would have identified the causative agent for the dog of the present report. If superficial lamellar keratectomy is performed, histologic examination of a corneal biopsy specimen can be valuable as a diagnostic tool. The present report highlighted the use of superficial lamellar keratectomy and topical administration of voriconazole to successfully diagnose and treat dematiaceous fungal keratitis in a dog.

a.

SL-15, Kowa Co Ltd, Tokyo, Japan.

b.

Vantage Plus wireless binocular indirect ophthalmoscope, Keeler Instrument Inc, Bromall, Pa.

c.

Tropicacyl, Akorn Inc, Lake Forest, Ill.

d.

Schirmer tear test, Schering-Plough Animal Health, Union, NJ.

e.

TonoVet, Jorgensen Laboratories, Loveland, Colo.

f.

Proparacaine hydrochloride ophthalmic solution USP, 0.5%, Falcon Pharmaceuticals, Hünenberg, Switzerland.

g.

Microbrush fine size tube series, Microbrush International, Grafton, Wis.

h.

Bio Glo, HUB Pharmaceuticals LLC, Rancho Cucamonga, Calif.

i.

Tobramycin 0.3% ophthalmic solution, Falcon Pharmaceuticals, Hünenberg, Switzerland.

j.

Atropine sulfate solution, 1%, Falcon Pharmaceuticals, Hünenberg, Switzerland.

k.

GenTeal severe gel, Novartis Pharmaceutical Corp, East Hanover, NJ.

l.

Deramaxx, Novartis Animal Health Inc, East Hanover, NJ.

m.

Vfend IV, Pfizer Inc, New York, NY.

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Contributor Notes

Dr. Allbaugh's present address is Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

Address correspondence to Dr. Pucket (pucket@vet.k-state.edu).
  • Figure 1—

    Photographs of the clinical progression of a corneal lesion in the left eye of a 9-year old castrated male Bichon Frise that was referred to a teaching hospital because of a nonhealing corneal ulcer of 3-weeks' duration. Histologic evaluation of a corneal biopsy specimen obtained by superficial lamellar keratectomy led to a diagnosis of dematiaceous fungal keratitis, and the dog was successfully treated with topical administration of voriconazole. A—In the left eye during initial ophthalmic examination at the teaching hospital prior to keratectomy and treatment with voriconazole, notice the brown superficial avascular pigmentation of the cornea that prevented visual examination of intraocular structures. B—In the left eye 1 week after keratectomy, the corneal lesions are sufficiently improved to allow evaluation of intraocular structures. C—In the left eye 8 weeks after keratectomy (1 week after stopping topical voriconazole treatment), notice the complete resolution of the keratitis with minimal scarring.

  • Figure 2—

    Photomicrograph of a tissue section from the superficial corneal stroma of the left eye of the dog in Figure 1. Notice the dematiaceous fungal organisms (asterisk) throughout the section. H&E stain; bar = 20 μm.

  • 1.

    Ben-Shlomo G, Plummer C, Barrie K, et al. Curvularia keratomycosis in a dog. Vet Ophthalmol 2010; 13:126130.

  • 2.

    Bernays ME, Peiffer RL Jr. Ocular infections with dematiaceous fungi in two cats and a dog. J Am Vet Med Assoc 1998; 213:507509.

  • 3.

    Labelle AL, Hamor RE, Barger AM, et al. Aspergillus flavus keratomycosis in a cat treated with topical 1% voriconazole solution. Vet Ophthalmol 2009; 12:4852.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Marlar AB, Miller PE, Canton DD, et al. Canine keratomycosis: a report of eight cases and literature review. J Am Anim Hosp Assoc 1994; 30:331340.

    • Search Google Scholar
    • Export Citation
  • 5.

    Rampazzo A, Kuhnert P, Howard J, et al. Hormographiella aspergillata keratomycosis in a dog. Vet Ophthalmol 2009; 12:4347.

  • 6.

    Deepe GS, Bullock WE. Immunological aspects of fungal pathogenesis. Eur J Clin Microbiol Infect Dis 1990; 9:567579.

  • 7.

    Rinaldi MG. Phaeohyphomycosis. Dermatol Clin 1996; 14:147153.

  • 8.

    Wilhelmus KR. Climatology of dematiaceous fungal keratitis. Am J Ophthalmol 2005; 140:11561157.

  • 9.

    Wilhelmus KR, Jones DB. Curvularia keratitis. Trans Am Ophthalmol Soc 2001; 99:111130.

  • 10.

    Jacobson ES. Pathogenic roles for fungal melanins. Clin Microbiol Rev 2000; 13:708717.

  • 11.

    Badiee P, Nejabat M, Alborzi A, et al. Comparative study of Gram stain, potassium hydroxide smear, culture and nested PCR in the diagnosis of fungal keratitis. Ophthalmic Res 2010; 44:251256.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Bharathi MJ, Ramakrishnan R, Vasu S, et al. Epidemiological characteristics and laboratory diagnosis of fungal keratitis. A three-year study. Indian J Ophthalmol 2003; 51:315321.

    • Search Google Scholar
    • Export Citation
  • 13.

    Andrew SE. Corneal fungal disease in small animals. Clin Tech Small Anim Pract 2003; 18:186192.

  • 14.

    Boonpasart S, Kasetsuwan N, Puangsricharern V, et al. Infectious keratitis at King Chulalongkorn Memorial Hospital: a 12-year retrospective study of 391 cases. J Med Assoc Thai 2002; 85(suppl 1):S217S230.

    • Search Google Scholar
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