Combination of symptoms, history indicate diagnosis of fungal keratitis

Issue: September 2006

ByMarc D. Myers, OD, FAAO

ByAndrew S. Gurwood, OD, FAAO

Many organisms have the ability to infect human tissue. Of these organisms, some have developed a propensity for tissues of the eye. Bacteria, viruses and, less often, fungi result in mild to severe infections that have the ability to affect the adnexae and superficial ocular surface as well as tissue of the posterior pole.

Mycoses, infections caused by fungi invading the cornea, have recently been seen in increasing numbers, raising concerns and increasing the overall awareness of their signs, symptoms and clinical skills necessary to treat these potentially vision-threatening diseases.

As members of the kingdom Monera, bacteria are prokaryotic cells, which are cells without nuclei that possess membrane-bound organelles. Vastly different and consisting of more than 100,000 species, the kingdom Fungi are eukaryotic cells — single-celled or multicellular organisms whose cells contain a distinct membrane-bound nucleus. Although numerous fungi are capable of causing ocular infections, the common members belong to the phylum or division Ascomycota. These fungi (Fusarium, Candida, Curvularia and Aspergillus) have the capability of producing virulent corneal infections.

Similar to the way in which bacterial ocular infections are seeded, fungal infections may be transmitted by traumatic events (where organisms infect directly contacted ocular tissue that has come into proximity with plant or vegetable matter), by ocular and/or systemic disease, through poor habits associated with contact lens wear or by increased host susceptibility secondary to the application of topical or oral corticosteroids.

Fusarium keratitis: Corneal infections due to fungi usually have a dirty gray color with associated granular or feathery appearing infiltrates, giving the lesion indistinct margins.
Image: University of Iowa

Etiology of an infection

Differentiating the etiology of an infection begins with a thorough history and also requires knowledge of traditional clinical presentations. In cases that involve nonspecific clinical features, even the best clinician may be presented with a dilemma when using only clinical findings to determine a diagnosis.

While fungal infections are slow moving and progressive, they are capable of manifesting 24 to 48 hours following the initial incidence of contact. Corneal infections due to fungi usually have a dirty gray color with associated granular or feathery appearing infiltrates, giving the lesion indistinct margins. Minimal stromal inflammation is hallmark, but severe infections may break this rule, producing enough damage to render the cornea completely opaque. The presence of an anterior chamber reaction or a hypopyon also connotes an increased level of virulence.

Laboratory studies used to accurately confirm the diagnosis of ocular fungal infection include both stains and cultures. Gram’s and Giemsa stains are routinely used to rule out ocular fungal infection. Gomori’s methenamine silver stain and periodic acid-Schiff stain are considered optional. Culture media may include Sabouraud’s dextrose agar without cyclohexamide, blood agar at room temperature or brain-heart infusion agar with gentamicin added.

It must be noted that when a fungal infection of the cornea is suspected, scrapings from deep within the base of the ulcer are necessary. Most fungal organisms display a pattern of growth within a week of culturing, but some fungi may take up to 2 weeks. If laboratory testing is negative despite a strong suspicion that the infection is fungal, corneal biopsy may be indicated.

Symptoms of fungal keratitis

Common symptoms of a patient with a fungal keratitis may include pain, photophobia, conjunctival injection, tearing, discharge (usually mucopurulent) and foreign-body sensation. In addition, these patients may report a persistent corneal problem that has already failed traditional anti-infective regimens. These findings in conjunction with added historical and clinical findings strongly suggest the diagnosis of fungal keratitis.

Fungal keratitis treatment

When the diagnosis of fungal keratitis is made, the treatment of choice for a lesion involving the anterior stroma is Natacyn (natamycin 5% ophthalmic suspension, Alcon) — the only commercially available ophthalmic antifungal preparation. The customary dosage of Natacyn is one drop every hour while awake and every 2 hours at night until improvement of the lesion is observed. In addition to the antifungal medication, cycloplegia using atropine 1%, homatropine 5% or scopolamine 0.25% helps with pain reduction.

In the event that an inflammatory response results in a significant elevation in intraocular pressure, a topical beta-blocker is recommended for the acute management of the response. It is critical to avoid the use of topical steroids in fungal keratitis management. If the patient is using a topical steroid to manage a separate ocular condition, that medicine should be tapered abruptly.

Cases of worsening or recalcitrant fungal keratitis should be referred to a corneal specialist for more aggressive medical or surgical treatment. Medical therapy is challenging for even the most experienced specialist, as organisms have the potential to be resistant to the available prescription preparations. In fact, the low solubility of these drugs in solution reduces their ability to enter the tissue of the eye. It is important to note that most of the preparations result in local ocular toxicity even with conservative use.

Off-label treatment options

A parenteral antifungal drug that has been used for topical ocular therapy is amphotericin B. While this use is off label, it is considered customary and within the standard of care. Typically, a solution of 0.15% is made from the commercial intravenous preparation intended for systemic use. Amphotericin, classified as a polyene, disrupts the function of the fungal cell membrane and alters its selective permeability, allowing the escape of essential intracellular constituents.

Acute management using the 0.15% solution commonly includes dosing every hour while awake and every 2 to 4 hours overnight. Perhaps the greatest limitation of amphotericin is that it has a propensity to cause ocular surface toxicity because of the vehicle that maintains the drug in solution. This side effect poses serious challenges when a prolonged period of therapy (6 to 10 weeks) is required.

In addition to the topical use of amphotericin, subconjunctival injections have also been used off label in the management of fungal corneal ulcers. Here, the principal side effect is that these injections may result in permanent yellowing of the cornea as well as salmon-colored conjunctival nodules at the site of injection.

Miconazole has been used subconjunctivally, intravenously and in 0.1% to 1.0% topical preparations for off-label treatment of corneal infections caused by Candida and Aspergillus. The antifungal mechanism of action of miconazole includes a fungistatic component that alters cell membrane permeability, along with a fungicidal action of damaging the cell membrane. Unlike amphotericin, miconazole has no associated major adverse reactions involving ocular tissue.

Clotrimazole also may be prepared as a 0.1% to 1.0% solution for off-label treatment of fungal keratomycosis. Considered quite effective for the treatment of infections due to Aspergillus, clotrimazole is used one drop every hour while awake. Newer generations of antifungal preparations that are being considered for managing corneal fungal infections include itraconazole, voriconazole and micafungin.

Final option: Surgery

When medical intervention fails, the surgical option used to preserve vision is penetrating keratoplasty. The incidence of success in these cases depends upon the health of the host cornea, whose intact infrastructure is necessary to support the graft.

Fungal keratitis is a potentially vision-threatening entity that requires timely accurate diagnosis and aggressive management to limit complications. When diagnosed and managed properly, it will respond to topical therapies; however, in complicated or recalcitrant cases, it should be referred to a corneal specialist so all options can be investigated.

For more information:

Andrew S. Gurwood, OD, FAAO, is an associate professor of clinical sciences and an attending optometric physician at The Eye Institute of the Pennsylvania College of Optometry. He is also a member of the clinical staff in the Department of Ophthalmology at Albert Einstein Medical Center in Philadelphia. He was recognized by the American Optometric Association as Young Optometrist of the Year in 1998. Dr. Gurwood can be reached at the Pennsylvania College of Optometry, 1200 West Godfrey Ave., Philadelphia, PA 19141; (215) 276-6134; fax: (215) 276-1329; e-mail: Agurwood@pco.edu.

Marc D. Myers, OD, FAAO, is a staff optometrist in the southern New Jersey area in an ocular disease and refractive surgery practice. He completed a primary care residency at the Eye Institute of the Pennsylvania College of Optometry. He can be reached at (856) 691-8188. Drs. Gurwood and Myers have no direct financial interest in the products mentioned in this article, nor are they a paid consultant for any companies mentioned.

Suggested reading

Al-Mezaine H, Wagoner MD, King Khaled Eye Specialist Hospital Cornea Transplant Study Group. Repeat penetrating keratoplasty: Indications, graft survival, and visual outcome. Br J Ophthalmol. 2006;90(3):324-327.

Beckingsale P, Mavrikakis I, Al-Yousuf, Mavrikakis E, Daya SM. Penetrating keratoplasty: outcomes from a corneal unit compared to national data. Br J Ophthalmol. 2006;90(6):728-731.

Bharathhi MJ, Ramakrishnan R, Vasu S, Meenakshi R, Palaniappan R. Epidemiological characteristics and laboratory diagnosis of fungal keratitis. A three-year study. Indian J Ophthalmol. 2003;51(4):315-321.

Centers for Disease Control and Prevention (CDC). Fusarium keratitis — multiple states, 2006. MMWR Morb Mortal Wkly Rep . 2006;55(14):400-401.

Centers for Disease Control and Prevention (CDC). Update: Fusarium keratitis — United States, 2005-2006. MMWR Morb Mortal Wkly Rep. 2006;55(20):563-564.

Cornea: fungal keratitis. In: Kunimoto DY, Kunal D, Kunitkar KD, Makar M. The Wills Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease, 4^th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:57.

Elliot D, Gollamundi SR. Cornea: fungal keratitis. In: Varma R. Essentials of Eye Care: The Johns Hopkins Wilmer Handbook. Philadelphia, PA: Lippincott-Raven; 1997:177-178.

Garcia-Valenzuela E, Song CD. Intracorneal injection of amphothericin B for recurrent fungal keratitis and endophthalmitis. Arch Ophthalmol. 2005;123(12):1721-1723.

Kalavathy CM, Parmar P, Kaliamurthy J, et al. Comparison of topical itraconazole 1% with topical natamycin 5% for the treatment of filamentous fungal keratitis. Cornea. 2005;24(4):449-452.

Kumari N, Xess A, Shahi SK. A study of keratomycosis: our experience. Indian J Pathol Microbiol. 2002;45(3):299-302.

Lalitha P, Prajna NV, Kabra A, Mahadevan K, Srinivasan M. Risk factors for treatment outcome in fungal keratitis. Ophthalmology. 2006;113(4):526-530.

Matsumoto Y, Dogru M, Goto E, Fujishima H, Tsubota K. Successful topical application of a new antifungal agent, micafungin, in the treatment of refractory fungal corneal ulcers: Report of three cases and literature review. Cornea. 2005;24(6):748-753.

Microbiology and Immunology On-line, University of South Carolina School of Medicine. Part Five: Mycology, Chapters one through five. Available at http://pathmicro.med.sc.edu/book/welcome.htm.

Mirza SH, Hart CA. Fungal keratitis due to fusarium solani. J Coll Physicians Surg Pak. 2005;15(9):576-577.

Mselle J. Use of topical clotrimazole in human keratomycosis. Ophthalmologica. 2001;215(5):357-360.

Ritterband DC, Seedor JA, Shah MK, Koplin RS, McCormick SA. Fungal keratitis at the New York Eye and Ear Infirmary. Cornea. 2006;25(3):264-267.

Sangwan VS, Ramamurthy B, Shah U, Garg P, Sridhar MS, Rao GN. Outcome of corneal transplant rejection: A 10-year study. Clin Experiment Ophthalmol. 2005;33(6):623-627.

Sponsel W, Chen N, Dang D, et al. Topical voriconazole as a novel treatment for fungal keratitis. Antimicrob Agents Chemother. 2006;50(1):262-268.

Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004;15(4):321-327.

Sukhija J, Jain AK. Outcome of therapeutic penetrating keratoplasty in infectious keratitis. Ophthalmic Surg Lasers Imaging. 2005;36(4):303-309.

Thomas PA. Fungal infections of the cornea. Cambridge Ophthalmological Symposium 2003;17(8):852-862.