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Cladosporium keratitis – a case report and literature review
© Cheng et al. 2015
Received: 8 January 2015
Accepted: 28 July 2015
Published: 19 August 2015
Fungal keratitis is one of the major causes of infectious keratitis in tropical countries. Symptoms of fungal keratitis consist of blurred vision, redness, tearing, photophobia, pain and foreign body sensation. If not treated effectively, it could lead to blindness. Common causes include Candida spp., Fusarium spp. and Aspergillus spp.. With the limited choices of topical antifungal agents, we were faced with Cladosporium keratitis, a rare cause of fungal keratitis.
A 62-year-old Asian male construction worker came to us with intense ocular pain, injection of the conjunctiva, blurred vision, and foreign body sensation in his left eye. His visual acuity was 20/40 OD and 20/400 OS. Slit-lamp exam revealed a corneal ulcer with feathery margin and Descemet’s membrane folding. The culture yielded Cladosporium species.. The patient did not show improvements after applying topical natamycin (5 %), topical amphotericin B (1mg/ml), topical fluconazole (2mg/ml) and oral ketoconazole (200mg). After shifting the medical regimen to voriconazole via topical and systemic routes (1mg/ml and 200mg respectively), the keratitis was controlled.
Fungal keratitis remains a challenge for ophthalmologists as there is no evidence suggesting any particular drug or combination of drugs is more effective than another. A review of common topical antifungal agents was done. Voriconazole could be a good choice for treating corneal infection by Cladosporium species.
Causative agents for Fungal Keratitis
Molds Dematiaceous fungi
Natamycin is the only drug approved by the United States Food and Drug Administration for treating fungal keratitis. Reports on Cladosporium corneal infection have been scarce . The patient was refractory to a combination of topical and systemic agents.
After switching to voriconazole, we have successfully treated our patient.
The patient was a 62-year-old Asian male construction worker who worked in a dusty environment. Debris made up of cement hit his left eye during work on the 22nd of November 2014. He experienced intense, sharp, and constant pain. Blurred vision, red eye and foreign body sensation were the main clinical manifestations. Photophobia, swelling and watery discharge were also noted. He was referred to our hospital from a local medical clinic 4 days after the incident. His integumentary system was intact without signs of fungal infection. According to the patient’s statement, he had hypertension and diabetes mellitus under medical control for years. He was not a user of contact lenses. The patient claimed that he had a fungal keratitis in his left eye 10 years ago after trauma. Natamycin was used for more than 3 months during that episode.
Leber first documented fungal keratitis in 1879 [7, 8]. Fungal keratitis has preponderance in males with a male to female ratio of 2.25:1 . Molds are far more common than yeast . Patients with ocular trauma were 5.33 times more likely to develop microbial keratitis . The association of trauma was higher for fungal and parasitic keratitis. Out of all fungal keratitis, 81.9 % was caused by trauma . The reason is obvious in that trauma was more often associated with outdoor occupation (e.g. agriculture and manual labor).
Treating fungal keratitis is a laborious process often requiring months.
A literature search using “Fungal keratitis”, “Cladosporium” and “ophthalmic antifungal agents” as keywords in relevant databases (including Medline, Cochrane Library, and PubMed) was performed.
Common topical agents for fungal keratitis
1st day: Q30mins
Nephrotoxic, bone marrow suppression, anemia, headache
2nd day onward: Q1H
5 times a day
Burning, irritation, punctate keratitis, chemosis
Azole – Imidazole derivatives
Punctate epithelial erosions, pruritus, irritation
Ointment: 2 %
Irritation, punctate keratopathy, hepatotoxic, diarrhea, nausea
Q4H ~ QID
Gynecomastia, impotence, hepatotoxic
Azole – Triazole derivatives
Irritation, burning sensation
Visual disturbances, skin rash
Irritation, itching, burning sensation, nausea, vomit, diarrhea
In a general sense, triazoles were used for yeasts and amphotericin B was used for molds. A good initial treatment would be a combination of natamycin 5 % drops and amphotericin B 0.15 % drops. Additional topical, subconjunctival and or systemic treatment could then be considered depending on the depth and severity of the infection and the culture result. The treatment regimen should be adjusted according to the clinical progression based on biomicroscopic signs, repeated corneal scrapings and tolerance of medications. It is also important to put the patient’s compliance into account.
Amphotericin B alters the stability of the membrane by binding to ergosterol and forms pores. It is insufficiently absorbed from the GI tract and due to its poor ocular penetration, administration of higher doses via the intravenous route is needed . Amphotericin also binds to mammalian cholesterol albeit with lower affinity. Thus explaining its side effects. It causes chills and fever and it is notorious for its nephrotoxicity . It is the drug of choice for Candida keratitis. Though also effective against filamentous fungi, it has no activity against Fusarium sp..
Natamycin is the only ophthalmic agent approved by the Food and Drug Administration. It also binds to ergosterol. However, it does not alter the membrane permeability. In stead, it prevents the ergosterol-dependent fusion of vacuoles and membrane fusion and fission . It has good activity against Candida, Aspergillus and Fusarium spp. Though being used as a standard care, the penetration is poor and the bioavailablity is only about 2 % after topical administration . It is therefore not the drug of choice for deep, severe infection.
Corticosteroids (imidazoles or triazoles) inhibit sterol demethylation of lanosterol to ergosterol in fungal membranes. Fluconazole is a safe agent that can be administered orally, intravenously, subconjunctivally or topically. The penetration is well with few side effects . It is limited by its narrow spectrum of antifungal activity. It is inactive against Aspergillus and Fusarium spp. Miconazole has a broad spectrum of activity however, it is toxic systematically and could lead to epithelial erosions topically. It is used as a second-line agent to natamycin .
Voriconazole was first tested for retinal toxicity in rodent animal models . No electroretinographic or histological abnormality was reported with an intravitreal voriconazole concentrations up to 25 μg/mL. Voriconazole has an excellent susceptibility profile against both yeasts and molds. It does not depend on the state of the epithelial surface . The ocular penetration of voriconazole after two 400mg doses of voriconazole 12 h apart was measured at 1.13 μg/mL (53 % of plasma levels) . The safety profile of voriconazole has been reviewed . Visual disturbances including photophobia and/or color change and skin rashes were mild and transient. Even with continued therapy, they typically resolve within 1 month. Oral and IV formulations were approved by FDA for deadly fungal infections in 2002. The broad spectrum of antifungal activity includes species that are resistant to other antifungal agents . In the high-risk group population for developing fungal keratitis or endophthalmitis, voriconazole can also be used as a prophylactic agent .
Despite the recent advancement in diagnosis and treatment of fungal keratitis, 15–27 % require surgery . Surgical mode of treatment includes debridement, penetrating keratoplasty, evisceration, bandage contact lens and corneal transplantation. Surgical intervention is carried out in a significantly larger number of patients with fungal keratitis compared to bacterial and parasitic keratitis thus indicating the poor response of fungal keratitis to medical treatment .
In conclusion, voriconazole could be a good choice for refractory fungal keratitis. We were able to control the Cladosporium keratitis by combining oral and topical voriconazole.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the consent form is available for review by the Editor of this journal.
The authors acknowledge Chang Gang Memorial Hospital for the funding about this manuscript submission (CMRPG6D0361A).
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- Gupta A, Gupta V, Gupta A, Dogra MR, Pandav SS, Ray P, et al. Spectrum and clinical profile of post cataractsurgery endophthalmitis in north India. Indian J Ophthalmol. 2003;51(2):139–45.PubMedGoogle Scholar
- Collier L, Balows A, Sussman M. Topley and Wilson's Microbiology and Microbial Infections, vol. 4. 9th ed. London: (Distributed by Oxford University Press, New York.) Arnold; 1998.Google Scholar
- Liesegang TJ, Forster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol. 1980;90(1):38–47.View ArticlePubMedGoogle Scholar
- Thomas PA. Current Perspectives on Ophthalmic Mycoses. Clinical Microbiology Reviews. 2003;16(4):730–97.View ArticlePubMedPubMed CentralGoogle Scholar
- Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness- A globalperspective. Bull World Health Organ. Bulletin of the World Health Organization. 2001;79(3):214–21.PubMedPubMed CentralGoogle Scholar
- Marconmini LAG, da Silva GCM, Faria-e-Souza SJ. Encouraging Result of Voriconazole Treatment for Cladosporium Corneal Keratitis. Vision Pan-America. 2013;12(4):116–9.Google Scholar
- Chick EW, Conant NF. Mycotic ulcerative keratitis: a review of 148 cases from the literature. lnvest Ophthal. 1962;1.Google Scholar
- Leber T. Keratomycosis aspergillina als ursache von hypopyon keratitis Graefes. Archives of ophthalmology (Arch Ophthal). 1879;25:285–301.Google Scholar
- Ormerod LD et al. Epidemiology of microbial keratitis in southern California. A multivariate analysis. Ophthalmology. 1987;94(10):1322–33.View ArticlePubMedGoogle Scholar
- Pate JC, Jones DB, Wilhelmus KR. Prevalence and spectrum of bacterial co-infection during fungal keratitis. Br J Ophthalmol. 2006;90(3):289–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Gopinathan U et al. Review of epidemiological features, microbiological diagnosis and treatment outcome of microbial keratitis: experience of over a decade. Indian J Ophthalmol. 2009;57(4):273–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Ramage G et al. Our current understanding of fungal biofilms. Crit Rev Microbiol. 2009;35(4):340–55.View ArticlePubMedGoogle Scholar
- Zhang X et al. Keratitis-associated fungi form biofilms with reduced antifungal drug susceptibility. Invest Ophthalmol Vis Sci. 2012;53(12):7774–8.View ArticlePubMedGoogle Scholar
- FlorCruz Nilo V, Peczon Ildefonso V, Evans Jennifer R. Medical interventions for fungal keratitis. Cochrane Database of Systematic Reviews. 2012. doi:10.1002/14651858.CD004241.pub3.PubMedGoogle Scholar
- Bunya VY, Hammersmith KM, Rapuano CJ, Ayres BD, Cohen EJ. Topical and oral voriconazole in the treatment of fungal keratitis. Am J Ophthalmol. 2007;143(1):151–3.View ArticlePubMedGoogle Scholar
- Prajna NV, Krishnan T, Mascarenhas J, Srinivasan M, Oldenburg CE, Toutain-Kidd CM, et al. Predictors of outcome in fungal keratitis. Eye. 2012;26(9):1226–31.View ArticlePubMedGoogle Scholar
- Ramakrishnan TC, Marios J, Vishal V, Rasik B. Factors Affecting Treatment Outcomes with Voriconazole. Cornea. 2013;32(4):445–9.View ArticlePubMedGoogle Scholar
- te Welscher YM, Jones L, van Leeuwen MR, Dijksterhuis J, de Kruijff B, Eitzen G, et al. Natamycin inhibits vacuole fusion at the priming phase via a specific interaction with ergosterol. Antimicrob Agents Chemother. 2010;54(6):2618–25.View ArticleGoogle Scholar
- Seal DV, Pleyer U. Ocular Infection: Investigation and Treatment in Practice. 2nd ed. 2007. CRC Press. 385.View ArticleGoogle Scholar
- Sonego-Krone S et al. Clinical results of topical fluconazole for the treatment of filamentous fungal keratitis. Graefes Arch Clin Exp Ophthalmol. 2006;244(7):782–7.View ArticlePubMedGoogle Scholar
- Foster CS, Stefanyszyn M. Intraocular penetration of miconazole in rabbits. Arch Ophthalmol. 1979;97(9):1703–6.View ArticlePubMedGoogle Scholar
- Espinel-Ingroff A, Boyle K, Sheehan DJ. In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature. Mycopathologia. 2001;150(3):101–15.View ArticlePubMedGoogle Scholar
- Thiel MA, Zinkernagel AS, Burhenne J, Kaufmann C, Haefeli WE. Voriconazole concentration in human aqueous humor and plasma during topical or combined topical and systemic administration for fungal keratitis. Antimicrob Agents Chemother. 2007;51(1):239–44.View ArticlePubMedGoogle Scholar
- Hariprasad SM, Mieler WF, Lin TK, Sponsel WE, Graybill JR. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. 2008;92(7):871–8.View ArticlePubMedGoogle Scholar
- Sen P, Gopal L, Sen PR. Intravitreal voriconazole for drug-resistant fungal endophthalmitis: case series. Retina. 2006;26(8):935–9.View ArticlePubMedGoogle Scholar
- Shokohi T, Nowroozpoor-Dailami K, Moaddel-Haghighi T. Fungal keratitis in patients with corneal ulcer in Sari, Northern Iran. Arch Iran Med. 2006;9(3):222–7.PubMedGoogle Scholar