Abstract
Fungal keratitis remains a challenging and often elusive diagnosis in geographic regions where it is endemic. Marred by delays in diagnosis, the sequelae of corneal fungal infections, though preventable, can be irreversible. Recent studies and advances in the arena have broadened the approach and treatment to mycotic keratitis. This review will discuss current diagnostic modalities of fungal keratitis and will particularly focus on treatment regimens. It will also explore future therapeutic models and critique the potential benefit of each.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Wong TY, Ng TP, Fong KS, Tan DT. Risk factors and clinical outcomes between fungal and bacterial keratitis: a comparative study. CLAO J. 1997;23:275–81.
• Sharma N, Chacko J, Velpandian T, et al. Comparative Evaluation of Topical versus Intrastromal Voriconazole as an Adjunct to Natamycin in Recalcitrant Fungal Keratitis. Ophthalmology 2012. Important trial that compared topical and intrastromal voriconazole in adjunct to natamycin. Showed no significant difference between topical and intrastromal voriconazole in best corrected visual acuity.
Bharathi MJ, Ramakrishnan R, Meenakshi R, Padmavathy S, Shivakumar C, Srinivasan M. Microbial keratitis in South India: influence of risk factors, climate, and geographical variation. Ophthalmic Epidemiol. 2007;14:61–9.
Leck AK, Thomas PA, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal keratitis. Br J Ophthalmol. 2002;86:1211–5.
Sharma S. Diagnosis of fungal keratitis: current options. Expert Opin Med Diagn. 2012;6:449–55.
Hamrah P, Dana MR. Corneal antigen-presenting cells. Chem Immunol Allergy. 2007;92:58–70.
Tarabishy AB, Aldabagh B, Sun Y, et al. MyD88 regulation of Fusarium keratitis is dependent on TLR4 and IL-1R1 but not TLR2. J Immunol. 2008;181:593–600.
Thomas PA, Kaliamurthy J. Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect. 2013;19:210–20.
Sun RL, Jones DB, Wilhelmus KR. Clinical characteristics and outcome of Candida keratitis. Am J Ophthalmol. 2007;143:1043–5.
Gower EW, Keay LJ, Oechsler RA, et al. Trends in fungal keratitis in the United States, 2001 to 2007. Ophthalmology. 2010;117:2263–7.
•• Gopinathan U, Garg P, Fernandes M, Sharma S, Athmanathan S, Rao GN. The epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in South India. Cornea. 2002;21:555–9. This review presented the epidemiological features and laboratory results of the largest series of fungal keratitis ever reported in literature. Identified demographic features and risk factors that contributed to our knowledge of how FK is aquired.
Sirikul T, Prabriputaloong T, Smathivat A, Chuck RS, Vongthongsri A. Predisposing factors and etiologic diagnosis of ulcerative keratitis. Cornea. 2008;27:283–7.
Srinivasan M, Gonzales CA, George C, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India. Br J Ophthalmol. 1997;81:965–71.
Foster CS. Fungal keratitis. Infect Dis Clin North Am. 1992;6:851–7.
Pepose JS, Wilhelmus KR. Divergent approaches to the management of corneal ulcers. Am J Ophthalmol. 1992;114:630–2.
Chin GN, Hyndiuk RA, Kwasny GP, Schultz RO. Keratomycosis in Wisconsin. Am J Ophthalmol. 1975;79:121–5.
Doughman DJ, Leavenworth NM, Campbell RC, Lindstrom RL. Fungal keratitis at the University of Minnesota: 1971–1981. Trans Am Ophthalmol Soc. 1982;80:235–47.
Jones DB, Sexton R, Rebell G. Mycotic keratitis in South Florida: a review of thirty-nine cases. Trans Ophthalmol Soc U K. 1970;89:781–97.
Rosa Jr RH, Miller D, Alfonso EC. The changing spectrum of fungal keratitis in south Florida. Ophthalmology. 1994;101:1005–13.
Bullock JD, Elder BL, Khamis HJ, Warwar RE. Effects of time, temperature, and storage container on the growth of Fusarium species: implications for the worldwide Fusarium keratitis epidemic of 2004–2006. Arch Ophthalmol. 2011;129:133–6.
Jones BR. Principles in the management of oculomycosis. XXXI Edward Jackson memorial lecture. Am J Ophthalmol. 1975;79:719–51.
Dahlgren MA, Lingappan A, Wilhelmus KR. The clinical diagnosis of microbial keratitis. Am J Ophthalmol. 2007;143:940–4.
•• Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol. 2010;128:672–8. Important study that compared the use of natamycin and voriconazole in fungal keratitis, and to establish voriconazole as a worthy agent in FK.
McLeod SD, Kolahdouz-Isfahani A, Rostamian K, Flowers CW, Lee PP, McDonnell PJ. The role of smears, cultures, and antibiotic sensitivity testing in the management of suspected infectious keratitis. Ophthalmology. 1996;103:23–8.
Zhang W, Yang H, Jiang L, Han L, Wang L. Use of potassium hydroxide, Giemsa and calcofluor white staining techniques in the microscopic evaluation of corneal scrapings for diagnosis of fungal keratitis. J Int Med Res. 2010;38:1961–7.
•• Sharma S, Kunimoto DY, Gopinathan U, Athmanathan S, Garg P, Rao GN. Evaluation of corneal scraping smear examination methods in the diagnosis of bacterial and fungal keratitis: a survey of eight years of laboratory experience. Cornea. 2002;21:643–7. Determined the sensitivity, specificity, and predictive values of Gram and potassium hydroxide with calcofluor white stains in the diagnosis of early and advanced microbial keratitis. Found that KOH prep with calcofluor white is a reliable lab test in the diagnosis of mycotic keratitis.
McGinnis M. Laboratory handbook of medical mycology. New York: Academic Press; 1980.
Dursun D, Fernandez V, Miller D, Alfonso EC. Advanced Fusarium keratitis progressing to endophthalmitis. Cornea. 2003;22:300–3.
Keay LJ, Gower EW, Iovieno A, et al. Clinical and microbiological characteristics of fungal keratitis in the United States, 2001–2007: a multicenter study. Ophthalmology 2011.
Ferrer C, Alio JL. Evaluation of molecular diagnosis in fungal keratitis. Ten years of experience. Journal of Ophthalmic Inflammation and Infection. 2011;1:15–22.
Erie JC, McLaren JW, Patel SV. Confocal microscopy in ophthalmology. Am J Ophthalmol. 2009;148:639–46.
• Vaddavalli PK, Garg P, Sharma S, Sangwan VS, Rao GN, Thomas R. Role of confocal microscopy in the diagnosis of fungal and acanthamoeba keratitis. Ophthalmology. 2011;118:29–35. Prospective, double masked study that evaluated the sensitivity, specificity, NPV and PPV of confocal microscopy. Proposed it as an accurate and reliable diagnostic modality in the diagnosis of fungal and Acanthamoeba keratitis.
Florcruz NV, Peczon I, Jr. Medical interventions for fungal keratitis. Cochrane database of systematic reviews 2008:CD004241.
Yoon KC, Jeong IY, Im SK, Chae HJ, Yang SY. Therapeutic effect of intracameral amphotericin B injection in the treatment of fungal keratitis. Cornea. 2007;26:814–8.
Thomas PA. Fungal infections of the cornea. Eye. 2003;17:852–62.
Green WR, Bennett JE, Goos RD. Ocular penetration of amphotericin B: a report of laboratory studies and a case report of postsurgical cephalosporium endophthalmitis. Arch Ophthalmol. 1965;73:769–75.
Natamycin approved--first U.S. drug for fungal keratitis. FDA Drug Bull 1978;8:37–8.
Medoff G, Kobayashi GS. Strategies in the treatment of systemic fungal infections. N Engl J Med. 1980;302:145–55.
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;24:449–52.
Tanure MA, Cohen EJ, Sudesh S, Rapuano CJ, Laibson PR. Spectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania. Cornea. 2000;19:307–12.
•• Marangon FB, Miller D, Giaconi JA, Alfonso EC. In vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens. Am J Ophthalmol. 2004;137:820–5. Experimental study that used a large microbiology database to investigate the susceptbility profile of the most common fungal pathogens in keratitis. First proposed the role of voriconazole in the therapeutic management of Candida and Aspergillus ocular infections.
Lalitha P, Shapiro BL, Srinivasan M, et al. Antimicrobial susceptibility of Fusarium, Aspergillus, and other filamentous fungi isolated from keratitis. Arch Ophthalmol. 2007;125:789–93.
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;92:871–8.
Ramakrishnan T, Constantinou M, Jhanji V, Vajpayee RB. Factors affecting treatment outcomes with voriconazole in cases with fungal keratitis. Cornea. 2013;32:445–9.
Prajna NV, Nirmalan PK, Mahalakshmi R, Lalitha P, Srinivasan M. Concurrent use of 5 % natamycin and 2 % econazole for the management of fungal keratitis. Cornea. 2004;23:793–6.
Panda A, Sharma N, Angra SK. Topical fluconazole therapy of Candida keratitis. Cornea. 1996;15:373–5.
Rao SK, Madhavan HN, Rao G, Padmanabhan P. Fluconazole in filamentous fungal keratitis. Cornea. 1997;16:700.
Mahdy RA, Nada WM, Wageh MM. Topical amphotericin B and subconjunctival injection of fluconazole (combination therapy) versus topical amphotericin B (monotherapy) in treatment of keratomycosis. J Ocul Pharmacol Ther. 2010;26:281–5.
Sonego-Krone S, Sanchez-Di Martino D, Ayala-Lugo R, et al. Clinical results of topical fluconazole for the treatment of filamentous fungal keratitis. Graefes Arch Clin Exp Ophthalmol. 2006;244:782–7.
Fitzsimons R, Peters AL. Miconazole and ketoconazole as a satisfactory first-line treatment for keratomycosis. Am J Ophthalmol. 1986;101:605–8.
Perez-Balbuena AL, Vanzzini-Rosano V, Valadez-Virgen Jde J, Campos-Moller X. Fusarium keratitis in Mexico. Cornea. 2009;28:626–30.
Anane S, Ben Ayed N, Malek I, et al. Keratomycosis in the area of Tunis: epidemiological data, diagnostic and therapeutic modalities. Ann Biol Clin (Paris). 2010;68:441–7.
Mahdy RA, Nada WM, Wageh MM, Kader MA, Saleh MM, Alswad MM. Assessment safety and efficacy of a combination therapy of topical amphotericin B and subconjunctival fluconazole for the treatment of fungal keratitis. Cutan Ocul Toxicol. 2010;29:193–7.
Li L, Wang Z, Li R, Luo S, Sun X. In vitro evaluation of combination antifungal activity against Fusarium species isolated from ocular tissues of keratomycosis patients. Am J Ophthalmol. 2008;146:724–8.
Xie L, Dong X, Shi W. Treatment of fungal keratitis by penetrating keratoplasty. Br J Ophthalmol. 2001;85:1070–4.
Sharma N, Agarwal P, Sinha R, Titiyal JS, Velpandian T, Vajpayee RB. Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series. Br J Ophthalmol 2011.
Siatiri H, Daneshgar F, Siatiri N. Khodabande A. Cornea: The effects of intrastromal voriconazole injection and topical voriconazole in the treatment of recalcitrant Fusarium keratitis; 2011.
Prakash G, Sharma N, Goel M, Titiyal JS, Vajpayee RB. Evaluation of intrastromal injection of voriconazole as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J Ophthalmol. 2008;146:56–9.
Wei LC, Tsai TC, Tsai HY, Wang CY, Shen YC. Comparison of voriconazole concentration in the aqueous humor and vitreous between non-scraped and scraped corneal epithelium groups after topical 1 % voriconazole application. Curr Eye Res. 2010;35:573–9.
•• Xie L, Zhai H, Shi W. Penetrating keratoplasty for corneal perforations in fungal keratitis. Cornea. 2007;26:158–62. Retrospective study that determined penetrating keratoplasty (PKP) an effective surgical treatment of antifungal refractory mycotic keratitis.
Garg P, Gopinathan U, Nutheti R, Rao GN. Clinical experience with N-butyl cyanoacrylate tissue adhesive in fungal keratitis. Cornea. 2003;22:405–8.
Tseng SC. Amniotic membrane transplantation for ocular surface reconstruction. Biosci Rep. 2001;21:481–9.
Chen HC, Tan HY, Hsiao CH, Huang SC, Lin KK, Ma DH. Amniotic membrane transplantation for persistent corneal ulcers and perforations in acute fungal keratitis. Cornea. 2006;25:564–72.
Bell NP, Karp CL, Alfonso EC, Schiffman J, Miller D. Effects of methylprednisolone and cyclosporine A on fungal growth in vitro. Cornea. 1999;18:306–13.
Price Jr FW, Price MO. Descemet's stripping with endothelial keratoplasty in 50 eyes: a refractive neutral corneal transplant. J Refract Surg. 2005;21:339–45.
Reddy JC, Hammersmith KM, Nagra PK, Rapuano CJ. The role of penetrating keratoplasty in the era of selective lamellar keratoplasty. Int Ophthalmol Clin. 2013;53:91–101.
Qu LJ, Xie LX. Changing indications for lamellar keratoplasty in Shandong, 1993–2008. Chin Med J (Engl). 2010;123:3268–71.
•• Xie L, Shi W, Liu Z, Li S. Lamellar keratoplasty for the treatment of fungal keratitis. Cornea. 2002;21:33–7. These studies evaluated lamellar keratoplasty as an effective surgical intervention in the setting of antifungal refractory FK.
Xie L, Zhong W, Shi W, Sun S. Spectrum of fungal keratitis in north China. Ophthalmology. 2006;113:1943–8.
Hu JZ, Xie LX. Clinical study on the recurrence of fungal keratitis after lamellar keratoplasty. [Zhonghua yan ke za zhi]. Chinese Journal of Ophthalmology. 2008;44:111–5.
Anshu A, Parthasarathy A, Mehta JS, Htoon HM, Tan DT. Outcomes of therapeutic deep lamellar keratoplasty and penetrating keratoplasty for advanced infectious keratitis: a comparative study. Ophthalmology. 2009;116:615–23.
Xie L, Zhai H, Zhao J, Sun S, Shi W, Dong X. Antifungal susceptibility for common pathogens of fungal keratitis in Shandong Province, China. Am J Ophthalmol. 2008;146:260–5.
Khairallah SH, Byrne KA, Tabbara KF. Fungal keratitis in Saudi Arabia. Doc Ophthalmol. 1992;79:269–76.
Bhartiya P, Daniell M, Constantinou M, Islam FM, Taylor HR. Fungal keratitis in Melbourne. Clin Experiment Ophthalmol. 2007;35:124–30.
Sponsel WE, Graybill JR, Nevarez HL, Dang D. Ocular and systemic posaconazole(SCH-56592) treatment of invasive Fusarium solani keratitis and endophthalmitis. Br J Ophthalmol. 2002;86:829–30.
Tu EY, McCartney DL, Beatty RF, Springer KL, Levy J, Edward D. Successful treatment of resistant ocular fusariosis with posaconazole (SCH-56592). Am J Ophthalmol. 2007;143:222–7.
Acknowledgement
NIH Center Core Grant P30EY014801, RPB Unrestricted Award and Career Development Awards Dr. Galor, Department of Defense (DOD- Grant#W81XWH-09-1-0675)
Compliance with Ethics Guidelines
ᅟ
Conflict of Interest
Zubair Ansari declares that he has no conflict of interest.
Darlene Miller declares that she has no conflict of interest.
Anat Galor declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ansari, Z., Miller, D. & Galor, A. Current Thoughts in Fungal Keratitis: Diagnosis and Treatment. Curr Fungal Infect Rep 7, 209–218 (2013). https://doi.org/10.1007/s12281-013-0150-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12281-013-0150-1