Background
Fungal keratitis was first described by Leber in 1879. This entity is not a common cause of corneal infection, but it represents one of the major causes of infectious keratitis in tropical areas of the world. Considering fungus as a possible cause of infectious keratitis is important because devastating ocular damage can result if it is not diagnosed and treated promptly and effectively. See the images below.
Fungal corneal ulcer. 
Fungal ulcer in an elderly woman. 
Fungal keratitis. 
Fungal infection. 
Fungal infection. 
Fungal ulcer. 
Fungal corneal ulcer, with excessive vascularization. Fungal keratitis is a general term meaning any inflammation of the cornea. Fungi can infect (and therefore inflame) the cornea. The term fungal keratitis refers to a corneal infection caused by fungi. One type of fungus that can infect the cornea is Fusarium. When Fusarium infects the cornea, the eye disease is referred to as Fusarium keratitis.
Fungal keratitis remains a diagnostic and therapeutic challenge to the ophthalmologist. Difficulties are related to establishing a 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; even if the diagnosis is made accurately, management remains a challenge because of the poor corneal penetration and the limited commercial availability of antifungal agents.
Moreover, the incidence of fungal keratitis has increased over the past 30 years. This increased occurrence of fungal keratitis is a result of the frequent use of topical corticosteroids and antibacterial agents in treating patients with keratitis, the rise in the number of patients who are immunocompromised, and better laboratory diagnostic techniques that aid in its diagnosis.
Classification
Of the 70 different fungi that have been implicated as causing fungal keratitis, the 2 medically important groups responsible for corneal infection are yeast and filamentous fungi (septate and nonseptate).
Yeast produces characteristic creamy, opaque, pasty colonies on the surface of culture media. Candida is the most representative pathogen in this group, primarily affecting those corneas already compromised by topical steroids, surface pathology, or both.
A feathery or powdery growth on the surface of culture media is produced by septate filamentary fungi, which are the most common cause of fungal keratitis.
Pathophysiology
Many fungal organisms associated with ocular infections are ubiquitous, saprophytic organisms and have been reported as causes of infection only in the ophthalmic literature. Fungal isolates have been classified into the following groups: Moniliaceae (nonpigmented filamentary fungi, including Fusarium and Aspergillus species), Dematiaceae (pigmented filamentary fungi, including Curvularia and Lasiodiplodia species), and yeasts (including Candida species).
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.
Fungi are not a common cause of microbial keratitis. Fungi cannot penetrate the intact corneal epithelium and do not enter the cornea from episcleral limbal vessels. They need a penetrating injury or a previous epithelial defect to enter the cornea. Once within the cornea, however, they are able to proliferate.
Organisms that infect preexisting epithelial defects belong to the normal microflora of the conjunctiva and adnexa. The most common pathogen that invades a preexisting epithelial defect is Candida. Filamentous fungi are the principal causes of posttraumatic infection. The intrinsic virulence of fungi depends on the fungal substances produced and the host response generated.
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.
Corneal trauma is the most frequent and major risk factor for fungal keratitis. In fact, the physician should have a high level of suspicion in a patient with a history of corneal trauma, particularly with plant or soil matter.
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.
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, corneal surgery, chronic keratitis, and immunosuppressive diseases.
Epidemiology
Frequency
United States
The incidence of fungal keratitis varies according to geographical location and ranges from 2% of keratitis cases in New York to 35% in Florida. Fusarium species are the most common cause of fungal corneal infection in the southern United States (45-76% of fungal keratitis), while Candida and Aspergillus species are more common in northern states.
In a large series of fungal keratitis from south Florida, Rosa et al reported that Fusarium oxysporum was the most common isolate (37%), followed by, in order of decreasing frequency, Fusarium solani (24%), Candida, Curvularia, and Aspergillus species.[1]
Fusarium species are commonly found in soil, in water, and on plants throughout the world, particularly in warmer climates. Past studies of Fusarium keratitis have found that most incidences of Fusarium keratitis have been caused by an eye injury with vegetative matter (eg, being hit in the eye with a palm branch).
An estimated 30 million persons in the United States wear soft contact lenses. The annual incidence of microbial keratitis is estimated to be 4-21 per 10,000 soft contact lens users, depending on whether users wear lenses overnight.
A number of individuals have contracted Fusarium keratitis from contact lens wear, especially through the use of the Bausch & Lomb ReNu with Moisture Lock contact lens solution. This number is generally very small, particularly in the northern part of the United States.
On March 8, 2006, the Centers for Disease Control and Prevention (CDC) received a report from an ophthalmologist in New Jersey regarding 3 patients with contact lens-associated Fusarium keratitis during recent months. Initial contact with several corneal disease specialty centers in the United States revealed that other centers also had seen recent increases in Fusarium keratitis.
The CDC began an investigation of the Fusarium keratitis outbreak. There were 130 confirmed cases of Fusarium keratitis. Over 60% of people with confirmed Fusarium keratitis had used Bausch & Lomb ReNu with Moisture Lock contact lens solution, and 37 of these cases resulted in cornea transplant surgery.
The US Food and Drug Administration (FDA) recalled Bausch & Lomb ReNu with Moisture Lock contact lens solution.
According to Bausch & Lomb, "unique characteristics of the formulation of the ReNu with Moisture Lock product in certain unusual circumstances can increase the risk of Fusarium infection."
International
Aspergillus species is the most common isolate in fungal keratitis worldwide. Large series of fungal keratitis from India report that Aspergillus species is the most common isolate (27-64%), followed by Fusarium (6-32%) and Penicillium (2-29%) species.
Mortality/Morbidity
Fungal organisms can extend from the cornea into the sclera and intraocular structures. Fungi can cause severe infections, such as scleritis, endophthalmitis, or panophthalmitis. These infections are usually very difficult to treat and may result in severe visual loss or even loss of the eye.
Sex
Fungal keratitis is more common in males than in females and often occurs in patients with a history of outdoor ocular trauma.
Haynes KA, Westerneng TJ, Fell JW, Moens W. Rapid detection and identification of pathogenic fungi by polymerase chain reaction amplification of large subunit ribosomal DNA. J Med Vet Mycol. Sep-Oct 1995;33(5):319-25. [Medline].
Vaddavalli PK, Garg P, Sharma S, et al. Role of confocal microscopy in the diagnosis of fungal and acanthamoeba keratitis. Ophthalmology. Jan 2011;118(1):29-35. [Medline].
Matsumoto Y, Murat D, Kojima T, Shimazaki J, Tsubota K. The comparison of solitary topical micafungin or fluconazole application in the treatment of Candida fungal keratitis. Br J Ophthalmol. Oct 2011;95(10):1406-9. [Medline].
Accensi F J, Cano L, Figuera, ML Abarca and FJ. Cabañes. New PCR methods to differentiate species in the Aspergillus niger aggregate. FEMS Microbiol. Lett. 1999;180:191-196.
Alexandrakis G, Jalali S, Gloor P. Diagnosis of Fusarium keratitis in an animal model using the polymerase chain reaction. Br J Ophthalmol. Mar 1998;82(3):306-11. [Medline].
Avunduk AM, Beuerman RW, Varnell ED, Kaufman HE. Confocal microscopy of Aspergillus fumigatus keratitis. Br J Ophthalmol. Apr 2003;87(4):409-10. [Medline].
Borne MJ, Elliott JH, O'Day DM. Ocular fluconazole treatment of Candida parapsilosis endophthalmitis after failed intravitreal amphotericin B. Arch Ophthalmol. Oct 1993;111(10):1326-7. [Medline].
Chen YC, Eisner JD, Kattar MM, Rassoulian-Barrett SL, LaFe K, Yarfitz SL, et al. Identification of medically important yeasts using PCR-based detection of DNA sequence polymorphisms in the internal transcribed spacer 2 region of the rRNA genes. J Clin Microbiol. Jun 2000;38(6):2302-10. [Medline].
Chowdhary A, Singh K. Spectrum of fungal keratitis in North India. Cornea. Jan 2005;24(1):8-15. [Medline].
Donnenfeld ED, Perry HD, Snyder RW, Moadel R, Elsky M, Jones H. Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin. Arch Ophthalmol. Feb 1997;115(2):173-6. [Medline].
Driebe WT Jr, Mandelbaum S, Forster RK, Schwartz LK, Culbertson WW. Pseudophakic endophthalmitis. Diagnosis and management. Ophthalmology. Apr 1986;93(4):442-8. [Medline].
Dunlop AA, Wright ED, Howlader SA, Nazrul I, Husain R, McClellan K. Suppurative corneal ulceration in Bangladesh. A study of 142 cases examining the microbiological diagnosis, clinical and epidemiological features of bacterial and fungal keratitis. Aust N Z J Ophthalmol. May 1994;22(2):105-10. [Medline].
Einsele H, Hebart H, Roller G, Löffler J, Rothenhofer I, Muller CA. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol. Jun 1997;35(6):1353-60. [Medline].
Esteve-Zarzoso B, Belloch C, Uruburu F, Querol A. Identification of yeasts by RFLP analysis of the 5.8S rRNA gene and the two ribosomal internal transcribed spacers. Int J Syst Bacteriol. Jan 1999;49 Pt 1:329-37. [Medline].
Ferrer C S, Frases F, Colom, J L Alio, J L Abad, and M E. Mulet. Molecular diagnosis of fungal ocular infections in an animal model. Rev. Iberoam. Micol. 2000;17:S134.
Florakis GJ, Moazami G, Schubert H, Koester CJ, Auran JD. Scanning slit confocal microscopy of fungal keratitis. Arch Ophthalmol. Nov 1997;115(11):1461-3. [Medline].
Forster RK, Abbott RL, Gelender H. Management of infectious endophthalmitis. Ophthalmology. Apr 1980;87(4):313-9. [Medline].
Garg P, Mahesh S, Bansal AK, Gopinathan U, Rao GN. Fungal infection of sutureless self-sealing incision for cataract surgery. Ophthalmology. Nov 2003;110(11):2173-7. [Medline].
Guzek JP, Roosenberg JM, Gano DL, Wessels IF. The effect of vehicle on corneal penetration of triturated ketoconazole and itraconazole. Ophthalmic Surg Lasers. Nov 1998;29(11):926-9. [Medline].
Hidalgo JA, Alangaden GJ, Eliott D, Akins RA, Puklin J, Abrams G. Fungal endophthalmitis diagnosis by detection of Candida albicans DNA in intraocular fluid by use of a species-specific polymerase chain reaction assay. J Infect Dis. Mar 2000;181(3):1198-201. [Medline].
Jaeger EE, Carroll NM, Choudhury S, Dunlop AA, Towler HM, Matheson MM, et al. Rapid detection and identification of Candida, Aspergillus, and Fusarium species in ocular samples using nested PCR. J Clin Microbiol. Aug 2000;38(8):2902-8. [Medline].
Jordan JA. PCR identification of four medically important Candida species by using a single primer pair. J Clin Microbiol. Dec 1994;32(12):2962-7. [Medline].
Kauffman CA, Bradley SF, Vine AK. Candida endophthalmitis associated with intraocular lens implantation: efficacy of fluconazole therapy. Mycoses. Jan-Feb 1993;36(1-2):13-7. [Medline].
Keyhani K, Seedor JA, Shah MK, Terraciano AJ, Ritterband DC. The incidence of fungal keratitis and endophthalmitis following penetrating keratoplasty. Cornea. Apr 2005;24(3):288-91. [Medline].
Knox CM, Cevellos V, Dean D. 16S ribosomal DNA typing for identification of pathogens in patients with bacterial keratitis. J Clin Microbiol. Dec 1998;36(12):3492-6. [Medline].
Kumar M, Shukla PK. Use of PCR targeting of internal transcribed spacer regions and single-stranded conformation polymorphism analysis of sequence variation in different regions of rrna genes in fungi for rapid diagnosis of mycotic keratitis. J Clin Microbiol. Feb 2005;43(2):662-8. [Medline].
Lott TJ, Kuykendall RJ, Reiss E. Nucleotide sequence analysis of the 5.8S rDNA and adjacent ITS2 region of Candida albicans and related species. Yeast. Nov 1993;9(11):1199-206. [Medline].
Mabon M. Fungal keratitis. Int Ophthalmol Clin. 1998;38(4):115-23. [Medline].
Makimura K, Murayama SY, Yamaguchi H. Detection of a wide range of medically important fungi by the polymerase chain reaction. J Med Microbiol. May 1994;40(5):358-64. [Medline].
Miyakawa Y, Mabuchi T, Kagaya K, Fukazawa Y. Isolation and characterization of a species-specific DNA fragment for detection of Candida albicans by polymerase chain reaction. J Clin Microbiol. Apr 1992;30(4):894-900. [Medline].
Okhravi N, Adamson P, Mant R, Matheson MM, Midgley G, Towler HM. Polymerase chain reaction and restriction fragment length polymorphism mediated detection and speciation of Candida spp causing intraocular infection. Invest Ophthalmol Vis Sci. May 1998;39(6):859-66. [Medline].
Panda A, Sharma N, Das G, Kumar N, Satpathy G. Mycotic keratitis in children: epidemiologic and microbiologic evaluation. Cornea. May 1997;16(3):295-9. [Medline].
Prajna NV, John RK, Nirmalan PK, Lalitha P, Srinivasan M. A randomised clinical trial comparing 2% econazole and 5% natamycin for the treatment of fungal keratitis. Br J Ophthalmol. Oct 2003;87(10):1235-7. [Medline].
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. Nov 2004;23(8):793-6. [Medline].
Reiss E, Tanaka K, Bruker G, Chazalet V, Coleman D, Debeaupuis JP. Molecular diagnosis and epidemiology of fungal infections. Med Mycol. 1998;36 Suppl 1:249-57. [Medline].
Riggsby WS, Torres-Bauza LJ, Wills JW, Townes TM. DNA content, kinetic complexity, and the ploidy question in Candida albicans. Mol Cell Biol. Jul 1982;2(7):853-62. [Medline].
Rosa RH Jr, Miller D, Alfonso EC. The changing spectrum of fungal keratitis in south Florida. Ophthalmology. Jun 1994;101(6):1005-13. [Medline].
Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. Aug 2004;15(4):321-7. [Medline].
Tang CM, Holden DW, Aufauvre-Brown A, Cohen J. The detection of Aspergillus spp. by the polymerase chain reaction and its evaluation in bronchoalveolar lavage fluid. Am Rev Respir Dis. Nov 1993;148(5):1313-7. [Medline].
Thomas PA. Fungal infections of the cornea. Eye. Nov 2003;17(8):852-62. [Medline].
Upadhyay MP, Karmacharya PC, Koirala S, Tuladhar NR, Bryan LE, Smolin G. Epidemiologic characteristics, predisposing factors, and etiologic diagnosis of corneal ulceration in Nepal. Am J Ophthalmol. Jan 15 1991;111(1):92-9. [Medline].
Weissgold DJ, Orlin SE, Sulewski ME, Frayer WC, Eagle RC Jr. Delayed-onset fungal keratitis after endophthalmitis. Ophthalmology. Feb 1998;105(2):258-62. [Medline].
White TJ, Bruns T, Lee S, Tailor S. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. In: Innins MA, Gelfand DH, Sninsky JJ, White TJ, eds. PCR Protocols. A Guide to Methods and Applications. San Diego, CA: Academic Press, Inc; 1990:315-22.
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