Fungal Keratitis Treatment & Management
- Author: Daljit Singh, MBBS, MS, DSc; Chief Editor: Hampton Roy, Sr, MD more...
Antifungal agents are classified into the groups below.
Polyenes include natamycin, nystatin, and amphotericin B. Polyenes disrupt the cell by binding to fungal cell wall ergosterol and are effective against both filamentous and yeast forms.
Amphotericin B is the drug of choice to treat patients with fungal keratitis caused by yeasts.
Although polyenes penetrate ocular tissue poorly, amphotericin B is the drug of choice for treatment of fungal keratitis caused by Candida. In addition, it has efficacy against many filamentous fungi. Administration is every 30 minutes for the first 24 hours, every hour for the second 24 hours, and then is slowly tapered according to the clinical response.
Natamycin has a broad-spectrum of activity against filamentous organisms. The penetration of topically applied amphotericin B is found to be less than that of topically applied natamycin through the intact corneal epithelium.
Natamycin is the only commercially available topical ophthalmic antifungal preparation. It is effective against filamentous fungi, particularly for infections caused by Fusarium. However, because of poor ocular penetration, it has primarily been useful in cases with superficial corneal infection.
Azoles (imidazoles and triazoles) include ketoconazole, miconazole, fluconazole, itraconazole, econazole, and clotrimazole. Azoles inhibit ergosterol synthesis at low concentrations, and, at higher concentrations, they appear to cause direct damage to cell walls.
Oral fluconazole and ketoconazole are absorbed systemically with good levels in the anterior chamber and the cornea; therefore, they should be considered in the management of deep fungal keratitis.
Imidazoles and triazoles are synthetic chemical antifungal agents. High cornea levels of ketoconazole and fluconazole have been demonstrated in animal studies. Because of excellent penetration in ocular tissue, these medications, given systemically, are the preferred treatment of keratitis caused by filamentous fungi and yeast.
The adult dose of ketoconazole is 200-400 mg/d, which can be increased to 800 mg/d. However, because of the secondary effects, increasing the dose should be done carefully. Gynecomastia, oligospermia, and decreased libido have been reported in 5-15% of patients who have been taking 400 mg/d for a long period.
The potential role of itraconazole in treatment of fungal keratitis is still unclear. However, it may be a helpful adjunctive agent in fungal keratitis.
Fluorinated pyrimidines, such as flucytosine, are other antifungal agents. Flucytosine is converted into a thymidine analog that blocks fungal thymidine synthesis. It usually is administered in combination with an azole or amphotericin B; it is synergistic with these medications. Otherwise, if flucytosine is the only drug used in therapy for candidal infections, emergence of resistance rapidly develops. Therefore, flucytosine should never be used alone.
Treatment should be instituted promptly with topical fortified antifungal drops, initially every hour during the day and every 2 hours over night.
Subconjunctival injections may be used in patients with severe keratitis or keratoscleritis. They also can be used when poor patient compliance exists.
An oral antifungal (eg, ketoconazole, fluconazole) should be considered for patients with deep stromal infection. Antifungal therapy usually is maintained for 12 weeks, and patients are monitored closely.
Fluconazole has been shown to penetrate better into the cornea after systemic administration compared to other azoles and may be associated with fewer adverse effects.
A study by Matsumoto et al has shown that topical 0.1% micafungin eye drops are comparable to 0.2% fluconazole in the treatment of fungal keratitis no matter patient’s age, gender, or ulcer size.
In vitro antifungal sensitivities often are performed to assess resistance patterns of the fungal isolate. However, in vitro susceptibility testing may not correspond with in vivo clinical response because of host factors, corneal penetration of the antifungal, and difficulty in standardization of antifungal sensitivities. Therefore, they should be performed in a standardized method at a reference laboratory.
The promotion of fungal growth by corticosteroid treatment is well recognized; therefore, corticosteroid drops should not be used in the treatment of fungal keratitis until after 2 weeks of antifungal treatment and clear clinical evidence of infection control. Steroids should only be used when the active inflammation is believed to be causing significant damage to the structure of the cornea and/or vision. The steroid is always used in conjunction with the topical antifungal.
Therapy may be modified.
Decisions about alternate therapy must be based on the biomicroscopic signs and on the tolerance of the topical medications. Improvement in clinical signs may be difficult to detect during the initial days of antifungal therapy. However, some of the biomicroscopic signs that may be helpful to evaluate efficacy are as follows:
Blunting of the perimeters of the infiltrate
Reduction of the density of the suppuration
Reduction in cellular infiltrate and edema in the surrounding stroma
Reduction in anterior chamber inflammation
Loss of the feathery perimeter of the stromal inflammation
Successful antifungal therapy for fungal keratitis requires frequent drug administration for prolonged periods (ie, at least 12 wk). Some corneal manifestations of toxicity are as follows:
Protracted epithelial ulceration
Punctuate corneal epithelial erosion
Diffuse stromal haze
In the developing countries, owing to the paucity of medications and good laboratory facilities, it is highly practical to start treatment by using an antiseptic. The author routinely uses silver nitrate 0.75%, followed by Lugol iodine. The ulcer is first dried, followed by silver nitrate application with a swab stick. This is immediately followed by Lugol solution application with a swab stick. With this treatment, the surface of the ulcer is coated with a thin layer of silver iodide. It is expected that silver nitrate shall start ionizing, thus releasing nascent oxygen that has the capacity to destroy the fungal wall. This is followed by whatever antifungal medication is available. The author has been using this initial treatment for more than 20 years and treats more than 200 corneal ulcer cases (most of them fungal) every year.
Patients who do not respond to medical treatment of topical and oral antifungal medications usually require surgical intervention, including corneal transplantation. Approximately 15-27% of patients require surgical intervention. In some cases, though, even corneal surgery will not restore vision, and patients will be blind or otherwise visually impaired. Therefore, early diagnosis coupled with appropriate treatment is critical to recovery from keratitis.
Frequent corneal debridement with a spatula is helpful; it debulks fungal organisms and epithelium and enhances penetration of the topical antifungal agent.
Approximately one third of fungal infections fail to respond to medical treatment and may result in corneal perforation. In these cases, a therapeutic penetrating keratoplasty is necessary.
Penetrating keratoplasty generally should be performed within 4 weeks of presentation. A small number of patients have been treated successfully with a conjunctival flap. The main goals of surgery are to control the infection and to maintain the integrity of the globe. Topical antifungal therapy, in addition to systemic fluconazole or ketoconazole, should be continued following penetrating keratoplasty. The use of topical corticosteroids in the postoperative period remains controversial.
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. 1995 Sep-Oct. 33(5):319-25. [Medline].
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 Jan. 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. 2011 Oct. 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. 1998 Mar. 82(3):306-11. [Medline].
Avunduk AM, Beuerman RW, Varnell ED, Kaufman HE. Confocal microscopy of Aspergillus fumigatus keratitis. Br J Ophthalmol. 2003 Apr. 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. 1993 Oct. 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. 2000 Jun. 38(6):2302-10. [Medline].
Chowdhary A, Singh K. Spectrum of fungal keratitis in North India. Cornea. 2005 Jan. 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. 1997 Feb. 115(2):173-6. [Medline].
Driebe WT Jr, Mandelbaum S, Forster RK, Schwartz LK, Culbertson WW. Pseudophakic endophthalmitis. Diagnosis and management. Ophthalmology. 1986 Apr. 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. 1994 May. 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. 1997 Jun. 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. 1999 Jan. 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. 1997 Nov. 115(11):1461-3. [Medline].
Forster RK, Abbott RL, Gelender H. Management of infectious endophthalmitis. Ophthalmology. 1980 Apr. 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. 2003 Nov. 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. 1998 Nov. 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. 2000 Mar. 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. 2000 Aug. 38(8):2902-8. [Medline].
Jordan JA. PCR identification of four medically important Candida species by using a single primer pair. J Clin Microbiol. 1994 Dec. 32(12):2962-7. [Medline].
Kauffman CA, Bradley SF, Vine AK. Candida endophthalmitis associated with intraocular lens implantation: efficacy of fluconazole therapy. Mycoses. 1993 Jan-Feb. 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. 2005 Apr. 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. 1998 Dec. 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. 2005 Feb. 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. 1993 Nov. 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. 1994 May. 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. 1992 Apr. 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. 1998 May. 39(6):859-66. [Medline].
Panda A, Sharma N, Das G, Kumar N, Satpathy G. Mycotic keratitis in children: epidemiologic and microbiologic evaluation. Cornea. 1997 May. 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. 2003 Oct. 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. 2004 Nov. 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. 1982 Jul. 2(7):853-62. [Medline].
Rosa RH Jr, Miller D, Alfonso EC. The changing spectrum of fungal keratitis in south Florida. Ophthalmology. 1994 Jun. 101(6):1005-13. [Medline].
Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004 Aug. 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. 1993 Nov. 148(5):1313-7. [Medline].
Thomas PA. Fungal infections of the cornea. Eye. 2003 Nov. 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. 1991 Jan 15. 111(1):92-9. [Medline].
Weissgold DJ, Orlin SE, Sulewski ME, Frayer WC, Eagle RC Jr. Delayed-onset fungal keratitis after endophthalmitis. Ophthalmology. 1998 Feb. 105(2):258-62. [Medline].
White TJ, Bruns T, Lee S, Tailor S. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. 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.