MS NO: ICO201711

CLINICAL SCIENCE

Update on Fungal Keratitis From 1999 to 2008

Elvin H. Yildiz, MD, Yasmine F . Abdalla, MD, Ahmed F. Elsahn, MD, Christopher J. Rapuano, MD, Kristin M. Hammersmith, MD, Peter R. Laibson, MD, and Elisabeth J. Cohen, MD
agents is not as good as the response of bacterial infections to antibiotics in part because of poor corneal penetration of the antimycotic agents.1 Over the past few years, there have been many reports worldwide of an increased rate of contact lensrelated fungal keratitis. The use of ReNu with MoistureLoc (ReNu ML) (Bausch & Lomb, Rochester, NY) contact lens solution was found to be a signicant risk factor associated with Fusarium infection.2 The rst evidence of the problem was reported in Hong Kong and Singapore, which resulted in the suspension of the sales of this product in these locations in February of 2006.3 This was followed by reports of similar ndings sent to the Centers for Disease Control and Prevention by American ophthalmologists in March of the same year. Studies conducted by Alfonso et al,4 Gorscak et al,5 Bernal et al,6 and Jeng et al7 all reported an outbreak of Fusarium keratitis between 2004 and 2006. A multistate outbreak was reported in the Journal of the American Medical Association in which the only signicant association found after multivariate analysis was the use of ReNu ML solution.2 Despite the in vitro efcacy of this contact lens solution, it lost its biocidal efcacy in clinical use. It was voluntarily recalled from the market worldwide in May 2006. After the recall of ReNu ML from the market, Jeng et al7 reported 4 cases of contact lensrelated Fusarium keratitis, none of which was associated with the recall product. In this study, we evaluated the number of cases, risk factors, treatment, and prognosis of fungal keratitis during the period from April 1999 to the end of 2008, at Wills Eye Institute, to put the recent Fusarium outbreak into a broader context and to update the trends and outcomes of fungal keratitis at our institute since the study by Tanure et al8 10 years ago.

Purpose: To report trends in fungal keratitis from a single institution

between 1999 and 2008.

Methods: Retrospective chart review of the patients presenting to the cornea service with fungal keratitis from April 1999 to December 2008. Results: Seventy-eight eyes of 76 patients were identied. The most
common predisposing factors included contact lens use (35.9%), trauma (21.8%), and history of penetrating keratoplasty (15.4%). There was a signicant increase in the rate of contact lensrelated Fusarium infections over time, which peaked in 2005 and 2006 (P = 0.021). Almost 40% of fungal keratitis cases [11 of 28 eyes (39.3%)] were soft contact lensrelated Fusarium infections in 2005 and 2006, and this decreased to less than 10% [2 of 25 eyes (8%)] in 2007 and 2008. The odds of having a contact lensrelated Fusarium infection in 20052006 compared with 20072008 was 4.40 (95% condence interval of 0.6032.50) (P = 0.178). Despite the decrease in contact lensrelated Fusarium infections, the number of fungal infections remained elevated in 2007 (10 eyes) and 2008 (14 eyes), including contact lensrelated infections (3 in 2007 and 6 in 2008).

Conclusions: A denite increase in the number of fungal keratitis cases began in 2004 and continued through 2006 during the Fusarium outbreak associated with ReNu with MoistureLoc. Despite the decrease in contact lensrelated Fusarium infections, the overall number of fungal keratitis cases remained high through 2008. Fungal keratitis was more often associated with contact lens use than with trauma in this time.
Key Words: infectious keratitis, fungal keratitis, contact lens, Fusarium, Candida, fungal ocular infection, ocular mycosis, corneal ulcers (Cornea 2010;29:14061411)

ungal keratitis is less common than bacterial keratitis and more devastating. Fungi can penetrate deep into the stroma and through an intact Descemet membrane, gaining access to the anterior chamber. Deep infection can be very hard to eradicate. Furthermore, the response of fungi to antimycotic

MATERIALS AND METHODS

All patients diagnosed with fungal keratitis presenting to the Cornea Service at Wills Eye Institute between April 1, 1999 (this date was chosen to follow the period studied previously by Tanure et al8 at our institute) and December 31, 2008 were identied through a computerized diagnosis code search of our patient database. Institutional review board approval was obtained, and charts were retrospectively reviewed. All patients with culture-positive fungal infection (dened as fungal growth on 2 separate culture media), histopathological diagnosis of fungal keratitis, and culturenegative cases that were diagnosed clinically on the basis of the response to antifungal treatment after failure of antibiotic therapy were included.
Cornea  Volume 29, Number 12, December 2010

Received for publication April 3, 2009; revision received January 27, 2010; accepted February 21, 2010. From the Cornea Service, Wills Eye Institute, Department of Ophthalmology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA. Elisabeth J. Cohen, MD, was paid by lawyers representing patients against Bausch & Lomb. Reprints: Elisabeth J. Cohen, Cornea Service, Wills Eye Institute, 840 Walnut St, Suite 920, Philadelphia, PA 19107 (e-mail: ecohen@willseye.org). Copyright 2010 by Lippincott Williams & Wilkins

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Demographic data, dates of the onset of symptoms, and referral and diagnosis were noted. Predisposing risk factors were identied, including trauma and contact lens use. Prereferral treatment, visual acuity (VA) at the time of presentation, clinical features, microbiology and/or pathology results, and treatment were analyzed. Visual outcome, recurrent infection, and need for surgery were also evaluated. A Fisher exact test and an exact logistic regression test were used to test whether there was a change in the rate of contact lensrelated infections over time (from 1999 to 2008). SAS version 9.2 statistical software (PROC.FREQ) (SAS Institute, Inc, Cary, NC) was used for exact conditional tests. Relative risks for contact lensrelated Fusarium keratitis between 2005 and 2006, and 2007 and 2008 were estimated.

RESULTS
Seventy-eight eyes of 76 patients were identied; 1 patient had an infection in each eye 1 year apart and 1 had simultaneous bilateral infections. Of these, 35 (46.1%) were males and 41 (53.9%) were females. The mean age was 58.0 6 19.3 years (range 1989 years). The right eye was affected in 27 cases, the left eye in 47 cases, and 2 patients had bilateral infections. Twenty-ve patients presented in the summer, 19 in the winter, 15 in the spring, and 19 in the fall. Seven Fusarium keratitis cases presented in the summer, 8 in the winter, 9 in the spring, and 5 in the fall. The number of contact lensrelated fungal infections increased beginning in 2004. Before then, the average was 4 cases every year. In 2004, there was a 2-fold increase in the total number of cases, including 3 contact lensrelated infections, caused by lamentous fungi (2 Fusarium and 1 Aspergillus). The Fusarium contact lens outbreak peaked in 2005 with 7 contact lensrelated cases. An overall increase in fungal infections (15 cases) was also experienced in 2005.

This number remained stable in 2006 with 13 cases, 5 of which were contact lensrelated lamentous infections (4 Fusarium and 1 Aspergillus). There was a signicant increase in contact lensrelated Fusarium infections over time (P = 0.021) with the highest numbers in 20052006, but no analogous trend over time for Candida (P =1.00) or other fungal infections (P = 0.577) (Table 1). During 2005 and 2006, 6 of 11 contact lensrelated Fusarium keratitis cases (54.5%) presented in winter, whereas only 24.3% (19 of 78) of total cases presented in winter. The number of cases with contact lensrelated Fusarium keratitis decreased in subsequent years, with only 2 of 25 cases (8%) in 2007 and 2008. The odds of having a contact lens related Fusarium infection in 20052006 compared with 20072008 were 4.40 (95% condence interval of 0.60 32.50) (P = 0.178). Although there were 10 fungal cases in 2007, the number of contact lensrelated infections dropped to 3 cases (2 Fusarium and 1 yeast). One of the Fusarium cases in 2007 was using ReNu ML even though it was taken off the worldwide market in May 2006 and the other was using ReNu Multiplus. In 2008, 6 of 14 patients (46.1%) had contact lens related fungal infections (1 Candida, 2 Alternaria, 3 Paecilomyces). Both patients with Alternaria keratitis were using ReNu Multipurpose solution, 2 cases with Paecilomyces keratitis were using Optifree Replenish solution (Alcon Laboratories, Inc, Fort Worth, TX), and another Paecilomyces keratitis case was using a generic brand solution manufactured by Bausch & Lomb, Inc. The Food and Drug Administration and Centers for Disease Control and Prevention were notied about these Alternaria and Paecilomyces infections in February 2009. The use of contact lenses was the most common risk factor for fungal keratitis seen in 28 eyes (35.9%). A history of trauma [17 eyes (22.4%)], a history of penetrating keratoplasty

TABLE 1. Fungal Infections by Year

Fusarium Years 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Total No. Cases 1 5 4 3 2 7 12 11 8 14 67*** CL related 1 0 1 0 0 2 7* 4* 2* 0* 17 **P = 0.02 Not CL related 0 2 0 1 0 0 2 3 0 4 12 CL related 0 0 0 0 0 0 0 0 1 1 2 **P = 1.000 Candida Not CL related 0 1 1 1 2 2 2 2 4 2 17 CL related 0 1 0 0 0 1 0 1 0 5 8 **P = 0.58 Others Not CL related 0 1 2 1 0 2 1 1 1 2 11

*Odds of having contact lensrelated Fusarium infection 4.4 times greater in 20052006 (95% condence interval of 0.6032.50) compared with subsequent years of 20072008. **Statistically signicant increase in contact lensrelated Fusarium keratitis over time, with the highest numbers in 20052006. The number of cases with contact lensrelated Fusarium keratitis decreased in subsequent years. No analogous trend over time for Candidiaor other infections. ***Culture-negative cases [11 of 78, (14.1%)] are not included. The diagnosis was conrmed in 3 of 11 culture-negative cases by cultures and/or histopathology of PK specimens. Of these 8 nonconrmed cases, 1 occurred in 1999, 1 in 2002, 1 in 2003, 2 in 2005, 1 in 2006, and 2 in 2007. CL, contact lens.

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(PK) [12 eyes (15.8%)], and a history of herpetic eye disease [9 eyes (11.5%) (6 herpes simplex and 3 herpes zoster)] were also common risk factors in our series (Table 2). Overall, among 28 contact lens users, almost half of them used group IV soft contact lenses [13 of 28 patients, (46.4%)], made of high water content ionic polymers. Whereas 10 of 28 patients (35.7%) used an unspecied type of soft contact lens, the others used several contact lenses, including Acuvue 2 (12 patients), Acuvue Oasys (2 patients), Acuvue extended wear soft contact lens (1 patient), Focus N & D (1 patient), Hydraclear (1 patient), and rigid gaspermeable contact lens (1 patient). Fusarium was isolated in 17 of 28 (64.3%) contact lensrelated infections in this study. Eight of the contact lens patients in this study used ReNu ML. Five patients used ReNu MultiPurpose solution, 1 used Complete Multi purpose solution, and 3 used unspecied multipurpose solutions (Table 3). Most patients had multiple previous diagnoses and were treated with numerous agents before referral. Sixty-eight eyes (87.2%) were on antibiotics. Sixteen eyes (20.5%) were prescribed antiviral medications. Ten eyes (12.8%) were on antifungal treatment. Twenty-nine (37.2%) were using steroids before diagnosis, 4 of which were combination steroid/antibiotics. The clinical presentation of our patients was variable (Table 4). Typical nding of fungal infections were present in 12 eyes (15.4%) with a feathery inltrate and in 11 eyes (14.1%) with satellite lesions. Nine eyes (11.5%) had an intact epithelium. More than half of the eyes [46 eyes (58.9%)] had nonspecic inltrates. The mean size of the stromal inltrates was 9.1 6 11.6 mm2 (range: 0.156 mm2). The mean Snellen VA at the time of presentation was 20/800 (range: 20/20 to no light perception), equivalent to a mean logarithm of the minimum angle of resolution (logMAR) VA of 1.6 6 1.1 (range: 03). One eye had no light perception and 2 eyes had light perception vision. The mean time from initial presentation elsewhere to referral to our institute was 12.3 days (range: 170 days). The mean time lapse between presentation and diagnosis at our

institution was 4 6 9 days (range: 060 days). Twenty-seven patients (35.5%) were admitted to the hospital for an average of 7.4 6 2.8 days (range: 314 days). Sixty-six cases (86.8%) had positive cultures. One was determined to be fungus but was not further identied. Eleven patients were culture negative, but there was a strong clinical evidence of fungal infection with a favorable response to antifungal therapy, after failure of antibiotics. Histopathology was positive for fungal organisms in 3 of these 11 culturenegative patients. Although it is difcult to identify fungal species by histological criteria, periodic acidSchiff stain disclosed rare fungal elements described as yeast in 2 culturenegative cases. Fusarium, the most common organism, was isolated in 29 of 78 eyes (37.2%), 17 (58.6%) of which were associated with contact lens wear. Other lamentous fungi were isolated in 15 eyes (19.2%). Candida and other yeasts were isolated from 22 eyes (28.2%) (Table 5). Twenty-one of the 78 eyes (26.9%) in this series were treated with a single topical agent, 45 (57.7%) used a combination of topical and systemic antifungal agents, and 12 (15.4%) used a combination of more than one topical agent. Two cases (2.6%) required intracameral injections of antifungal agents. Steroids were used in 8 eyes (10.2%), after a minimum of 14 days of antifungal treatment (average 45.6 days). Before use of voriconazole, amphotericin was the drug of choice for yeast infections including Candida and was used in 17 of 22 cases (77.2%), either alone or in combination with other topical or oral agents. The second most common agent used for yeasts was voriconazole. Natamycin was the most common antifungal agent used empirically in 7 of the 11 culture-negative cases (63.6%) and for 32 of the 44 lamentous infections (72.7%). Use of voriconazole began in 2003 for the treatment of fungal keratitis. Almost half of the infections [34 of the 78 eyes (43.6%)] were treated with voriconazole as either a single topical agent (1% solution) or an oral agent combined with other topical agents. Eighty-ve percent (29 of 34) of the eyes treated with voriconazole healed

TABLE 2. Risk Factors of Fungal Keratitis

Risk Factor Contact lens Trauma PK History of HSV/HZV Ocular surface DM Lid anomalies LASIK Neurotrophic K Systemic steroids No risk factor Multiple risk Total no. eyes* 1999 1 1 1 1 2000 1 2 2 1 1 4 2001 1 1 1 1 1 1 1 3 5 2002 1 2 1 4 2003 2 1 3 2004 3 2 1 1 1 1 8 2005 8 2 1 1 1 1 1 2 2 15 2006 5 5 2 1 1 1 5 13 2007 3 1 2 1 2 2 1 10 2008 6 2 2 3 2 2 1 1 5 15 Total 28 17 12 9 7 5 4 3 2 1 4 19 % 35.9 22.4 15.8 11.5 9.2 6.6 5.2 3.9 3.2 1.6 5.2 22.6

*The number of risk factors might not add up to the number of eyes each year because more than 1 factor may occur in the same patient. DM, diabetes mellitus; HSV, herpes simplex virus; HZV, herpes zoster virus; LASIK, laser in situ keratomeleuis.

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TABLE 3. Contact LensRelated Fungal Keratitis Cases, Risk Factors, and Causative Organisms
Year 1999 2001 2004 Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 2006 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Organism Fusarium Fusarium Trichosporum Aspergillus Fusarium Fusarium Fusarium Negative Fusarium Fusarium Fusarium Fusarium Fusarium Fusarium Fusarium Fusarium Fusarium Fusarium Aspergillus Fusarium Fusarium Candida Paecilomyces Altenaria Altenaria Bipolaris Paecilomyces Paecilomyces Contact Lens SCL RGP Focus N & D Acuvue EW SCL EW Acuvue 2 Acuvue FR FR Acuvue Acuvue Acuvue Acuvue 2 Solution Unknown Unknown Unknown Unknown Unknown Complete Unknown ReNu ML ReNu ML Unknown Unknown ReNu ML ReNu ML ReNu ML Unknown ReNu ML ReNu ML ReNu ReNu ML ReNu ReNu Optifree replenish ReNu MultiPurpose ReNu MultiPurpose Unknown Optifree Overwear/EW +/2 2/2 2/2 2/2 +/2 2/2 2/2 2/2 2/2 2/2 2/2 2/+ 2/2 2/2 2/2 2/2 2/2 2/2 2/2 2/2 2/2 2/+ 2/+ 2/+ Accompanying Conditions Plant trauma Graves Dump truck driver Plant trauma A history of herpetic stromal keratitis on topical steroid before infection Dry eye syndrome Pemphigoid Water exposure (lake) Water exposure (lake) Well water exposure A history of herpetic stromal keratitis on topical steroid before infection Graves Sinus infection Reuse solution Viral keratoconjunctivitis Swimming in contacts Dog scratch Corneal scratch removing lens

2005

2 2 2 2

2007

2008

Conv SCL Acuvue 2 Acuvue 2 Acuvue Oasys SCL Acuvue 2 Hydroclear Unknown Acuvue 2 Oasys Acuvue Unknown Acuvue 2 FR

Conv, conventional; EW, extended wear; Focus N & D, Focus night and day; FR, frequent replacement; RGP, rigid gas permeable; SCL, soft contact lens.

with scaring. Of the remaining 5 eyes treated with voriconazole, 3 required urgent PK and 2 required glue application because of perforation. The average duration of antifungal treatment was 81 6 68.8 days (range: 20 days to 1 year). Intensive topical treatment (hourly during the day and every 2 hours at night) was given for a mean duration of 15 6 10 days (range: 245 days). Oral antifungal agents were required in addition to topical treatment in 54 patients (69.2%) because of the presence of deep corneal infection, nonresponsiveness to topical therapy, and/or suspicion of endophthalmitis. The duration of oral therapy ranged from 16 to 185 days (mean, 60 6 41.7 days). The time taken to heal (dened as resolution of inltrate and epithelial healing) was variable, ranging from 8 to 300 days (mean 56.8 6 51 days). Nine eyes required urgent therapeutic PKs, 6 of which were because of perforation and 3 were because of uncontrolled infection. Recurrence of infection after clinical improvement occurred in 5 patients, 27 months after the rst infection was diagnosed (average 4.6 months). None of the patients were on antifungal agents in the time of recurrence, and all responded well to antifungal treatment. The median duration
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of total treatment was 129 days (range: 60365 days, not including time off treatment) for patients with recurrences compared with 81 days (range 20365 days) for patients without recurrent infections. The mean Snellen best-corrected VA at 3 months after institution of treatment was 20/125 (equivalent to logMAR VA of 0.79 6 0.82) compared with average Snellen of 20/800 (equivalent to logMAR 1.6 6 1.1) at presentation. The mean Snellen best-corrected VA was 20/200 (equivalent to logMAR of 1.0) at 3 months after surgery in patients with therapeutic PKs.

DISCUSSION
Fungal keratitis among soft contact lens wearers increased beginning in 2004.27 Before the recent international outbreak of Fusarium keratitis in 20052006, the rate of contact lensassociated corneal infections caused by fungal agents ranged from 2% to 20%.914 In a comparative series from our institution, the rate of contact lensassociated fungal keratitis increased from 2.2% in the period between 1969 and 197715 to 49.6% in the period between 2004 and 2005.16 After the outbreak of Fusarium keratitis in 2005 and 2006 and the
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TABLE 4. The Presenting Features of the Eyes

Clinical Presentation Frank epithelial defect Inltrates Nonspecic Feathery Satellite Immune ring Peripheral inltrate Hypopyon Anterior chamber reaction Intact epithelium Endothelial plaque Corneal melting Dendritiform epithelial lesion Epitheliopathy Endophthalmitis No. Eyes (%) 57 (73.1) 46 12 11 4 2 28 13 9 8 3 2 2 2 (58.9) (15.4) (14.1) (5.1) (2.6) (35.9) (16.6) (11.5) (10.2) (3.9) (2.6) (2.6) (2.6)

recall of ReNu ML, it is important to determine whether or not the outbreak of contact lensrelated fungal infections ended and to update the trends and outcomes of fungal keratitis at our institute since the study by Tanure et al8 10 years ago. In our series, although the odds of having a contact lensrelated Fusarium infection in 20052006 compared with 20072008 were 4.40, the difference was not statistically signicant probably because of small sample size. Unlike our previous study, where most fungal infections were evenly distributed among the warmer seasons (spring, summer, and fall) and were less common in the winter, the number of patients presenting in the winter in this series (19 patients) was similar to the number in the summer. This change is probably because of the overall increase in contact lensrelated fungal infections (33.9%), especially during the Fusarium outbreak. Interestingly, despite the recall of ReNu ML in May of 2006, 2 of the patients with contact lensrelated Fusarium infections presenting later in 2006 were still using it,
TABLE 5. Culture Results
Organism Fusarium Alternaria Paecilomyces Aspergillus Curvularia Scedosporium apiospermum Unidentied lamentous Wangiella Total lamentous Candida albicans C. parapsilosis Malassezia furfur Trichosporon Unidentied yeast Total yeasts Unidentied fungus Negative cultures/smears Number 29 3 3 2 2 2 2 1 44 17 2 1 1 1 22 1 11

in addition to one patient who presented in 2007. This underscores the importance of asking patients what solutions they use and educating them to discard solutions that have been withdrawn from the market. Although the index of suspicion was high among ophthalmologists during the Fusarium outbreak, the majority of patients were misdiagnosed at the time of presentation. This nding is similar to our previous study 8 and studies from other institutions.17 The nonspecic nature of the corneal inltrates, as noted in 58.9% of our patients, makes the diagnosis of fungal keratitis difcult. Twenty-nine patients were treated with steroids or an antibiotic/steroid combination before diagnosis, which exacerbates fungal infections, especially in the absence of antifungal treatment.1820 Although there is some controversy on the use of topical steroids in the initial management of microbial keratitis,21,22 the possibility of fungal infection must be considered, and we recommend steroids be avoided in the initial management of suspected microbial keratitis before determination of the cause by corneal cultures.23 Eight patients were culture negative and were diagnosed based on clinical appearance and response to antifungal treatment after failing antibiotic treatment. This may be attributed to the deep nature of the inltrates, which makes it difcult to reach the organisms by corneal scraping and obtain a positive culture. Although including these cases may contribute to selection bias, it gives a more accurate picture of fungal keratitis in a tertiary cornea practice where the cultures may be a negative and the infection not conrmed, if PK is avoided because of a positive response to antifungal treatment. Repeat cultures and biopsies can be helpful in the diagnosis, but they can still be negative in very deep infections.24 Obtaining cultures from the contact lens itself may sometimes give a clue to the possible organisms involved in cases of microbial keratitis in which the corneal cultures are negative.25 Natamycin, alone or in combination with other oral or topical agents, was the most common antifungal medication used in our series, not only because it is the only commercially available topical antifungal agent but also because of its reported efcacy against Fusarium and other lamentous fungi.26 Although high minimum inhibitory concentration of natamycin to the Fusarium sp. has been reported,7 there are no established breakpoints for antifungal minimum inhibitory concentrations in the eye. Voriconazole, a relatively new triazole approved by the Food and Drug Administration for systemic use in 2002, has been shown in several in vitro studies to have the broadest spectrum activity against yeast, dematiaceous, and hyaline lamentous fungi.2730 In our series, voriconazole, either in oral or in topical form, was used in treating 34 of our patients (43.6%) beginning in 2003. Voriconazole is now often used as the initial antifungal agent because it is our impression that voriconazole is more effective than natamycin, although natamycin is sometimes used because it is commercially available and does not require frequent renewal. In conclusion, fungal keratitis, in general, is still diagnosed at an increased rate despite a decrease in the number of cases of contact lensrelated Fusarium infection in 2007 2008, down to 02 cases per year, a number similar to that
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before the outbreak. We are particularly concerned with the nding of the occurrence of 5 contact lensrelated fungal keratitis caused by unusual fungal organisms, Alternaria and Paecilomyces, in 2008. Despite increased awareness of fungal keratitis and advances in antifungal treatment, fungal keratitis can be associated with severe vision loss. REFERENCES
1. Alfonso EC, Rosa RH, Miller D. Fungal keratitis. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea and External Disease: Clinical Diagnosis and Management. 2nd ed. Philadelphia, PA: Elsevier: Mosby; 2005:11011113. 2. Chang DC, Grant GB, ODonell K, et al. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA. 2006;296: 953963. 3. Khor WB, Aung T, Saw SM, et al. An outbreak of Fusarium keratitis associated with contact lens wear in Singapore. JAMA. 2006;295:28672873. 4. Alfonso EC, Cantu-Dibildox J, Munir WM, et al. Insurgence of Fusarium keratitis associated with contact lens wear. Arch Ophthalmol. 2006;124: 941947. 5. Gorscak JJ, Ayres BD, Bhagat N, et al. An outbreak of Fusarium keratitis associated with contact lens use in the northeastern United States. Cornea. 2007;26:11871194. 6. Bernal MD, Acharya NR, Lietman TM, et al. Outbreak of Fusarium keratitis in soft contact lens wearers in San Francisco. Arch Ophthalmol. 2006;124:10511053. 7. Jeng BH, Hall GS, Schoeneld L, et al. The Fusarium keratitis outbreak: not done yet? Arch Ophthalmol. 2007;125:981983. 8. Tanure MA, Cohen EJ, Sudesh S, et al. Spectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania. Cornea. 2000;19:307312. 9. Rattanatam T, Heng WJ, Rapuano CJ, et al. Trends in contact lens related corneal ulcers. Cornea. 2001;20:290294. 10. Cohen EJ, Fulton JC, Hoffman CJ, et al. Trends in contact lens associated corneal ulcers. Cornea. 1996;15:566570. 11. Mah-Sadorra JH, Yavuz SG, Najjar DM, et al. Trends in contact lens related corneal ulcers. Cornea. 2005;24:5158. 12. Liesegang TJ. Contact lensrelated microbial keratitis: Part I: Epidemiology. Cornea. 1997;16:125131. 13. Liesegang TJ. Contact lensrelated microbial keratitis: Part II: Pathophysiology. Cornea. 1997;16:265273. 14. Wong TY, Fong KS, Tan DT. Clinical and microbial spectrum of fungal keratitis in Singapore: a 5-year retrospective study. Int Ophthalmol. 1997; 21:127130.

15. Liesegang TJ, Foster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol. 1980;90:3847. 16. Alfonso EC, Miller D, Cantu-Dibildox J, et al. Fungal keratitis associated with non-therapeutic soft contact lenses. Am J Ophthalmol. 2006;142: 154155. 17. Iyer SA, Tuli SS, Wagoner RC. Fungal keratitis: emerging trends and treatment outcomes. Eye Contact Lens. 2006;32:267271. 18. Peponis V, Herz JB, Kaufman HE. The role of corticosteroids in fungal keratitis: a different view. Br J Ophthalmol. 2004;88:1227. 19. Stern GA, Buttross M. Use of corticosteroids in combination with antimicrobial drugs in the treatment of infectious corneal disease. Ophthalmology. 1991;98:847853. 20. Schreiber W, Olbrisch A, Vorwerk CK, et al. Combined topical uconazole and corticosteroid treatment for experimental Candida albicans keratomycosis. Invest Ophthalmol Vis Sci. 2003;44: 26342643. 21. Wilhelmus KR. Indecision about corticosteroids for bacterial keratitis. Ophthalmology. 2002;109:835844. 22. Miedziak AI, Miller MR, Rapuano CJ, et al. Risk factors in microbial keratitis leading to penetrating keratoplasty. Ophthalmology. 1999;106: 11661171. 23. Cohen EJ. The case against the use of steroid in the treatment of bacterial keratitis. Arch Ophthalmol. 2009;127:103104. 24. Strelow SA, Kent HD, Eagle RC Jr, et al. A case of contact lens related Fusarium solani keratitis. CLAO J. 1992;18:125127. 25. Das S, Sheorey H, Taylor HR. Association between cultures of contact lens and corneal scraping in contact lens related microbial keratits. Arch Ophthalmol. 2007;125:11821185. 26. Jones DB, Sexton R, Rebell G. Mycotic keratitis in South Florida: a review of thirty-nine cases. Trans Ophthalmol Soc U K. 1970;89: 781797. 27. Marangon FB, Miller D, Giaconi JA, et al. In vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens. Am J Ophthalmol. 2004;137:820825. 28. Thiel MA, Zinkernagel AS, Burhenne J, et al. Voriconazole concentration in human aqueous humor and plasma during topical or combined topical and systemic administration for fungal keratitis. Antimicrob Agents Chemother. 2007;51:239244. 29. Lalitha P, Shapiro BL, Srinivasan M. Antimicrobial susceptibility of Fusarium, Aspergillus, and other lamentous fungi isolated from keratitis. Arch Ophthalmol. 2007;125:789793. 30. Bunya VY. Hammersmith KM, Rapuano CJ. Topical and oral voriconazole in the treatment of fungal keratitis. Am J ophthalmol. 2006;143: 151154.

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