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Insurgence of Fusarium Keratitis Associated With Contact Lens Wear
Eduardo C. Alfonso, MD;
Jorge Cantu-Dibildox, MD;
Wuqaas M. Munir, MD;
Darlene Miller, DHSc, MPH;
Terrence P. O’Brien, MD;
Carol L. Karp, MD;
Sonia H. Yoo, MD;
Richard K. Forster, MD;
William W. Culbertson, MD;
Kendall Donaldson, MD;
Jill Rodila, MD;
Yunhee Lee, MD
Arch Ophthalmol. 2006;124:941-947. Published online June 12, 2006 (doi:10.1001/archophthalmol.124.7.ecs60039).
ABSTRACT
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Objective To describe the clinical presentation and course of patients who developed keratitis due to Fusarium while wearing nontherapeutic soft contact lenses.
Methods A retrospective review of microbiologic records from January 1, 2004, through April 15, 2006, was performed, identifying all patients with corneal ulceration and a culture positive for Fusarium species. Medical records of 34 patients were reviewed for clinical characteristics, treatment regimens, and microbiologic features.
Results The most common antimicrobial medications administered prior to Fusarium diagnosis were antibacterials in 31 of 34 patients. No distinct preponderance of any one brand of either contact lens or solution was identified. The microbiologic corneal cultures found Fusarium oxysporum in 20 cases, Fusarium solani in 3 cases, Fusarium species not further identifiable in 10 cases, and no growth in 1 case. Patients with a delayed onset of treatment had a tendency for prolonged treatment until cure.
Conclusions Fusarium has previously been an unusual organism in the etiology of infectious keratitis in the setting of nontherapeutic soft contact lens wear. A delay in proper diagnosis and intervention may contribute to a prolonged treatment course. The microbial spectrum of contact lens–related keratitis may be evolving with higher participation of Fusarium species compared with prior reports.
INTRODUCTION
Ocular infections caused by fungal organisms can have devastating consequences on ocular structures and vision. Keratomycosis can be associated with contiguous spread to the anterior chamber as a consequence of the ability of fungi to penetrate an intact Descemet membrane.1-2 Eventually, severe fungal keratitis may lead to endophthalmitis.3 Topical corticosteroids, whose use has grown in recent decades, enhance the invasive abilities of fungi.4
Soft contact lens wear has long been associated with microbial keratitis.5 However, fungal keratitis in particular has a historically low prevalence in association with soft contact lens wear.3, 5-10 At our institution in south Florida, we reported only 3 cases of contact lens–associated fungal keratitis between the years of 1969 and 1977 of which only 1 case was in a nontherapeutic contact lens user.8 From 1977 to 1982, we reported only 2 such contact lens–associated keratomycoses,5 and an additional 5 cases were reported between 1982 and 1992.3 Tanure and colleagues10 presented 5 cases of contact lens–associated keratomycosis over the span of 1991 to 1999. In stark contrast to this historical context, we present 34 clinical cases of fungal keratitis associated with nontherapeutic soft contact lens wear from January 2004 to April 2006.
METHODS
This study was approved by the institutional review board at the University of Miami, Fla. All cases of fungal keratitis between January 1, 2004, and April 15, 2006, were identified from the records of the ocular microbiology laboratory at the Bascom Palmer Eye Institute. Cases of Fusarium species with a concurrent history of nontherapeutic soft contact lens wear at the time of symptom onset were selected for study, and 34 patients were identified. Techniques for specimen collection as well as recommended culture media have been previously described.8, 11 In addition to taking corneal scrapings for smear and direct plating into solid agar plates, we also sampled contact lenses, solutions, solution bottles (tip, inside of cap, rim), and contact lens cases, when they were available, for microbial culture. A positive culture was defined by (1) growth on multiple media; (2) a positive smear and confirmatory growth on at least 1 medium; or (3) clinical diagnosis of fungal keratitis with growth on at least 1 medium for patients already receiving antifungal therapeutic agents. Isolates were identified by the Bascom Palmer Eye Institute ocular microbiology laboratory and/or the Texas Fungus Testing Laboratory, San Antonio. Confocal microscopy using the Confoscan 3 (Nidek, Fremont, Calif) was performed when possible in several patients to aid in the clinical diagnosis (Figure 1).
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Figure 1. Confocal microscopy showing abundance of fungal elements.
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Medical records of 34 patients were available. Age and sex were noted. Data regarding the onset of symptoms such as redness, tearing, discomfort or pain, and impaired vision were used to determine the time of onset of the corneal process. The time at which antifungal therapy was started was used to define the treatment start date. Treatments prior and subsequent to this date were noted. Information on contact lenses and solutions such as brands and wearing schedules was recorded when available. Visual acuity at initial examination and at the last visit was obtained. The size and location of the infiltrate as well as the presence of a hypopyon at the first recorded visit were also classified and used to develop severity scales. The need for surgical interventions such as corneal gluing for perforation or therapeutic penetrating keratoplasty was noted. The time to cure was then determined to be either the date of antifungal therapy cessation or the date of therapeutic penetrating keratoplasty.
RESULTS
Between January 1, 2004, and April 15, 2006, we identified 34 patients with a culture positive for Fusarium species and concomitant nontherapeutic soft contact lens wear. The average age was 34.9 years (median, 32 years) with a range of 13 to 92 years. There were 14 male patients (41%) and 20 female patients (59%). An analysis of the past medical and ocular history as well as a review of systems did not disclose any active disease that would predispose to the development of an infectious ulceration. There were no cases of antecedent ocular trauma prior to the onset of ulceration.
Most patients (31/34, 91%) were initially treated for a presumed bacterial keratitis prior to diagnosis of keratomycosis (Table 1). The most common antibiotics prescribed were tobramycin 0.3% or 14 mg/mL (20/34, 59%), moxifloxacin 0.5% (14/34, 41%), and cefazolin 50 mg/mL (11/34, 32%). Antiviral medications were prescribed in 4 cases (12%), and antifungal therapy was empirically started before the diagnosis was made in 2 patients (6%). Nine patients received corticosteroid therapy prior to the diagnosis of keratomycosis (Table 1). The brand of contact lens was identified in 14 patients (Table 2) and brand of contact lens solution in 13 patients (Table 3). The average number of days from onset of symptoms to diagnosis was 9.1 days (median, 4 days) with a range of 0 to 140 days. Central corneal infiltrates (defined as ulcers encroaching on the central 3 mm of the visual axis) were present in 20 (63%) of 32 cases and peripheral corneal infiltrates (defined as those ulcers occurring outside the central 3 mm of the visual axis) in 12 (37%) of 32 cases (Table 4). The size of the infiltrate at initial examination was an overall average of 3.31 mm with a range of 1 to 8 mm. A hypopyon was present in 6 (19%) of 32 cases, all of which were associated with central corneal ulcers.
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Table 1. Treatment Regimen Prior to Fusarium Diagnosis: Pretreatment by Case*
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Table 2. Contact Lens Usage Profile
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Table 3. Contact Lens Solution Usage Profile
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Table 4. Fusarium Corneal Infiltrate Characteristics by Location
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Culture results of corneal scrapings were positive for Fusarium oxysporum in a majority of patients (59%), followed by Fusarium species not otherwise identifiable (29%), and Fusarium solani (9%) (Table 5). Gram- or Giemsa-stained smears were obtained in 27 cases with the identification of hyphal elements in 12 cases (44%). Confocal microscopy was conducted in 5 patients, and hyphal elements were identified in all 5 patients (100%). Of these 5 patients, 4 patients also had corneal smears of which 2 were positive (50%). Cultures of the last used contact lenses were obtained in 11 patients, out of which 10 (91%) grew Fusarium (Table 5). Last used contact lens cases (n = 3) were culture positive in all samples while both contact lens solution bottles (tip, inside of cap, rim) and contact lens solutions (n = 5) were all culture negative (Table 5). All contact lenses and contact lens cases that were culture positive grew the same organism as isolated from the cornea with the exception of 1 case, which had positive contact lens cultures but negative corneal cultures.
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Table 5. Microbiologic Culture Results by Specimen Origin
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Topical and/or systemic antifungal medication was used for an average of 67.1 days with a range of 21 to 138 days. The most commonly used topical medication was natamycin 5% in 31 (91%) of 34 cases. Oral voriconazole 200 mg per day was used in 3 (9%) of 34 cases. Liver function test levels were monitored every 2 weeks in patients using oral voriconazole. No changes in their liver function test levels from baseline were observed in any of the patients. Surgical intervention was necessary in 2 cases, including placement of tissue adhesive glue in 1 case and therapeutic penetrating keratoplasty in 1 case. In the majority of the cases, corneal scrapings for debridement of the epithelium and necrotic tissue overlying the infiltrate was conducted to allow better penetration of the topical antifungal drops.
Delay of treatment, defined as the interval from the onset of symptoms until the antifungal treatment of Fusarium keratitis was initiated, was evaluated against a variety of outcomes. A number of trends were observed. The time until cure was prolonged in these cases when associated with delay of treatment beyond 7 days (Figure 2). The size of the infiltrate was compared with delay of treatment as well and showed the greatest infiltrate size when ulcers were 4 to 7 days old. Finally, visual acuities at initial examination and at cure were compared with delay of treatment (Figure 3 and Figure 4). Of the 10 patients with pretreatment visual acuities worse than 20/100, 6 patients (60%) had fewer than 4 days of treatment delay. Posttreatment visual acuity was better than 20/25 in 7 eyes with 4 eyes having fewer than 4 days of treatment delay. However, 5 of the 8 eyes with posttreatment visual acuities less than 20/100 were also in the group with fewer than 4 days of treatment delay.
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Figure 2. Time until cure in days vs number of days the treatment of Fusarium keratitis was delayed.
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Figure 3. Initial pretreatment visual acuity vs treatment delay in days.
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Figure 4. Final posttreatment visual acuity vs treatment delay in days.
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REPORT OF CASES
CASE 1
A 16-year-old, male soft contact lens wearer was examined for a corneal ulceration in the left eye. He previously underwent therapy with topical moxifloxacin 0.5% and gentamicin 0.3% of 4 days duration with worsening of the ulcerative keratitis prior to our evaluation. On initial examination, best-corrected visual acuity was 20/25 OD and 20/40 OS. Slitlamp examination disclosed a 3-mm central stromal infiltrate with a surrounding inflammatory ring along with a 1-mm hypopyon (Figure 5). The cornea was scraped for smears and culture, and the left eye contact lens was obtained for microbiologic testing. Microscopic examination of smears with Gram stain was negative for organisms. The patient was initiated on topical fortified tobramycin 14 mg/mL and cefazolin 50 mg/mL every 1 hour. The contact lens solution (ReNu MoistureLoc, Bausch & Lomb, Rochester, NY) was later acquired and processed for microbial culture. Confocal microscopic examination was consistent for fungal elements. Anterior chamber optical coherence tomography demonstrated the central stromal infiltrate along with an endothelial plaque as well as the hypopyon (Figure 6). Six days following initial culture, the microbiology laboratory identified Fusarium oxysporum growth from the cultures of the contact lens. Cultures from corneal scraping and contact lens solution showed no growth. The patient was started on topical natamycin 5% every 2 hours, voriconazole 100 mg twice a day orally, and topical moxifloxacin 0.5% 4 times a day. Recurrent debridement of healing epithelium and necrotic material overlying the infiltrate was performed to enhance penetration of topical antifungal medication. After 40 days of treatment, his visual acuity improved to 20/20 with resolution of the hypopyon and stromal infiltrate with a faint residual anterior stromal corneal scar.
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Figure 5. Slitlamp photograph showing central stromal infiltrate and surrounding inflammatory ring with hypopyon.
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Figure 6. Anterior segment optical coherence tomography revealing central corneal ulcer, endothelial plaque, and hypopyon.
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CASE 2
A 55-year-old, female soft contact lens wearer arrived for evaluation following a 2-week history of pain and impaired vision secondary to an ulcerative keratitis of the right eye. Prior therapy included topical moxifloxacin 0.5%, tobramycin 0.3%, and prednisolone acetate 1%. Best-corrected visual acuity was hand motions at 3 feet OD and 20/25 OS. Slitlamp examination disclosed a 5-mm central stromal infiltrate with a 3-mm layered hypopyon. No vitritis was present on contact B scan ultrasonography. Corneal scraping was performed, demonstrating hyphal elements on Gram-stained smears. Topical natamycin 5% was prescribed every 2 hours, and topical fortified cefazolin 50 mg/mL and tobramycin 14 mg/mL were started 4 times a day. Corneal culture results were positive for growth of Fusarium species. Four days after initial examination, the patient had a corneal perforation in the area of infiltration with a positive Seidel test. Cyanoacrylate tissue adhesive placement was successfully performed and a bandage soft contact lens was placed (Figure 7). Following 120 days of treatment with natamycin 5%, the best-corrected visual acuity improved to 20/200 with intact corneal glue and resolution of both the hypopyon and stromal infiltrate.
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Figure 7. Slitlamp photograph illustrating cyanoacrylate adhesive over perforated corneal ulcer with bandage contact lens.
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CASE 3
A 53-year-old, male soft contact lens wearer experienced a 5-day history of pain and blurry vision due to an ulcerative keratitis of the right eye. Prior treatment consisted of topical moxifloxacin 0.5% therapy. Best-corrected visual acuity was 20/80 OD and 20/25 OS. Examination with slitlamp biomicroscopy disclosed a 3-mm central stromal infiltrate (Figure 8). Gram-stain smears following corneal scraping demonstrated hyphae, and confocal microscopy was likewise positive for fungal elements. The patient began topical natamycin 5% every hour and continued moxifloxacin 0.5% 4 times daily. Corneal cultures grew Fusarium oxysporum. Multiple corneal scrapings were performed to enhance penetration of topical antifungal medication. The keratitis resolved following 53 days of treatment with residual corneal scar (Figure 9).
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Figure 8. Slitlamp photograph showing central stromal infiltrate.
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Figure 9. Slitlamp photograph illustrating resolution of corneal infiltrate with residual scar.
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COMMENT
Fungal keratitis, a common cause of corneal infection and blindness after trauma in the developing world, is frequently caused by Fusarium species.8 Yet Fusarium keratitis is a relatively rare ocular infection after trauma in developed areas demonstrating significant geographic variability.3 Fusarium keratitis in association with nontherapeutic, cosmetic contact lens wear has hitherto been an even rarer occurrence.7, 9 Our present report describes the clinical and microbiologic features of the largest series of cases of culture-proven keratitis due to Fusarium species in association with nontherapeutic, soft contact lenses.
Numerous reports have documented the higher risk of microbial keratitis in association with soft contact lens wear.5-6 The association of severe keratitis due to virulent gram-negative pathogens, including Pseudomonas aeruginosa, has been well established among wearers of soft contact lenses.5-6 Treating clinicians have selected initial topical antimicrobial therapy based on epidemiological and microbiological evidence from prior case series identifying an assortment of gram-negative and gram-positive bacterial species as the most common causative pathogens.5-6 Prior to this report, clinical series of microbial keratitis in nontherapeutic soft contact lens users have not included Fusarium species as likely causative agents of keratitis in this clinical setting.
Based on the present report, ophthalmic clinicians should have a heightened clinical suspicion for possible Fusarium and other fungal pathogens as causative agents in cosmetic soft contact lens patients with ulcerative keratitis. The clinical and diagnostic approach should be adjusted to maximize the likelihood for detecting Fusarium and other fungal pathogens in this clinical setting. Confocal microscopy is a valuable aid in addition to microbial culture to help establish the diagnosis promptly and guide initial specific antifungal therapy. Corneal scrapings to obtain adequate material for smears and culture on selective microbiologic media are mandatory in central keratitis clinically graded of high severity. Smears stained with Giemsa, periodic acid-Schiff, and Gram stains should undergo microscopic analysis to look for hyphal fragments. Plating material on Sabouraud agar or brain heart infusion with gentamicin should be carried out for optimal isolation of fungal pathogens via culture. Cases of peripheral ulcerative keratitis of milder severity not immediately responsive to appropriate broad spectrum antibacterial therapy should be re-evaluated with a greater suspicion for possible fungal keratitis, including those due to Fusarium species. Based on treatment experience in this series, it is our clinical impression that earlier correct diagnosis with institution of proper specific antifungal therapy resulted in a speedier resolution of the keratitis.
Initial treatment of suspected microbial keratitis due to filamentous fungal pathogens is with a polyene antifungal agent, preferably topical natamycin 5 mg/mL suspension or, secondarily, amphotericin B 1.5 mg/mL. The agents should be administered at a high frequency of every hour initially and frequency should be modified based on clinical response. Periodic debridement of the epithelial layer may help with the penetration of natamycin suspension into the deeper corneal stroma. Newer antifungal agents such as voriconazole have demonstrated promise with in vitro susceptibility testing against ocular fungal isolates and in some clinical experience.12 Additional comparative clinical trials are warranted to demonstrate superior efficacy and safety to recommend voriconazole over natamycin as the preferred topical agent for Fusarium keratitis. Adjunctive systemic azole therapy such as voriconazole may also be considered to supplement frequent topical natamycin treatment in cases of severe Fusarium keratitis.
The precise cause for the rise in cases of soft contact lens–associated Fusarium keratitis is not completely understood.13-14 The method of review of the present large series does not allow us to identify the specific risk factor or factors responsible for the observed rise in frequency of this fungal pathogen as a causative factor for keratitis among users of soft contact lenses. Additional prospective controlled case series analysis may allow unraveling of specific factors associated with the rise in infections from Fusarium species.
Ulcerative keratitis in a soft contact lens wearer should suggest possible Fusarium or other fungal species in addition to bacteria, parasites, or viruses as causative organisms. Clinicians should conduct the necessary clinical and laboratory investigations to establish a specific diagnosis promptly to initiate the most specific, efficacious therapy.
Two ARCHIVES Express articles in this issue highlight a recent outbreak of Fusarium keratitis in 2 different geographic regions in the United States. Prior to this year, reports of Fusarium infection in soft contact lens wearers were rare. An association with ReNu MoistureLoc contact lens solution has prompted Bausch & Lomb to withdraw this particular solution initially in Singapore and more recently in April 2006 in the United States. These cases appear to be part of a more global emergence of Fusarium as a vision-threatening organism in otherwise healthy patients. An editorial addressing this topic will be published in the August issue of the ARCHIVES.
Daniel M. Albert, MD, MS
Leonard A. Levin, MD, PhD
Yasmin Bradfield, MD
Dennis Han, MD
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AUTHOR INFORMATION
Correspondence: Eduardo C. Alfonso, MD, Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL 33136 (ealfonso{at}med.miami.edu).
Published Online: June 12, 2006 (doi:10.1001/archophthalmol.124.7.ecs60039).
Submitted for Publication: May 5, 2006; final revision received May 10, 2006; accepted May 11, 2006.
Author Contributions: Dr Alfonso had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: This study was funded by an unrestricted grant from Research to Prevent Blindness.
Author Affiliations: Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, Fla.
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