Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You and Your Team.

Learn More →

An Outbreak of FusariumKeratitis Associated With Contact Lens Wear in Singapore

An Outbreak of FusariumKeratitis Associated With Contact Lens Wear in Singapore ContextFungal keratitis is a potentially blinding condition that is rarely seen with contact lens wear.ObjectiveTo describe a nationwide outbreak of fungal keratitis caused by Fusariumspecies among contact lens wearers in Singapore.Design, Setting, and PatientsNationwide, hospital-based case series. All cases of fungal keratitis among contact lens wearers in all ophthalmology departments in Singapore were reviewed along with the charts of all contact lens wearers with culture-proven fungal keratitis from March 2005 through May 2006. A standardized telephone interview was conducted to obtain additional clinical information.Main Outcome MeasureDiagnosis of Fusariumkeratitis associated with contact lens wear.ResultsDuring the study period, 66 patients (68 affected eyes) were diagnosed with Fusariumkeratitis associated with contact lens wear; the estimated annual national incidence is 2.35 cases per 10 000 contact lens wearers (95% confidence interval, 0.62-7.22). Patients ranged in age from 13 to 44 years (mean [SD], 27.1 [8.4] years), of which 32 (48.5%) were men. The vast majority (65 patients; 98.5%) wore soft, disposable contact lenses; 62 patients (93.9%) reported using 1 brand of contact lens cleaning solution (ReNu, Bausch & Lomb, Rochester, NY), including 42 patients (63.6%) who recalled using ReNu with MoistureLoc. Most patients (81.8%) reported poor contact lens hygiene practices, including overnight use of daily wear contact lenses (19.7%), and use of contact lenses past the replacement date (43.9%). The final best-corrected visual acuity ranged from 20/20 to 20/80. Five patients (5 eyes; 7.4%) required emergency therapeutic or tectonic corneal transplantation.ConclusionsA new and evolving epidemic of Fusariumkeratitis associated with contact lens wear was found in Singapore. Physicians and eye care practitioners worldwide need to be aware of the likelihood of similar outbreaks emerging among contact lens wearers.Infective keratitis is a potentially blinding condition that represents the most severe complication related to contact lens wear. The vast majority of these infections are caused by bacteria, especially Pseudomonas aeruginosa.Fungal keratitis from contact lens wear is rare, constituting less than 5%of microbial keratitis in patients who wear contact lenses for refractive error. The majority of such fungal infections have been attributed to ocular trauma, chronic ocular surface disease, and concomitant systemic immunosuppressive diseases.In certain tropical and subtropical regions, such as Singapore,southern Florida,and southern India,Fusariumspecies represent the most common pathogen for fungal keratitis. Species of Fusariumare ubiquitous hyaline filamentous fungi, widely distributed in soil, and commonly associated with plant roots; in humans, this organism has a predilection for infecting the cornea, and is an emerging cause of disease among immunocompromised patients.Outbreaks of fungal eye infections are rare; previous cases have been linked to specific circumstances, such as hospital construction,contaminated intraocular lens solutions,and an environmental reservoir.Since March 1, 2005, there was a sharp increase in the number of cases of Fusariumkeratitis associated with contact lens wear in Singapore. By February 2006, 54 patients nationwide had been identified as having this rare and unusual infection over the 1-year period. Alarmed by this apparent outbreak, we alerted Singapore's Ministry of Health, which issued an urgent health advisory. Since then, 12 additional cases have been identified between March and May 2006. Recent reports of Fusariumkeratitis in 122 patients in the United Statesand in 33 patients in Hong Konghave been confirmed and suggest that this phenomenon may be part of a global problem, with serious implications for millions of contact lens wearers worldwide. This article describes an outbreak of Fusariumkeratitis among contact lens wearers in Singapore.METHODSThis study was approved by the scientific and ethics committees of the Singapore Eye Research Institute. The attendance records and microbiology results of all ophthalmology departments in Singapore's public hospitals (Singapore National Eye Centre, Changi General Hospital, Tan Tock Seng Hospital, and National University Hospital) were searched for patients treated for infective keratitis associated with contact lens wear from March 1, 2005, to May 26, 2006. Only patients with contact lens wear and a diagnosis of fungal keratitis were included in this case series. A contact lens wearer was defined as an individual who wore contact lenses at least once per week for the correction of refractive error. This excluded individuals who wore therapeutic contact lenses (eg, bandage contact lens wear) for a previously diagnosed ocular disease.Fungal keratitis was defined as a corneal epithelial defect with underlying stromal infiltrate, which had a fungal organism isolated from a corneal sample (eg, corneal scrape, biopsy, or corneal button). Patients with classic features of fungal keratitis but negative corneal cultures were also included in the definition if a fungal organism could be isolated from the patient's contact lens or contact lens case. Any atypical, infiltrative lesion with ill-defined or irregular margins, satellite or branching lesions, and especially in the presence of a ring infiltrate would raise the suspicion of fungal keratitis.Patients were included in the study after informed consent (oral or written) was obtained. The following information was then extracted from the patients' charts: demographic profile (including ethnic group), the type of contact lenses and solutions used, contact lens care practices, and the management and subsequent progress up until the last follow-up review. Ethnic group refers to the patient's race that was declared by the individual on his/her national identity card. The population in Singapore is classified into the following 4 ethnic categories defined by the Singapore Department of Statistics: Chinese, Malay, Indian, and others. Because risk factors for disease prevalence may differ among different subpopulations in multiethnic Singapore, ethnic grouping is normally included in demographic profiling.Telephone interviews also were conducted by trained interviewers to obtain further detailed clinical information. To minimize the effects of recall bias, a standardized questionnaire was produced, which included a list of soft contact lenses and contact lens solutions sold in Singapore during this period. To preserve the uniformity of these interviews, only 3 of the study's investigators (W-B.K., J.L., S-B.L.) were responsible for administering the questionnaire.Patients with a clinical or presumed diagnosis of infective keratitis associated with contact lens wear were routinely cultured for microbial organisms in the ophthalmology departments in Singapore's public hospitals (Singapore National Eye Centre, Changi General Hospital, Tan Tock Seng Hospital, and National University Hospital) prior to treatment. Corneal samples or corneal biopsies were sampled from the edge or base of the infiltrate under biomicroscopy and sent for Gram staining, wet mount microscopy, and for culture by blood agar, chocolate agar, Sabouraud dextrose agar, brain-heart infusion broth, and thioglycollate broth. The patient's contact lenses, contact lens case, and current bottle of contact lens solution (when available) were also sent for microbiological testing. For cases in which the Fusariumspecies were isolated and available for further testing, identification was performed using 28S rRNA gene sequencing.Treatment of all cases was usually by a corneal specialist and therapy was modified according to culture results and clinical progress. The number of contact lens wearers in the country was estimated based on a Singapore population survey performed in 1998 reporting that 9% of the population wore contact lensesand by applying population figures for Singapore as of June 2005.This allowed us to estimate the annual incidence of Fusariumkeratitis in Singapore, which was computed as the proportion of new cases among contact lens wearers in Singapore per year. The 95% confidence intervals for the incidence rates were determined assuming a Poisson distribution,and were calculated using JavaStat (http://statpages.org/confint.html).RESULTSSixty-six patients (representing 68 affected eyes) were identified as contact lens wearers with fungal keratitis from March 2005 through May 2006 (Table). All 66 patients were identified from a search of the respective departments' medical records and microbiological results. Three patients (4.5%) were interviewed in person; information from the remaining patients was obtained from medical record reviews and telephone interviews.Table.Characteristics of Patients With FusariumKeratitisNo. (%) of Patients (N = 66)SexMen32 (48.5)Women34 (51.5)Age, y≤2017 (25.8)21-4043 (65.2)41-606 (9.1)Ethnicity*Chinese44 (66.7)Malay16 (24.2)Indian2 (3.0)Others4 (6.1)LateralityRight eye30 (45.5)Left eye34 (51.5)Both eyes2 (3.0)Contact lens typeSoft hydrogel disposable lensesMonthly52 (78.8)Every 14 d6 (9.1)Daily1 (1.5)Silicone hydrogel disposablelensesMonthly5 (7.6)Every 14 d1 (1.5)Rigid gas permeable1 (1.5)Contact lens solution†ReNu with MoistureLoc42 (63.6)ReNu Multiplus6 (9.1)ReNu solution (unspecified)14 (21.2)Complete solution3 (4.5)Opti-Free Express solution1 (1.5)Not specified3 (4.5)Suboptimal hygiene practices‡No manual cleaning beforestorage35 (53.0)Expired lenses29 (43.9)Overnight wear (daily wear lenses)13 (19.7)Swimming20 (30.3)Others§13 (19.7)Best-corrected visual acuity atpresentation∥20/60 or better51 (75.0)20/80 to 20/20011 (16.2)Counting fingers or worse6 (8.8)Best corrected visual acuity at last follow-up visit∥20/2027 (39.7)20/25 to 20/4038 (55.9)20/50 to 20/2003 (4.4)*Defined by the Singapore Department of Statistics.†Figures do not add up to 100% as patients may have been using multiple solutions.‡Figures do not add up to 100% as patients may have multiple suboptimal practices.§Including outdoor activities such as camping and water sports.∥Representing 68 affected eyes.There was a distinct trend that peaked in February 2006 when 15 cases were identified and declined between March 2006 and May 2006 (Figure 1). The patients were young (mean [SD] age, 27.1 [8.4] years), predominantly Chinese (reflecting the Chinese racial predominance in Singapore), and almost equally distributed by sex.Figure 1.Epidemic Curve for the Outbreak of FusariumKeratitis Associated With Contact Lens WearContact Lens Usage and PracticesThe average duration of contact lens use was 7.6 years. Contact lenses were worn between 6 and 24 hours each day on most days of the week. Almost all of the patients (98.5%) wore soft disposable lenses. The contact lenses worn by patients were from 8 different contact lens manufacturers. The majority of patients (78.8%) were using monthly disposable, soft hydrogel lenses. Six patients (9.1%) reported wearing disposable silicone-hydrogel lens; and 1 patient reported wearing rigid gas permeable lenses.Multipurpose solutions for cleaning, rinsing, and storage of contact lenses were used by the vast majority of patients, and more than half (53.0%) did not perform manual cleaning of the lenses before storage. A total of 62 patients (93.9%) reported using the same brand of multipurpose contact lens cleaning solution (ReNu, Bausch & Lomb, Rochester, NY) prior to the onset of his/her infection. Forty-two patients (63.6%) reported using ReNu with MoistureLoc, 6 (9.1%) reported using ReNu MultiPlus, and 11 (16.7%) reported using an unspecified ReNu multipurpose cleaning solution. Another 3 patients (4.5%) reported using more than 1 brand of solution in the 3 months prior to the infection, including an unspecified ReNu solution, while a fourth patient reported using the Complete brand (Advance Medical Optics, Santa Ana, Calif) of contact lens solution exclusively. The brand of contact lens solution used could not be determined for the remaining 3 patients (4.5%).Contact lens hygiene was classified as suboptimal in 81.8% of the patients, each of whom had at least 1 risk factor believed to predispose patients toward infections. The risk factors included the continued use of contact lenses after the planned replacement date (43.9%), the overnight use of daily wear contact lenses (19.7%), and swimming with contact lenses in swimming pools (30.3%), often without the use of goggles.Clinical FeaturesOf the patients with fungal keratitis, 30 had involvement of the right eye, 34 had involvement of the left eye, and 2 had bilateral eye involvement (68 infected eyes). Nine eyes (13.2%) had been treated with corticosteroid eye drops prior to the diagnosis of fungal keratitis. At presentation, the best-corrected Snellen visual acuity in the affected eye was 20/60 or better in 51 patients (75.0%), 20/80 to 20/200 in 11 patients (16.2%), and count fingers or worse in 6 patients (8.8%) (Table).Of the 68 eyes, 11 eyes (16.2%) had infiltrates that were described as central (involving the visual axis), 42 eyes (61.8%) had paracentral infiltrates, and 15 eyes (22.1%) had peripheral infiltrates. There were 25 eyes (36.8%) with classic fungal satellite lesions, 5 eyes (7.4%) with a ring infiltrate, and 47 eyes (69.1%) with documented anterior chamber inflammation (consisting of anterior chamber cells or frank hypopyon; Figure 2).Figure 2.Patients With Fungal KeratitisA, Patient 1 has classic characteristics of fungal keratitis, which include stromal infiltrate with indistinct, feathery edges, and satellite lesions. B, Patient 2 has severe fungal keratitis that eventually required an urgent therapeutic penetrating keratoplasty.Microbiological FindingsPositive culture results were available for all 68 eyes; 58 eyes (85.3%) had Fusariumspecies isolated from a corneal scrape or corneal specimen and 10 (14.7%) eyes had typical signs of fungal keratitis with negative corneal cultures but had Fusariumspecies isolated from their contact lenses (n = 7) or contact lens case (n = 3). Fusariumspecies were also cultured from 3 of the 5 corneal buttons obtained from the 5 patients who received transplants. Opened bottles of contact lens solution were provided by 10 patients; none had Fusariumspecies isolated on microbiological testing.Speciation was performed on isolates after the outbreak was recognized. However, most of the isolates collected prior to this were discarded. Speciation of the isolates was performed using 28S rRNA gene sequencing for 15 of the patients. There was 100% match with the sequence from Fusarium solaniCBS490.63 in GenBank (http://www.psc.edu/general/software/packages/genbank/genbank.html).Management and Clinical OutcomeA total of 44 patients (66.7%) had severe, sight-threatening lesions requiring inpatient management of their infection. The average hospital stay for the first visit was 6.5 days (range, 2-21 days). Readmissions were necessary in 4 patients (5.9%) because of infection recurrence.In Singapore, topical natamycin 5% and topical amphotericin B (1 mg/mL) are the first-line treatment for suspected fungal keratitis because Fusariumand Aspergillusspecies are the most commonly isolated organisms locally.In more severe cases with impending or presenting corneal perforation or scleral extension, systemic antifungals such as fluconazole and itraconazole are added. Second-line treatment with topical and systemic voriconazole for nonresponsive cases was also instituted because this agent had been reported to have a broad-spectrum fungal activity, greater bioavailability, and higher aqueous and vitreous levels in the eye.Topical voriconazole eye drops were produced in-house by the hospital pharmacy via dilution of the powdered intravenous form to a 1% concentration. Systemic voriconazole requires an intravenous loading dose of 400 mg given twice in 24 hours followed by an oral dose of 200 mg taken twice daily.For 11 eyes (16.2%) treated with topical antibacterial medications (typically with fortified cefazolin [50 mg/mL] and gentamicin [14 mg/mL]), infection resolved without the need for specific antifungal therapy; all 11 eyes had Fusariumspecies isolated from corneal scrapings. Forty-eight eyes (70.6%) were treated with either topical natamycin (n = 20), topical amphotericin B (n = 1), or a combination of both (n = 27). Two other eyes (2.9%) required the addition of topical voriconazole to their treatment. An additional 7 eyes (10.3%) with more severe disease required the addition of systemic antifungals; 1 patient received oral fluconazole (200 mg twice daily), 4 patients received systemic voriconazole, and 1 patient had received oral itraconazole (400 mg twice daily) before conversion to systemic voriconazole. Three of the patients recovered fully but 4 patients' disease continued to progress despite systemic therapy.In all, 5 eyes (7.4%) eventually required emergency therapeutic keratoplasty (1 for acute corneal perforation and 4 for disease progression with impending corneal perforation; Figure 2). Two patients subsequently required a second corneal transplant for primary graft failure at 12 days and 4 weeks.Of the 5 patients who underwent corneal transplantation during the acute phase of the infection, 4 were men and 1 was a woman and they were between the ages of 19 and 43 years. Only 1 patient had received corticosteroid eye drops prior to the diagnosis of fungal keratitis. One patient had been treated previously for herpetic keratitis; a second patient had been diagnosed with seronegative arthropathy but was not receiving corticosteroids or other immunosuppressant agents. The other 3 patients had no known immunocompromising medical conditions.Final visual outcome was fair in patients who required only medical therapy to achieve resolution of their infection (Table). The final best-corrected visual acuity was 20/40 or better at the last follow-up review for 62 eyes (91.2%). Of the 5 eyes that had surgical treatment, vision ranged from 20/25 to 20/80. The mean postgraft follow-up period was 15 weeks (range, 7 weeks to 6 months) and no recurrence of the fungal lesions has occurred to date. All grafts have remained clear and the transplants appear successful.COMMENTThis article reports a new and unusual outbreak of Fusariumkeratitis associated with contact lens wear in Singapore. Because fungal keratitis is potentially blinding and often misdiagnosed among contact lens wearers, physicians and eye care practitioners need to be aware of the likelihood of similar cases emerging.Worldwide, the incidence of fungal keratitis is generally low and infection among contact lens wearers is much rarer when compared with bacterial and Acanthamoebakeratitis. In a local case series conducted from 1991 to 1995 by Wong et alat the Singapore National Eye Centre, 15 of 29 patients with fungal keratitis were due to Fusariumspecies. Only 12 cases of Fusariumkeratitis were diagnosed at this center from 2000 to 2004 (A.-L.T., unpublished data, 2004) and 3 of which were related to contact lens wear. The Singapore National Eye Centre is the main referral center in Singapore. Prior to our current report, the 5-year case series by Wong et alwas the largest on fungal keratitis in Singapore. Extrapolating from their data, we estimated the baseline incidence of Fusariumkeratitis in Singapore to be between 3 and 5 cases per year and that the majority of cases would be due to trauma and that no more than 1 to 2 cases would be associated with contact lens wear.However, during the past 15 months, 66 patients have been identified with Fusariumkeratitis related to contact lens wear, 35 of whom were treated by the Singapore National Eye Centre. Based on local data, we estimate that there are 224 800 contact lens wearers in Singapore, which suggests the national incidence of Fusariumkeratitis to be 2.35 per 10 000 contact lens wearers per year (95% confidence interval, 0.62-7.22). This is an astounding figure, especially when compared with the annualized rates of all forms of contact lens–related microbial keratitis (ie, bacterial, Acanthamoeba, and fungal infections) reported in Europe (2.44/10 000 contact lens wearers in Scotlandand 2.67/10 000 contact lens wearers in Holland)and in Asia (3.39/10 000 contact lens wearers in Hong Kong).We are confident that this estimate is close to the actual national incidence rate because all patients from the public hospitals have been included. Only 1 other case of fungal infection associated with contact lens wear has been confirmed to have been treated independently in a private hospital or clinic (this information was obtained from the Singapore Ministry of Health, which has contacted all microbiology laboratories in Singapore and requested positive ophthalmic or contact lens–related fungal cultures). Therefore, we believe that Singapore is facing a new and unprecedented outbreak of Fusariumkeratitis and that this is the first time that such an outbreak has been reported among contact lens wearers anywhere in the world.While reviewing known risk factors for contact lens–associated microbial keratitis (eg, overnight use of contact lenses,swimming with lenses,etc), a majority of the patients were found to have suboptimal contact lens hygiene practices. Nonetheless, this finding cannot fully account for the outbreak. Breaches in contact lens hygiene at some point in time among contact lens users are likely to be relatively common and yet the incidence of fungal keratitis remains low.A noteworthy finding was that the majority of patients (93.9%) reported using contact lens cleaning solutions from the ReNu line of products prior to his/her infection. While we acknowledge that recall bias may be a confounding factor, this had been anticipated when we began this study and we were able to confirm that solution details obtained through the patients' chart review correlated accurately with patient interviews. In particular, all of the patients who had been documented in their charts as using a ReNu solution confirmed this during subsequent interviews. Specific data on the market share of ReNu in Singapore could not be obtained but was reported by the local media to be between 30% to 40% prior to February 2006 based on interviews with the Singapore Contact Lens Society and local optometric chains.Similar estimates were provided by contact lens solution manufacturers and by the Singapore Ministry of Health officials who were conducting a separate inquiry.It is too early to speculate as to the role of these products in the current outbreak. A national case-control study currently under way will shed further light on the probable risk factors for this outbreak, including the role of contact lens solutions. Even though all sales of ReNu solutions were stopped in Singapore on February 17, 2006,twelve cases of Fusariumkeratitis associated with contact lens wear were diagnosed between March and May 2006; 11 of these patients reported that they had continued to use ReNu contact lens solution despite media advisories to discontinue use of this product.The treatment of fungal keratitis is challenging and the relative risk of penetrating keratoplasty is estimated to be 5.86 times higher in fungal keratitis compared with bacterial keratitis.Despite intensive medical therapy, between 25% and 35.1%of fungal keratitis cases can still be expected to require a corneal transplant at some stage of their infection (usually after the acute infectious event) for the treatment and visual rehabilitation of a quiescent, noninfective corneal scar. In the outbreak of Fusariumkeratitis in Singapore, a significant percentage of patients (7.4%) needed urgent surgical intervention to treat or prevent acute corneal perforation and it is likely that additional cases may require subsequent corneal transplantation for residual scarring.In more than 15% of the cases, resolution occurred without specific antifungal therapy. These cases were all diagnosed at an early stage, presenting with small, superficial, paracentral or peripheral lesions. In our clinical experience with Fusariumkeratitis in the Singapore population, we have encountered spontaneous resolution in early or small lesions, presumably due to host immunoresponsiveness, or sometimes, cessation of topical steroid usage. We also could not exclude the possibility that they had received antecedent treatment with topical fluoroquinolones by the referring physician. Topical fluoroquinolones are widely prescribed by general practitioners in Singapore and have been shown to have activity against species of Fusarium.Recognizing this outbreak of Fusariumkeratitis, we alerted the Singapore Ministry of Health in February 2006. The Ministry issued an urgent health advisory to all medical practitioners and contact lens practitioners in Singapore on February 17, 2006, with regard to a possible outbreak of fungal keratitis related to contact lens wear and also drew attention to an apparent possible association with the ReNu line of multipurpose contact lens solutions. A news release to the general public was also issued on February 17th warning contact lens wearers about the increasing incidence of fungal keratitis.On that same day, Bausch & Lomb voluntarily stopped all sales of ReNu products in Singapore. As a result of actions taken by the Ministry of Health and Bausch & Lomb, the number of cases appeared to be decreasing in the subsequent months of March, April, and May 2006. Meanwhile, we have formed a team of investigators from the various ophthalmic, epidemiological, and research institutes in Singapore and in cooperation with the Ministry of Health are pursuing the risk factors and causes of this outbreak.Since February 2005, authorities in Hong Kong have reported a similar increase in the number of fungal keratitis cases, which resulted in the suspension of sales of ReNu in Hong Kong in February 2006. Further reports from Hong Kong have identified 33 patients with fungal keratitis since May 2005, of whom 29 reported using the ReNu contact lens solution prior to their infection.In the United States, the Centers for Disease Control and Prevention (CDC) issued a health dispatchand the Food and Drug Administration issued a news releasein April 2006 warning clinicians and the public about 109 cases of suspected Fusariumkeratitis in patients from 17 different states. On the same day, Bausch & Lomb suspended shipments of ReNu with MoistureLoc from its production plant in Greenville, SC, and on April 13, 2006,asked US retailers to stop the sale of the solution altogether. As of May 12, 2006, the CDC had received reports of 122 confirmed cases of Fusariumkeratitis, 15 possible cases and 60 cases still under investigation from 33 US states and territories.An earlier CDC news releasestated that 93 of the confirmed cases wore contact lenses, of which 59 cases (63%) reported using ReNu with MoistureLoc, 19 (20%) reported using ReNu MultiPlus, and 9 (10%) reported using an unspecified ReNu solution. The remaining 7 had used products from Advanced Medical Optics or Alcon while some of the cases had reported using multiple products prior to the infection.On May 15, 2006, Bausch & Lomb announced a permanent worldwide recall of ReNu with MoistureLoc.In a statement, Bausch & Lomb said that in having excluded contamination, tampering, counterfeiting, and sterility failure, the company had now concluded that “some aspect of the MoistureLoc formula may be increasing the relative risk of Fusariuminfection in unusual circumstances.”In a letter to the American Academy of Ophthalmology, Bausch & Lomb specifically mentioned alexidine, which is a disinfecting agent found in the MoistureLoc solution. While the company noted that alexidine was safe and effective, it acknowledged that under certain extreme conditions (eg, when the solution is allowed to evaporate, the solution is not regularly replaced in the lens case, when the bottle is kept open in between uses, or when the case is not cleaned properly or changed regularly) “the concentration of polymers included in the formula to enhance comfort may make the solution more likely to be contaminated with Fusariumin the environment.”CONCLUSIONSIn summary, we report a new and unprecedented outbreak of Fusariumkeratitis involving contact lens wearers in Singapore. Reports from Hong Kong and the United States suggest that similar outbreaks of Fusariumkeratitis may also rapidly emerge in other populations. By highlighting this series of Fusariumkeratitis among contact lens wearers in Singapore, we hope to alert physicians and other eye care clinicians worldwide to maintain a high index of suspicion for fungal infection when evaluating and treating patients with contact lens–associated microbial keratitis.Corresponding Author:Donald T. H. Tan, FRCS(Glasg), Singapore Eye Research Institute, 11 Third Hospital Ave, Singapore 168751 (snecdt@pacific.net.sg).Author Contributions:Dr Khor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Khor, Aung, Saw, Wong, Tambyah, D. Tan.Acquisition of data: Khor, Aung, Tambyah, A.-L. Tan, L. Lim, Chan, Heng, J. Lim, Loh, Lee.Analysis and interpretation of data: Khor, Aung, Saw, Wong, Tambyah, Beuerman, Chan, Lee, D. Tan.Drafting of the manuscript: Khor, Aung, Saw, Wong, Tambyah, Chan, J. Lim, Loh, D. Tan.Critical revision of the manuscript for important intellectual content: Khor, Aung, Saw, Wong, Tambyah, A.-L. Tan, Beuerman, L. Lim, Heng, Lee, D. Tan.Statistical analysis: Aung, Saw, Wong.Obtained funding: D. Tan.Administrative, technical, or material support: Khor, Aung, Saw, Tambyah, Beuerman, Heng, J. Lim, Loh, Lee, D. Tan.Study supervision: Aung, Saw, L. Lim, Heng, D. Tan.Financial Disclosures:None reported.Funding/Support:The funding and administrative support for this study was provided by the Singapore Eye Research Institute.Role of the Sponsor:The Singapore Eye Research Institute is a government-funded national institution. No commercial sponsorship was involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript.REFERENCESEAlfonsoSMandelbaumMJFoxRKForsterUlcerative keratitis associated with contact lens wear.Am J Ophthalmol19861014294333963102ODScheinLDOrmerodEBarraquerMicrobiology of contact lens-related keratitis.Cornea198982812852805716DTTanCPLeeASLimCorneal ulcers in two institutions in Singapore: analysis of causative factors, organisms and antibiotic resistance.Ann Acad Med Singapore1995248238298838989AChatterjeeJKwartzAERidgwayJKStoreyDisposable soft contact lens ulcers: a study of 43 cases seen at Manchester Royal Eye Hospital.Cornea1995141381417743794DSLamEHouangDSFanDLyonDSealEWongHong Kong Microbial Keratitis Study GroupIncidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America.Eye20021660861812194077CFFongCHTsengFRHuIJWangWLChenYCHouClinical characteristics of microbial keratitis in a university hospital in Taiwan.Am J Ophthalmol200413732933614962425JHMah-SadorraSGYavuzDMNajjarPRLaibsonCJRapuanoEJCohenTrends in contact lens-related corneal ulcers.Cornea200524515815604867KRWilhelmusReview of clinical experience with microbial keratitis associated with contact lenses.CLAO J1987132112143331130KRWilhelmusNMRobinsonRAFontMBHamellDBJonesFungal keratitis in contact lens wearers.Am J Ophthalmol19881067087143195650TJLiesegangRKForsterSpectrum of microbial keratitis in South Florida.Am J Ophthalmol19809038477395957RHRosaJrDMillerECAlfonsoThe changing spectrum of fungal keratitis in south Florida.Ophthalmology1994101100510138008340TYWongKSFongDTTanClinical and microbial spectrum of fungal keratitis in Singapore: a 5-year retrospective study.Int Ophthalmol1997211271309587828MJBharathiRRamakrishnanSVasuRMeenakshiRPalaniappanEpidemiological characteristics and laboratory diagnosis of fungal keratitis: a three-year study.Indian J Ophthalmol20035131532114750619MSrinivasanCAGonzalesCGeorgeEpidemiology and aetiological diagnosis of corneal ulceration in Madurai, South India.Br J Ophthalmol1997819659719505820PAThomasCurrent perspectives on ophthalmic mycoses.Clin Microbiol Rev20031673079714557297PENelsonMCDignaniEJAnaissieTaxonomy, biology, and clinical aspects of Fusariumspecies.Clin Microbiol Rev199474795047834602KFTabbaraALal JabartiHospital construction-associated outbreak of ocular aspergillosis after cataract surgery.Ophthalmology19981055225269499785THPettitRJOlsonRYFoosWJMartinFungal endophthalmitis following intraocular lens implantation: a surgical epidemic.Arch Ophthalmol198098102510397190003SKFridkinFBKremerLABlandAPadhyeMMMcNeilWRJarvisAcremonium kiliense endophthalmitis that occurred after cataract extraction in an ambulatory surgical center and was traced to an environmental reservoir.Clin Infect Dis1996222222278838176Fusariumkeratitis update [press release].Atlanta, Ga: Centers for Disease Control and Prevention; May 12, 2006. http://www.cdc.gov/od/oc/media/fusariumKeratitis/r060512.htm. Accessed May 16, 2006Update on cases of fungal corneal infections [press release].Hong Kong, China: Centre for Health Protection; May 16, 2006. http://www.chp.gov.hk/view_content.asp?lang=en&info_id=6523. Accessed May 17, 2006Singapore Department of Statistics Web sitePopulation census 2000: concepts and definitions.http://www.singstat.gov.sg/keystats/glossary/cglossary.html. Accessed May 26, 2006CHennequinEAbachinFSymoensIdentification of Fusariumspecies involved in human infections by 28S rRNA gene sequencing.J Clin Microbiol1999373586358910523557YCLeeCWLimSMSawDKohThe prevalence and pattern of contact lens use in a Singapore community.CLAO J200026212510656305Singapore Department of Statistics Web siteSingapore residents by age group, ethnic group and sex through June 2005.http://www.singstat.gov.sg/keystats/mqstats/mds/mds22.pdf. Accessed March 1, 2006MSzkloFJNietoEpidemiology Beyond the Basics.Sudbury, Mass: Jones and Bartlett Publishers Inc; 2004SMHariprasadWFMielerERHolzDetermination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans.Arch Ophthalmol2004122424714718293FBMarangonDMillerJAGiaconiECAlfonsoIn vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens.Am J Ophthalmol200413782082515126145WSponselNChenDDangTopical voriconazole as a novel treatment for fungal keratitis.Antimicrob Agents Chemother20065026226816377696DVSealCMKirknessHGBennettMPetersonKeratitis Study GroupPopulation-based cohort study of microbial keratitis in Scotland: incidence and features.Contact Lens Anterior Eye199922495716303406KHChengSLLeungHWHoekmanIncidence of contact-lens-associated microbial keratitis and its related morbidity.Lancet199935418118510421298ODScheinRJGlynnECPoggioJMSeddonKRKenyonMicrobial Keratitis Study GroupThe relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses: a case-control study.N Engl J Med19893217737782671733JKGDartFStapletonDMinassianContact lenses and other risk factors in microbial keratitis.Lancet19913386506531679472ODScheinPOBuehlerJFStamlerDDVerdierJKatzThe impact of overnight wear on the risk of contact lens-associated ulcerative keratitis.Arch Ophthalmol19941121861908311770JKStehr-GreenTMBaileyFHBrandtJHCarrWWBondGSVisvesvaraAcanthamoebakeratitis in soft contact lens wearers: a case-control study.JAMA198725857603586292Channel NewsAsia Web siteRise in number of fungal infections among contact lens users [February 21, 2006].http://www.channelnewsasia.com/stories/singaporelocalnews/view/194315/1/.html. Accessed February 22, 2006TODAYOnline Web siteReNu link: has fungus mutated [February 22, 2006]?http://www.todayonline.com/articles/102460.asp. Accessed February 22, 2006Channel NewsAsia Web siteMOH advises against use of ReNu contact lens solution for time being [February 20, 2006].http://www.channelnewsasia.com/stories/singaporelocalnews/view/194089/1/.html. Accessed February 22, 2006TYWongTPNgKSFongDTTanRisk factors and clinical outcomes between fungal and bacterial keratitis: a comparative study.CLAO J1997232752819348453MATanureEJCohenSSudeshCJRapuanoPRLaibsonSpectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania.Cornea20001930731210832689LXieXDongWShiTreatment of fungal keratitis by penetrating keratoplasty.Br J Ophthalmol2001851070107411520759EAlfonsoDMillerImpact of 4th generation fluoroquinolones on growth rate and detection time of fungal pathogens.Presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2005; Fort Lauderdale, FlaPublic alert on increasing incidence of contact lens related fungal corneal infections [press release].Singapore: Ministry of Health; February 17, 2006. http://www.moh.gov.sg/corp/about/newsroom/pressreleases/details.do?id=36044801. Accessed February 17, 2006Centers for Disease Control and PreventionFusariumkeratitis: multiple states, 2006 [health dispatch on April 10, 2006].http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55d410a1.htm. Accessed April 10, 2006US Food and Drug AdministrationInvestigation of serious eye infections associated with soft contact lens use and contact lens solution [April 10, 2006].http://www.fda.gov/bbs/topics/NEWS/2006/NEW01354.html. Accessed April 10, 2006Bausch & Lomb asks retailers to remove US-manufactured Renu with MoistureLoc from shelves [press release].Rochester, NY: Bausch & Lomb; April 13, 2006. http://www.bausch.com/us/vision/about/news/pressrelease.jsp?pressRelease=2006_4_13_retailers.html. Accessed April 17, 2006Fusariumkeratitis update [press release].Atlanta, Ga: Centers for Disease Control and Prevention; May 9, 2006. http://www.cdc.gov/od/oc/media/pressrel/r060509.htm. Accessed May 10, 2006Bausch & Lomb voluntarily recalls MoistureLoc worldwide [press release].Rochester, NY: Bausch & Lomb; May 15, 2006. http://www.bausch.com/us/vision/about/news/pressrelease.jsp?pressRelease=2006_5_15_recall.html. Accessed May 16, 2006American Academy of Ophthalmology Web siteReNu with MoistureLoc identified as likely cause of increased infection risk.Available at: http://www.aao.org/public/fungal_keratitis.cfm#messages. Accessed May 16, 2006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Loading next page...
 
/lp/american-medical-association/an-outbreak-of-fusariumkeratitis-associated-with-contact-lens-wear-in-nDEBaJ04oA
Publisher
American Medical Association
Copyright
Copyright 2006 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.295.24.2867
pmid
16804153
Publisher site
See Article on Publisher Site

Abstract

ContextFungal keratitis is a potentially blinding condition that is rarely seen with contact lens wear.ObjectiveTo describe a nationwide outbreak of fungal keratitis caused by Fusariumspecies among contact lens wearers in Singapore.Design, Setting, and PatientsNationwide, hospital-based case series. All cases of fungal keratitis among contact lens wearers in all ophthalmology departments in Singapore were reviewed along with the charts of all contact lens wearers with culture-proven fungal keratitis from March 2005 through May 2006. A standardized telephone interview was conducted to obtain additional clinical information.Main Outcome MeasureDiagnosis of Fusariumkeratitis associated with contact lens wear.ResultsDuring the study period, 66 patients (68 affected eyes) were diagnosed with Fusariumkeratitis associated with contact lens wear; the estimated annual national incidence is 2.35 cases per 10 000 contact lens wearers (95% confidence interval, 0.62-7.22). Patients ranged in age from 13 to 44 years (mean [SD], 27.1 [8.4] years), of which 32 (48.5%) were men. The vast majority (65 patients; 98.5%) wore soft, disposable contact lenses; 62 patients (93.9%) reported using 1 brand of contact lens cleaning solution (ReNu, Bausch & Lomb, Rochester, NY), including 42 patients (63.6%) who recalled using ReNu with MoistureLoc. Most patients (81.8%) reported poor contact lens hygiene practices, including overnight use of daily wear contact lenses (19.7%), and use of contact lenses past the replacement date (43.9%). The final best-corrected visual acuity ranged from 20/20 to 20/80. Five patients (5 eyes; 7.4%) required emergency therapeutic or tectonic corneal transplantation.ConclusionsA new and evolving epidemic of Fusariumkeratitis associated with contact lens wear was found in Singapore. Physicians and eye care practitioners worldwide need to be aware of the likelihood of similar outbreaks emerging among contact lens wearers.Infective keratitis is a potentially blinding condition that represents the most severe complication related to contact lens wear. The vast majority of these infections are caused by bacteria, especially Pseudomonas aeruginosa.Fungal keratitis from contact lens wear is rare, constituting less than 5%of microbial keratitis in patients who wear contact lenses for refractive error. The majority of such fungal infections have been attributed to ocular trauma, chronic ocular surface disease, and concomitant systemic immunosuppressive diseases.In certain tropical and subtropical regions, such as Singapore,southern Florida,and southern India,Fusariumspecies represent the most common pathogen for fungal keratitis. Species of Fusariumare ubiquitous hyaline filamentous fungi, widely distributed in soil, and commonly associated with plant roots; in humans, this organism has a predilection for infecting the cornea, and is an emerging cause of disease among immunocompromised patients.Outbreaks of fungal eye infections are rare; previous cases have been linked to specific circumstances, such as hospital construction,contaminated intraocular lens solutions,and an environmental reservoir.Since March 1, 2005, there was a sharp increase in the number of cases of Fusariumkeratitis associated with contact lens wear in Singapore. By February 2006, 54 patients nationwide had been identified as having this rare and unusual infection over the 1-year period. Alarmed by this apparent outbreak, we alerted Singapore's Ministry of Health, which issued an urgent health advisory. Since then, 12 additional cases have been identified between March and May 2006. Recent reports of Fusariumkeratitis in 122 patients in the United Statesand in 33 patients in Hong Konghave been confirmed and suggest that this phenomenon may be part of a global problem, with serious implications for millions of contact lens wearers worldwide. This article describes an outbreak of Fusariumkeratitis among contact lens wearers in Singapore.METHODSThis study was approved by the scientific and ethics committees of the Singapore Eye Research Institute. The attendance records and microbiology results of all ophthalmology departments in Singapore's public hospitals (Singapore National Eye Centre, Changi General Hospital, Tan Tock Seng Hospital, and National University Hospital) were searched for patients treated for infective keratitis associated with contact lens wear from March 1, 2005, to May 26, 2006. Only patients with contact lens wear and a diagnosis of fungal keratitis were included in this case series. A contact lens wearer was defined as an individual who wore contact lenses at least once per week for the correction of refractive error. This excluded individuals who wore therapeutic contact lenses (eg, bandage contact lens wear) for a previously diagnosed ocular disease.Fungal keratitis was defined as a corneal epithelial defect with underlying stromal infiltrate, which had a fungal organism isolated from a corneal sample (eg, corneal scrape, biopsy, or corneal button). Patients with classic features of fungal keratitis but negative corneal cultures were also included in the definition if a fungal organism could be isolated from the patient's contact lens or contact lens case. Any atypical, infiltrative lesion with ill-defined or irregular margins, satellite or branching lesions, and especially in the presence of a ring infiltrate would raise the suspicion of fungal keratitis.Patients were included in the study after informed consent (oral or written) was obtained. The following information was then extracted from the patients' charts: demographic profile (including ethnic group), the type of contact lenses and solutions used, contact lens care practices, and the management and subsequent progress up until the last follow-up review. Ethnic group refers to the patient's race that was declared by the individual on his/her national identity card. The population in Singapore is classified into the following 4 ethnic categories defined by the Singapore Department of Statistics: Chinese, Malay, Indian, and others. Because risk factors for disease prevalence may differ among different subpopulations in multiethnic Singapore, ethnic grouping is normally included in demographic profiling.Telephone interviews also were conducted by trained interviewers to obtain further detailed clinical information. To minimize the effects of recall bias, a standardized questionnaire was produced, which included a list of soft contact lenses and contact lens solutions sold in Singapore during this period. To preserve the uniformity of these interviews, only 3 of the study's investigators (W-B.K., J.L., S-B.L.) were responsible for administering the questionnaire.Patients with a clinical or presumed diagnosis of infective keratitis associated with contact lens wear were routinely cultured for microbial organisms in the ophthalmology departments in Singapore's public hospitals (Singapore National Eye Centre, Changi General Hospital, Tan Tock Seng Hospital, and National University Hospital) prior to treatment. Corneal samples or corneal biopsies were sampled from the edge or base of the infiltrate under biomicroscopy and sent for Gram staining, wet mount microscopy, and for culture by blood agar, chocolate agar, Sabouraud dextrose agar, brain-heart infusion broth, and thioglycollate broth. The patient's contact lenses, contact lens case, and current bottle of contact lens solution (when available) were also sent for microbiological testing. For cases in which the Fusariumspecies were isolated and available for further testing, identification was performed using 28S rRNA gene sequencing.Treatment of all cases was usually by a corneal specialist and therapy was modified according to culture results and clinical progress. The number of contact lens wearers in the country was estimated based on a Singapore population survey performed in 1998 reporting that 9% of the population wore contact lensesand by applying population figures for Singapore as of June 2005.This allowed us to estimate the annual incidence of Fusariumkeratitis in Singapore, which was computed as the proportion of new cases among contact lens wearers in Singapore per year. The 95% confidence intervals for the incidence rates were determined assuming a Poisson distribution,and were calculated using JavaStat (http://statpages.org/confint.html).RESULTSSixty-six patients (representing 68 affected eyes) were identified as contact lens wearers with fungal keratitis from March 2005 through May 2006 (Table). All 66 patients were identified from a search of the respective departments' medical records and microbiological results. Three patients (4.5%) were interviewed in person; information from the remaining patients was obtained from medical record reviews and telephone interviews.Table.Characteristics of Patients With FusariumKeratitisNo. (%) of Patients (N = 66)SexMen32 (48.5)Women34 (51.5)Age, y≤2017 (25.8)21-4043 (65.2)41-606 (9.1)Ethnicity*Chinese44 (66.7)Malay16 (24.2)Indian2 (3.0)Others4 (6.1)LateralityRight eye30 (45.5)Left eye34 (51.5)Both eyes2 (3.0)Contact lens typeSoft hydrogel disposable lensesMonthly52 (78.8)Every 14 d6 (9.1)Daily1 (1.5)Silicone hydrogel disposablelensesMonthly5 (7.6)Every 14 d1 (1.5)Rigid gas permeable1 (1.5)Contact lens solution†ReNu with MoistureLoc42 (63.6)ReNu Multiplus6 (9.1)ReNu solution (unspecified)14 (21.2)Complete solution3 (4.5)Opti-Free Express solution1 (1.5)Not specified3 (4.5)Suboptimal hygiene practices‡No manual cleaning beforestorage35 (53.0)Expired lenses29 (43.9)Overnight wear (daily wear lenses)13 (19.7)Swimming20 (30.3)Others§13 (19.7)Best-corrected visual acuity atpresentation∥20/60 or better51 (75.0)20/80 to 20/20011 (16.2)Counting fingers or worse6 (8.8)Best corrected visual acuity at last follow-up visit∥20/2027 (39.7)20/25 to 20/4038 (55.9)20/50 to 20/2003 (4.4)*Defined by the Singapore Department of Statistics.†Figures do not add up to 100% as patients may have been using multiple solutions.‡Figures do not add up to 100% as patients may have multiple suboptimal practices.§Including outdoor activities such as camping and water sports.∥Representing 68 affected eyes.There was a distinct trend that peaked in February 2006 when 15 cases were identified and declined between March 2006 and May 2006 (Figure 1). The patients were young (mean [SD] age, 27.1 [8.4] years), predominantly Chinese (reflecting the Chinese racial predominance in Singapore), and almost equally distributed by sex.Figure 1.Epidemic Curve for the Outbreak of FusariumKeratitis Associated With Contact Lens WearContact Lens Usage and PracticesThe average duration of contact lens use was 7.6 years. Contact lenses were worn between 6 and 24 hours each day on most days of the week. Almost all of the patients (98.5%) wore soft disposable lenses. The contact lenses worn by patients were from 8 different contact lens manufacturers. The majority of patients (78.8%) were using monthly disposable, soft hydrogel lenses. Six patients (9.1%) reported wearing disposable silicone-hydrogel lens; and 1 patient reported wearing rigid gas permeable lenses.Multipurpose solutions for cleaning, rinsing, and storage of contact lenses were used by the vast majority of patients, and more than half (53.0%) did not perform manual cleaning of the lenses before storage. A total of 62 patients (93.9%) reported using the same brand of multipurpose contact lens cleaning solution (ReNu, Bausch & Lomb, Rochester, NY) prior to the onset of his/her infection. Forty-two patients (63.6%) reported using ReNu with MoistureLoc, 6 (9.1%) reported using ReNu MultiPlus, and 11 (16.7%) reported using an unspecified ReNu multipurpose cleaning solution. Another 3 patients (4.5%) reported using more than 1 brand of solution in the 3 months prior to the infection, including an unspecified ReNu solution, while a fourth patient reported using the Complete brand (Advance Medical Optics, Santa Ana, Calif) of contact lens solution exclusively. The brand of contact lens solution used could not be determined for the remaining 3 patients (4.5%).Contact lens hygiene was classified as suboptimal in 81.8% of the patients, each of whom had at least 1 risk factor believed to predispose patients toward infections. The risk factors included the continued use of contact lenses after the planned replacement date (43.9%), the overnight use of daily wear contact lenses (19.7%), and swimming with contact lenses in swimming pools (30.3%), often without the use of goggles.Clinical FeaturesOf the patients with fungal keratitis, 30 had involvement of the right eye, 34 had involvement of the left eye, and 2 had bilateral eye involvement (68 infected eyes). Nine eyes (13.2%) had been treated with corticosteroid eye drops prior to the diagnosis of fungal keratitis. At presentation, the best-corrected Snellen visual acuity in the affected eye was 20/60 or better in 51 patients (75.0%), 20/80 to 20/200 in 11 patients (16.2%), and count fingers or worse in 6 patients (8.8%) (Table).Of the 68 eyes, 11 eyes (16.2%) had infiltrates that were described as central (involving the visual axis), 42 eyes (61.8%) had paracentral infiltrates, and 15 eyes (22.1%) had peripheral infiltrates. There were 25 eyes (36.8%) with classic fungal satellite lesions, 5 eyes (7.4%) with a ring infiltrate, and 47 eyes (69.1%) with documented anterior chamber inflammation (consisting of anterior chamber cells or frank hypopyon; Figure 2).Figure 2.Patients With Fungal KeratitisA, Patient 1 has classic characteristics of fungal keratitis, which include stromal infiltrate with indistinct, feathery edges, and satellite lesions. B, Patient 2 has severe fungal keratitis that eventually required an urgent therapeutic penetrating keratoplasty.Microbiological FindingsPositive culture results were available for all 68 eyes; 58 eyes (85.3%) had Fusariumspecies isolated from a corneal scrape or corneal specimen and 10 (14.7%) eyes had typical signs of fungal keratitis with negative corneal cultures but had Fusariumspecies isolated from their contact lenses (n = 7) or contact lens case (n = 3). Fusariumspecies were also cultured from 3 of the 5 corneal buttons obtained from the 5 patients who received transplants. Opened bottles of contact lens solution were provided by 10 patients; none had Fusariumspecies isolated on microbiological testing.Speciation was performed on isolates after the outbreak was recognized. However, most of the isolates collected prior to this were discarded. Speciation of the isolates was performed using 28S rRNA gene sequencing for 15 of the patients. There was 100% match with the sequence from Fusarium solaniCBS490.63 in GenBank (http://www.psc.edu/general/software/packages/genbank/genbank.html).Management and Clinical OutcomeA total of 44 patients (66.7%) had severe, sight-threatening lesions requiring inpatient management of their infection. The average hospital stay for the first visit was 6.5 days (range, 2-21 days). Readmissions were necessary in 4 patients (5.9%) because of infection recurrence.In Singapore, topical natamycin 5% and topical amphotericin B (1 mg/mL) are the first-line treatment for suspected fungal keratitis because Fusariumand Aspergillusspecies are the most commonly isolated organisms locally.In more severe cases with impending or presenting corneal perforation or scleral extension, systemic antifungals such as fluconazole and itraconazole are added. Second-line treatment with topical and systemic voriconazole for nonresponsive cases was also instituted because this agent had been reported to have a broad-spectrum fungal activity, greater bioavailability, and higher aqueous and vitreous levels in the eye.Topical voriconazole eye drops were produced in-house by the hospital pharmacy via dilution of the powdered intravenous form to a 1% concentration. Systemic voriconazole requires an intravenous loading dose of 400 mg given twice in 24 hours followed by an oral dose of 200 mg taken twice daily.For 11 eyes (16.2%) treated with topical antibacterial medications (typically with fortified cefazolin [50 mg/mL] and gentamicin [14 mg/mL]), infection resolved without the need for specific antifungal therapy; all 11 eyes had Fusariumspecies isolated from corneal scrapings. Forty-eight eyes (70.6%) were treated with either topical natamycin (n = 20), topical amphotericin B (n = 1), or a combination of both (n = 27). Two other eyes (2.9%) required the addition of topical voriconazole to their treatment. An additional 7 eyes (10.3%) with more severe disease required the addition of systemic antifungals; 1 patient received oral fluconazole (200 mg twice daily), 4 patients received systemic voriconazole, and 1 patient had received oral itraconazole (400 mg twice daily) before conversion to systemic voriconazole. Three of the patients recovered fully but 4 patients' disease continued to progress despite systemic therapy.In all, 5 eyes (7.4%) eventually required emergency therapeutic keratoplasty (1 for acute corneal perforation and 4 for disease progression with impending corneal perforation; Figure 2). Two patients subsequently required a second corneal transplant for primary graft failure at 12 days and 4 weeks.Of the 5 patients who underwent corneal transplantation during the acute phase of the infection, 4 were men and 1 was a woman and they were between the ages of 19 and 43 years. Only 1 patient had received corticosteroid eye drops prior to the diagnosis of fungal keratitis. One patient had been treated previously for herpetic keratitis; a second patient had been diagnosed with seronegative arthropathy but was not receiving corticosteroids or other immunosuppressant agents. The other 3 patients had no known immunocompromising medical conditions.Final visual outcome was fair in patients who required only medical therapy to achieve resolution of their infection (Table). The final best-corrected visual acuity was 20/40 or better at the last follow-up review for 62 eyes (91.2%). Of the 5 eyes that had surgical treatment, vision ranged from 20/25 to 20/80. The mean postgraft follow-up period was 15 weeks (range, 7 weeks to 6 months) and no recurrence of the fungal lesions has occurred to date. All grafts have remained clear and the transplants appear successful.COMMENTThis article reports a new and unusual outbreak of Fusariumkeratitis associated with contact lens wear in Singapore. Because fungal keratitis is potentially blinding and often misdiagnosed among contact lens wearers, physicians and eye care practitioners need to be aware of the likelihood of similar cases emerging.Worldwide, the incidence of fungal keratitis is generally low and infection among contact lens wearers is much rarer when compared with bacterial and Acanthamoebakeratitis. In a local case series conducted from 1991 to 1995 by Wong et alat the Singapore National Eye Centre, 15 of 29 patients with fungal keratitis were due to Fusariumspecies. Only 12 cases of Fusariumkeratitis were diagnosed at this center from 2000 to 2004 (A.-L.T., unpublished data, 2004) and 3 of which were related to contact lens wear. The Singapore National Eye Centre is the main referral center in Singapore. Prior to our current report, the 5-year case series by Wong et alwas the largest on fungal keratitis in Singapore. Extrapolating from their data, we estimated the baseline incidence of Fusariumkeratitis in Singapore to be between 3 and 5 cases per year and that the majority of cases would be due to trauma and that no more than 1 to 2 cases would be associated with contact lens wear.However, during the past 15 months, 66 patients have been identified with Fusariumkeratitis related to contact lens wear, 35 of whom were treated by the Singapore National Eye Centre. Based on local data, we estimate that there are 224 800 contact lens wearers in Singapore, which suggests the national incidence of Fusariumkeratitis to be 2.35 per 10 000 contact lens wearers per year (95% confidence interval, 0.62-7.22). This is an astounding figure, especially when compared with the annualized rates of all forms of contact lens–related microbial keratitis (ie, bacterial, Acanthamoeba, and fungal infections) reported in Europe (2.44/10 000 contact lens wearers in Scotlandand 2.67/10 000 contact lens wearers in Holland)and in Asia (3.39/10 000 contact lens wearers in Hong Kong).We are confident that this estimate is close to the actual national incidence rate because all patients from the public hospitals have been included. Only 1 other case of fungal infection associated with contact lens wear has been confirmed to have been treated independently in a private hospital or clinic (this information was obtained from the Singapore Ministry of Health, which has contacted all microbiology laboratories in Singapore and requested positive ophthalmic or contact lens–related fungal cultures). Therefore, we believe that Singapore is facing a new and unprecedented outbreak of Fusariumkeratitis and that this is the first time that such an outbreak has been reported among contact lens wearers anywhere in the world.While reviewing known risk factors for contact lens–associated microbial keratitis (eg, overnight use of contact lenses,swimming with lenses,etc), a majority of the patients were found to have suboptimal contact lens hygiene practices. Nonetheless, this finding cannot fully account for the outbreak. Breaches in contact lens hygiene at some point in time among contact lens users are likely to be relatively common and yet the incidence of fungal keratitis remains low.A noteworthy finding was that the majority of patients (93.9%) reported using contact lens cleaning solutions from the ReNu line of products prior to his/her infection. While we acknowledge that recall bias may be a confounding factor, this had been anticipated when we began this study and we were able to confirm that solution details obtained through the patients' chart review correlated accurately with patient interviews. In particular, all of the patients who had been documented in their charts as using a ReNu solution confirmed this during subsequent interviews. Specific data on the market share of ReNu in Singapore could not be obtained but was reported by the local media to be between 30% to 40% prior to February 2006 based on interviews with the Singapore Contact Lens Society and local optometric chains.Similar estimates were provided by contact lens solution manufacturers and by the Singapore Ministry of Health officials who were conducting a separate inquiry.It is too early to speculate as to the role of these products in the current outbreak. A national case-control study currently under way will shed further light on the probable risk factors for this outbreak, including the role of contact lens solutions. Even though all sales of ReNu solutions were stopped in Singapore on February 17, 2006,twelve cases of Fusariumkeratitis associated with contact lens wear were diagnosed between March and May 2006; 11 of these patients reported that they had continued to use ReNu contact lens solution despite media advisories to discontinue use of this product.The treatment of fungal keratitis is challenging and the relative risk of penetrating keratoplasty is estimated to be 5.86 times higher in fungal keratitis compared with bacterial keratitis.Despite intensive medical therapy, between 25% and 35.1%of fungal keratitis cases can still be expected to require a corneal transplant at some stage of their infection (usually after the acute infectious event) for the treatment and visual rehabilitation of a quiescent, noninfective corneal scar. In the outbreak of Fusariumkeratitis in Singapore, a significant percentage of patients (7.4%) needed urgent surgical intervention to treat or prevent acute corneal perforation and it is likely that additional cases may require subsequent corneal transplantation for residual scarring.In more than 15% of the cases, resolution occurred without specific antifungal therapy. These cases were all diagnosed at an early stage, presenting with small, superficial, paracentral or peripheral lesions. In our clinical experience with Fusariumkeratitis in the Singapore population, we have encountered spontaneous resolution in early or small lesions, presumably due to host immunoresponsiveness, or sometimes, cessation of topical steroid usage. We also could not exclude the possibility that they had received antecedent treatment with topical fluoroquinolones by the referring physician. Topical fluoroquinolones are widely prescribed by general practitioners in Singapore and have been shown to have activity against species of Fusarium.Recognizing this outbreak of Fusariumkeratitis, we alerted the Singapore Ministry of Health in February 2006. The Ministry issued an urgent health advisory to all medical practitioners and contact lens practitioners in Singapore on February 17, 2006, with regard to a possible outbreak of fungal keratitis related to contact lens wear and also drew attention to an apparent possible association with the ReNu line of multipurpose contact lens solutions. A news release to the general public was also issued on February 17th warning contact lens wearers about the increasing incidence of fungal keratitis.On that same day, Bausch & Lomb voluntarily stopped all sales of ReNu products in Singapore. As a result of actions taken by the Ministry of Health and Bausch & Lomb, the number of cases appeared to be decreasing in the subsequent months of March, April, and May 2006. Meanwhile, we have formed a team of investigators from the various ophthalmic, epidemiological, and research institutes in Singapore and in cooperation with the Ministry of Health are pursuing the risk factors and causes of this outbreak.Since February 2005, authorities in Hong Kong have reported a similar increase in the number of fungal keratitis cases, which resulted in the suspension of sales of ReNu in Hong Kong in February 2006. Further reports from Hong Kong have identified 33 patients with fungal keratitis since May 2005, of whom 29 reported using the ReNu contact lens solution prior to their infection.In the United States, the Centers for Disease Control and Prevention (CDC) issued a health dispatchand the Food and Drug Administration issued a news releasein April 2006 warning clinicians and the public about 109 cases of suspected Fusariumkeratitis in patients from 17 different states. On the same day, Bausch & Lomb suspended shipments of ReNu with MoistureLoc from its production plant in Greenville, SC, and on April 13, 2006,asked US retailers to stop the sale of the solution altogether. As of May 12, 2006, the CDC had received reports of 122 confirmed cases of Fusariumkeratitis, 15 possible cases and 60 cases still under investigation from 33 US states and territories.An earlier CDC news releasestated that 93 of the confirmed cases wore contact lenses, of which 59 cases (63%) reported using ReNu with MoistureLoc, 19 (20%) reported using ReNu MultiPlus, and 9 (10%) reported using an unspecified ReNu solution. The remaining 7 had used products from Advanced Medical Optics or Alcon while some of the cases had reported using multiple products prior to the infection.On May 15, 2006, Bausch & Lomb announced a permanent worldwide recall of ReNu with MoistureLoc.In a statement, Bausch & Lomb said that in having excluded contamination, tampering, counterfeiting, and sterility failure, the company had now concluded that “some aspect of the MoistureLoc formula may be increasing the relative risk of Fusariuminfection in unusual circumstances.”In a letter to the American Academy of Ophthalmology, Bausch & Lomb specifically mentioned alexidine, which is a disinfecting agent found in the MoistureLoc solution. While the company noted that alexidine was safe and effective, it acknowledged that under certain extreme conditions (eg, when the solution is allowed to evaporate, the solution is not regularly replaced in the lens case, when the bottle is kept open in between uses, or when the case is not cleaned properly or changed regularly) “the concentration of polymers included in the formula to enhance comfort may make the solution more likely to be contaminated with Fusariumin the environment.”CONCLUSIONSIn summary, we report a new and unprecedented outbreak of Fusariumkeratitis involving contact lens wearers in Singapore. Reports from Hong Kong and the United States suggest that similar outbreaks of Fusariumkeratitis may also rapidly emerge in other populations. By highlighting this series of Fusariumkeratitis among contact lens wearers in Singapore, we hope to alert physicians and other eye care clinicians worldwide to maintain a high index of suspicion for fungal infection when evaluating and treating patients with contact lens–associated microbial keratitis.Corresponding Author:Donald T. H. Tan, FRCS(Glasg), Singapore Eye Research Institute, 11 Third Hospital Ave, Singapore 168751 (snecdt@pacific.net.sg).Author Contributions:Dr Khor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Khor, Aung, Saw, Wong, Tambyah, D. Tan.Acquisition of data: Khor, Aung, Tambyah, A.-L. Tan, L. Lim, Chan, Heng, J. Lim, Loh, Lee.Analysis and interpretation of data: Khor, Aung, Saw, Wong, Tambyah, Beuerman, Chan, Lee, D. Tan.Drafting of the manuscript: Khor, Aung, Saw, Wong, Tambyah, Chan, J. Lim, Loh, D. Tan.Critical revision of the manuscript for important intellectual content: Khor, Aung, Saw, Wong, Tambyah, A.-L. Tan, Beuerman, L. Lim, Heng, Lee, D. Tan.Statistical analysis: Aung, Saw, Wong.Obtained funding: D. Tan.Administrative, technical, or material support: Khor, Aung, Saw, Tambyah, Beuerman, Heng, J. Lim, Loh, Lee, D. Tan.Study supervision: Aung, Saw, L. Lim, Heng, D. Tan.Financial Disclosures:None reported.Funding/Support:The funding and administrative support for this study was provided by the Singapore Eye Research Institute.Role of the Sponsor:The Singapore Eye Research Institute is a government-funded national institution. No commercial sponsorship was involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript.REFERENCESEAlfonsoSMandelbaumMJFoxRKForsterUlcerative keratitis associated with contact lens wear.Am J Ophthalmol19861014294333963102ODScheinLDOrmerodEBarraquerMicrobiology of contact lens-related keratitis.Cornea198982812852805716DTTanCPLeeASLimCorneal ulcers in two institutions in Singapore: analysis of causative factors, organisms and antibiotic resistance.Ann Acad Med Singapore1995248238298838989AChatterjeeJKwartzAERidgwayJKStoreyDisposable soft contact lens ulcers: a study of 43 cases seen at Manchester Royal Eye Hospital.Cornea1995141381417743794DSLamEHouangDSFanDLyonDSealEWongHong Kong Microbial Keratitis Study GroupIncidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America.Eye20021660861812194077CFFongCHTsengFRHuIJWangWLChenYCHouClinical characteristics of microbial keratitis in a university hospital in Taiwan.Am J Ophthalmol200413732933614962425JHMah-SadorraSGYavuzDMNajjarPRLaibsonCJRapuanoEJCohenTrends in contact lens-related corneal ulcers.Cornea200524515815604867KRWilhelmusReview of clinical experience with microbial keratitis associated with contact lenses.CLAO J1987132112143331130KRWilhelmusNMRobinsonRAFontMBHamellDBJonesFungal keratitis in contact lens wearers.Am J Ophthalmol19881067087143195650TJLiesegangRKForsterSpectrum of microbial keratitis in South Florida.Am J Ophthalmol19809038477395957RHRosaJrDMillerECAlfonsoThe changing spectrum of fungal keratitis in south Florida.Ophthalmology1994101100510138008340TYWongKSFongDTTanClinical and microbial spectrum of fungal keratitis in Singapore: a 5-year retrospective study.Int Ophthalmol1997211271309587828MJBharathiRRamakrishnanSVasuRMeenakshiRPalaniappanEpidemiological characteristics and laboratory diagnosis of fungal keratitis: a three-year study.Indian J Ophthalmol20035131532114750619MSrinivasanCAGonzalesCGeorgeEpidemiology and aetiological diagnosis of corneal ulceration in Madurai, South India.Br J Ophthalmol1997819659719505820PAThomasCurrent perspectives on ophthalmic mycoses.Clin Microbiol Rev20031673079714557297PENelsonMCDignaniEJAnaissieTaxonomy, biology, and clinical aspects of Fusariumspecies.Clin Microbiol Rev199474795047834602KFTabbaraALal JabartiHospital construction-associated outbreak of ocular aspergillosis after cataract surgery.Ophthalmology19981055225269499785THPettitRJOlsonRYFoosWJMartinFungal endophthalmitis following intraocular lens implantation: a surgical epidemic.Arch Ophthalmol198098102510397190003SKFridkinFBKremerLABlandAPadhyeMMMcNeilWRJarvisAcremonium kiliense endophthalmitis that occurred after cataract extraction in an ambulatory surgical center and was traced to an environmental reservoir.Clin Infect Dis1996222222278838176Fusariumkeratitis update [press release].Atlanta, Ga: Centers for Disease Control and Prevention; May 12, 2006. http://www.cdc.gov/od/oc/media/fusariumKeratitis/r060512.htm. Accessed May 16, 2006Update on cases of fungal corneal infections [press release].Hong Kong, China: Centre for Health Protection; May 16, 2006. http://www.chp.gov.hk/view_content.asp?lang=en&info_id=6523. Accessed May 17, 2006Singapore Department of Statistics Web sitePopulation census 2000: concepts and definitions.http://www.singstat.gov.sg/keystats/glossary/cglossary.html. Accessed May 26, 2006CHennequinEAbachinFSymoensIdentification of Fusariumspecies involved in human infections by 28S rRNA gene sequencing.J Clin Microbiol1999373586358910523557YCLeeCWLimSMSawDKohThe prevalence and pattern of contact lens use in a Singapore community.CLAO J200026212510656305Singapore Department of Statistics Web siteSingapore residents by age group, ethnic group and sex through June 2005.http://www.singstat.gov.sg/keystats/mqstats/mds/mds22.pdf. Accessed March 1, 2006MSzkloFJNietoEpidemiology Beyond the Basics.Sudbury, Mass: Jones and Bartlett Publishers Inc; 2004SMHariprasadWFMielerERHolzDetermination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans.Arch Ophthalmol2004122424714718293FBMarangonDMillerJAGiaconiECAlfonsoIn vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens.Am J Ophthalmol200413782082515126145WSponselNChenDDangTopical voriconazole as a novel treatment for fungal keratitis.Antimicrob Agents Chemother20065026226816377696DVSealCMKirknessHGBennettMPetersonKeratitis Study GroupPopulation-based cohort study of microbial keratitis in Scotland: incidence and features.Contact Lens Anterior Eye199922495716303406KHChengSLLeungHWHoekmanIncidence of contact-lens-associated microbial keratitis and its related morbidity.Lancet199935418118510421298ODScheinRJGlynnECPoggioJMSeddonKRKenyonMicrobial Keratitis Study GroupThe relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses: a case-control study.N Engl J Med19893217737782671733JKGDartFStapletonDMinassianContact lenses and other risk factors in microbial keratitis.Lancet19913386506531679472ODScheinPOBuehlerJFStamlerDDVerdierJKatzThe impact of overnight wear on the risk of contact lens-associated ulcerative keratitis.Arch Ophthalmol19941121861908311770JKStehr-GreenTMBaileyFHBrandtJHCarrWWBondGSVisvesvaraAcanthamoebakeratitis in soft contact lens wearers: a case-control study.JAMA198725857603586292Channel NewsAsia Web siteRise in number of fungal infections among contact lens users [February 21, 2006].http://www.channelnewsasia.com/stories/singaporelocalnews/view/194315/1/.html. Accessed February 22, 2006TODAYOnline Web siteReNu link: has fungus mutated [February 22, 2006]?http://www.todayonline.com/articles/102460.asp. Accessed February 22, 2006Channel NewsAsia Web siteMOH advises against use of ReNu contact lens solution for time being [February 20, 2006].http://www.channelnewsasia.com/stories/singaporelocalnews/view/194089/1/.html. Accessed February 22, 2006TYWongTPNgKSFongDTTanRisk factors and clinical outcomes between fungal and bacterial keratitis: a comparative study.CLAO J1997232752819348453MATanureEJCohenSSudeshCJRapuanoPRLaibsonSpectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania.Cornea20001930731210832689LXieXDongWShiTreatment of fungal keratitis by penetrating keratoplasty.Br J Ophthalmol2001851070107411520759EAlfonsoDMillerImpact of 4th generation fluoroquinolones on growth rate and detection time of fungal pathogens.Presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2005; Fort Lauderdale, FlaPublic alert on increasing incidence of contact lens related fungal corneal infections [press release].Singapore: Ministry of Health; February 17, 2006. http://www.moh.gov.sg/corp/about/newsroom/pressreleases/details.do?id=36044801. Accessed February 17, 2006Centers for Disease Control and PreventionFusariumkeratitis: multiple states, 2006 [health dispatch on April 10, 2006].http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55d410a1.htm. Accessed April 10, 2006US Food and Drug AdministrationInvestigation of serious eye infections associated with soft contact lens use and contact lens solution [April 10, 2006].http://www.fda.gov/bbs/topics/NEWS/2006/NEW01354.html. Accessed April 10, 2006Bausch & Lomb asks retailers to remove US-manufactured Renu with MoistureLoc from shelves [press release].Rochester, NY: Bausch & Lomb; April 13, 2006. http://www.bausch.com/us/vision/about/news/pressrelease.jsp?pressRelease=2006_4_13_retailers.html. Accessed April 17, 2006Fusariumkeratitis update [press release].Atlanta, Ga: Centers for Disease Control and Prevention; May 9, 2006. http://www.cdc.gov/od/oc/media/pressrel/r060509.htm. Accessed May 10, 2006Bausch & Lomb voluntarily recalls MoistureLoc worldwide [press release].Rochester, NY: Bausch & Lomb; May 15, 2006. http://www.bausch.com/us/vision/about/news/pressrelease.jsp?pressRelease=2006_5_15_recall.html. Accessed May 16, 2006American Academy of Ophthalmology Web siteReNu with MoistureLoc identified as likely cause of increased infection risk.Available at: http://www.aao.org/public/fungal_keratitis.cfm#messages. Accessed May 16, 2006

Journal

JAMAAmerican Medical Association

Published: Jun 28, 2006

References