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Increased recovery of non-bacterial pathogens in contact lens-associated ulcerative keratitis
Terrence P. O’Brien, MD: Contact lenses are effective medical devices that can successfully correct refractive error in many patients. Advances in refractive surgery have provided patients additional options in the treatment of refractive error. In the next year, ophthalmic surgeons will perform approximately 2 million refractive surgery procedures in the United States.1 What impact has the popularity of refractive surgery had on the number of contact lens users?
Francis S. Mah, MD: The number of contact lens users has increased over the past 5 to 10 years. Currently there are more than 34 million contact lens users in the United States alone.1
Eduardo C. Alfonso, MD: The number of patients with presbyopia increases as the population’s age increases. Since IOLs are the only successful refractive surgery technique that eliminates the need for glasses or contact lenses, I believe there will be an increase of presbyopic-aged patients choosing contact lenses to solve presbyopic problems.
O’Brien: Are the same trends holding in Europe and Asia?
Alfonso: There has not been as large of an increase in Europe. In Asia, the number of patients using contact lenses is growing at a greater rate than in the United States and Europe.2
O’Brien: Has the total number of contact lens users increased due to the growth in population and widespread availability of contact lenses, or has the contact lens industry done a better job of addressing tolerance and issues with allergies and dry eye such that a greater number of individuals continue comfortable use?
The contact lens-associated microbial keratitis epidemic: A gathering storm?Terrence P. O’Brien, MD Under the right conditions, virtually any microbial pathogen can cause infectious keratitis. Traditionally, fungal keratitis is associated with trauma to the epithelium. Cases of patients who wore bandage or therapeutic contact lenses who developed fungal keratitis have been reported; although rare, such occurrences were anticipated due to the patient’s preexisting eye disease or trauma weakening local defense mechanisms, the reason for the placement of therapeutic lenses. It was, however, previously a rare occurrence for an ophthalmologist to encounter cosmetic contact lens-associated fungal keratitis.1-5 The traditional idea of contact lens-associated fungal keratitis changed in 2006 when ophthalmologists from Singapore and Hong Kong reported an increase in the number of patients with contact lens-associated keratitis. Soon after in the United States, a report of three cases of contact lens-associated fungal keratitis was given to the Centers for Disease Control and Prevention from one ophthalmologist.6 At the time of that report, researchers at the Bascom Palmer Eye Institute were comparing data of contact lens-related keratitis compiled from 2004-2005 to historical laboratory data. The comparison demonstrated a major increase in the number of patients with contact lens-associated keratitis.6-9 Similar reports of an increase in contact lens-associated keratitis propagated from 26 different states and one territory in the United States. In spring 2006, 130 confirmed cases of contact lens-associated Fusarium keratitis were confirmed from multiple states.10 Many were severe, and therapeutic penetrating keratoplasty was performed on 30% of those patients to prevent the infection from intraocular spread. The United States Department of Health and Human Services released an alert about the Fusarium keratitis outbreak.11 Case studies conducted in the United States and internationally found the increase in Fusarium keratitis was more prevalent when a patient used a specific multipurpose contact lens solution, ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY). The manufacturer recalled this solution through the FDA when the correlation between Fusarium keratitis and the solution was made. 10 During the investigation of the Fusarium epidemic, ophthalmologists also discovered an increase in another rare infection, contact lens-associated Acanthamoeba keratitis. Researchers connected this increase to a different multipurpose contact lens solution, Complete MoisturePlus (Advanced Medical Optics, Santa Ana, CA). The manufacturer recalled the product when their data were presented.12,13 The ophthalmic community now has the task of unraveling the sources of infection through identification of specific risk factors in order to determine the cause of the contact lens-associated Fusarium and Acanthamoeba keratitis epidemics and to prevent future occurrences. References
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Alfonso: The contact lens industry has done an excellent job of addressing and minimizing discomfort factors. More importantly, the industry is doing a better job educating patients on proper lens care to minimize the chance of failure when patients start using contact lenses. Patients are now more tolerant of contact lenses.
Mah: It is a combination of an increasing population using contact lenses and better technology. In the past, a limited number of contact lens and contact lens solution options were available. If patients were unable to tolerate the select varieties, then they did not wear contact lenses. Today, patients have more options and can be fit comfortably with contact lenses. The industry continues to make contact lenses more comfortable by treating some of the ocular conditions that limited contact lens wear, such as dry eyes and allergies.
Microbial keratitis
O’Brien: Soft contact lens wear has long been a significant risk factor associated with microbial keratitis.3 What has been the traditional approach to management of a patient wearing contact lenses who presents with ocular discomfort, redness, photophobia and early signs of epithelial abnormality?
R. Doyle Stulting, MD, PhD: The most common treatment is to discontinue contact lens wear, treat the patient with topical antibiotics and reevaluate the patient in 1 or 2 days. In most cases, this is an effective treatment for patients with contact lens-associated microbial keratitis.
Alfonso: In the more advanced stages of infection, the patient presents with either a visually significant infiltrate on the visual axis or a much larger peripheral infiltrate. The traditional treatment involves culturing to identify an unusual organism or organism resistant to commercially available antibiotics. However, in a surveillance study of keratitis in contact lens users, clinicians used a commercially available antibiotic without obtaining a culture, and the resolution rate of those ulcers was high.4
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Stephen D. McLeod, MD: It is important for ophthalmologists to distinguish between contact lens-associated inflammatory sterile keratitis and early infectious keratitis. The distinction is difficult but significant. Corticosteroids are the primary treatment method for sterile keratitis, whereas infectious keratitis is treated with antibiotics. Ophthalmologists are forced to initiate empirical therapy, but the relative frequency of administration of corticosteroid versus antibiotic is based on the ophthalmologist’s impression of the primary pathogenetic process: inflammation versus infection.
O’Brien: Should ophthalmologists routinely obtain material from corneal scrapings for microbial cultures from patients with contact lens-associated keratitis?
Stulting: Ideally, cultures would be taken from patients presenting with corneal infiltrates that might represent infectious keratitis. But that is not standard care in the ophthalmic community at initial patient presentation. Cultures are often unnecessary as most common bacterial infections respond to the broad spectrum antibiotics that are available today. In addition, an argument can be made that cultures are not cost-effective. The recent outbreaks of contact lens-associated fungal keratitis and Acanthamoeba keratitis have raised the awareness of the possibility of uncommon pathogens that will not respond to available topical antibacterial medications.
When patients do not respond to initial therapy, ophthalmologists should consider atypical pathogens and culture the infiltrate.
McLeod: My colleagues and I conducted a survey prior to the emergence of fungal and Acanthamoeba keratitis as more frequent causes of contact lens-associated infectious keratitis, in which one of the questions asked of ophthalmologists who were not cornea specialists was whether they would obtain material for microbiological study prior to initiating empirical treatment of a small to moderate mid-peripheral contact lens-associated corneal infiltrate. A majority responded that they would treat empirically and, overwhelmingly, respondents chose a fluoroquinolone antibiotic as the first agent.
O’Brien: Certainly a clinical assessment of the severity of the suspected infectious process is essential to guide decision-making regarding obtaining material for culture prior to initiating empirical antimicrobial therapy. Empiric therapy with antifungal or antiamoebic agents is probably seldom warranted without biopsy or tissue confirmation to confirm the process.
What are the traditional theories regarding pathogenesis of contact lens-associated microbial keratitis?
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Image provided courtesy of Terrence P. O'Brien, MD |
Mah: Clinicians theorized that patients were noncompliant, had poor hygiene, were sleeping in contact lenses and extended the use of contact lenses past the recommended usage. Sleeping in lenses increases the risk of infectious keratitis by approximately 80%.5 Many clinicians believed that patients suffered anoxia from the contact lenses due to poor hygiene, which led to microtrauma to the ocular surface and infectious keratitis.
McLeod: Corneal epithelial hypoxia and microtrauma promote bacterial adherence to the epithelium, which is the first critical step in the establishment of infectious keratitis. The presence of a contact lens is thought to trap bacteria adherent to mucin and shed epithelial cells, increasing the load of invasive organisms.
Stulting: I believe most cases of contact lens-associated keratitis are caused by microbial colonization of the contact lens case, transfer of microbes to the eye by the contact lens and trauma to the epithelium by insertion and removal of the lens.
The surface of the eye is not sterile, even in the absence of contact lenses. The natural resistance created by tear flow, antimicrobial components of the tear film and the epithelial barrier prevent infections. Repeated inoculation of high numbers of bacteria carried to the eye by the contact lens, interference with tear flow by the lens and damage to the epithelial barrier created by the contact lens and contact lens care solutions increase the chance of infection. The more microbes introduced to the eye and greater interference with natural resistance mechanisms mean a greater likelihood of infection.
Alfonso: Oliver D. Schein, MD, MPH, MBA, and colleagues conducted a case-controlled study that identified risk factors for keratitis. In the study, the preeminent risk factor was overnight wear of contact lenses. 6
O’Brien: Based on those studies conducted by Schein, Poggio and others, how did recommendations for contact lens wear regimens and hygienic practices recommendations change in the late 1980s and early 1990s?
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Alfonso: The recommendation from clinicians was to eliminate the overnight wear of contact lenses. The studies found other potential risk factors such as a higher incidence of keratitis found in smokers and women, but those risk factors did not pan out to the same extent as overnight wear. In those studies, contact lens care, hygiene and regimens did not play a prominent role as a risk factor. It was an important risk factor, but the hypoxia caused by overnight wear was of major prominence.
O’Brien: How did patients respond to the ophthalmic practitioners’ recommendations to eliminate overnight contact lens wear?
McLeod: Most patients seem to be aware that the risk of infection is increased by overnight wear, but a minority of patients still weighs the risk against the convenience of overnight wear.
Daily disposable contact lenses
O’Brien: The popularity of daily disposable contact lenses increased when clinicians educated patients about the risk factors associated with overnight contact lens wear. How did the recommendation for frequent replacement of contact lens cases and disposable contact lenses evolve?
Mah: The first recommendation was not to sleep in contact lenses, and then the use of extended wear contact lenses fell out of favor. Contact lens technology improved, lenses became thinner and more comfortable and Dk ratios were increasing. Clinicians believed that the risk for infection decreased with daily disposable contact lenses. Patients who had risk factors or who were infected were advised to switch to daily disposable contact lenses. In addition, the cost of manufacturing daily disposable contact lenses decreased and more patients were able to afford the lenses.
O’Brien: Daily disposable contact lenses were greeted with enthusiasm by ophthalmic clinicians who treated patients with contact lens-associated ulcerative keratitis. Many clinicians thought disposable contact lenses would be the answer to eliminate the risk for infection. What was the effect of disposable contact lenses on the problem of ulcerative keratitis?
Alfonso: Surveillance studies found that the rate of keratitis was higher in daily disposable contact lens wearers.7
McLeod: Numerous case reports have described bacterial and fungal keratitis in patients who wear daily disposable contact lenses.8-11 Typically, these reports describe individuals who have limited lens wear to 12 hours or less, have removed and discarded the lenses daily, and have not slept in the lenses.
O’Brien: Was the higher rate of keratitis initially reported with the disposable contact lens systems a result of patients being less hygienic, thinking that with disposable lenses they were not at risk for infection? Did patients try to economize by extending the recommended wearing time in order to save the cost of the frequent contact lens replacement?
Alfonso: Studies were conducted researching the incidence of patients changing their contact lens care regimen and extending the use of recommended wearing time, but those reasons were not found as a clear cause for the higher incidence of keratitis in disposable contact lens wearers.7 The conclusion was the increase in keratitis was a direct relationship between soft contact lenses and the ocular surface. I believe more studies should be conducted to answer those questions.
O’Brien: The emergence of daily disposable contact lenses could reintroduce concerns about patients not following recommended guidelines for replacement by properly disposing of the daily lens at the end of the day.
Mah: It would be worse if patients did not dispose the contact lenses and, for example, placed them back in the solution the lenses were packaged in.
O’Brien: What is the actual composition of the solution that bathes the new contact lens as provided by the manufacturer in the contact lens packaging? Is there an effective disinfectant agent?
Mah: It is saline with an added surfactant. Some manufacturers add a wetting agent to increase comfort upon insertion. The lenses are packed in a sterile solution but there is no disinfecting agent.
O’Brien: How does the lack of disinfectant in the solution bathing the new disposable contact lens in the package affect infection?
Alfonso: One theory as to why daily wear disposable contact lens users have a rate of keratitis similar to the rate for planned replacement contact lens users is because exposure to a disinfectant antiseptic may be beneficial to an eye suffering microtrauma from contact lens wear. Putting on a contact lens that carries a slight disinfectant solution may be protective. Since daily disposable contact lenses are not packaged with a disinfectant, planned replacement contact lenses may be the safer choice.
My suggestion to patients is to have both disposable and planned replacement contact lenses. I tell them to use the planned replacement lenses as their standard lens and to use the disposable lenses when patients are in situations where they are unable to properly care for their lenses, such as when they are traveling. I believe most patients accept this as a good method for contact lens wear.
Increased recovery of nonbacterial pathogens in contact lens-associated ulcerative keratitisEduardo C. Alfonso, MD The traditional belief of ophthalmologists as to the cause of microbial keratitis was bacterial pathogens on the eye. As a result, antibiotics were used empirically to treat patients with keratitis and patients tended to do well following antibiotic treatment in the early stages of infection. Historically, there has been a low prevalence of fungal and Acanthamoeba keratitis.1 In the past, ophthalmologists believed soft contact lenses were protective against fungal keratitis, to the point that ophthalmologists dismissed the idea of contact lens wear in a patient with fungal keratitis. When the rates of fungal keratitis increased, researchers at the Bascom Palmer Eye Institute reviewed data collected in their microbiology laboratory. The researchers studied the data from an epidemiological perspective in an attempt to document an increase in non-bacterial keratitis in soft contact lens users. The data reviewed all culture-positive keratitis records from January 2004 to December 2005 and compared it to the historical data from the laboratory. 2-4 No change had occurred in the criteria for determining a positive culture for fungi from when the historical data were recorded. No new dynamic procedure for diagnosing infection could account for any difference. The review comprised 1,500 cases isolated from 1,400 corneal cultures. The range of age of patients was 13 to 95 years with an equal distribution of male and female subjects. Non-bacterial pathogens were found in 147 of these cases, with 79 cases involving subjects who wore contact lenses. When compared to the historical data, the non-bacterial culture-positive rates of contact lens wearers showed a dramatic increase. In 1986, 1.7% of contact lens wearers had non-bacterial pathogens.3 In 2004-2005, the number was 12.5%. When dissected to look at specific pathogens, in 1986 the fungal keratitis percentage was 3.1%. In 2004-2005, the number rose to 19.6%. In 1980 and 1986, the historical controls showed no cases of Acanthamoeba keratitis, which is unusual since it is primarily seen in contact lens wearers.2-3 In 2000, 3.3% of the contact lens-wearing patients developed keratitis due to Acanthamoeba.4 In 2004-2005, 25% of the patients infected with contact lens-associated keratitis were culturing out Acanthamoeba. This finding was significant as it is more difficult for a general ophthalmologist to diagnose Acanthamoeba keratitis compared to bacterial keratitis. It is also more difficult to treat as it will not respond to the same antibiotics used to treat bacterial keratitis. Although there were still more cases of fungal pathogens compared to Acanthamoeba, this was an indication of an epidemic. After discovering these increases in keratitis, researchers alerted and worked closely with local health authorities to determine the reasons for the epidemic. References
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Contact lens maintenance
O’Brien: An evolution has occurred in contact lens hygiene and cleaning/disinfection regimens. In the early days of soft contact lenses, patients would place their lenses in a device similar to a crock pot that would heat the lenses overnight. After several hours of thermal processing, the contact lenses would be disinfected and ready to wear. Today many types of multipurpose contact lens solutions are available and offer more convenience for patients. How have contact lens hygiene practices evolved more recently and has the shift to convenience over safety had an impact on infection?
Alfonso: As contact lens care evolved, more emphasis was placed on convenience rather than safety. The industry minimized the effort to maintain a contact lens system to convince more patients to wear contact lenses. In retrospect, safety issues were not addressed at the same level as convenience factors.
Mah: Maintaining contact lenses started with heating the lenses, and then hydrogen peroxide was recommended, and then multi-step regimens, and so on. The emphasis was on convenience. As the regimens evolved, patients would not need to be convinced to wear contact lenses and buy all of the equipment needed to take care of the lenses. Patients could then buy contact lenses with the easier regimens, immerse the lenses in a solution and place the lenses back in their eyes. It was much simpler than buying different equipment and going through additional maneuvers just to wear contact lenses.
That convenience has led to poor lens hygiene. Researchers studied the effects of contact lens maintenance regimens and found heating the lenses worked best, followed by hydrogen peroxide. Multipurpose solutions were worst in terms of eradicating the viral pathogens that can cause infections in the eyes.12
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O’Brien: Some of the older methods of cleaning contact lenses, such as heat sterilization and hydrogen peroxide, while technically more time consuming and cumbersome, appeared more effective in some ways at reliably cleaning and disinfecting contact lenses. Should patients revert to these older, hands-on methods of cleaning and disinfecting?
Stulting: In response to the recent outbreaks of contact lens-associated microbial keratitis, there should be a return to more effective disinfecting systems and a labeling emphasis on safe contact lens care practices, rather than convenience. The FDA should require efficacy labeling that focuses on practices that make contact lens wear safer, rather than practices that increase convenience while reducing efficacy of disinfection products. The FDA should mandate testing protocols that duplicate real world use of contact lens products and require testing with a variety of contact lens polymers. Manufacturers should perform internal testing to mimic conditions of actual use and emphasize safe contact lens care practices on product labels, as well as other marketing materials. Practitioners should teach their patients how to care for contact lenses in a way that minimizes risk, and contact lens wearers should not trivialize the potential risk of contact lens wear.
Finally, physicians should consider the possibility that, over a lifetime, refractive surgery may be a less expensive and safer way of correcting refractive errors than contact lenses.
Mah: I do not believe the answer is to revert to the older methods of sterilization, but to look at the problem of infection as a multifactorial issue. It is not just an issue of the solutions, but also the contact lens materials, the human component of hygiene, the tear film, defense mechanisms and other factors. Ophthalmologists need to understand that each of these factors has an effect on the others and, with more study, ophthalmologists will be able to advise an optimal system for contact lens wear that eliminates bacteria, parasites and fungus.
McLeod: I advocate daily disposable contact lenses over any disinfecting regimen.
O’Brien: We strive for convenience in other areas of life, and it would be desirable to find a convenient multipurpose maintenance regimen with similar safety and efficacy yet greater ease. Though it should be noted that some of the major advances in conveniences with “one-drop stopping” helped expand the number of comfortable, satisfied contact lens users.
In the early days of contact lenses, there was more of an emphasis on safety. Clinicians would interact with patients and instruct them on proper care and use of lenses. Over time patients were introduced to different avenues to attain their lenses, including toll-free numbers and the Internet. This method of obtaining lenses nearly eliminates clinicians, including proper fitting as well as information on proper care and wear of contact lenses. How do these alternate methods of obtaining lenses affect safety?
Alfonso: It is a factor of concern, but results from studies have been mixed. Some of the results show proper teaching of contact lens use and continued surveillance and education of the contact lens wearer are important. Other studies seem to negate the value of that education.13
Ophthalmologists hear anecdotal stories about patients who do not take care of their contact lenses and do not suffer from infection. And then there are other cases of patients who are diligent with their contact lens care yet develop an infection.
I do not believe ophthalmologists can point to the different avenues of acquiring the contact lenses as the reason for the rise of infection. However, ophthalmologists want their patients to take good care of their contact lenses, and that often means proper instruction from an ophthalmologist or optometrist.
O’Brien: What is the role of the FDA in contact lens product regulation, product manufacturing, labeling, supply and distribution?
Stulting: The FDA is responsible for assuring the safety and efficacy of new products. They are also responsible for approving labeling.
I do not believe that the FDA’s testing methods reflect real life use of contact lens care products. For example, Fusarium can live and multiply in the film left on contact lens cases by some “no rub” contact lens disinfecting solutions, especially those that claim to improve wetting of contact lenses.14 The ability of the film to support the growth of fungi is simply not revealed by the standard methods of testing for efficacy of contact lens disinfecting solutions.
Mah: There are trials for contact lens materials, but there are no trials for solutions. Manufacturers have a list of products they can choose from, and they can release the product once it has met the criteria the FDA has set.
Contact lens disinfection: Are we trading convenience for safety?R. Doyle Stulting, MD, PhD During the recent Fusarium keratitis epidemic, studies found 164 cases of Fusarium infection in the United States, with 154 of those cases associated with ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY).1 A study from Singapore found 68 cases of Fusarium keratitis associated with poor contact lens hygiene and ReNu MoistureLoc.2 The contact lens-associated keratitis epidemic exposed safety issues in contact lens maintenance programs. As technology improved, manufacturers developed more comfortable lenses and convenient methods of maintaining lenses. This led to multipurpose solutions that do not require neutralization or a rub step, and the introduction of new wetting agents. These advances increased the convenience of contact lenses, but reduced the efficacy of the disinfection process. In addition, patients who store their cases wet and top off the disinfecting solution instead of using new, full-strength solution created an environment that supported infectious microbes. A team of researchers from Emory University and Georgia State University cultured the cornea, contact lens cases and neck and applicator of the lens solution of eight patients. Three patients presented with corneal staining. Two patients had positive corneal cultures. Cultures were positive in the right well of four of the lens cases, and positive in the left well in all eight lens cases. One of the patients presented a positive culture from the neck and applicator of their solution.3 The team also compared the effects of a rinsing and rubbing regimen to a regimen of only rinsing. The results of the testing found that the additional rubbing step decreased organism colonization on the lens. ConclusionsTesting found that dilution and drying of ReNu with MoistureLoc partitions the solution into microenvironments that permit selective growth of Fusarium within the residue. Fusarium can penetrate soft contact lenses, though penetration is species and polymer dependent. In order to combat contact lens-associated keratitis, the ophthalmic community needs to emphasize efficacy instead of convenience, develop in vitro test methods that simulate actual contact lens use and test new materials for interactions that might occur in actual use. References
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Public awareness
O’Brien: How did the ophthalmic community become aware of the epidemics of contact lens-associated keratitis, initially with an insurgence of fungal pathogens and subsequently or perhaps simultaneously with an increased recovery of amoebic pathogens?
McLeod: The ophthalmic community is indebted to astute practitioners who recognized these atypical cases and alerted the Centers for Disease Control and Prevention (CDC) as well as the broader ophthalmic community. Moreover, the CDC played a leadership role in investigating and informing both eye care professionals and consumers.
O’Brien: Investigations suggested that the multipurpose, no-rub ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY) was disproportionately associated with the Fusarium epidemic and Complete MoisturePlus (Advanced Medical Optics, Santa Ana, CA) was associated with the Acanthamoeba epidemic.1 Both products were recently involved in a voluntary global recall from the marketplace by the manufacturers when data suggested the association. What was the process of getting the product failures and recalls in the public eye?
Alfonso: The CDC’s surveillance mechanism is based on reports given to local health departments. The first report came from New Jersey. A clinician reported to his local health department an increased incidence of fungal keratitis in soft contact lens wearers. The health department reported this increase to the CDC.
Clinicians and local health department authorities in Miami were reviewing the increase of contact lens-associated keratitis at the same time. When it was obvious there was a significant number of patients with fungal keratitis, the CDC put together a task force in their epidemiology department and in conjunction with the local health authorities to help decipher the problem. The CDC performed a study similar to a case-controlled study. They called patients who were diagnosed with fungal keratitis to determine who wore soft contact lenses and identify which product could be at fault, if any. Through this method, the CDC found a correlation with ReNu with MoistureLoc and the increase in Fusarium keratitis.
Stulting: The CDC acted quickly to establish the relationship between contact lens care products and recent outbreaks of Fusarium and Acanthamoeba keratitis, and manufacturers removed the contact lens products from the market as soon as the data were available. The FDA inspected manufacturing facilities, and products were tested for contamination. But neither agency recognized the mechanism by which the first epidemic of Fusarium keratitis occurred. Recent studies demonstrated that Fusarium can grow in the film of MoistureLoc that remains on the cases of contact lens wearers and that it can be transmitted to the eye in large numbers by contact lenses stored in these cases.14 Furthermore, the lack of a rub step in the contact lens care regimen makes the fungal colonization of contact lenses more severe (Figure 2).
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Image courtesy of R. Doyle Stulting, MD., PhD, adapted from Zhang S, Simmons RB, Ahearn DG, et al. Firm Attachment to and Penetration of Silicone Hydrogel Contact Lenses by Representatives of Fusarium Oxysporum - F. Solani Complexes. Paper 739/B514, presented at the annual meeting of the Association for Research in Vision and Ophthalmology. May 6, 2007; Fort Lauderdale, Fla. |
O’Brien: What problems did the CDC encounter when conducting their case-controlled study?
Alfonso: The study was difficult. The task force spent 3 consecutive days, 24 hours a day, making phone calls and deciphering the data. Patient recall was abominable. Patients did not know what products they were using. Even when the task force was able to show patients pictures of products, they oftentimes picked the wrong product. When patients brought the task force the products they were using, it was often not the one they had picked out of the picture.
O’Brien: Was this confusion in part due to the similar appearance of packaging for brand name products versus generic products with the generic trying to simulate a brand name product appearance on the shelves of retailers?
Alfonso: This inability to recall does not just happen with contact lens solutions. For example, most people cannot remember the brand of toothpaste they use. Contact lens users are in the same category of poor recall and oftentimes the patients can only remember the store where they bought the products. It is then incumbent on the task force to find which products are sold at that store. It was obvious to the CDC that it was not an ideal system for the study.
O’Brien: The CDC publishes a weekly report that alerts practitioners to developments in areas of medicine and public health contributing to morbidity and mortality. Was that Morbidity and Mortality Weekly Report the first official report of the fungal keratitis problem?
Alfonso: That was the first alert that was published in terms of this problem.The role the press played in alerting the public of the problem was significant and effective. The means that the CDC had to communicate this to the general population was not as effective as the press.
O’Brien: How does the FDA interact with the CDC, or are they charged with a different task in terms of product regulation?
Alfonso: The CDC was in communication with the FDA, but the CDC was involved in trying to decipher the cause of the problem to let the FDA know if a product recall was necessary.
O’Brien: Was there a problem with communication between governmental agencies?
Alfonso: There was communication between the CDC and the FDA.
Responsibilities were split, and the CDC had the resources to investigate the cause of the problem. The FDA is a regulatory approval agency, whereas the CDC is in charge of investigating problems that arise.
O’Brien: Unfortunately, representatives from governmental agencies are not present here to share in this open dialogue. Were the CDC and FDA both quick and efficient in their response?
Alfonso: The response was as quick as possible considering the circumstances. Better surveillance mechanisms should be established to better alert the public of any impending problems.
Mah: I agree.The CDC does not have the resources available specifically for problems that arise with the eye. They are excellent in terms of other epidemics, but they need help with the eyes. The CDC was forced to work with outside resources instead of having all of the resources in-house. It might benefit the CDC to have an ophthalmic epidemiologist that has access to surveillance across the country to help identify problems faster.
The CDC did its due diligence as quickly as possible. It attempted to gather all of the data to make sure the problem was a true phenomenon. Once that determination was made, the CDC alerted the press.
O’Brien: The CDC relies upon reporting from the field by clinical observers of specific conditions. Some medical diseases and conditions are mandated to be reported to the public health bureaus given the threat they pose to overall public health. Should there be a mandate of reporting certain ophthalmologic infections such as Acanthamoeba or fungal keratitis with contact lens wearers?
Alfonso: I have had discussions with the CDC regarding reporting. Unless the CDC creates an internal mechanism to deal with reports, then it is dangerous to think that reporting will result in action being taken. I believe it is a good idea to start a reporting mechanism, but it is more important to have an internal system to quickly act upon those reports. The CDC had to put together a task force due to the lack of an internal system. In this case, the task force did an efficient job in identifying the cause of the problem.
O’Brien: It seems there was a differential response by the public to the Fusarium outbreak versus recent rises in cases of contact lens-associated keratitis due to Acanthamoeba. The magnitude of the problem was different, but the CDC showed the impact to the public was not effective in the Acanthamoeba reporting. What lessons were learned to improve upon identification of the problem and methods to provide and alerts to the public?
Mah: One reason Acanthamoeba reporting was not effective is that the epidemic fell on the heels of the Fusarium report. The Fusarium report was first, and it was big. There was a misconception that the Acanthamoeba report was a different variant of the Fusarium report and that it was not big news. The CDC published reports and alerted the media. The media did not pick up the story as an important or novel news item.
O’Brien: The FDA requires a period of rather intense post-approval scrutiny with reporting of adverse events from the marketplace, and often the industry may find trends through their own internal reports. Should industry have a more significant role with the CDC investigations of contact lens-associated infectious outbreaks?
Mah: I believe it is a difficult situation for industry. The FDA has done its due diligence before the products reach the market. Manufacturers must deal with many calls about problems with their products. But if they see a preponderance of clinicians or contact lens wearers reporting the same problem, then they should investigate the issue or present it to the FDA.
O’Brien: Do patients play a significant and important role in investigations of potential problems?
Alfonso: Patients can play an important role in mobilizing investigation efforts. It was especially important in the Acanthamoeba epidemic. An effort was made over the Internet to alert other patients of this potential problem. I believe the use of communicating through the Internet will lead to a more rapid response and the reporting system will be more effective.
Epidemics and challenges in AsiaDonald Tan, MD In 2006, reports from international sources of an increase in contact lens-associated Fusarium keratitis due to use of the multipurpose contact lens solution ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY) led to the global withdrawal of the product.1,2 One year later, another solution, Complete MoisturePlus (Advanced Medical Optics, Santa Ana, CA), was recalled due to an association with Acanthamoeba keratitis.3 These product recalls were due in part to rising rates of microbial keratitis in Asia. For example, in Singapore, the number of positive cultures submitted to the Singapore National Eye Center went up 122% from 79 cases in 1996 to 201 cases in 2006.The scraping and culturing techniques had not changed in that period, which eliminated the possibility of the increase due to lab procedures. The organisms cultured in 2006 were 85.8% bacterial, 10% fungal and 4.2% parasitic. The results showed a rising trend of cases of all three types of pathogens. These rising trends are not limited to Singapore; they have been reported throughout Asia. ReNu with MoistureLoc was recalled directly in relation to the reported increase in contact lens-associated Fusarium keratitis, as it was partially responsible for the increase in the rates of microbial keratitis in Singapore and other parts of Asia. In addition to the increase of bacterial, fungal and parasitic pathogens, a new disease has been reported in Asia, microsporidial keratoconjunctivitis.4-5 This pathogen was first found in patients who had contracted HIV in the late 1980s and early 1990s. The pathogen caused a superficial keratoconjunctivitis in those immunocompromised individuals. The new reports are from non-HIV infected contact lens wearers. In Singapore, 66 cases of microsporidial keratoconjunctivitis have been confirmed, with 21 coming in 2006. Challenges of treating infectionTreating eye infections in Asia presents different challenges when compared to treating eye infections in the United States. Ophthalmologists in Asia have to treat many different types of infections that respond differently to commercially available antibiotic treatments. There are different risk factors in urban and rural communities. There are differences in antibiotic resistance factors based on location, and economic barriers to receiving the latest antibiotics. The ophthalmic community needs to collate data on antibiotic resistance patterns at local or regional levels to determine which antibiotics should be used for which infections, and where. In addition, the ophthalmic community needs industry support in addressing the major causes of infection in Asia, including fungal, bacterial and parasitic pathogens. References
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Patient compliance
O’Brien: The first response some ophthalmic practitioners instinctively have when dealing with a contact lens-associated infection is to blame it on poor patient compliance. Compliance has been suboptimal since the beginning of contact lens wear. But this does not necessarily lead to infection, as there are patients who are noncompliant and do not develop infections and other patients who are compliant and develop infections. There may be other significant host factors causing infection that eye care practitioners do not know about or fully understand.
Do patients follow the recommended manufacturer-provided contact lens wear and replacement schedules?
Mah: Patients often do not follow the recommendations for contact lens wear and replacement. I believe patients who are conscientious of the schedule sometimes lose track and wear their lenses an extra day and find it did not cause any problems. They then extend their lens wear until their eyes are irritated before switching them.
O’Brien: There are some economic incentives to extending the use of lenses past the recommendations. Studies have shown that nearly half of patients do not wear the lenses according to the recommended replacement schedules.15-16
Patients put their contact lenses at risk using old or unclean lens cases that may have developed adherent biofilms. Do patients replace their cases as recommended or clean them appropriately?
Stulting: Wearing lenses longer than recommended may increase the likelihood that they will transmit microbes to the surface of the eye, but I believe care of the case and solutions is a more significant risk factor for microbial keratitis than the lens replacement schedule (Table). The lens case is a reservoir for bacteria, fungi and Acanthamoeba. Failure to clean the case regularly, storing it wet instead of dry and topping off the solution in a case instead of replacing the solution provides an environment that encourages growth of organisms that can be transferred to the eye by the contact lens.15
| Table: Association of Acanthamoeba Keratitis with Lens Care and Complete MoisturePlus Multipurpose Solution Data adapted from Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol. 2007;144(2):169-180. |
Mah: Contact lens cases are an interesting component of the problem. What is the recommendation for contact lens cases? How often should a patient replace contact lens cases? I have spoken with multiple optometrists who answer every 2 or 3 months. Other optometrists recommend every month. There is no general recommendation for contact lens case replacement. Often, clinicians recommend boiling the case once a month: heat water until it boils, turn off the heat, place the contact lens case in the water, and when it cools take it out for use. But that method does not avoid all of the potential problems with contact lens cases.
Alfonso: Many questions arise when discussing a boiling and replacement schedule for contact lens cases. If you boil the case, do you compromise the plastic in some way so that it is now more prone to harboring microbes that can form a biofilm? If you replace the initial case and buy a cheaper one, is it as effective at keeping lenses free of microbes? Clinicians who make any recommendations on contact lens case replacement are often left wondering, “Is what I am saying backed by any scientific evidence?”
O’Brien: Data have shown that fewer than one half of the patients follow the manufacturer’s recommendations for case replacement, and only 40% clean it after each use. Most of the patients who clean their cases do so improperly.16-17
Another significant issue is the common practice of topping off the solution in a case instead of replacing the solution. There is an economic incentive to not throw out the solution but to simply freshen it up by adding more multipurpose solution. What problems does topping off the solution create and what additional risks are posed by this practice?
Mah: One hypothesis of the Fusarium and Acanthamoeba outbreaks is contact lens hygiene. Ophthalmologists and optometrists need to teach patients better hygiene and proper contact lens care. This includes putting in new, full-strength multipurpose solution in the case every use. One theory regarding the rise of infection is that biocides are absorbed into the newer generation contact lenses, which leaves fewer biocides in the contact lens solution. If the solution is not at full strength, then it will not eliminate the Fusarium and Acanthamoeba.
O’Brien: Some patients use tap water to clean their lens cases. What is the risk to patients who use tap water to clean their lens cases?
Alfonso: Surveillance studies have been conducted on water sources and their ability to harbor different microorganisms.18 Microorganisms that are difficult to eliminate are also difficult to treat if they cause an infection. Pathogens found in tap water include fungi, amoebas and mycobacteria. Studies have looked at tap water from different sources, including well water and chlorinated water. Both have organisms present. Eye wash stations that are supposed to be sterile have microorganisms in them. These microorganisms should not present a problem for healthy eyes. If the eye is unhealthy or weaker by a contact lens wearing regimen, then microorganisms in tap water may present a problem.
O’Brien: Is the answer to the problem of infection to switch patients to daily disposable contact lenses and remove contact lens cases from the equation?
McLeod: While daily wear lenses are not a panacea and definitive epidemiological studies are not available, some of the risks suggested by an understanding of the pathophysiologic mechanisms of infection can be reduced by daily disposable lens wear and eliminating overnight wear.
Mah: The market for daily disposable contact lenses has increased, partially because of the scare of infection. The perception of daily disposable contact lenses and the reduced risk for infection have increased in the market. It will eliminate the need for contact lens case hygiene, but it remains to be seen whether it will reduce the risk of infectious keratitis.
O’Brien: How does the specific formulation of multipurpose contact lens solutions impact the risk for corneal infection?
Stulting: The active disinfecting ingredient in multipurpose solutions is not as effective as those in the older disinfection systems that require rinsing or neutralization before lenses could be inserted into the eye. Furthermore, the ingredients that are designed to wet the lenses make it more difficult to wash the disinfecting solution off of the case and bottles. If the disinfecting solution becomes less effective with drying and retained moisture creates an environment that is conducive to microbial growth, it is a recipe for disaster, which is what I believe happened with the Fusarium epidemic.
O’Brien: How does the potency of a multipurpose lens solutions change over time?
Mah: Studies show the potency of solutions changes over time, due to a lack of biocide in the contact lens cases.19 The biocide, especially smaller molecules, are absorbed by the contact lens. This absorption leads to less biocide for the disinfection of pathogens in the solution and contact lens case.
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O’Brien: Will there ever be a universally omnipotent chemoprotectant for contact lens solutions?
Alfonso: I do not believe there will ever be a totally sterile contact lens system. Microbes are on the surface of the eye. They are in our environment and will always become resistant to the disinfecting methods that are developed. Ophthalmologists need to minimize some of the effects contact lens wearing may have on the immune mechanism of the eye.
O’Brien: Based on the numbers of microbes in and around the environment of contact lens use along with the millions of users, it is a tribute to the natural host defense mechanisms that infections occur so rarely with contact lens wear. A robust natural host defense system is in place to protect the ocular surface from development of infection.
Corneal staining
O’Brien: Cornea specialists are aware of the importance of the corneal epithelial barrier as a defense against infection. Though data about corneal staining with certain lens types and solutions have been published, ophthalmologists have not focused on the significance of corneal staining. What is corneal staining, and what is the significance in a contact lens wearer?
Stulting: Staining of the cornea indicates that the epithelial cells are not healthy. In contact lens wearers, this can result from mechanical damage from the lens or the process of insertion and removal. It can also be caused by solutions that are used to disinfect or wet the contact lens. Organisms on the surface of the eye are more likely to grow if they encounter an environment with reduced defenses, and corneal staining is a marker for reduced defenses.
O’Brien: How does corneal staining affect the ocular surface and response mechanisms?
McLeod: Corneal staining suggests ongoing compromise of the tear film, which is the first line of defense against bacterial infection. Although bacterial adherence is the first critical step in the establishment of infection, ophthalmologists should consider the conditions that led to the bacterial adherence. A healthy tear film is critical in providing antimicrobial agents including IgA, lysozyme, lactoferrin and phospholipase A2. It hosts sessile nonpathogenic bacteria that produce bacteriocins to restrain the growth of pathogenetic strains. Epithelial cells secrete proteins into the tear film that contribute to innate immunity including human beta defensin-2 and ocular surface epithelial mucins that provide a physical barrier between the epithelium and the tear film as well as bind and trap bacteria that can then be cleared by blinking. Corneal surface staining suggests a compromised tear film and a risk of breakdown of these complex defense mechanisms.
O’Brien: Observations from studies of contact lens wearers often show small areas corneal staining. Can a patient have a small area of staining and still not suffer any consequences or is any staining a potential threat?
Alfonso: In terms of pathogens, if a patient has a small area of staining but a large microbial load delivered to that area, it is almost as bad as if the patient has a large area of staining but a small microbial load delivered to that area. It is a balance between the outside environment entering the eye and staining. I believe any staining is of some significance because studies have shown that a denuded or broken epithelium increases the chances for microorganisms to adhere to the epithelium. This has been shown with bacteria such as staphylococci and pseudomonas and fungi such as Candida.
O’Brien: Does chronic staining of the ocular surface pose a greater risk factor than acute evanescent staining?
Mah: Zero staining is optimal. Chronic staining is worse than acute staining because the eye is at risk every day. Chronic staining also increases inflammation of the cornea and vascularization of the cornea which can lead to suboptimal corneal epithelium and increase the chance of infection.
O’Brien: Damaged epithelial cells release proinflammatory mediators and other cytokines that may diminish the other normal host response mechanisms, including recruitment of various protective inflammatory cells, which could increase the risk of infection.
How does the intrinsic properties of the contact lens material affect corneal staining and concomitant risk?
Alfonso: Contact lens material is an important factor in corneal staining and ophthalmologists need to study the interaction of the contact lens material with the corneal epithelium as well as the interaction of the lens material with the products that are used in lens maintenance. Another area of future investigation is the impact of contact lens material and the products used to maintain contact lenses on the tear film. What is the role of the tear film in contact lens wear with regard to the protective mechanisms against the onset of microbial keratitis? The sequestering of inflammatory mediators in a soft contact lens environment is different than the sequestering of inflammatory mediators in a hard contact lens environment. This sequestering takes place in the tear film. There are not enough data to point to a reason why soft contact lenses have a higher incidence of microbial keratitis than hard contact lenses, but I believe it will be an interesting area of future research.
Mah: Generally, the newer contact lenses with higher Dk ratios have a rougher surface than the older contact lenses. The rougher surface may play a role in terms of causing some microtrauma to the ocular surface.
O’Brien: The stiffer material of the newer class IV contact lenses may have a more direct mechanical effect on the ocular surface. In addition, some of the disinfecting solutions had surfactants added to reduce the amount of staining and increase comfort, which created an environment for organisms to thrive because of biofilms developing in the case and on the lens surface itself.
Acanthamoeba keratitis: Difficulties, solutions and responseFrancis S. Mah, MD The Acanthamoeba keratitis epidemic presented difficulties that were unique compared to the Fusarium keratitis epidemic. First, Acanthamoeba keratitis is a difficult infection to diagnose. Cultures require special capabilities that are not available to all ophthalmic institutions. Confocal microscopy is helpful in diagnosing Acanthamoeba, but the exam is rarely reimbursed by insurance companies. Another difficulty is that the FDA has no amoebic disinfection standards for contact lens care solutions, which would aid in decreasing the problem of Acanthamoeba keratitis. Finally, the Environmental Protection Agency (EPA) has decreased water chlorination and does not measure or regulate amoeba in public water supplies. Water harbors microbes that can enter the eye and cause infection. SolutionsThe ophthalmic community, government agencies and the contact lens industry can take steps to solve the problem of Acanthamoeba. The FDA, EPA, clinical, research and industry leaders need to combine their resources to determine the scope and direction the community should take to solve the Acanthamoeba problem, starting with an approved treatment that is available to patients. The groups need to mandate educating patients on better lens hygiene including the dangers of tap water rinses and showering, bathing and swimming in contact lenses. The contact lens industry should be involved with this mandate by putting those warnings on the labels of solutions and contact lenses. The groups should push for confocal microscopy as a valuable tool in diagnosis so that insurance companies will recognize it as a valuable resource for eye centers. The FDA needs to establish an adequate standard for amoebic disinfection in solutions. Research needs to be conducted to combine the efforts of advances in contact lens material technology and solutions to determine optimal combinations. Advances in contact lenses and advances in solutions should not be independent of each other; advances should be combined since they are related and used by patients. Government responseOn May 26, 2007, the Centers for Disease Control and Prevention (CDC) reported a correlation between Acanthamoeba keratitis and patients using Complete MoisturePlus multipurpose contact lens solution (Advanced Medical Optics, Santa Ana, CA). Two months later, the CDC reported multiple cases of Acanthamoeba after the initial report. Contact lens users in at least four of the cases continued to use the Complete MoisturePlus solution and developed symptoms of infection after the initial manufacturer recall in November 2006.1 In the second report, released July 31, 2007, the CDC published results of a survey of contact lens users. Of the 151 patients interviewed, only 52.3% were aware of the Complete MoisturePlus recall. Among those who were aware of the recall, only 26.8% could identify the product by name. Of 15 people who reported using Complete MoisturePlus in April 2007, 80% were unaware of the recall and were still using the product. These data show the CDC and the ophthalmic community were unsuccessful in alerting the public to the dangers of Complete MoisturePlus.2 In response to the Acanthamoeba epidemic and the inadequate reporting to the public, the American Society of Cataract and Refractive Surgery’s infectious disease task force published a White Paper to educate clinicians about the infection.3 The White Paper provided recommendations on the treatment of the infection and how to advise their patients of the problems with the Complete MoisturePlus solution (Table). References
Data adapted from Mah FS, Alfonso EC, Chan T, et. al. |
Lessons learned, future considerations
O’Brien: What lessons were learned from the recent contact lens-associated microbial keratitis epidemics and how can clinicians, patients, industry and governmental regulatory agencies improve?
McLeod: The recent clinical experience with the microbial keratitis epidemics indicates that clinical acumen and sound diagnostic skills remain important even in an age of antimicrobial pharmaceutical advances. Good patient outcomes rely on the first antibiotic agent chosen. Misdiagnosis of the infection and an ineffective initial antibiotic agent allow the infection to progress with subsequent scarring and other corneal complications.
O’Brien: One of the current debates in the ophthalmic community is whether eye care providers should try to reduce the contact lens wearing population by recommending refractive surgery. The complication rates for modern laser vision correction procedures are generally safe, but other problems such as ectasia and infection after LASIK have not been eliminated. Would it be safer to perform refractive surgery than to continue chronic contact lens wear?
Mah: The rates of infection are higher with refractive surgery than they are with contact lenses. Contact lenses are an excellent way of correcting a patient’s refractive error and can be safe and effective. But it is important that the current safety issues with contact lenses are addressed by ophthalmologists and by the industry.
O’Brien: How often should clinicians monitor patients who use contact lenses?
Alfonso: Patients should be checked on a periodic basis in order to minimize the chance of infection. Clinicians can find hypoxia, vascularization and staining with regular exams. A patient whose ocular surface is suffering from the use of contact lenses can be treated before the ocular surface is so weakened that an infection starts.
O’Brien: Should newer diagnostic methods of examining the ocular surface in patients such as high-resolution confocal microscopy and spectral domain optical coherence tomography (OCT) be the new standards in identifying patients at risk?
Mah: Newer methods of examining patients aid in making a diagnosis. Some methods, such as confocal microscopy, have an advantage because it is a non-contact examination. The test is quick and easy for patients to undergo, but culturing and identifying the organisms in the eye is still the gold standard.
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O’Brien: Lens material is an important issue in the safety of contact lens use. Do the disadvantages of class IV silicone hydrogel polymer materials outweigh the advantages, and are newer, safer materials available?
Mah: Technology will always improve and there will be newer materials. But it is important that the industry looks at the contact lens system as a whole to make safety improvements.
O’Brien: Most of the research for contact lens-related ulcerative keratitis involves nonhuman models such as mice or rats, where transgenic subjects and immunologic reagents are available. Can ex vivo or in vivo systems be developed to better understand the effect of contact lens-related keratitis on humans?
Alfonso: Newer systems will help ophthalmologists study the contact lens wearer in humans much better than in the past. New biochemical assays are being developed, as well as imaging systems such as the high-resolution and ultra-resolution OCT that will help study contact lens-wearing patients. The widespread availability of confocal microscopy will provide more research on humans that, in the past, had to be performed on animal models. As researchers study the human situation, they will learn more than what has been learned from animal models.
McLeod: Researchers will benefit from a better understanding of the physiology of the defense systems of the eye, so that materials and strategies can be employed to exploit or work in concert with these innate systems.
O’Brien: How can the clinical and microbiological surveillance system be improved?
Alfonso: Surveillance is an important factor with contact lenses. Early detection of nonbacterial pathogens will often result in successful treatment without significant visual loss. Ophthalmologists need to have a surveillance mechanism for diagnosing nonbacterial pathogens. A surveillance mechanism will reduce the morbidity associated with contact lens-associated keratitis. Future research should focus on creating easier detection methods for ophthalmologists. The goal is to create a more efficient bedside method to diagnose nonbacterial pathogens so early treatment can be started instead of waiting 1 to 2 months mistreating the patient with antibiotics or antiviral medication. Better industry-wide and government-wide surveillance mechanisms will need to be developed as well.
O’Brien: Ophthalmic practitioners need to support ocular microbiology laboratories. Few laboratories exist in the United States that serve as repositories of microbial organism and epidemiologic information.
McLeod: I agree. Very few ocular microbiology laboratories survive in the United States today; these are important resources to maintain at academic centers to provide surveillance and community service, and ophthalmologists should advocate regulatory support of these facilities.
Mah: Though the improvement of surveillance methods is important, education is still the key. Just as patients need to be educated on the proper care of their contact lenses, clinicians need to be educated on how to teach patients the proper care of contact lenses.
A consortium that involves government agencies, industry, clinicians and researchers would be useful in identifying risks and solutions to contact lens-associated keratitis instead of having all of those groups try to reinvent the wheel.
O’Brien: I would like to thank the panel members for coming to the Bascom Palmer Eye Institute to share their comments and expert contributions with valuable recommendations and Vindico Medical Education for sponsoring this symposium.
References
- Chang DC, Grant GB, O’Donnell K, et al. Multistate outbreak of Fusarium keratitis associated with use of contact lens solution. JAMA. 2006;296:953-63.
- Evans BJ. Monovision: A review. Ophthalmic Physiol Opt. 2007;27(5):417-439.
- Alfonso EC, Mandelbaum S, Fox MJ, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol. 1986;101:429-433.
- Schein OD, McNally JJ, Katz J, et al. The incidence of microbial keratitis among wearers of a 30-day silicone hydrogel extended-wear contact lens. Ophthalmology. 2005;112(12): 2172-2179.
- American Academy of Ophthalmology. Bacterial Keratitis: Preferred Practice Pattern® Guideline. September 2005. San Francisco, Calif.
- Schein OD, Poggio EC. Ulcerative keratitis in contact lens wearers: Incidence and risk factors. Cornea. 1990;9:S55-8.
- Keay L, Stapleton F. Development and evaluation of evidence-based guidelines on contact lens-related microbial keratitis. Cont Lens Anterior Eye. 2007 Nov 19; [Epub ahead of print].
- Munneke R, Lash SC, Prendiville C. A case of a pseudomonas corneal ulcer in an occasional use daily disposable contact lens wearer. Eye Contact Lens. 2006;32(2):94-95.
- Le Liboux MJ, Ibara SA, Quinio D, Moalic E. Fungal keratitis in a daily disposable soft contact lens wearer. J Fr Ophtalmol. 2004;27(4):401-403. [Article in French.]
- Su DH, Chan TK, Lim L. Infectious keratitis associated with daily disposable contact lenses. Eye Contact Lens. 2003;29(3):185-186.
- Choi DM, Goldstein MH, Salierno A, Driebe WT. Fungal keratitis in a daily disposable soft contact lens wearer. CLAO J. 2001;27(2):111-112.
- Kowalski RP, Sundar-Raj CV, Romanowski EG, Gordon YJ. The disinfection of contact lenses contaminated with adenovirus. Am J Ophthalmol. 2001;132(5):777-779.
- Keay L, Edwards K, Naduvilath T, et al. Factors affecting the morbidity of contact lens-related microbial keratitis: a population study. Invest Ophthalmol Vis Sci. 2006;47(10):4302-4308.
- Zhang S, Ahearn DG, Noble-Wang JA, et al. Growth and survival of Fusarium solani-F. oxysporum complex on stressed multipurpose contact lens care solution films on plastic surfaces in situ and in vitro. Cornea. 2006;25(10):1210-1216.
- Ahearn DG, Simmons RB, Zhang S, et al. Attachment to and penetration of conventional and silicone hydrogel contact lenses by Fusarium solani and Ulocladium sp. in vitro. Cornea. 2007;26(7):831-839.
- Contact Lens Council Press Release; August 8, 2007.
- Stone R. The importance of compliance: focusing on the key steps. Poster presented at BCLA. May 2007; Manchester, UK.
- Marangon FB, Alfonso EC, Miller D. Update and invitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens. Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology. Fort Lauderdale, Florida; May 4-9, 2003.
- Rosenthal RA, Dassanayake NL, Schlitzer RL, et al. Biocide uptake in contact lenses and loss of fungicidal activity during storage of contact lenses. Eye Contact Lens. 2006;32(6):262-266.