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Experts agree on need to standardize testing for contact lens products
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Most scientific experts concur that existing testing methods for contact lenses and solutions should be reviewed. In September, the U.S. Food and Drug Administration Center for Devices and Radiological Health along with organized ophthalmology and optometry hosted a workshop involving scientists, clinicians and industry experts with the goal of formulating a consensus for new standards and guidelines for improving microbiological test methods as well as patient education.
While the panelists did not reach a complete consensus on all the issues addressed in the workshop, they did find some agreement in several key areas. This included adding Acanthamoeba to the current testing panel, reviewing the testing strains, increasing educational efforts for patients and working toward more real-world testing conditions.
“We are delighted to have partnered with the American Academy of Optometry, the American Optometric Association, the Contact Lens Association of Ophthalmologists and the American Academy of Ophthalmology in this unique goal of improving contact lens safety for U.S. patients,” Malvina Eydelman, MD, said in the opening statements of the daylong workshop.
“The 2007 outbreak was quite a surprise,” Eydelman said. “We’re here today to hopefully avoid another one. In 2007, most of the contact lens community did not talk about Acanthamoeba keratitis as an organism that is commonly associated, so much so that it was not even included in our premarket panel of assessment of organisms, nor was there any consensus about the best ways to test for it. Multipurpose contact solutions used in the past were very good and well accepted, but risks are different now than they were 10 years ago, according to Elmer Y. Tu, MD.
“Today, we’re taking the next step,” she said. “We’re hoping to try to predict what will cause the next contact lens-related outbreak.”
Multipurpose contact solutions used in the past were very good and well accepted, but risks are different now than they were 10 years ago, according to Elmer Y. Tu, MD.
Image: Mark Janowicz
Emerging pathogens in contact lens keratitis
The current preclinical test methods for contact lenses and care products include the standalone and regimen tests, Jeffrey Brocious, MS, discussed in his presentation.
Both tests include the bacteria Staphylococcus aureus, Pseudomonas aeruginosa and Serratia marcescens as well as the fungi Candida albicans and Fusarium solani.
Loretta Szczotka-Flynn
Moderated by Loretta Szczotka-Flynn, OD, PhD, the first set of panelists addressed the current panel of pathogens and whether it was acceptable for disinfection efficacy testing.
“It will be impossible to test against all pathogens in the microbial world,” Eduardo C. Alfonso, MD, said. “Any pathogen can gain dominant access to a cornea injured by the normal wearing of a contact lens. A sterile contact lens wearing environment within a patient’s eye will never exist.”
Panelist Mark Willcox, PhD, added: “Over the last 20 years, we’ve maintained the same level of microbial keratitis, it seems, in extended wear or daily wear. So, perhaps, if we change nothing, it may result in not increasing or decreasing the current rates.”
Willcox encouraged the addition of Acanthamoeba as a test organism in the panel but also noted the importance of testing organisms that are easily isolated from the disease.
“[We should] certainly [include] Pseudomonas and Staphylococcus, and I would encourage us to keep Serratia as well,” he said. “Candida is not a huge pathogen in contact lens-related infections, but as a yeast maybe that’s good as well.”
Michelle Callegan, PhD, and Suzanne Fleiszig, OD, PhD, also confirmed that the current panel is adequate but questioned whether it accurately represents the current strains of the pathogens.
“The S. aureus strain dates back to 1938, so these pathogens have evolved over the years,” Fleiszig said. “The sorts of strains that are infecting people change.”
“In looking at the ATCC (American Type Culture Collection) strains, it’s alarming that except for the Serratia strains, none of these genomes have been sequenced,” Callegan said. “If we look at the sequence of the ATCC strains and compare them with a few of the current pathogens, we can see where the disconnect is.”
Fleiszig noted that the bacteria can change during processing, even before they are entered into the ATCC system.
Elmer Y. Tu, MD, said that it was not possible to have an all-encompassing panel.
“This test is simply a proxy for the disinfection efficacy of the solution system. It’s not meant to cover every single organism,” he said. “We just need to pick those most likely [to infect] and the ones that have shown to be infective.”
Addition of viruses
Szczotka-Flynn asked the panelists whether or not viruses should be added to the panel.
Eduardo C. Alfonso
“We have not had a regimented way to clinically culture viruses out of a patient’s eye when they present with a contact lens-related keratitis,” Alfonso said. “So we’re in ignorance, total ignorance.”
“Viruses might be a problem,” Fleiszig said. “No research has been done in this area, so it would be difficult at this point to say we need to have a standard that addresses something we don’t even know is a problem. The first thing is to do the science.”
Adding test methods
The panelists then discussed the appropriate test methods for the pathogens that should be added to the panel.
“It depends on what results you want to get,” Fleiszig said. “Do you want to have a test that doesn’t work for any microbe, or do you want a test that’s going to work for all of them? We probably want to be somewhere in the middle.”
She recommended making the test methods stricter and standardizing the process.
“When the strain comes from ATCC, there should be handling standards for the microbe,” she said. “They can change and mutate if you handle them the wrong way.”
Additionally, Fleiszig noted that some testing processes are optional and make the microbes more susceptible to killing, including centrifugation, filtering and using rich broths. By eliminating these steps, the microbes would be tested in an environment more representative of a real-world scenario, she said.
Callegan also supported decreasing processing variability to attain more reliable results.
“There’s a wide variety in the ISO standard,” she said. “If it’s completely spread out across the board in terms of vendors, you might get different outcomes and different tests in different laboratories.”
Tu asked the other panelists if there was a way to test the strains and confirm their consistency.
“If we bring the newer science into the testing and develop a set of tests and do the same thing every time, you probably don’t need to worry about this,” Fleiszig said. “You don’t really want to make everything so cumbersome that it becomes impossible.”
Inclusion of biofilm form
The panelists next discussed the biofilm form of the pathogens and if they should also be included in the testing panel.
“Biofilm growth is going to make them more resistant, so if you do that, the solution is not going to work very well,” Fleiszig said.
“It’s going to be very difficult to make something work with a biofilm and not kill the eye,” Willcox said. “There’s got to be some more research.”
Tu shared his experience as a cornea specialist and how such testing would help in a clinical setting.
“One of the things that we struggle with as clinicians, once we see an outbreak, is not knowing the characteristics of the disinfectants,” he said.
This knowledge would help clinicians determine why a particular solution may have failed, he said.
Szczotka-Flynn noted that “certain solutions have been shown to be effective against biofilm,” including peroxide.
“Biofilms are certainly relevant, but if you add a biofilm test, you’re adding a level of complexity that you may not want to approach at this point without further research,” Callegan said.
Modifying pathogen strains
Lastly, the panelists addressed whether pathogen strains currently on the panel needed modification.
“They should all be updated to strains that actually come from corneal infections, preferably that were caused by contact lens wear, and as recent as possible,” Fleiszig said.
She also said that, in her opinion, both of the Pseudomonas aeruginosa subtypes should be added — a cytotoxic strain as well as an invasive strain — because Pseudomonas is “the most common problem when infections occur during contact lens wear, and either strain type can be involved.”
The majority of the panelists agreed that pathogens already on the panel should be updated to current strains.
“I agree with using strains from the particular infections and more recent strains,” Willcox said. “I’d also like us to consider surveillance type systems being put in place so we can see if there are emerging pathogens that we may need to add to these types of systems in the future.”
“We’re working a little bit in a bubble here,” Tu said. “We’re guessing as to what particular disinfection standards are going to be representative or adequate for contact lenses. If there are no population-based studies looking at the effects of these changes, it will be another 20 years before we know whether or not they were adequate.”
The panelists also stressed the need for genome sequencing because it can help limit variability and encourage comparisons between strains.
Callegan noted the importance of sequencing the genomes of the strains used so they can be compared 10 years down the road.
Several of the panelists agreed to share their strains with the ATCC in hopes of updating the current panel as well as contributing further guidance regarding the test parameters.
Efficacy standards for Acanthamoeba testing
Concern has grown among practitioners over the ability to test for Acanthamoeba in contact lens products, but there remains no universally accepted method for testing disinfection efficacy against such microbes, according to a press release from the AAO.
Currently, ISO standard 14729 does not recommend acanthamoebicidal testing, Daniel P. Fedorko, PhD, said in his workshop presentation.
Fedorko detailed the FDA proposed protocol for Acanthamoeba testing, which includes the use of A. castellanii and bacterized trophozoite production. He acknowledged, however, that there is no universally accepted protocol and that published methods vary widely in critical components.
Fedorko encouraged the panelists to move toward the standardization of efficacy testing for Acanthamoeba.
In considering A. castellanii as the most suitable strain for testing, many of the panelists explained that it was an easy strain to obtain and work with, thus supporting it as an appropriate choice.
But Tu said that the strain is outdated and not representative of the strain currently seen in patients.
“Having an isolate from 1978 from a human keratitis specimen gives me pause, especially with the potential that we’re dealing with new strains and virulence over the last several years. It may not reflect, in any way, some of the virulence factors that we’re seeing in the most recent outbreak,” he said.
The other panelists reviewed the rationale for the current strain and shared some suggestions for adding new strains.
“When we start looking at new strains, we have to remember that we have to get them into the ATCC culture system in order to maintain a realistic understanding of how that organism is going to perform long term,” Ralph Stone, PhD, said.
Patient education, water use
Addressing the role of water in ocular infection, Tu said that small geographic variations have been shown even within a city.
“To do a study, you would need to go into homes and not only measure Acanthamoeba, but also disinfectant levels and everything else,” he said. “It’s far from conclusive that the U.S. outbreak had nothing to do with tap water. I think the exact opposite. The overarching theme here is that the multipurpose solutions were very good and they were very well-accepted. But things change, and we’re faced with a different risk now than 10 years ago.”
Eydelman discussed how educational efforts could be improved, noting that the FDA has made a large effort in educating patients and doctors and would like other organizations to contribute parallel efforts.
“We don’t regulate doctors and patients,” she said. “What we do regulate is devices. And as such we can have premarket requirements of certain safety standards prior to getting these devices on the market. I agree in that whatever we do in the realm of education needs to be done in parallel with continuing to try to strengthen our premarketing activities. And that’s what the goal of today’s workshop is.”
The panel members were asked if they believe that gas permeable lens wearers would stop rinsing their lenses in tap water even with educational campaigns and labeling changes.
“History tells us that it’s difficult to change behaviors,” Tu said. “If it’s an effective campaign, you might be able to improve patients’ behavior. It’s worthwhile because education is important. All of us, as eye care professionals, have suffered from reduced compensation and reimbursement for actually spending time with our patients to talk to them about lens care, and I think that’s something they need on a one-on-one basis, which, historically, has been the most effective.”
Deepinder K. Dhaliwal
Deepinder K. Dhaliwal, MD, LAc, recounted a specific situation with one of her patients who developed Acanthamoeba after using water with her gas permeable contact lenses and was not aware of the risk.
“When I told her that rinsing in tap water is definitely a problem with contact lens wear, she said, ‘You know, I wish someone had told me that. If someone had told me that, I would have done whatever they recommended,’” she said. “When patients know that blinding infections can result, they change their behavior.”
Szczotka-Flynn acknowledged the importance of providing patients with the necessary tools to change their behaviors.
“As a clinician, I tell my patients not to use tap water to rinse their gas permeable lenses. However, a majority of them say, ‘Well, I’ve been doing it for 30 years. Why should I change now?’ And the second thing is, ‘What do I rinse it with?’” she said.
The attendees debated about which products should be used to provide copious rinses of harsh cleaners from gas permeable lenses and which, if any, current products on the market are approved for gas permeable lenses, but there was no consensus on these products’ efficacy or safety.
Eydelman encouraged the present eye care organizations to speak with manufacturers about delivering an alternative solution.
Conclusion
Several of the panelists expressed a desire to continue the discussion among themselves and their organizations to completely standardize testing protocols and improve the health and safety of their patients.
“The most important topic that keeps being reiterated in the summary remarks is that we’re not done,” Eydelman said. “Today should be viewed as just the beginning of the next stage. We have made enormous progress, but I want to urge you to look at this as a springboard. There are some really good, strong recommendations that came out from each of the panels, and we’re going to be reaching out to all four organizations to try to see if we can put together some kind of working group that can proceed and actually bring this to a reality.” – by Chelsea Frajerman
Editor’s note: Adapted from “Experts agree on need to standardize testing for contact lens products,” Primary Care Optometry News, November issue, and “Experts support development of efficacy standards for Acanthamoeba testing,” Primary Care Optometry News, December issue, in press.
Jeffrey Brocious, MS, is a microbiologist in the Contact Lenses and Retinal Devices Branch in the Division of Ophthalmic and Ear, Nose and Throat Devices at the FDA. He can be reached at dice@fda.hhs.gov.
Michelle Callegan, PhD, is a professor in the departments of ophthalmology, microbiology and immunology at the Oklahoma Center for Neuroscience, where she is also an associate director for research, as part of the University of Oklahoma Health Sciences Center. She can be reached at michelle-callegan@ouhsc.edu.
Deepinder K. Dhaliwal, MD, LAc, is a cornea specialist at the University of Pittsburgh and the associate medical director of the Campbell Ocular Microbiology Lab. She can be reached at dhaliwaldk@upmc.edu.
Malvina Eydelman, MD, is the director of the Division of Ophthalmic, Neurological and Ear, Nose and Throat Devices and the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. She can be reached at dice@fda.hhs.gov.
Daniel P. Fedorko, PhD, is a microbiologist at the FDA’s Diagnostic and Surgical Devices Branch of the Division of Ophthalmic and Ear, Nose and Throat Devices. He can be reached at daniel.fedorko@fda.hhs.gov.
Suzanne Fleiszig, OD, PhD, is a professor of optometry and vision science at the School of Optometry at the University of California, Berkeley, where she also holds appointments in the graduate group in microbiology and the graduate program in infectious disease and immunity. She can be reached at fleiszig@berkeley.edu.
Ralph Stone, PhD, retired from Alcon Laboratories in 2006 and is currently the president of R.P. Stone Consulting. He can be reached at ralphsuestone@prodigy.net.
Loretta Szczotka-Flynn, OD, PhD, is the director of the Contact Lens Service at University Hospitals Case Medical Center in Ohio and a professor of ophthalmology at the CWRU School of Medicine. She can be reached at loretta.szczotka-flynn@uhhospitals.org.
Elmer Y. Tu, MD, is a professor of clinical ophthalmology and the director of cornea service at the University of Illinois Eye and Ear Infirmary. He can be reached at etu@uic.edu.
Mark Willcox, PhD, is the director of research at the School of Optometry and Vision Science at the University of New South Wales in Australia. He can be reached at m.willcox@unsw.edu.au.
Disclosures: Alfonso, Brocious, Callegan, Fedorko and Stone have no relevant financial interests. Dhaliwal receives research funding from Abbott Medical Optics, Avedro and Eleven Biotherapeutics. Eydelman is an employee of the FDA. Fleiszig has been a paid consultant for Allergan and a paid expert panel member for Johnson & Johnson Vision Care in the past year, while Allergan and Alcon have funded research projects undertaken in her laboratory. Szczotka-Flynn receives research funding from Alcon and Vistakon and additional honoraria from Alcon. Tu has an interest in Seattle Genetics. Willcox consults for or receives funding from Allergan, Bausch + Lomb, Cochlear, CooperVision, Johnson & Johnson Vision Care, Minomic International, Ophtec and Warm Contacts.
What strength of solution or killing criteria are acceptably effective against Acanthamoeba?
Most lens care systems cannot deal with Acanthamoeba cysts
Simon Kilvington
Before you can start talking about acceptance criteria, you need to have a standardized method of determining the susceptibility of trophozoites and cysts to these products. Modern contact lens solutions, those based on dual biocidal agents, are pretty effective against trophozoites, and you would exceed one log kill.
You are always going to struggle to kill the cysts, and you just have to accept that most contact lens care systems cannot deal with Acanthamoeba cysts. Stasis is not acceptable because we are saying then it is fine for the cysts to be alive but not existing in contact lens solution. If they are alive and viable, they will hatch out and cause infection.
What will you do about the solutions on the market today that give you less than one log kill? They are used quite successfully, it seems. They are not being implicated in outbreaks of Acanthamoeba or other forms of keratitis, but what will you do about solutions if you start setting acceptance criteria that are currently on the market and would not meet these standards?
Simon Kilvington, PhD, is a senior lecturer associated with the Department of Infection, Immunity & Inflammation at the University of Leicester. Disclosure: Kilvington has no relevant financial disclosures.
Biocidal uptake affects efficacy
Mary Mowery-McKee
We have to be careful that we are not going to damage the cornea. If you increase the concentrations of the microbial agent, you are going to most likely cause damage to the corneal epithelium and then make it even more susceptible to infection because you have already damaged it.
Manal Gabriel has data showing that biocidal uptake with different lenses, with different solutions, does affect efficacy. At the Contact Lens Institute, we developed a method that is now in ISO and it will become a standard at the end of this year, 18259. It is measuring the disinfecting efficacy of a solution in the lens case, with various contact lenses, with a panel of organisms in organic soil — the panel that is in 14729.
[Furthermore], there needs to be a big educational effort so that patients do not abuse their lenses or use water. They have to know that water is a huge risk factor for keratitis, and I would assume from ocular infections that people are not aware of that.
Mary Mowery-McKee, PhD, has worked on development of contact lenses and lens care products for more than 37 years. She is now retired from CIBA Vision and is active in developing standards for disinfection of contact lenses and lens products. Disclosure: Mowery-McKee is a consultant for Alcon.
Editor’s note: Adapted from “Experts support development of efficacy standards for Acanthamoeba testing,” Primary Care Optometry News, December issue, in press.