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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 optometry and ophthalmology 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.
This first part of our two-part special report on the workshop proceedings will address the participants’ discussion on emerging pathogens in keratitis and the components of an organic soil model of ocular tear film.
Workshop participants recommended the addition of Acanthamoeba to the current panel of
test pathogens.
Image: Tu E
“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 day-long 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.
“Today, we’re taking the next step,” she continued. “We’re hoping to try to predict what will cause the next contact lens-related outbreak.”
Emerging pathogens in contact lens keratitis
The current preclinical test methods for contact lenses and care products include the stand-alone 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. If the product passes the primary criteria of the stand-alone test, it is accepted, if not, it must pass the secondary criteria and the regimen test.
Brocious also noted that current test methods are limited because they do not evaluate other bacteria or fungal organisms, solutions with organic soil or Acanthamoeba, and they should not include viruses.
He suggested that the workshop participants analyze the current panel of organisms and the inclusion of organic soil and develop a disinfection efficacy testing method for Acanthamoeba.
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.
Loretta Szczotka-Flynn
Eduardo Alfonso
“It will be impossible to test against all pathogens in the microbial world,” Eduardo Alfonso, MD, said in the discussion. “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,” he said, “and I would encourage us to keep Serratia as well. 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.”
Fleszig noted that the bacteria can change during processing, even before they are entered into the ATCC system.
Elmer Tu, MD, expressed 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 also asked the panelists whether or not viruses should be added to the panel.
“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 agreed. “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 acknowledged. “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 has noted that some testing processes are both 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 explained.
“It’s going to be very difficult to make something work with a biofilm and not kill the eye,” Willcox added. “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 recommended.
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 – as Pseudomonas is “the most common problem when infections occur during contact lens wear, and either strain type can be involved.”
The majority of the other 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, as that 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.
Organic soil model of ocular tear film
The FDA recommends the use of organic soil for a regimen test, which includes heat-killed Saccharomyces cerevisiae and heat-inactivated bovine serum albumin, according to Lt. Cmdr. Scott Steffen, PhD. However, he noted that the ISO 14729 standard does not require this.
Steffen presented recommendations for the preparation and inoculation of organic soil, but acknowledged the limitations of the current methods, stating that there are numerous soil recipes and they may not represent real-world conditions.
Additionally, their effectiveness can be affected by test type, the order of addition, the recipe and components of the test. Steffen encouraged the panel to consider the appropriate composition of organic soil, in terms of its similarity to natural tears, its reproducibility and its universal acceptance.
“We have the potential for a new dimension in terms of assessing efficacy of the disinfecting systems, and it’s important, but difficult,” moderator Michael Dueñas, OD, said as he addressed the second panel. “There’s no standardization, and the soil recipes, while quite intoxicating, all have different properties that are both advantageous and not advantageous. The ability to come to consensus is needed if we’re going to actually create this new dimension. The other problem is that we need to make sure that it’s reproducible.”
Callegan acknowledged the implausibility of leaving the workshop with a clear answer, but also the need for a real-world scenario.
“The recipe right now for the heat-inactivated serum and the heat inactivated yeast is not real world,” she said. “We know that artificial tears are going to influence disinfection efficacy, and this is moving us a bit closer to this real-world standard that we would like to have.”
Fleiszig had several recommendations based on observations she has made in her lab.
“If you expose Pseudomonas – and it’s likely to be true for other bacteria, too – to tear fluid, it actually changes gene expression in the bacteria including genes that are involved in resistance to killing,” she said. “It would be good to have a method that incorporates a longer exposure of the microbe to the tear fluid or organic soil, whatever that happens to be, before the testing to take into account how that organic soil impacts the microbe and not just how it impacts the disinfectant.
Carol Lakkis, BScOptom, PhD, PGCertOcTher, FAAO, FACO, FBCLA, agreed with the need for more clinically relevant testing conditions, but admitted that it will be a challenge to develop a suitable organic soil model to mimic the tear film.
“There are a lot of different ways you can make organic soil,” she said, “and I think part of the challenge, in the past and ongoing, is going to be reaching consensus on how we actually want to standardize it.
“The type of soil that you use will depend on what the question is,” she continued. “Are we actually interested in understanding cleaning or are we more interested in what effect it has on disinfection?”
Ralph Stone, PhD, focused on disinfection efficacy testing.
“Very low numbers of organisms are on a contact lens when you take it out of the eye,” he said. “We handle them with our hands, so we add organic load from our hands, as well as from the tears. The combination of materials in there are much more complex than a simple tear model.”
He also stressed that whatever standard was decided upon must be able to be sterilized.
“The soil we have today is reasonably easy to sterilize,” Stone said. “It’s more complex as we try to make these systems any more real world and make them even more complex. It is going to be very difficult, if not impossible, to sterilize and maintain the composition of the material.
“In terms of disinfection, I just want to be clear,” he said later in the panel. “I’m not in the camp of making a change in the base standard. Additional standards should be considered. I’m not so convinced we need a change in the composition of the organic soil.”
His opinion was not shared by the other panelists, who reiterated that a clear definition is necessary for future research.
“I agree with Carol that every step should be clearly defined,” Fleiszig said. “Where you don’t have the step clearly defined, people are going to do whatever is going to work the best for their system. And then you don’t have standardization.”
She cautioned that it would be unrealistic to set concrete standards at the meeting and that there are different facets of the situation that need to be thoroughly thought through before arriving at a clear consensus.
Malvina Eydelman
Eydelman then brought up the question of whether or not organic soil should be used in both regimen and standalone testing, which is not the current ISO standard.
The panelists acknowledged that it was always an option and had no issue with using organic soil in both.
The panelists were also asked if using a standardized soil for both cleaning and disinfection made the most sense, as the industry would want a single solution to work in the same environment for both.
“In an ideal world, I agree it would be great to have the same for both,” Lakkis responded. “The artificial tear fluids where you have all the different proteins, lipids and tear components are very complex, they are very expensive and they are very hard to standardize.
“If we’re really just talking about disinfection efficacy testing, if there’s a simpler way to do it that still gives you the same answer, that’s what I would try to do,” she continued. “If there’s not and we have to do something more complex, then that would be the second approach.”
Stone stated that he has found patient-worn lenses the best to use when researching cleaning efficacy.
“When we try to develop models, we’re always making compromises,” he said. “My advice to everybody is to use real-world, human-worn lenses for cleaning.”
He also recommended that sample sizes be robust enough to account for the dissimilarities among patients.
Lyndon Jones
Lyndon Jones, BSc, PhD, FCOptom, DipCLP, DipOrth, FAAO, FIACLE, gave his own recommendations based on work he has done in his lab at the University of Waterloo developing artificial tear models.
“This is not easy,” he said. “I would urge extreme caution. Please make the tear film surrogate as simple as possible, because reproducibility is so difficult whenever you change any of the included components. It’s also extraordinarily expensive, and the ability to sterilize the artificial tear component is virtually impossible.”
Jones said his lab has also spent much time on cleaning efficacy.
“It’s difficult to standardize,” he said. “An artificial tear model for looking at disinfection efficacy and a model for looking at cleaning have to be different. I cannot see how they could possibly be the same.”
Dueñas summarized the discussion: “[Soil] is an important dimension that needs to be included in order to understand the true efficacy of the disinfectant solutions. The methodology currently being used by the FDA could be tweaked in a number of different ways.
“That’s going to take bringing people together and building consensus,” he continued, “in a way to develop a soil model that will not mimic the tear film exactly, but closely enough to better enable the disinfectant systems to be safe and efficacious for the population using them.”
See part 2 of this report in the December issue of Primary Care Optometry News, which will address disinfection efficacy test methods for Acanthamoeba. – by Chelsea Frajerman
For more information:
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 and 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.
Michael Dueñas, OD, is the chief public health officer for the American Optometric Association. He can be reached at mduenas@aoa.org.
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.
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.
Lyndon Jones, BSc, PhD, FCOptom, DipCLP, DipOrth, FAAO, FIACLE, is a professor at the University of Waterloo and director of the Centre for Contact Lens Research. He can be reached at lwjones@uwaterloo.ca.
Carol Lakkis, BScOptom, PhD, PGCertOcTher, FAAO, FACO, FBCLA, is a clinical research fellow and biological sciences leader at Johnson & Johnson Vision Care Inc. She can be reached at clakkis@its.jnj.com.
Lt. Cmdr. Scott Steffen, PhD, is a microbiologist in the Contact Lenses and Retinal Devices Branch in the Division of Ophthalmic and Ear, Nose, and Throat Devices in the FDA’s Center for Devices and Radiological Health. He can be reached at DICE@fda.hhs.gov.
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.