Has Claude Anger’s May 2008 Literature Review Strengthened AMO’s Defense?

Armand Rossetti

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In the May edition of Eye & Contact Lens 34(5): 247-253, 2008 entitled, “Acanthamoeba: A Review of Its Potential to Cause Keratitis, Current Lens Care Solution Disinfection Standards and Methodologies, and Strategies to Reduce Patient Risk” (abstract linked here), authors Anger and Lally present a comprehensive assessment of the lack of standardization with respect to Acanthamoeba efficacy testing.

In reading the Anger paper, the first thing that comes to mind is whether AMO might use the paper as an opportunity to buttress their defense; i.e., that because there is no standardized Acanthamoeba testing, all results are suspect. Here are some reasons why it is not likely that AMO will be able to use lack of standardized Acanthamoeba testing as a defense.

Those of us who are somewhat familiar with the FDA required 510(k) process know that manufacturers must satisfy certain standards before the FDA grants marketing approval for contact lens or multipurpose contact lens solutions. And Acanthamoeba has never been one of the challenge organisms required for challenge testing to meet FDA requirements.

In a Presentation to the FDA Advisory Panel on Contact Lens Care Solutions, Dr. Louise Scalfani, et al. have outlined a host of additional considerations the FDA should review and possibly adopt in order to strengthen the FDA guidance document for pre-market testing.

Those considerations include:

• Testing solutions under more realistic conditions;

• Testing under known conditions of intractable non-compliance

• Improving labeling

• Assessing the pathogenicity of challenge organisms

• Using more resistant standardized challenge organisms

• Testing with Rub and Rinse Regimen on demand increased ‘cidal activity

• Testing with organic soil and /or biofilm

• Testing with actual lens and case materials to determine activity and toxicity

• Using less time-consuming, expensive or laborious directions

• Addressing patient’s who don’t or won’t follow directions

• Addressing patients who do not wash their hands

• Compensating for topping off solutions in use

• Considering the pitfalls of no rub n o rinse regimens

• Addressing the use of dirty lens cases, and

• Addressing the effect of solution evaporation

While the Anger paper may probably be one of the best reviews on the subject of the need for standardized Acanthamoeba testing, the concept of “standardized” remains illusive. Therefore, AMO will gain nothing from trying to use the Angus paper as an addition to its defense armamentarium. Here are some interesting quotes from Mr. Angus' paper juxtaposed with observations from Dr. Scalfani:

Mr.Anger:

"Contact lens storage cases are often colonized with Acanthamoeba, regardless of whether the user develops infection."

Dr. Scalfani:

“[W]e are asking the FDA to test the products under those situations of intractable non-compliance such as poor hand washing and dirty cases. Some recent work by Phillip Morgan at the University of Manchester may shed some light on the potential for improvement.”

"Differences in these parameters [Acanthamoeba testing] may significantly affect the level of antimicrobial resistance of the resulting cells, thus, these parameters require standardization.

Mr. Anger

"Differences in these parameters [Acanthamoeba testing] may significantly affect the level of antimicrobial resistance of the resulting cells, thus, these parameters require standardization."

Dr. Scalfani:

“The use of the American Type Culture Collection (which tests for ATTC= PA, SA, Serratia, Candida, Fusarium) isolates is limited and needs to be updated as the strains have become overused and new ones begin to prevail. Based on climate and resistance, the common may become less common. In fact, Serratia is becoming a more prevalent pathogen for contact lens induced microbial keratitis in countries such as Australia. We know that Acanthamoeba Keratitis may be uncommon, but given that more than 90% of AK infections are in contact lens wearers, to our patient population it is significant. We know it is difficult to kill the cyst form and that there are many variations in how these organisms are cultured. We feel that a more standardized testing process should be developed and used by the FDA, prior to approval, as well as to compare efficacy between products so that a practitioner can make better judgments when prescribing solutions.”

Therefore, scientists have to address standardization across the entire spectrum of all challenge test organisms, including Acanthamoeba.

Mr. Anger:

"Recently, Beattie et al. performed the same test on Complete Moisture Plus after it was withdrawn from the market and found it to demonstrate a trophozoite reduction of 3.0 logs in 4 hr contact and a cyst reduction of 0.6 log at 4 hr and 2.0 logs at 24 hr contact. This activity was considered an increase in efficacy compared with other tested Multi Purpose Solution containing 0.0001% PHMB."

Dr. Scalfani:

“The ‘cidal activity could be tested utilizing in-vitro organic soil to better simulate those conditions in which microorganisms have a potential food source. As we have seen with some recalled solutions, the ingredients may have contributed to proliferation of microorganisms because they had a source of nutrition. This should be part of standardized testing. The creation of a biofilm on the lens case and bottles also contributes to contamination, increased virulence, and reduced bioavailability of the ‘cidal agent. The ability to simulate these conditions and test the efficacy of these solutions under these conditions could become standard. In addition, there are trends emerging in anti-microbial technology using silver, furanones, selenium and cationic peptides as coatings or composite materials in lenses, cases or solution bottles. As these novel products come to market, they should be re-tested with the intended solution and labeling should reflect if compatibility has been achieved. Hence, we are hopeful that the microbial issues of today will be made inconsequential by new technologies of the future.”

Dr. Scalfani’s suggestions point to a need for more “real world” testing conditions, and a need to test as many variables as possible, whether they are anticipated or unanticipated.

Mr. Anger:

"Acanthamoeba is a highly prevalent organism in the environment, and once introduced into the eye carries a small but significant risk for ocular infection in wearers of SCLs (soft contact lenses) who are at risk because of either direct ocular injury or trauma, or contact lens wear."

Dr. Scalfani:

“It has become apparent that the materials to which the solution will be exposed—the actual lens and case—is another area of concern. Recent studies by industry and practitioner experience have shown that undesired effects from poor lens/solution combinations can occur just as medications have poor drug interactions. One area that is currently being investigated is the amount of solution that is being absorbed by the contact lens or case thereby reducing the availability of the biocide.

Toxicity due to lens uptake of solution and changes in lens parameters are two other possible effects and we are requesting testing of preservative uptakes. This information should be available to the practitioner so that they can make the appropriate choices for patients.”

In conclusion, since the entire spectrum of challenge testing needs revision, lack of standardization for Acanthamoeba testing, by itself, presents no new defense for AMO. The key to efficacy and safety has always been and probably should remain longer term clinical testing using larger populations. This is especially true when the FDA and manufacturers, alike, were aware of the lack of standardization regarding challenge testing.