Fusarium Keratitis: Special Report
This roundtable discussion focused on the events that led to the withdrawal of MoistureLoc from the market.
Joseph T. Barr, OD, MS, FAAO: We're here to discuss recent investigations into the Fusarium keratitis issue and Bausch & Lomb's recent decision to withdraw its lens care product, ReNu with MoistureLoc, as a result of these probes.
Our goal is to gain perspective on some of the circumstances, the investigational outcomes, and the lessons that have been learned from this experience. Joining me on this distinguished panel are:
■ Jack Schaeffer, OD, President, Schaeffer Eye Centers, Birmingham, Ala.
■ Christopher Snyder, OD, professor of optometry and Chief of Contact Lens Patient Care at the University of Alabama at Birmingham.
■ Angela Panzarella, corporate vice president of Bausch & Lomb Global Vision Care, the company's contact lens and lens care division.
■ Praveen Tyle, PhD, corporate senior vice president and chief scientific officer for Bausch & Lomb.
■ Gary Orsborn, OD, director of medical marketing for Bausch & Lomb.
We will start by asking Ms. Panzarella to provide an overview of developments that unfolded in the marketplace. Dr. Tyle will then discuss the scientific aspects of the investigations.
OVERVIEW OF FUSARIUM SOLANI ISSUE
Angela Panzarella: In November 2005, the Ministry of Health officials in Hong Kong contacted us to ask us for information in connection with reports of an increased incidence of contact lens keratitis in their country. Bausch & Lomb's contact lens care products were not disproportionately represented in the case reports. In other words, patients reported using various lens care products, and the number who reported using our products was roughly equivalent to our market share in the region about 40%.
We tested retained samples from Hong Kong and found that they were well within specifications. We provided this information, along with some other requested data, to the Ministry of Health. At that point, the keratitis cases appeared to us to be part of an isolated local outbreak, and no further action was required.
In mid-February 2006, shortly after the Hong Kong cases had been closed, the Singapore Ministry of Health reported to us that it was seeing an unusually high number of Fusarium keratitis cases and that most of the affected patients were using ReNu. Based on inquiries from Singapore, the Health Department in Hong Kong reported that they, too, were now seeing unusual trends in Fusarium infection associated mostly with ReNu. In both markets, ReNu with MoistureLoc was the only ReNu formula sold for the past year. Because of the statistical association with MoistureLoc, we immediately suspended sales of the product in both Hong Kong and Singapore.
We started a massive investigation involving thousands of tests of the product and our manufacturing facilities. None of those tests revealed evidence that the product was contaminated or ineffective against the Fusarium solani fungus when used under normal conditions.
THE FDA AND THE CDC ENTER THE PICTURE
While investigating these cases, we maintained regular contact with regulatory authorities around the world, including the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control (CDC). We also reached out to major eyecare centers across the globe, as well as to leading experts in the field of fungus and corneal infections. One of our goals was to determine if unusual trends in fungal keratitis had developed in other countries.
This was a challenge because we were working primarily with anecdotal reports, not solid epidemiological data. Our other challenge, working within the Health Insurance Portability and Accountability Act (HIPAA), was getting access to U.S. patient information quickly. As a result, the CDC's involvement was very helpful in gaining speedy access to patient information. On April 10, the CDC reported it was investigating about 100 suspected cases of Fusarium keratitis in the United States. Of the confirmed cases, most reported using MoistureLoc.
While we had initially suspected the outbreak might be a local phenomenon associated with the tropical conditions in Hong Kong and Singapore, it now appeared there might be an association with the manufacturing facility in Greenville, the facility that had supplied MoistureLoc to the United States, as well as Singapore and Hong Kong.
We immediately suspended worldwide sales of ReNu with MoistureLoc produced at our facility in Greenville, S.C. A few days later, we asked retailers to remove the product from store shelves and asked patients to stop using the product.
At this point, I will turn the discussion over to Dr. Tyle, who can provide a thorough review of the scientific aspects of our overall investigation and its conclusion.
ANTIMICROBIAL EFFICACY STUDIES
Praveen Tyle, PhD: We were puzzled because MoistureLoc had been shown to perform very well against Fusarium solani. In comparative antimicrobial efficacy studies published when Bausch & Lomb launched the solution, MoistureLoc demonstrated a 4 log reduction for fungus (Fusarium solani) and yeast (Candida albicans), well beyond the 1 log reduction required by the International Organization for Standardization (ISO).
You may recall from CDC reports and scientific literature, the risk of developing, any type of microbial keratitis is approximately 4/10,000 in daily soft lens wear and approximately 21/10,000 for extended soft lens wear, or a five times greater relative risk. The reported Fusarium keratitis infection rate associated with the use of MoistureLoc solution is extremely low, 2/1,000,000 units sold (1,000 times fewer) or less then 5/1,000,000 soft contact lens users (400 times fewer) compared to extended soft lens wearers.
This very low incidence rate made a single cause and effect for the infections very unlikely, and it also made the design of experiments a significant challenge. Nonetheless, we carefully studied multivariate circumstances with concurrent investigations.
One of our inquiries focused on Bausch & Lomb's manufacturing facility in Greenville, S.C., which supplied MoistureLoc to the three countries where Fusarium keratitis had been first reported. The FDA and the CDC conducted environmental monitoring of sterile and nonsterile areas at the plant and found no Fusarium solani. We examined all records and conducted risk analyses and uncovered no potential causes for lots associated with the infections.
We also analyzed the process used in manufacturing MoistureLoc, and we identified no significant differences between the facility in Greenville and our plant in Milan, Italy, where MoistureLoc was being manufactured for other European markets where we had not seen unusual increases in Fusarium keratitis cases.
We compiled a database of more than 500 lots of ReNu with MoistureLoc to determine if common ingredients or manufacturing equipment were associated with complaints. We found no evidence of sterility failure, contamination, tampering or counterfeiting for any products shipped from Greenville.
We worked with a Fusarium solani genetics expert at a major university to identify and genotype isolates sent to us from ophthalmologists and health authorities. He concluded the following:
1) The isolates from the keratitis infections were typical of Fusarium found in bathroom drains and sinks.
2) The Fusarium solani strains we had been provided were not of the same origin (appearing to rule out contamination from a single source).
In addition, results of all microbiology testing including ISO/FDA Stand-alone Biocidal Efficacy tests and real-use clinical testing with worn lenses demonstrated that MoistureLoc was highly efficacious against the standard reference American Type Culture Collection (ATCC) and the recovered clinical isolate strains of Fusarium solani.
■ No issue at the Greenville manufacturing facility
■ No contamination or failure of the MoistureLoc product as it was delivered to the market
■ Not a single or exotic strain of Fusarium solani associated with the infections
■ No significant differences in process and components between the two MoistureLoc manufacturing facilities.
People have speculated about possible causes of the Fusarium keratitis. Below are questions that we answered with our research.
■ Did the active disinfecting agent in MoistureLoc easily sequester into a contact lens, rendering the solution biocidally ineffective?
Previously worn soft lenses (FDA Group IV) were inoculated with approximately 1 million CFUs of Fusarium solani, rinsed with MoistureLoc, and placed in the solution for 4 hours, as indicated by the product label. Results of testing and recovery demonstrated that the lenses and the MoistureLoc soaking solution passed the acceptance criteria required in ISO/FDA regimen testing.
Patients in a separate study were asked to process their lenses (Group IV) under normal circumstances using ReNu with MoistureLoc and other multipurpose solutions for 3 days. Lenses were then inoculated with a clinical isolate of Fusarium solani that had been sent to us from one of these keratitis cases. Results showed a 4-log reduction for Fusarium solani for ReNu with MoistureLoc solution, far exceeding efficacy standards.
■ Did MoistureLoc contain ingredients, such as Polyquaternium 10 (Polymer JR), that supported the growth of microorganisms based on the ingredients' cellulose moiety?
We evaluated each component of ReNu with MoistureLoc, including the active disinfecting agent, alexidine. These formulations demonstrated greater than 4-log reduction when challenged with Fusarium solani, as measured by the ISO/FDA Stand-alone Biocidal Efficacy test.
We also evaluated 21 formulations
of individual components of MoistureLoc, or combinations of key components, and
inoculated these without alexidine. In 19 of 21 cases, samples demonstrated no increase
in Fusarium solani after 28 days of incubation. In fact, many samples, including
Polyquaternium 10 (Polymer JR), caused a decrease in the number of Fusarium colony
forming units, definitively refuting the belief that Polyqua-
ternium 10 (Polymer JR) might promote the growth of Fusarium solani.
■ Could MoistureLoc be associated with increased risk of infection when it was subjected to stressful conditions?
We focused on Polyquaternium 10 (Polymer JR), Tetronic and Pluronic F127, which give the product the highest level of polymers of any major lens care product. These unique ingredients also included alexidine, the new disinfecting agent. At extremely high temperatures and humidity levels, the solution was found to be biocidally efficacious and passed ISO requirements for a disinfecting solution.
NONCOMPLIANCE A FACTOR?
Another key question for us was whether ReNu with MoistureLoc increased risk of infection among patients who did not comply with their prescribed care regimens.
Our analysis of used lens cases from patients who had been infected showed that the cases were contaminated, dirty and, in some cases, cracked. We also saw dirty and contaminated caps and tips from returned bottles. Finally, we had learned that many patients were topping off their solutions. We attempted to replicate the possible impact of some of these noncompliant habits in the laboratory, including poor hand-washing or rinsing, not cleaning or replacing lens cases regularly, leaving bottles open, and leaving filled lens cases open.
By reducing the water content in MoistureLoc to 2x and 4x concentrations, we attempted to simulate the evaporative effects of a lens case being left open or a bottle being exposed to air from an open cap. We tested all components, including the disinfectant, using the ISO/FDA Stand-alone Biocidal Efficacy test. ReNu with MoistureLoc demonstrated a significant loss in efficacy against Fusarium solani that was not evident in identical tests of MultiPlus.
The results showed that MoistureLoc was apparently more sensitive to concentration effects due to evaporation under certain noncompliance practices by lens wearers. A reduction of disinfecting ability identified in the test may have been caused by micelle or film formation due to the higher concentration of polymers in MoistureLoc.
EXTREME CONDITIONS TESTING
The next question was whether the polymer film left on a lens case from evaporation or residue buildup could support or protect Fusarium solani. We added an inoculum of Fusarium solani to MoistureLoc (without the disinfecting active ingredient alexidine) and allowed the product to dry, creating a polymer film containing Fusarium solani. When dry, the lens case was challenged with different strengths of MoistureLoc and checked for viable Fusarium solani after 4 hours.
The ATCC strain did not recover from being dried with the MoistureLoc excipients in the lens cases. It did not recover from subsequent reconstitutions of MoistureLoc that contained 0%, 25%, 50% and 100% (full strength) alexidine. However, a New Jersey patient's Fusarium solani isolate did survive being dried down with the MoistureLoc excipient in the lens case. The isolate was recovered after it was exposed to the solution at full strength, 50% strength, 25% strength, and with a placebo. We also found that the number of colonies of Fusarium solani increased as the concentration of alexidine decreased.
MultiPlus, meanwhile, performed well against both strains and did not show viable Fusarium solani in the product film. Additional laboratory testing has tended to confirm differences in how MoistureLoc and MultiPlus function under simulated noncompliance situations.
We now believe that multiple factors, which may have converged in unusual circumstances, could have allowed some ReNu with MoistureLoc users to contract Fusarium keratitis. Below, in summary, are some of the key factors:
■ Noncompliant reuse and topping off of solution in the lens case result in some loss of disinfecting efficacy of the formulation. Evaporation/concentration of ReNu with MoistureLoc can result in a reduction of biocidal efficacy which could develop when lens cases were left open.
■ Other noncompliant behaviors, which were inconsistent with package instructions, are known to have occurred and to have been associated with the infections.
■ Fusarium solani needs
to be present in the environment, as confirmed by a Fusarium solani
expert. Fusarium solani can adapt and be protected by polymer films on the surfaces of lens cases and bottle tips as well as in the solution.
■ Overall, the formulation was found to show reduced efficacy as the concentration of all components, including the total polymer package (used to promote comfort of contact lens wear), increases with evaporation.
Although the ReNu with MoistureLoc formulation still met every regulatory criterion for safety and effectiveness, and no Fusarium solani contamination had been found in our manufacturing facility, Bausch & Lomb's inquiry focused on whether there was an aspect of this formulation that, in combination with noncompliant usage, could put lens wearers at greater risk of contracting a Fusarium solani infection.
RENU MULTIPLUS AND MULTI-PURPOSE SOLUTIONS
It is important to note that the CDC has determined MoistureLoc is the only multipurpose solution to have a significant association with Fusarium keratitis in contact lens wearers. ReNu MultiPlus and the original Multi-Purpose solutions have not been implicated because they are not disproportionately represented in the case reports.
These solutions, which are completely different from MoistureLoc, have replaced MoistureLoc in starter packs and on store shelves. They have been longtime consumer favorites (MultiPlus since 1997 and Multi-Purpose Solution since 1987) and also have unsurpassed records of safety and effectiveness. In fact, more than 30 million consumers have used ReNu MultiPlus since it was introduced in 1997. Each formula offers unsurpassed biocidal efficacy against the full range of ocular pathogens, including Fusarium solani, as required in the ISO/FDA Stand-alone Biocidal Efficacy test.
In addition, MultiPlus has been shown to be highly effective in extreme testing conditions, such as the evaporation and the polymer film studies conducted as part of our investigations. There are no unusual trends in Fusarium solani infections in markets where only ReNu MultiPlus and Multi-Purpose solutions are sold, including Canada, Japan and Taiwan.
In Japan, three times the number of consumers use ReNu MultiPlus as those who were using MoistureLoc in Hong Kong and Singapore. Yet not one case of Fusarium keratitis has been reported. This is significant because the medical monitoring and reporting systems in these three countries are among the most vigilant in the world.
We have also conducted studies using ReNu MultiPlus to show effective mean log reduction in ISO/FDA Stand-alone Biocidal Efficacy testing against 54 clinical isolates of Fusarium solani species, including clinical isolates known to have caused some of the recent keratitis cases.