By Bruce Flickinger
Although the outbreak last month of contact lens-related Fusarium keratitis bore the initial markings of a manufacturing-related contamination problem, government and industry officials involved with the investigation are close to fingering a combination of product factors in the field as the likely cause.
Following reports in February that clusters of F. keratitis had appeared among contact lens wearers in Singapore, Hong Kong, and Malaysia, similar infections began surfacing in the US. In early May, the CDC reported 122 confirmed cases of fungal keratitis in 17 different states, roughly two-thirds of which involved Bausch & Lomb’s ReNu® with MoistureLoc® solution from multiple product lots originating from the company’s Greenville, South Carolina, manufacturing plant. This prompted concerns about a direct link between the product and the infections. Bausch & Lomb, headquartered in Rochester, New York, voluntarily suspended new shipments of ReNu with MoistureLoc, and the FDA initiated a full investigation of the facility. The company has since issued a worldwide recall of the product.
“The FDA’s inspectors are very adept at finding contamination in manufacturing plants, but they’ve been at [the Greenville plant] for over four weeks, and they haven’t found anything,” says Arthur Epstein, OD, chair of the Contact Lens and Cornea Section of the American Optometric Association (AOA). “This tells us that the likelihood of contamination originating at plant is bordering on impossible and it is most likely occurring in the field.”
While the FDA and Bausch & Lomb declined to comment while the investigation is ongoing, they appear to be heading toward the same conclusion. Environmental testing at the Greenville plant has confirmed that the facility is in compliance with good manufacturing practices and tested product lots are within sterility specifications, Bausch & Lomb reported. Company President and CEO Ron Zarella said in a prepared statement that company and government scientists had looked at more than 100 possible factors, including chemical ingredients, batch tanks, production lines, and packaging and shipping procedures, and “through all of that analysis, we haven’t found a correlation with anything.”
So why are there an inordinate number of infections associated with a particular product from a particular manufacturing site? “This is the case of unanticipated elements coming into play,” Epstein says. “It’s a combination of factors that have created a complex, unprecedented, and unfortunate situation.”
By Epstein’s estimation, two likely causative factors have emerged from the growing body of information about the outbreak: the absorption of disinfectant agents into soft contact lenses that reduces their effectiveness over time, and new polymer materials used in the ReNu with MoistureLoc solution that not only compromise the inhibition of microbial growth, but might possibly foster it once organisms have gained a foothold. Both of these factors are exacerbated by poor handling and storage practices by end users.
Eyeing possibilities
Contact lens solutions are complex entities, Epstein says, comprising both disinfecting and moisturizing agents that directly contact one of the body’s most sensitive organs and which have to retain their functionality under variable handling and storage conditions once in the wearer’s hands. Research from the past several years is painting a picture of how disinfection agents commonly used in solutions, including ReNu with MoistureLoc, “absorb into lenses at such high rate that they become ineffective,” Epstein says. Papers presented at last year’s Contact Lens and Eyecare Symposium (CLES) and in April at the Association for Research in Vision and Ophthalmology (ARVO) meeting most recently have added to the understanding of this phenomenon.
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In particular, small molecules such as alexidine, a biguanide disinfectant used in ReNu with MoistureLoc, might be more prone to adsorb out of the solution and into the lens. “So, D-values fall off precipitously,” Epstein says. “And because Fusarium is difficult to kill in terms of time required, the environment becomes selective for Fusarium to survive.”
Additionally, polyquaternium 10, one of the “new-generation” moisturizing and conditioning agents in ReNu with MoistureLoc, is a naturally occurring cellulosic backbone that “theoretically can act as fungus food,” Epstein says. “So the organisms not only survive, they begin to grow. After a while, the growth rate exceeds the kill rate significantly.”
Contact lenses and their disinfection and storage solutions are subject to two types of testing. One is a Regimen Test, which assays antimicrobial activity after a prescribed rubbing, rinsing, and storage protocol. This largely has been superseded by the second, the Stand Alone test, introduced in 1997 with the advent of FDA’s 510(k) Guidance Document for Contact Lens Care Products and ISO/DIS 14729 Contact Lens Care Products Microbiological Requirements and Test Methods for Products and Regimens for Hygienic Management of Contact Lenses.
In the Stand Alone test, a specified amount of solution is inoculated with challenge organisms, and microbial kill activity is measured over time (D-value). Challenge organisms include three Gram-positive bacteria, Staphylococcus aureus, Serratia marcescens, and Pseudomonas aeruginosa, and two fungi, Fusarium solani and Candida albicans. The sum of the average log reductions for the three bacteria must be equal to or greater than 5.0 logs within the recommended soaking period, and a minimum average log reduction of 1.0 log must be obtained for any single bacterium. Stasis must be observed for yeast and mold.
Epstein says a further compounding factor could be involved in the current outbreak: When the lens is inserted into the eye, the disinfectant releases from the lens, causing chemical trauma that disrupts the cornea and creates a portal for infection. The lens also covers the cornea, blocking the body’s natural defense mechanisms from getting to the site of infection and creating conditions even more conducive to growth of the offending organisms.
“This is an unfortunate but valuable lesson for our industry,” Epstein says. “The AOA, CDC, and FDA are committed to figuring out exactly what has occurred in these outbreaks. The answers will benefit the entire contact lens manufacturing industry.”