Changes Loom for Scientists Working with Antibacterials

Moms, doctors, and researchers all agree that good hygiene practices such as washing your hands and keeping a clean household are the best guards against many diseases. Disinfectants, soap, and water remain the old standbys for keeping homes and hands clean. However, antibacterial compounds added to dishwashing detergents, lotions, and even fabric have taken the marketplace by storm. Although many scientists in industry believe these products give consumers an added edge against bacteria and other pathogens, some researchers are concerned that widespread use is unnecessary in the home and could render these products--and even antibiotics--ineffective in settings where they're needed most. BOTTOMS UP: Microban's impregnated plastic retains antibacterial properties through the lifetime of the product. When particles on the surface of an article are removed through abrasion, antibacterial compounds quickly migrate up to the surface to replace them. However, recent actions by the U.S. Environmental Protection Agency have put this home health revolution temporarily on hold. In April, the agency issued a draft of revised regulations that could significantly change registration procedures and testing methods for many products treated with antibacterials. EPA drafted clarifications of regulations in response to the growing presence in the marketplace of unregistered "treated articles" claiming to protect consumers from disease-causing bacteria, according to Walter C. Francis, a senior advisor in the antimicrobials division of EPA's pesticide program. Under the Federal Insecticide, Fungicide, and Rodenticide Act, EPA gained the authority to regulate products containing a pesticide or antimicrobial. But under a 10-year-old rule EPA limited its reach by not requiring registration of a product treated with compounds for the sole purpose of protecting the product itself. For example, railroad ties treated with creosote are exempt from registration. "What we've seen over the last two years is that this exemption, which was for materials preservation only, has been utilized by a number of companies promoting antibacterial-treated products with various health benefits associated with the treated article," Francis says. "The need for clarifications has become apparent. It's gone wild out there in the marketplace in terms of the number of products using the treated article exemption well beyond anything the authors of the law intended." EPA efforts to strengthen the law come just about a year after the agency began a series of enforcement actions against some manufacturers and marketers of products treated with antibacterials. For example, EPA forced Hasbro Inc., Pawtucket, R.I., to stop making health claims in connection with a line of toys made from plastic impregnated with an antibacterial compound. The agency brought similar enforcement actions against Minnesota Mining and Manufacturing (3M), St. Paul, Minn., for its antibacterial sponge, and EKCO Housewares Inc., Franklin Park, Ill., for its line of sponges and plastic cutting boards. Hasbro decided to discontinue its line of products made from impregnated plastics in April. Under the revised EPA rules, products incorporating antimicrobials for aesthetic purposes, such as the preservation of the product's appearance or the prevention of odors from the product, no longer will be eligible for exemption. The EPA draft document notes that the benefit of such antimicrobial uses is directed primarily at consumers rather than at the product itself. Articles containing additives intended to protect against microbiological organisms that cause degradation or spoilage will still be exempt from registration. As always, EPA will require the registration and submission of efficacy data for products containing compounds directed at pathogens such as Salmonella or E. coli. James C. Wright, a Manassas, Va., attorney who specializes in regulatory issues related to the use of antimicrobials and pesticides, says the EPA revision to require registration of products making aesthetic claims is surprising, but it could stimulate high demand for laboratories capable of providing testing services. In the past, EPA extended exemption to companies making aesthetic claims such as the prevention of odor and discoloration of the product, he notes. "But there have been so many abuses of the exemption that EPA has found that it is necessary to no longer permit exemption for these kinds of claims," Wright explains. "The prime motive behind this revision was that some aesthetic claims implicitly, if not explicitly, led consumers to believe that there was a public health benefit derived from the product. The agency may eventually back down on this provision, but I think [EPA officials] have made it clear that they want to prohibit all aesthetic claims for unregistered products to avoid any suggestive labeling language." Labeling of treated products has been a major issue at EPA, and new regulations reflect those concerns. An "article" that may come in contact with food must have a label that warns consumers that the product does not protect against foodborne disease, and normal sanitary measures are still necessary to help prevent illness, according to the draft document. Similar warnings must be given for products such as bedpans and sheets, where contact with human bodily fluids is possible. Additionally, manufacturers and marketers are prohibited from using terms such as "antibacterial" and "germicidal," which tend to imply public health benefits to consumers. YOUTHFUL INSIGHT: As a high school student, Merri C. Moken, now a freshman at Princeton, demonstrated that disinfectants could induce resistance to antibiotics in bacteria. To many young scientists, the prospects for making a significant discovery are dim. Years of specialized study, expensive laboratory equipment, and the backing of big grants seem to be prerequisites in the process of discovery. But to Merri C. Moken, a freshman at Princeton University, good science requires only an inquisitive mind and lots of tenacity. At the age of 13, she began a high school science project that would lead to a published paper and significant insight on how bacteria acquire resistance to disinfectants and antibiotics. Moken wanted to measure the efficacy of various household disinfectants against bacteria. The science project grew when she observed bacteria colonies growing on dishes treated with pine oil. Moken hypothesized that the resistant bacteria were solicited by the disinfectant. She then proved that the multiple antibiotic resistance, or mar, gene was expressed in the mutant bacteria and that the gene was turned on by the disinfectant. The study then was duplicated by Tufts University microbiologists Laura M. McMurry and Stuart B. Levy and reported last December (M.C. Moken et al., Antimicrobial Agents and Chemotherapy, 41[12]: 2770-2, 1997) Moken says the study has significance for both consumers and manufacturers of disinfectants and other antimicrobials. "The study shows that antibiotics are not the only thing that can cause resistance to develop," she explains. "While people think they're helping themselves by using disinfectants, the study shows that they actually can do harm by creating disinfectant and antibiotic-resistant bacteria." Other researchers caution that the results of the study have to be carefully interpreted. Elias Shaheen, product leader for microbiology at Oakland, Calif.-based Clorox Co., explains that resistance typically is induced using significantly diluted concentrations of pine oil. For example, in a study led by William A. Rutala, an investigator in the division of infectious diseases at the University of North Carolina School of Medicine, antibiotic-resistant bacteria were induced using concentrations of disinfectant under 15 parts per million (ppm) (W.A. Rutala et al., Infection Control and Hospital Epidemiology, 18[6]:417-21, 1997). Concentrations in normal use range from 400 ppm to 500 ppm. The research team concluded that disinfection and housekeeping practices at hospitals did not need to be changed. "In contrast to Moken's study, much higher concentrations of the disinfectant are normally used in the household and, therefore, make the development of resistant strains extremely unlikely," Shaheen says. "But the study certainly highlights the need to use disinfectant products properly."--SPH Wright, however, notes that the new rules are far from perfect, and revisions and challenges can be expected. For example, EPA does express the intent to regulate products making aesthetic claims, but it has not specified what data will be required to establish efficacy. "Many companies have stated a desire to provide data supporting their efficacy claims, but the agency does not know what kind of specific studies it will require from them," Wright says. "This has put a lot of companies who want to work with EPA in an awkward position because [the companies] don't know what they need to do to stay legal." He also notes that by definition, imported articles treated with antimicrobials made outside the United States will be unregistered and illegal. "The regulation makes it almost impossible for companies engaged in offshore production to sell their goods in the United States," Wright says. Foreign products are put at a competitive disadvantage because they are illegal even if they are identical to registered products made in the United States. Unless changes are made, you can expect that the law will be challenged as a violation of GATT and other foreign trade agreements." The scientific community also has issued challenges to antibacterial products. Stuart B. Levy, a professor of molecular biology and microbiology and medicine at Tufts University, is concerned that the overuse of antibacterial compounds in consumer products such as soaps, lotions, toys, and cutting boards could ultimately reduce the efficacy of these compounds where they're needed most. Levy, who directs Tufts' Center for Adaptation Genetics and Drug Resistance and leads the Alliance for the Prudent Use of Antibiotics, says that the use of antibacterials in consumer products needs to be carefully reconsidered by consumers, manufacturers, and scientists. Like antibiotics, the compounds can promote the growth of resistant strains and possibly allow previously nonviable bacteria to proliferate due to the elimination of competing microbes. Unlike disinfectants such as alcohol and bleach, which quickly kill pathogens and then evaporate off surfaces, antibacterials can leave a residue that continues to kill benign bacteria and encourage resistance long after application. Most concerning to Levy, bacteria sometimes carry genes that confer resistance to both antibacterials and antibiotics when activated. While the use of antibacterials such as triclosan in lotions and soaps has had demonstrated efficacy in hospitals (J. Faoagali et al., American Journal of Infectious Control, 23[6]: 337-43, 1995), Levy says there is no evidence that these enhanced products reduce the spread of disease in households. Within the last two years, triclosan has found its way into a variety of consumer goods, including dishwashing detergent, hand lotion, and even fabric used to make sheets and underwear. "This fad is disturbing to researchers like myself and most health care workers," Levy observes. "It is not at all apparent that these products produce any benefit in the households of healthy people. If we're wasting these highly effective products in healthy homes, then we're doing nothing more than what we've been doing with antibiotics--we're simply selecting for hardier, resistant bacteria." FEARS UNFOUNDED: Glenn Cueman, president and cofounder of Microban, says fears over antibacterials inducing antibiotics resistance are unfounded. Other scientists, however, downplay Levy's concerns. Glenn Cueman, president and CEO of Huntersville, N.C.-based Microban Products Co., says fears over resistance being promoted by triclosan-treated products are unfounded. Cueman, a biomedical engineer, helped to develop a method for impregnating antibacterial compounds into plastic. In the mid-1980s, he cofounded Microban. His company has come to dominate the impregnated plastics market and forge partnerships with industrial giants, including Wilmington, Del.-based E.I. Dupont de Nemours and Co. and Wooster, Ohio-based Rubbermaid Inc. Unlike other antimicrobial coatings applied to surfaces, Microban's impregnated plastics retain their antibacterial properties through the lifetime of the product and can be incorporated into fabrics. When Cueman and a team of biomedical engineers began to explore ways to inject antibacterials into plastics and fibers, they deliberately chose triclosan as the active ingredient. In addition to being approved by EPA for use as a preservative in fibers and plastics, the compound has been approved by the Food and Drug Administration for use in toothpaste for fighting gingivitis. An FDA joint meeting of the Nonprescription Drug and Anti-Infective Drug Advisory committees also conducted a review of scientific literature and concluded that no link between the use of antibacterials such as triclosan and antibiotic resistance has been established. "Triclosan was an ideal candidate for us because it has been used effectively and safely for over 30 years in lotions, soaps, and other products used in hospitals," Cueman says. "Not once has there been a documented case of resistant organisms developing in a clinical setting because of use of this product." He argues that it is unlikely that the impregnated plastics could induce antibiotic-resistant bacteria. In contrast to antibiotics and other antibacterials, triclosan is not ingested by bacteria. "The mechanism of action is completely different," Cueman explains. "It disrupts the cell wall, affecting the bacteria so that it cannot metabolize nutrients or reproduce. An appropriate analogy would be to attack with a sword versus poison, which in this case would not contribute to the development of resistant organisms." He also notes that Microban products do not leave a continually acting residue that can encourage bacterial resistance. Antibacterial properties in the plastic are activated when surface moisture reaches levels optimal for the growth of bacteria. Levy cautions, however, that scientific evidence shows that you cannot rule out the development of resistant strains owing to the use of antibacterials. He recently led an investigation that showed that antibiotic-resistant strains of bacteria could develop from exposure to pine oil disinfectants. "While we don't know the mechanism of action of pine oil, we were able to select for bacteria that could pump out the disinfectant and resist antibiotics as well," Levy explains. "This has been our proof in principle that even simple household products under certain circumstances can select for antibiotic-resistant bacteria. I am not suggesting that people stop cleaning their homes or that they completely stop using antibacterials when they are needed. The manufacturers just haven't proven that antibacterials in the normal home are necessary. Ultimately, the question will be one of relative costs and benefits from these products." PROVEN BENEFITS: Arizona's Charles Gerba notes that treated products such as antibacterial sponges have been shown to reduce cross-contamination in the kitchen. Scientists say that there is a definite use in the home for products treated with antibacterials, but efficacy testing has not yet established the exact health benefits gained from them. Charles Gerba, a professor of soil, water, and environmental sciences at the University of Arizona, notes that some manufacturers have shown that treated products can reduce the spread of bacteria in the home. For example, 3M's antibacterial sponge has been effective at reducing cross-contamination in the kitchen. He also says products such as antibacterial sinks would be an asset to any kitchen. "If I were a microbiologist from another planet, I would want to wash my hands in your toilet, and [defecate] in your sink," Gerba says. "The kitchen sink is probably the most contaminated area of the household and a major source of disease-causing bacteria." While many companies have attempted to capitalize on the need for antibacterials in the home, Gerba says most have not demonstrated that the products are actually effective in real world settings. An EPA scientific advisory committee reached the same conclusion in September. The committee recommended that better methods of testing are needed to simulate conditions commonly encountered in the real world that can inhibit the activity of antimicrobial products. For example, microbes on household and industrial surfaces often develop biofilms, which inhibit the penetration of antibacterials and protect pathogens. In contrast, disinfectants used in a variety of real world settings have been shown to reduce the incidence of common illnesses. For example, Joseph R. Rubino, senior technical director for biological and analytical science at Reckitt and Colman Inc. in Montvale, N.J., recently led a study that demonstrated the positive impact of an infection control program on illness in children at the preschool center (L.R. Krilov et al., American Journal of Infection Control, 24[3]:167-73, 1996). A major part of the program included regularly disinfecting toys. This practice along with other measures produced significant decreases in viral and bacteria illnesses among the children. Gerba sums it up: "These kinds of studies have given us some proof that cleanliness matters. But [this] doesn't necessarily mean that if you make a toy out of an antibacterial-impregnated plastic, then you will get the same results. This is the major problem with antimicrobial products. Their efficacy in real world settings has not been shown. The typical display of efficacy is in the petri dish where they show that a piece of the product cuts down on bacteria. But this is not convincing. As a consumer and scientist, I want to know if treated cutting boards really do cut down on pathogens in the kitchen." Even if antibacterial products prove highly effective in the home against bacteria, they are not expected to take over the role of disinfectants in the war against disease. "Unlike disinfectants, antibacterials have not been shown to be effective against viruses, a common source of illness," Rubino notes. "For this reason, bleaches, ammonia, and alcohol always will play a major part in sanitary practices in hospitals, at home, or at work."

Changes Loom for Scientists Working with Antibacterials

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