Use of Antimicrobial Agents in Consumer Products

ANTIMICROBIAL resistance has been a major public health issue for many years, and many aspects of this issue have been addressed in expert reviews and guidelines.^{1 - 11} Herein we consider whether the use of antimicrobial agents in consumer products such as antibacterial hand lotions and soaps might be a significant source of antimicrobial resistance with negative implications for public health.

We conducted literature searches in the MEDLINE database for articles published between 1966 and 2001 using the search term resistance qualified with the terms consumer product(s), OR soap, OR lotion, OR triclosan and found 104 references. Forty-three English-language references contained information relevant to the use of antimicrobial agents in consumer products and resistance, and these 43 were examined further. Additional references were culled from the bibliographies of these 43 pertinent references. We also searched LexisNexis news databases and the World Wide Web for current developments using the search strategy antimicrobial resistance AND consumer product.

Many types of antimicrobial ingredients are used in antiseptics (products that prevent infection by inhibiting the growth of infectious agents) and disinfectants (products that prevent infection by destroying or inhibiting the growth or activity of infectious agents on and in any surface). These include the alcohols, aldehydes, biguanides, anilides, halogen-releasing agents, quaternary ammonium compounds (QACs), peroxygens, bis-phenols, and many others.¹² Herein, we focus specifically on the ingredients commonly used in topical, over-the-counter antimicrobial consumer products such as soaps and lotions. These ingredients are primarily anilides (such as triclocarban), bis-phenols^{12 - 16} (particularly triclosan), QACs (such as cetylpyridium chloride), and to a lesser extent the biguanides^{17 - 18} (particularly chlorhexidine) (Table 1).¹² These products are to be distinguished from the therapeutic antibiotics, such as the fluoroquinolones and cephalosporins, which are used to treat pathogenic bacterial infections in humans.

Scientific data are lacking to indicate that use of these antimicrobial ingredients in consumer products such as hand care products, soaps, and food preparation products has any proven infection-prevention benefit.^{19 - 20} Despite this lack of data, more than 45% of consumer soaps contain an antimicrobial agent.²⁰ In preparing its position statement on the use of antimicrobial household products, the Association for Professionals in Infection Control and Epidemiology (APIC) performed a systematic search of the current literature and analyzed data provided by as many as 11 companies.²¹ A nonprofit, international organization, APIC is recognized for its leadership in infection control, with more than 110 regional chapters in the United States and more than 12 000 members worldwide. The APIC Guidelines Committee concluded that "the literature yielded no scientific data supporting the use of antimicrobial agents in household products as a means to prevent infection."¹⁹ Additionally, the Committee stated that data supplied by manufacturers in response to APIC's request for information did not substantiate product label claims.²¹ The APIC Position Statement on the use of antimicrobial household products concludes that "there is no proven infection benefit in the use of these products. APIC does not advocate the use of antimicrobial household products which are marketed with the implication of preventing infections."¹⁹

However, significant data exist to indicate that use of antimicrobial wash products containing some of the antimicrobial ingredients described above (eg, triclosan, chlorhexidine) has an important role in preventing nosocomial infections in clinical settings such as hospitals, nursing homes, and neonatal nursery facilities.^{13 - 14 ,22 - 29} These studies suggest that when used properly, these antimicrobial agents significantly decrease the incidence of infection caused by a variety of gram-positive bacteria and, in the case of chlorhexidine, fungi. It is important to note that the patterns of use of these antimicrobial agents in the clinical setting are dramatically different from those in the consumer environment and thus efficacy in the clinical environment will not necessarily translate to efficacy for the consumer.

Resistance to antimicrobial products can occur via 2 mechanisms. Intrinsic resistance is due to a natural property of the organism and therefore is an innate characteristic of the microbial genome.^{12 ,30 - 31} Acquired resistance, which is the form of significant concern, occurs via mutation or by acquisition of a plasmid or transposable element carrying the gene(s) for resistance. Thus, the natural resistance of gram-negative bacteria to many antimicrobial agents because of the barrier properties of the outer membrane is an example of intrinsic resistance, while the acquisition of multidrug resistance by Salmonella is an example of acquired resistance. Since the effect of antimicrobial resistance on public health results primarily from acquired resistance, this report considers only acquired resistance issues with respect to the antimicrobial ingredients used in consumer products.

It is important to note that methods of antimicrobial use differ between consumer and therapeutic applications, and so the therapeutic standard of measuring resistance may be inappropriate for consumer products. Thus, measurement of the minimum inhibitory concentrations is not always appropriate. In fact, while an increase of an antibiotic's minimum inhibitory concentration will have significant therapeutic consequences such as treatment failure, similar minimum inhibitory concentration increases in antiseptic consumer products do not always coincide with failure.^{12 ,30} Additionally, studies of bacterial resistance to the antimicrobial ingredients used in consumer products are limited in number and are hindered by technical difficulties associated with the methods used to determine resistance to these agents because of their mode of action and patterns of use.^{12 ,30} For example, while antibiotics are prescribed for internal use and continuously maintained at an effective concentration within the body, the antimicrobials used in consumer products are used topically and over varying time periods and dosages. Thus, data on the emergence of bacteria resistant to the antimicrobial ingredients used in consumer products must be interpreted with these limitations in mind.

There are no data indicating resistance to triclocarban, but because the anilides have very little clinical application, this could also reflect lack of research interest in this group of compounds. With respect to the other common antimicrobial agents used in consumer products, the bis-phenols, QACs, and biguanides, mounting data indicate that acquired bacterial resistance to these agents is increasing.^{12 ,30 ,32 - 38} Of particular importance is that preliminary indications suggest that acquired resistance to these antimicrobial products is due not only to mutations within the bacterial genome, but also to plasmid transfer.¹² The presence of resistance factors on plasmids that are transferable raises the possibility that once an organism becomes resistant, it may pass this resistance on to other bacteria as well.

Thus, data show that Escherichia coli possessing the plasmid R124, which alters the OmpF outer membrane protein, are more resistant to cetrimide (a QAC) than E coli without the R124 plasmid.³⁹ Additionally, it has been shown that Staphylococcus strains carrying resistance plasmids to gentamicin also possess increased resistance to QACs, chlorhexidine, and other antimicrobial agents.^{38 ,40 - 41} This is because the genes responsible for gentamicin resistance encode proton-dependent export proteins that facilitate the efflux of the antibiotic from the bacteria. This same mechanism thus also provides the bacteria with resistance against QACs and chlorhexidine.^{42 - 43} This finding suggests that acquisition of resistance to antimicrobial agents such as QACs and chlorhexidine is probably due to preexisting resistance elements that developed as part of acquisition of resistance to antibiotics such as gentamicin. It thus can be argued that resistance to antimicrobial agents found in consumer products is unlikely to be due to their use in these products.

However, these data can also suggest that prolonged low-level exposure to antimicrobials like QACs and chlorhexidine may provide an environment that would select for organisms with efflux mechanisms that could then be adapted for use in resisting therapeutic antibiotics. This hypothesis is still being elucidated.¹² A recent study demonstrates that nontransferable resistance to chlorhexidine can be developed in Pseudomonas stutzeri by exposure to gradually increasing doses.³³ These resistant strains are also more resistant to triclosan and some antibiotics, although this varies from strain to strain. This finding suggests that resistance developed against one antimicrobial may impart cross-resistance to another antimicrobial or antibiotic. While the resistance against chlorhexidine in this case was believed to be caused by alterations in the cell membrane, these data support the need for further research into the above-mentioned hypothesis.

A recent study³² reports the appearance of methicillin-resistant Staphylococcus aureus with increased resistance to triclosan, but more studies are needed to confirm this finding.³¹ This situation is of some concern owing to the widespread use of triclosan in clinical settings to reduce skin colonization with Staphylococci and because triclosan is used by many health care facilities in eradication procedures for methicillin-resistant S aureus.^{14 ,22 - 24} Resistance of other bacteria to triclosan has been reported,^{15 ,44} and the mechanism of such resistance has now been elucidated. As with resistance to QACs and chlorhexidine, 1 mechanism of resistance to triclosan is via overexpression of genes encoding positive regulators of a multidrug efflux pump or of the gene encoding the pump itself.³⁴ This facilitates efflux of the antimicrobial agent from the bacteria.

Triclosan exerts its effects by inhibiting the bacterial fatty acid synthesis at the enoyl-acyl carrier protein reductase step. Thus, the second mechanism of resistance to triclosan in E coli has been linked to a missense mutation in the gene that codes for the enoyl-acyl reductase protein.⁴⁵ This has also been documented in Mycobacterium smegmatis, in which resistance to triclosan is linked to mutations in the gene for an enoyl reductase required for fatty acid synthesis.⁴⁴ Significantly, this same study showed that 2 of 3 resistant strains also demonstrated some resistance to isoniazid, a common antibiotic used in the treatment of tuberculosis.⁴⁴

The absence of data supporting the efficacy of antimicrobial ingredients such as triclosan in household and consumer products suggests that they may be ineffective and therefore unnecessary. Published reports on acquired resistance to these antimicrobial agents, coupled with their increased use in consumer products, suggest that a change may be occurring in the microbial flora of the home, specifically through the selection of resistant organisms.⁴⁶ Additionally, the possibility that the selection of organisms resistant to antimicrobials such as triclosan and chlorhexidine also may predispose these organisms to resistance against therapeutic antibiotics is troubling.^{31 ,47 - 48} Some data exist to support this concern, and research is continuing. It is unlikely, however, that resistance to therapeutic antibiotics resulting through this mechanism will prove to be a major factor in the current crisis in antibiotic resistance. Ultimately, health care practitioners must control antibiotic resistance through judicious use of these important drugs.

Despite the recent substantial increase in the use of antimicrobial ingredients in consumer products, the effects of this practice have not been studied extensively. No data support the efficacy or necessity of antimicrobial agents in such products, and a growing number of studies suggest increasing acquired bacterial resistance to them. Studies also suggest that acquired resistance to the antimicrobial agents used in consumer products may predispose bacteria to resistance against therapeutic antibiotics, but further research is needed. Many of these antimicrobial agents are used in the hospital setting to reduce surface colonization of bacteria, and this increased resistance may negatively affect such use. Studies also show that acquired bacterial resistance to antimicrobial agents used in consumer products may predispose the organisms to resistance against therapeutic antibiotics, but further research is needed. In light of these findings, there is little evidence to support the use of antimicrobial agents in consumer products such as topical hand lotions and soaps. However, there are insufficient studies to determine whether the use of antimicrobial agents in consumer products contributes to the general problem of increased resistance to therapeutic antibiotics. Considering the available data and the critical nature of the antibiotic resistance problem, it is prudent to avoid the use of antimicrobial agents in consumer products. Ultimately, antibiotic resistance is a major public health concern that also has to be controlled through changes in attitude toward, and more judicious use of, antibiotics by health care professionals and the public.

The following recommendations of the Council on Scientific Affairs were adopted by the American Medical Association in June 2000:

The American Medical Association

Accepted for publication October 24, 2001.

This report was presented at the Interim Meeting of the American Medical Association, San Francisco, Calif, December 1-5, 2000. The recommendations were adopted as amended and the remainder of the report was filed.

Members and staff of the Council on Scientific Affairs, American Medical Association, at the time this report was prepared: Members: Myron Genel, MD (chair), New Haven, Conn; Michael A. Williams, MD, Baltimore, Md (chair-elect); Roy D. Altman, MD, Miami, Fla; Scott D. Deitchman, MD, MPH, Duluth, Ga; J. Chris Hawk III, MD, Charleston, SC; John P. Howe III, MD, San Antonio, Tex; Hillary D. Johnson, St Louis, Mo; Nancy H. Nielsen, MD, PhD, Buffalo, NY; John F. Schneider, MD, PhD, Chicago, Ill; Melvyn L. Sterling, MD, Orange, Calif; Zoltan Trizna, MD, PhD, Galveston, Tex; Donald C. Young, MD, Iowa City, Ia. Staff: Litjen Tan, PhD; Barry D. Dickinson, PhD (secretary); James M. Lyznicki, MS, MPH (assistant secretary); Marsha Meyer (editor), Chicago.

Reprints: Barry Dickinson, PhD, Secretary to the Council on Scientific Affairs, American Medical Association, 515 N State St, Chicago, IL 60610 (e-mail: barry_dickinson@ama-assn.org).