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The SCENIHR opinion states:
3. SCIENTIFIC RATIONALE
3.1. Introduction
During the last decade, antibiotic resistance by various mechanisms has increased worldwide in bacterial pathogens leading to treatment failures in human and animal infectious diseases ([European Antimicrobial Resistance Surveillance System] EARSS 2005, Harbarth and Samore 2005, WHO 2007). Resistance against antibiotics by pathogenic bacteria is a major concern in the anti-infective therapy of both humans and animals. Bacteria are able to adapt rapidly to new environmental conditions such as the presence of antimicrobial molecules and, as a consequence, resistance increases with the antimicrobial use (Falagas and Bliziotis 2007, Jansen et al. 2006). Serious concerns about bacterial drug resistance from nosocomial, community-acquired and food-borne pathogens have been growing for a number of years and have been raised at both national and international levels (see Reports from EARSS 2005 [European Academies Science Advisory Council] EASAC 2005, [European Food Safety Authority] EFSA 2007 and WHO 2007, Jansen et al 2006).
Antimicrobial molecules include antibiotics and biocides having a bactericidal/bacteriostatic effect on bacteria (see the definition in section 3.2.1.1). The various antibiotic resistance strategies are well-described in the scientific literature. By comparison, resistance against other biocides has only been studied and characterised recently. Biocides and antibiotics may share some common behaviour and properties in their respective activity and in the resistance mechanisms developed by bacteria (Russell 2003, Sheldon 2005). Today, it is important to weigh the risks of selecting antibiotic resistant bacteria by biocide use correctly and to have a clear view of the corresponding emerging health risk. Moreover, understanding the selection and dissemination of biocide resistant pathogens is very important for combating the dissemination of health care associated diseases and foodborne pathogens.
In 2006, the market for biocides amounted to €10-11 billion with a growth of 4-5% per annum for the previous 15 years. Market expansion is predicted to continue (for further details, see www.pan-europe.info/Biocides.htm
). As a result, the hazard/risk of biocide use leading to the selection of antibiotic resistant bacteria followed by selection and dissemination of resistant pathogens is of increasing concern. Therefore, the aim of the present opinion is to assess the risk relating to the possible interactions between the use of biocides and the emergence of antibiotic resistance in pathogenic bacteria. The objective of this opinion is to review evidence on the emergence of biocide resistance and cross-resistance between biocides and antibiotics in bacteria, and to determine if the increasing use of biocides may be associated with an increase in antibiotic resistance in bacterial pathogens. Areas where information is scarce or not available and subsequent additional research will be highlighted.
3.2. Scope of opinion, definition of active substances considered
Within the scope of the mandate our proposition is to limit the definition of "antimicrobials" to substances that are primarily active against bacteria, and does exclude for example antifungal and antiprotozoal agents.
3.2.1. Definitions
3.2.1.1. Official definitions
According to the Directive 98/8/EC of the European Parliament and Council of the 16 February 1998, biocidal products are defined as active substances and preparations containing one or more active substances, put up in the form in which they are supplied to the user, intended to destroy, render harmless, prevent the action of, or otherwise exert a controlling effect on any harmful organism by chemical or biological means. In the Annex V of the Directive is presented a list of 23 product types with an indicative set of descriptions.
The active substances are without concern (Annex IA of the directive) or with concern about their inherent capacity to cause an adverse effect on humans, animals or the environment.
Within the scope of the mandates our proposition is to limit this definition to chemical means only and to apply the following definitions:
- Biocide: an active chemical molecule to control the growth of or kill bacteria in a biocidal product.
- Antibiotic: an active substance of synthetic or natural origin which is used to eradicate bacterial infections in humans or animals.
- Antimicrobial activity: an inhibitory or lethal effect of a biocidal product or an antibiotic.
[Article 2(2)(c) of Directive 2003/99/EC on the monitoring on zoonoses and zoonotic agents (OJ L 325, 12.12.2003, p. 31): "(c) ‘antimicrobial resistance’ means the ability of micro-organisms of certain species to survive or even to grow in the presence of a given concentration of an antimicrobial agent, that is usually sufficient to inhibit or kill micro-organisms of the same species."]
Source & ©: SCENHIR,
Scope of opinion, definition of active substances, p.
12-13
The SCENIHR opinion states:
3.2.1.2. Other definitions
The mandate to the Committee did not require the clarification of the terminology used to define resistance to biocides. The definitions used in this opinion are based on the experts' assessment of the currently used definitions in the peer-reviewed literature.
There are several definitions of resistance to antimicrobials biocides or/and antibiotics and several terms used to describe similar phenomena in the literature. A literal definition of resistance is the capacity of bacteria to withstand the effects of a harmful chemical agent.
The terms employed in the context of this mandate are defined below in order to avoid confusion in the definitions used to describe the level and type of resistance reported.
The following definitions are based partly on those put forward by Chapman and colleagues (Chapman 1998, Chapman et al. 1998), Russell and colleagues (Hammond et al. 1987, Russell 2003) and Cloete (2003).
The practical meaning of antibiotic resistance is to describe situations where (i) a strain is not killed or inhibited by a concentration attained in vivo, (ii) a strain is not killed or inhibited by a concentration to which the majority of strains of that organism are susceptible or (iii) bacterial cells that are not killed or inhibited by a concentration acting upon the majority of cells in that culture.
In the context of this mandate, when non-antibiotic antimicrobial agents (i.e. biocides) are considered, the word “resistance” is used in a similar way where a strain is not killed or inhibited by a concentration attained in practice (the in-use concentration) and in situations (ii) and (iii) described above.
These definitions reflect those given by EFSA [European Food Safety Authority] whereby “antimicrobial susceptibility or resistance is generally defined on the basis of in vitro parameters. The terms reflect the capacity of bacteria to survive exposure to a defined concentration of an antimicrobial agent, but different definitions are used depending on whether the objective of the investigation is clinical diagnostics or epidemiological surveillance” (EFSA 2008a, EFSA 2008b)
The term 'Multi-Drug Resistant’ (MDR) applies to a bacterium that is simultaneously resistant to a number of antibiotics belonging to different chemical classes by using various mechanisms (Depardieu et al. 2007). The EFSA uses the term multiple resistance (MR) or multi-resistance when a bacterial strain is resistant to several different antimicrobials or antimicrobial classes (EFSA 2008a, EFSA 2008b).
The term “cross-resistant” is used to denote a strain possessing a resistance mechanism that enables it to survive the effects of several antimicrobial molecules with mechanism(s) of action that are related or overlap.
Other terms such as “insusceptibility”, “tolerance” and “co-resistance” have been used in the published literature. Insusceptibility refers to an intrinsic (innate) property of a micro-organism, such as cell layer impermeability in mycobacteria and Gram-negative bacteria. Tolerance denotes a reduced susceptibility to an antimicrobial molecule characterised by a raised minimum inhibitory concentration (MIC), or a situation in which a preservative system no longer prevents microbial growth. Co-resistance specifically refers to genetic determinants (such as integrons, transposons or plasmids) encoding for unrelated resistance mechanisms, that are transferred in a single event and expressed jointly in a new bacterial host.
Source & ©: SCENHIR,
Scope of opinion, definition of active substances, p.
13-14
The SCENIHR opinion states:
3.2.2. Active substances
The number of biocides in use is large (see Annex – 1
[of the Commission Regulation of 4 December 2007, listing the identified existing active substances for evaluation EC/1451/2007]). In the context of this mandate, biocides used for their surfactant properties, and for which the primary purpose is not their antimicrobial activity, as well as antimicrobial peptides (for instance, bacteriocins), will not be considered. For the purpose of this document, only the most commonly used biocides for which information about bacterial resistance is available in the public domain, will be discussed. The list of such active substances classified on the basis of their chemical groups or their mode of action is presented in Table 1 and Table 2, respectively. Components of the formulation might have an effect on the antimicrobial activity of the biocide (pH, surfactants, antioxidants, chelating agents, aroma chemicals and alcohols, botanical and herbals, antimicrobial amphiphillic peptides [defensins, Cationic Antimicrobial Peptides (CAMP)], enzymatic antimicrobial systems), or several biocides might be used in the same formulation to increase the overall antimicrobial activity. The effects of combining two or more biocides can be defined as (i) additive when the combined action is no greater than the sum of the activities of the individual actives, (ii) synergistic when the combined action is greater than the sum of the activities of any actives on their own and (iii) antagonistic where the combined effect results in a lower activity than the sum of the activities of the individual actives. For a biocidal formulation containing more than two different active molecules, synergy is the goal.
Some of the components that are commonly found in household products are surface active agents (surfactants) and “membrane permeabilisers”. Surfactants have an intrinsic antibacterial activity (anionic, non-ionic, organic acids [active against Gram-positive bacteria] and compounds with alkyl chains [active against both Gram positive and negative bacteria]) (Birnie et al. 2000) and may increase the overall bactericidal activity of the associated products when used in combination. They are not usually described or labelled as active molecules of the products. Membrane permeabilisers and chaotropic agents (e.g. EDTA, detergents) increase the bactericidal efficacy of a product mainly against Gram-negative bacteria when used in combination with a biocide. Their mechanism of action has been well-described (Alakomi et al. 2006, Ayres et al. 1999, Denyer and Maillard 2002, Maillard 2005).
Table 1: List of active molecules in biocidal products classified on the basis of chemical groups.
Table 2: List of active substances in biocidal products and their mode of action
Source & ©: SCENHIR,
Scope of opinion, definition of active substances, p.14-18
The SCENIHR opinion states:
3.3. Production, use and fate of biocides
In contrast to the surveillance on the use of antibiotics used in human and animal health care, the use of biocides is not regularly monitored, and the amounts of products applied or used remains largely unknown (see Table 1 and Table 2). Only general figures, such as the estimated EU-market value of €10-11 billion in 2006, with a continuing increase, are available (www.pan-europe.info/Biocides.htm
). While most biocides are known to be high volume products, the Committee could not obtain any valid tonnage information despite several efforts. However, production volumes of many of these compounds are considered to be several orders of magnitude higher than those of antibiotics. It is conceivable that the huge amount of biocides disseminated in the environment may, per se, induce a biological hazard via the selective pressure* applied to bacterial populations.
*[Selective pressure: chemical, physical, or biological factors or constraints which select well-adapted bacteria or induce the expression of specific biological mechanisms involved in the bacterial response to external stresses.]
In general, Directive 98/8/EC on the placing of biocidal products on the market governs the use of active substances in biocidal products. In this Directive the prerequisites for placing of biocidal products on the market are defined, including detailed requirements of the pre-marketing approval process. Requirements are among others, the demonstration of efficacy, safety, analytical methods for detection and identification, toxicity, the control of residues including metabolites and degradation products (Art 2a-g) and ecotoxicological studies.
Source & ©: SCENHIR,
Section 3.3. Production, use and fate of biocides, p.
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