Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, UK
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Abstract |
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Keywords: mechanisms of action, mechanisms of resistance, antibiotic resistance
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Introduction |
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In recent years, there has been renewed interest in the antibacterial properties of triclosan. This stems from the finding that triclosan had a more specific mechanism of action than hitherto realized,9 and that there might be a link between triclosan usage and antibiotic resistance.10 These aspects have since been examined extensively, and it is the purpose of this short paper to consider four aspects that pertain to this issue: (i) the mechanism(s) of action of triclosan; (ii) the mechanism(s) of bacterial resistance to triclosan; (iii) the possible association between triclosan usage in the clinical and domiciliary environments and antibiotic resistance; and (iv) its current and future usage.
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Mechanism(s) of action of triclosan |
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The question then arises as to whether inhibition of a single enzyme by triclosan is responsible for its inhibitory and lethal actions.11,15,16 Triclosan is normally employed in practice at concentrations much greater than the MICs cited above against highly susceptible bacteria. At such concentrations triclosan is rapidly bactericidal,7,8 and this lethal activity extends to triclosan-resistant strains of E. coli.17 Triclosan-induced K+ leakage, indicative of membrane damage, occurs at bactericidal levels.7,8 Membrane-destabilizing effects have also been demonstrated by Villalain et al.18 Triclosan demonstrates a Z-pattern type of adsorption, which is indicative of the breakdown of a structure, presumably the membrane, and the generation of new adsorbing sites.19 As with other biocidal agents, triclosan possesses more than one type of action, and it is possible to delineate its growth-inhibitory and lethal effects.
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Bacterial resistance to triclosan |
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In P. aeruginosa, which is intrinsically resistant to triclosan, resistance could be due to a non-susceptible enoyl reductase (both triclosan-susceptible and -non-susceptible enzymes have been found20), an outer membrane permeability barrier or efflux. The permeabilizer, ethylenediamine tetraacetic acid (EDTA), does not increase susceptibility to triclosan,21 and efflux has been stated to be the major reason for triclosan non-susceptibility.2224
MRSA strains may or may not show elevated triclosan MICs.68,25 Fan et al.26 found that all S. aureus strains with elevated triclosan MICs overexpressed FabI production by three- to five-fold, and that strains with the highest MICs (12 mg/L) also had mutations in FabI.
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Possible association between triclosan and antibiotic resistance |
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Susceptibility of MRSA strains to triclosan has changed little over a 10 year period,6 and there does not seem to be any association between triclosan response in MRSA and other strains of S. aureus and antibiotic susceptibility or resistance.7,8
Both triclosan and the important antitubercular drug, isoniazid, inhibit enoyl reductase in M. smegmatis and Mycobacterium tuberculosis.14,27,28 In the former, mutations in the inhA gene produce increases in resistance to both triclosan and isoniazid. Triclosan binds in a similar manner to the enoyl reductase (InhA) of mycobacteria and that of E. coli. The InhA from M. tuberculosis is 36% identical and 65% similar to EnvM, and 87% identical and 97% similar to the InhA from M. smegmatis.14 Nevertheless, there are differences in the effects of triclosan and isoniazid27,28 such that inhibitors targeted at the enoyl substrate binding site could produce effective drugs against isoniazid-resistant strains of M. tuberculosis.27
It has been emphasized that laboratory studies have a useful role to play in evaluating mechanisms of action of and resistance to biocides, including triclosan, but that these should, wherever possible, be related to the clinical and other uses of these agents.15,16 Do biocides therefore select for antibiotic resistance?29 Certainly, there are some similarities in the manner in which bacteria resist the action of both types of antibacterial agents.30 Several authors have purported to show a relationship between the use of triclosan (or other biocides) and antibiotic resistance.3133 Others have cast doubt on this proposal,16,29,34,35 whilst emphasizing that, like all biocides, triclosan should be used only when appropriate.
Some recent surveys on the use of triclosan and other biocides add weight to these doubts. In the first,36 conducted over a 10 year period, it was found that there was no relationship between triclosan usage and antibiotic resistance in MRSA and P. aeruginosa. In the second,37 it was shown that there were no significant differences in overall titres of bacteria, potential pathogens or frequencies of antibiotic resistance in a single-time analysis of homes that did or did not use surface antibacterial agents. A comprehensive survey by Cole et al.38 could find no relationship between the use of triclosan and other biocides and antibiotic resistance in homes where biocidal products were or were not being used.
What, then, of the incorporation of triclosan into oral products? Will the use of triclosan in dental hygiene products result in the development of triclosan-resistant bacteria with reduced susceptibility to important antibiotics? An Expert Panel review concluded in 2000 that there was no evidence of resistant, opportunistic or pathogenic microorganisms developing.39 The short-term use of triclosan had no major impact on normal oral microflora or on the streptococcal susceptibility to antibiotics.40 Chronic exposure to triclosan did not demonstrate significant decreases in antibiotic susceptibility in dental bacteria.41 In general terms, the use of antimicrobial agents in dental care products in order to reduce plaque is considered to be justified.42
Overall, there is no convincing evidence to support the contention that triclosan usage has resulted in the clinical development of antibiotic-resistant Gram-negative bacteria, antibiotic-resistant cocci or isoniazid-resistant M. tuberculosis.16 Nevertheless, it would be wise to restrict the use of triclosan to areas where it has been shown to be effective.43
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Uses of triclosan |
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Finally, although it is sometimes stated that resistance to triclosan and other biocides is increasing,44 this conclusion is generally based upon MICs rather than bactericidal estimations. Bacterial resistance to disinfectants in general is most certainly not a new phenomenon, and there are known examples of reduced susceptibility being described over a century ago.49 Triclosan, of course, is of more recent vintage. Consequently, it is necessary to continue to monitor whether reduced susceptibility to it and to antibiotics occurs.
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Footnotes |
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References |
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