ReviewBacterial resistance to silver in wound care
Introduction
Ionic silver (Ag+) is considered to be effective against a broad range of micro-organisms, with low concentrations documented to have therapeutic activity.1, 2 Silver has been described as being ‘oligodynamic’ because of its ability to exert a bactericidal effect at minute concentrations.3 Consequently, a large number of healthcare products now contain silver, principally due to its antimicrobial activities and low toxicity to human cells. Such products include silver-coated catheters,4, 5 municipal water systems6, 7 and wound dressings.8
Wounds often provide a favourable environment for the colonization of micro-organisms.6, 8, 9, 10 In order to improve the opportunity for wound healing, it is important to create conditions that are unfavourable to micro-organisms and favourable for the host repair mechanisms, and topical antimicrobial agents are believed to facilitate this process. Antiseptic agents are now considered for the treatment of localized skin and wound infections because they have a lower propensity to induce bacterial resistance than antibiotics. One example of the early use of silver in wound care is silver sulphadiazine (AgSD) cream, developed in the 1960s, for the treatment of burns. Recently, a trend towards the use of wound cover dressings that contain silver has been evident, and today, a selection of foam, film, hydrocolloid, gauze and dressings with Hydrofiber® technology impregnated with silver are commercially available. However, concerns are being expressed regarding the overuse of silver and the possible emergence of bacterial resistance to silver, particularly within the clinical environment.11, 12 Silver-resistant bacteria have been reported since 197513, 14, 15, 16, 17, 18, 19, 20, 21, 22 and research within this area is clearly increasing.23 A preliminary understanding of the genetics underlying silver resistance has been known since 1998,24, 25 with a greater understanding of the biochemistry documented a year later.26 Clinical evidence of silver-resistant bacteria has been principally in hospitals, specifically in burns wards, where silver salts (in the form of silver nitrate) are used as antiseptic agents.13, 27
Many clinicians and researchers have questioned whether the widespread usage of silver could lead to cross-resistance to antibiotics, as has been suggested with a number of biocides, specifically triclosan, chlorhexidine and quaternary ammonium compounds (QACs).28, 29 However, in reference to the available evidence to date, this appears to represent an unjustifiable concern.
It is the purpose of this review to assess the likelihood of widespread resistance to silver and the potential for silver to induce cross-resistance to antibiotics, in light of its increasing usage within the healthcare setting.
Section snippets
Wound microbiology and antimicrobial agents
Wounds often provide a favourable environment for the colonization of micro-organisms which may both delay healing and cause infection. Bacteria found in wounds originate primarily from the mouth and colon, and constitute a unique collection of organisms that are potentially pathogenic. Consequently, broad-spectrum antimicrobial agents are required to control these mixed species populations to minimize the opportunity for infection. This has been reflected in the increased usage of silver in
Mode of action of Ag+
In bacteria, silver ions are known to react with nucleophilic amino acid residues in proteins, and attach to sulphydryl, amino, imidazole, phosphate and carboxyl groups of membrane or enzyme proteins that leads to protein denaturation.1, 19, 35 Silver is also known to inhibit a number of oxidative enzymes such as yeast alcohol dehydrogenase,36 the uptake of succinate by membrane vesicles37 and the respiratory chain of Escherichia coli, as well as causing metabolite efflux38 and interfering with
General resistance mechanisms
Resistance to an antimicrobial agent can occur either by ‘intrinsic’ or ‘acquired’ mechanisms. Acquired resistance can arise by either mutation or the acquisition of various types of genetic material in the form of plasmids, transposons and self-replicating extra-chromosomal DNA.52 Acquired resistance to a wide range of antibiotics has been observed in a variety of micro-organisms.53 Intrinsic resistance is a phenotype demonstrated by micro-organisms before the use of an antimicrobial agent,
Link between Ag+ usage, resistance and antibiotics
Ag+ resistance is most likely to be found in environments where greatest Ag+ usage of silver-containing products might be expected, such as in the dental setting where amalgams are known to contain 35% silver,74 burns units in hospitals75 or the use of silver-coated catheters.4
Some biocides disrupt cellular targets, and subsequent mutations in these targets may confer low-level cross-resistance to certain antibiotics used in humans. Whilst a number of laboratory-based studies have indicated a
Use of Ag+ in wound care
Silver has been used extensively for the treatment of burns,92, 93 with AgSD incorporated into bandages for use in large open wounds.94, 95 Many silver-coated and silver-containing dressings are now available for the treatment of wounds.
Although resistance to heavy metals, such as Ag+, has been studied and reported, exact mechanisms are not known and there is little current evidence of emerging microbial resistance to silver. Increased use of Ag+ in wound care has created some concern regarding
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