Silver, wound healing & infection, role of silver
The Role of Silver
THE ROLE OF SILVER
Dr Alan B.G. Lansdown, Skin Research and Wound Healing Laboratory,
Imperial College of Medicine, London
Studies on wound healing in recent years have increasingly focused upon the importance of wound bed preparation and the relevance of creating a conducive environment for epidermal regeneration and dermal repair. The value of debridement and maggot therapy in removing the necrotic burden is recognised. It is appreciated that chronic and delayed healing wounds are notoriously prone to and that the elimination of infections like Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and other organisms is of prima facie importance in wound healing. Silver as silver nitrate, colloidal silver or silver sulphadiazine cream has been a choice antibiotic for wound care for many generations and numerous clinical studies have substantiated its merits in treating venereal infections, warts, chronic ulcers and surgical incisions. Clearly, after a highly successful meeting of the European Tissue Repair Society in Cardiff in 2001 and the publication of three issues of 'The Silver Supplement' to the British Journal of Nursing, it is clear now that we have entered the new phase of 'sustained-silver release dressings'.
Recent advances in biotechnology and original research have provided unique opportunities to develop dressings which are closely tailored to the type of wound to be treated. They are biocompatable and are proving to be of great benefit in advancing healing in difficult wounds whilst alleviating patient discomfort and impaired mobility. At least ten new sustained silver-release dressings have reached late stages in development or are presently marketed in Europe and elsewhere. They vary greatly in composition but are variously designed to cope with moderately to heavily exudating wounds with unsociable odours, and pain and discomfort. Silver is presented to the wound as a broad spectrum antibacterial with claims for efficacy in the elimination of Gram positive and Gram-negative bacteria, yeasts/fungi, and the methicillin-resistant Staphylococcus aureus and vancomycin-resistant infections. Other materials present include polyurethane foam or lamina, hydro-colloids, charcoal-containing materials, nylon cloth or other substances to control odours and excessive wound exudates whilst maintaining a suitably moist environment to maximise healing. The term 'nanocrystalline' silver has been introduced and is held to represent a new entity in wound management.
Silver as an Antibacterial Agent
As a metal, silver is relatively inert and poorly absorbed by mammalian or bacterial cells. However, in the presence of wound fluids or other secretions, it readily ionises and becomes highly reactive in binding to proteins and cell membranes. The silver ion (Ag+) is absorbed by the bacterial or yeast cells and is lethal in sensitive strains. The biocidal effects of silver are complex, and different organisms respond to silver to varying extents. Evidence provided from the development of silver:copper filters in the sterilization of hospital water systems, suggests that silver is accumulated preferentially in sensitive bacterial strains and that concentrations of 105-107 ions per cell are lethal. Early pharmacologists coined the term oligodynamic to refer to the ability of sensitive bacteria to absorb and concentrate Ag+ from dilute solutions. They suggested that the lethal concentration of ion in a cell was equivalent to the number of bacterial cell enzymes present.
Studies designed to evaluate the efficacy of silver nitrate, silver sulphadiazine or the newer sustained silver release dressings, have routinely assessed their effect on the type and severity of infections present in wounds. Few have looked at the mechanism(s) of bactericidal action or discussed how or why different organisms exhibit varying sensitivity to the silver ion. Microbiological studies illustrate that the 'activated' silver ion (Ag+ or other species) can exert its lethality through action on the bacterial cell membrane (envelope) or binding to and inactivating intracellular proteins/enzymes and nuclear DNA.
Many studies have examined the biocidal action of silver ion and silver-release dressings on species of bacteria or yeasts in vitro. An example is provided by a bioactive glass containing silver oxide as an antibacterial developed for use in dentistry or orthopaedic medicine. This was highly effective against Pseudomonas aeruginosa, Staphylococcus aureus and E.coli at concentrations of 0.05-0.2 mg/ml, Ag+ leaching from the glass matrix was the active agent rather than any other effect (changes in pH, ionic strength, etc.) attributable to other biomaterials present. In vitro studies have provided evidence that this bacticidal effect is attributable largely to the binding of the silver ion to free sulphydryl groups in the bacterium or on its surface. Thus silver sulphadiazine and two other silver-containing products were shown to inhibit the growth of Candida albicana or E.coli through inactivation of the enzyme phosphomannose isomerase. Where the enzyme was mutated to replace the free cystine moiety with alanine (lacking -SH groups), inhibition was not seen.
More substantive information on the bactericidal action of silver relates to its accumulation in the bacterial cells and its opportunity to interact with the cytosolic proteins, mitochondrial enzymes and nuclear DNA or RNA synthesis. Substances in the medium (or it the wound bed) that chelate free silver ion or precipitate it as an insoluble sal, inhibit bacteriostasis. Thus sodium chloride (as possible found in wound exudates) has been shown to inhibit the antibacterial action of silver nitrate by precipitating the silver as insoluble silver chloride. On the other hand, EDTA or EGTA, have been shown to enhance the biocidal effect of silver nitrate, possibly through chelating silver binding substances.
Silver resistant strains of bacteria are a continuing problem in wound care despite many claims in the literature to the contrary. Accumulating evidence indicates that the bactericidal activity of silver is directly related to the amount of silver accumulating within the bacterial cell and its ability to denature or otherwise impair physiological processes. Silver-sensitive strains of Pseudomonas stut-zeri have been shown to produce a higher emission of hydrogen sulphide gas than the resistant strains. Slawson et al (1990) reviewing the interactions between bacteria and silver emphasised the influence of silver on mitochondrial activity and other energy dependant processes. They drew attention to the role of plasmids (cytoplasmic particles) in bacterial resistance. Further work revealed that silver resistance is related not only to the existence of plasmids in the bacterial cell, but their structure and type. Starodub and Trevors (1989) demonstrated two large plas-mids in silver resistant strains of E.coli isolated from a burns wound patient and their propensity to bind silver ion. They noted that by heating, they could alter the silver binding properties of these plasmids and influence bacterial resistance to silver. Transmission electron mi-croscopy and energy dispersive X-ray analysis of whole cell mounts from actively growing cultures confirmed that resistant strains did not accumulate silver whereas the sensitive strains exhibited numerous electron dense particles. In this strain of E.coli at least, the plasmid coded 'pJTI (83kb) seemed to be primarily responsible for silver resistance. Similar patterns of plasmid-modulated silver uptake are known to control the sensitivity of bacteria like Acenitobacter baumannii and Salmonella sp., but further work is urgently needed to examine mechanisms of silver sensitivity in bacterial and fungal strains commonly found in skin wounds and ulcers.
Silver and the Skin Wound
The literature is replete with clinical trials purporting to shown the benefits of silver therapeutics and silver-release dressings on wound repair and regeneration through its antimicrobial efficacy. Little is published, however, to show how the released silver ion influences the wound bed, or to what extent it is metabolised or deposited in the tissue. Nevertheless, silver is absorbed into the wound site, some serving an antimicrobial function, with the remainder being taken up by cells at the wound margin or diffusing into the circulation. It maybe that some of the silver ion is absorbed into the epidermis in the form of a reservoir and then released into the surrounding tissues, but there is evidence that silver uptake tends to be higher in partial thickness wounds where granulation tissue is more extensive.
In the wound bed, silver ion is biologically active and avidly combines with proteins, cell surface receptors (and sulphydryl groups) and wound debris. A contraindication for silver nitrate use in wound prophylaxis, is its profound ability to stain everything black. Although silver nitrate is an effective antibacterial agent and is still available, the tissue discoloration is usually unacceptable these days except in the treatment of severe burns. Although silver sulphadiazine and the new sustained-silver release dressings liberate silver ion into the wound bed, discolouration of the tissue is rarely a problem with silver sulphadiazine, and has not been recorded so far with products like Acticoat, Actisorb, Contreet, Arglaes or Avance. The reasons for this are not clear at the moment, but possibly relate to the nature/species of silver ion released and its reactivity with proteins in the wound bed.
Absorption of silver from wound care products and dressings by cells of the wound margin is not documented in most clinical studies, but regular mention is made of improved patterns of re-epithelialisation, wound closure and healing. This suggests that the silver ion is having a direct effect on the regenerating epidermis, or it is enhancing the local microenvironment in some way to promote the healing process. Reduced wound pain and patient discomfort might suggest that the silver is acting also on the inflammatory/granulation tissue phase of wound repair and upon the polymorphonuclear cells entering the site. However, we do know through experimental and clinical work, that silver permeating into the wound bed is taken up by epidermal cells at the wound margin and is accumulated in the wound debris and passes into the peripheral circulation to be deposited in the liver and kidney, with some voided in the urine.
Experimental studies in laboratory animal models have greatly aided our understanding of the action of silver in the wound. Porcine burn-like wounds, for example, have been shown to absorb silver from silver sulphadiazine leading to the preservation of 'viable' dermal tissue, improved wound contraction and activation of dermal myo-cytes (fibroblasts). In rat and guinea pig wounds, silver nitrate and silver sulphadiazine advanced wound repair and neovascularisation without obvious contraindica-tions.
Improved healing in rat wounds exposed to silver nitrate or silver sulphadiazine has prompted research into the mechanism of action of the silver ion in epithelial cells. Evidence was provided through immunocytochemical evaluation of key metal-binding metallothioneins, to show that silver induced these proteins and enhanced the local concentrations of zinc and copper. Both metals are essential micronutrients involved in epithelial cell proliferation. Increased zinc leading to enhanced production of RNA and DNA-synthetases, matrix metalloproteinases and other essential enzymes in the wound bed are held to contribute to the improved healing observed. Interestingly, increased calcium levels have been observed in experimental wounds treated with silver. The implications of this are unclear at the moment, but we do know that calcium is an essential component of haemostasis as Factor IV, and that increases in calcium in the wound margin are a normal feature of healing in acute skin wounds. Calcium serves as a central modulator at several different levels in wound repair and the importance of calcium gradients in homeostasis in the skin are documented. Clearly, at a time when calcium alginates are being introduced into wound dressings with or without silver as an antibacterial agents, there is an urgent need to study the interaction between the two metals in wound repair.
Clinical Aspects of Sustained-Silver Release Dressings in Wound Healing
Sustained silver release dressings have been developed over the past fifteen years. The dressings are increasingly tailored as broad spectrum antibiotics and barriers to infection, but are designed to handle the wound exudates, offensive odours and patient discomfort commonly associated with severe surgical wounds, graft and donor reactions, and chronic or delayed healing wounds including varicose ulcers, leg ulcers and diabetic wounds. Manufacturers stress the value of their products in treating these debilitating wounds emphasising the value to the silver in alleviating infections whilst improving conditions in the wound bed to promote, advance or 'kick start' the healing process.
Published clinical studies demonstrating the benefits of the new silver release dressings are limited at the moment, with patients selected for study varying greatly in age and clinical condition. The wound types discussed range from burn wounds, graft and donor sites, chronic ulcers, decubitus ulcers, toxic epidermal necrolysis and diabetic wounds to severe traumatic lesions. The underlying pathogenic mechanisms differ greatly and patients vary in age, health status and duration of the clinical problems. Comparison of the merits of the various dressings are understandably difficult, but in each case, infection was a recognised problem, occasionally with methicillin-resistant Staphylococci (MRSA) and vancomycin-resistant bacteria being identified. Some wounds were associated with immuno-suppression in affected patients, but no evidence has been provided so far to show that silver influences the immuno-suppressed state commonly seen in burns. (Cerium nitrate as used in burns wound therapy with or without silver sulphadiazine (Flammacerium), can suppress immune reactions attributable to substances like lipopro-teins liberated in wound sites.) In summary, there is undeniable evidence that all the sustained silver release dressings provide a highly commendable antibacterial activity with barrier function against re-infection, with efficacy closely related to the level of silver released and the duration of action. Most reports appreciate the advantages of the hydrocolloid and polyurethane foam and other components of the dressings in absorbing and managing wound exudates and odours, whilst controlling the moisture content in the wound bed to stimulate wound healing. With few exceptions, patient comfort and mobility is greatly improved.
Greatest clinical experience has been gained with Acticoat, which has been developed over the past 15 years for use in chronic wounds, autografts, burns, epidermal necolysis. Acticoat and related dressings have consistently demonstrated antibacterial action and barrier function, reduction in inflammatory mediation and stimulation of healing responses. Actisorb Silver 220 dressing is claimed to have particular advantages in eliminating wound odour through the charcoal component, but in other respects it is successful in suppressing granulation tissue, purulence and wound exudate. Additionally, it has proved highly beneficial in alleviating over-granulation and leakage in percutaneous, endoscopic gastronomy sites. Clinical studies with reference to case studies are available also to substantiate the value of other sustained silver release dressings like Arglaes in treating major surgical wounds, Con-treet Foam and Contreet Hydrocolloid in moderate to heavy exudating wounds, and Avance in the therapy of painful, macerating wounds with recurrent infection. Although useful comparative studies are available to show the value of the sustained silver release dressings in relation to older silver medicaments, the relative benefits of Actisorb, Acticoat, Arglaes, etc., in treating wounds of a comparable type in impartial investigations are not presently appreciated.
Contraindiations of Sustained Silver Release Dressings
Silver has been a choice antibacterial for use in wound dressings and therapeutics on account of its acknowledged low toxicity. Argyria as regularly encountered with silver nitrate and occasionally with silver sulphadiazine, does not seen to be a problem with Acticoat, Actisorb, Contreet, etc. However, the principle anxiety of silver allergy will remain. Silver allergy or hypersensitivity does affect a small proportion of the population and case reports relate to the use of silver nitrate as a topical antibacterial. Although not specifically identified so far, the possibility of allergic reactions arising through the use of newer silver wound treatments should be considered, and may prove a contraindication for their use in some patients. Other complications including leucopenia, bone marrow toxicity and renal or hepatic damage through silver deposition, as seen rarely with silver nitrate of silver sulphadiazine, are likely to be of marginal significance.
Future Research and Development
Recent research and new developments in wound dressings have provided clinicians with greatly improved methods for treating chronic and complicated wounds with the high risk of infections. Whilst clinical trials provide unequivocal observations on the advantages and benefits of the various dressings available, from a scientific and regulatory view, it is desirable now to investigate mechanisms of action and the fate of the silver ion. Animal models have provided considerable insight into mechanisms of action of silver and other wound medicaments. These could now be fruitfully employed to investigate such features as silver accumulation in wound sites in relation to healing patterns, patterns of silver metabolism in relation to trace metals like zinc and calcium, and the route and rates of silver excretion. Good comparative studies of the relative benefits of Acticoat, Arglaes, Actisorb, Contreet and Avance in a standard wound (e.g., the pig) can be of useful prognostic value.
(A detailed bibliography on the role of silver and silver containing dressings in wound care and as antibacterial agents is available for reference purposes.)
Alan B.G. Lansdown, PhD, FRCPath, FIBiol, Mimgt
Skin Research and Wound Healing Laboratory,
Department of Clinical Chemistry,
Division of Investigative Sciences,
Imperial College of Medicine,
St Dunstans Road,
London, W6 8RP