An historical overview of the use of silver in wound management, preservation and conservation.
Compounds have been medically used for thousands of years, the recent research focus on this element has led to a resurgence in interest, particularly in the field of wound care product development. The increasing problems of antibiotic resistance, combined with concerns over the safety and toxicity of topical antiseptics, has highlighted the need for a safe agent which can be used to treat colonized and infected wounds effectively. Wounds, notably chronic wounds, can support a wide variety of microorganisms, many of which are pathogens, and act as a source for cross-infection. While systemic antibiotics are justifiably recognized as the first-line treatment of choice for chronic wounds with spreading cellulitis and infected wounds in 'at risk' patients, not all infected wounds merit this treatment. There is now a rationale for the judicious use of suitable topical antisepsis in certain colonized, critically colonized, and infected wounds. The increasing evidence available on products containing silver suggests that this element can fulfil a valuable role in wound care. This review of the history of silver as an antibacterial covers the mode of action of preparations containing silver and concludes with a focus on silver as a component of the modern wound management products: Arglaes, Acticoat, Actisorb Silver 220 and Avance.
Man has been aware of the medicinal and preservative properties of silver for over 2000 years. The ancient Greek and Roman civilizations are credited with the use of silver vessels to keep drinking water drinkable. The addition of silver coins to containers of drinking water has continued to this day -- the water tanks on spacecraft are lined with silver.
The internal, or systemic use of silver certainly dates back to the work of Angelus Sola in the early 17th century (Gettler et al, 1927). He used silver nitrate to treat epilepsy, tabes and chorea. However, this practice ceased by the beginning of the 20th century.
ANTIMICROBIAL PROPERTIES OF SILVER AND SILVER COMPOUNDS
The antimicrobial or germicidal property of silver and its compounds has been the basis of its medicinal use since the 19th century. The chemical forms used have been salts, such as silver nitrate, as well as elemental and colloidal silver. MacLeod (1912) refers to his experience with colloidal silver -- Collosol Argentum -- introduced by Crookes Chemists in 1911 for the treatment of bacterial infections by topical, intravenous, hypodermic and oral dosage.
The topical dosing was for impetigo, acne, septic leg ulcers and ringworm. The interest in this preparation resulted in detailed research on its bactericidal action (Marshall and Killoh, 1915). The studies used commercial Collosol (a colloidal solution of silver) at 1 part in 2000 silver colloid, neat and diluted, on cultures of various pathogenic bacteria in vitro. The time and dilution required to kill the organisms were noted. Organisms killed successfully included Escherichia coli, Salmonella paratyphi A and B, Bacillus anthracis and Yersinia pestis.
The major silver preparations that have seen widespread clinical use this past century are the solution of silver nitrate, silver sulphadiazine (SSD) cream and a variety of dressings containing elemental or ionized silver. There have been some other products, such as silver-zinc-allantoinate (Margraf and Covey, 1977).
The use of different topical silver preparations is closely related to wound categories, e.g. SSD in burns. Without doubt, the single most studied aspect has been in burns therapy. This approach was probably first undertaken by Moyer et al (1965) using silver nitrate 0.5% solution. Clinical experience showed that the silver was rapidly deactivated and, to maintain efficacy, large quantities of dressings soaked in this solution had to be applied regularly to the burned area (Fox, 1983).
It is probable that, at the same time as Moyer et al (1965) were conducting their research, Fox (1983) was developing a compound of silver with an antibiotic, thus providing a double therapy. The antibiotics chosen for in vitro evaluation and in vivo animal model testing were penicillin and the sulphonamide sulphadiazine among others. While all were effective in vitro, only the sulphadiazine was effective topically in ointment formulation, particularly against pseudomonads. In addition, the sulphadiazine had the advantages of remaining white (where many other silver compounds oxidize to an unsightly black oxide) and was not deactivated by components of wound exudate. This was to become the silver sulphadiazine that is widely used today.
References to the use of silver on chronic wounds date back to studies on ulcers in the 17th and 18th centuries (Klasen, 2000a). According to Klasen (2000a), one of the earliest texts to mention silver nitrate was by John Woodall in 1617, where silver nitrate is referred to as either 'infernal stone' or 'lunar caustic'. It was regarded as an essential component of every surgeon's equipment and was used to treat venereal buboes and chancre, to open abscesses, and 'reduce proud flesh and sores'. In this context, the term 'proud flesh' refers to hypergranulation, a feature commonly seen in healing leg ulcers.
Later, in order to assist in application, silver nitrate was made into pencils. In all of these applications and formulations it is impossible to know the exact concentration used; it is highly likely that strong (10%+) preparations were used for their caustic effect rather than a subtle antibacterial effect.
The use of silver nitrate on burns and in ophthalmology appears to have begun in earnest in the early 19th century. We know from Klasen (2000a) that in 1830 Rust used a dilute solution (0.2%) successfully on third- degree burns. This led to widespread use, first in Germany, then later throughout Europe. Concentrations of the solution ranged from 0.2%2.5% with the weaker solutions being reserved for children.
It was at this time that interest in the causes for infection and antisepsis originated. The innovative works of Lister and Semmelweiss in the latter half of the 19th century focused attention on the link between microorganism and sepsis, and on the need for antiseptic precautions (Lawrence and Payne, 1984). The German obstetrician Crede began using 2% silver nitrate solution for gonococcal ophthalmia neonatorum from 1880. This led to successful clinical resolution of the problem and to his writing a monograph Silver Salts as Antiseptics in 1896 (Klasen, 2000a).
In America, the surgeon Halstead began using silver wire sutures and silver foil dressings to reduce postoperative sepsis (Halstead, 1895). Silver nitrate solutions continued in use throughout the two great wars for the treatment of burns and sepsis. With the advent of the antibiotics, penicillin and sulphonamides, interest in silver declined.
Renewed interest, stimulated by the Americal surgeon Moyer, began in the 1960s (Klasen, 2000b). Infection of burns remained a serious problem despite antibiotic use, so Moyer returned to solutions of silver nitrate applied on to thick cotton gauze dressings on both burns and grafted areas (Moyer et al, 1965). He found that this approach was effective against Staphylococcus aureus, Pseudomonas aeruginosa and haemolytic streptococci without the development of resistance.
At the same time, silver nitrate and sodium sulphadiazine was being formulated from silver nitrate and sodium sulphadiazine in order to combine the antibacterial effect of the sulphonamide moiety with the inhibitory effect of silver (Fox, 1983). The hydrophilic cream formulation, sold as Flamazine (Smith & Nephew Healthcare) in the UK, and Silvadene in the USA, became the most widely used topical antibacterial used in burns treatment (Fakhry et al, 1995).
ANTIMICROBIAL ACTION OF TOPICAL SILVER
Silver has been found to be active against a wide range of bacterial (Hoffmann, 1984; Hugo, 1992), fungal (Wright et al, 1999) and viral pathogens (Montes et al, 1986). Elemental silver will have the same mode of action whether or not it is compounded with other chemical moieties. The action of the silver can be differentiated from, for example, the sulphonamide antibiotic sulphadiazine in SSD (Lansdown et al, 1997).
The presentation of silver in the range of different products will also have an impact on efficacy, but not mode of action. Thus, silver may be available as a colloidal suspension, silver ions, or as elemental silver, depending on the product formulation.
Topical treatment of acute and chronic wounds is a selective approach to the prevention and treatment of infection. For any product to be effective in this respect, it must have certain chemical and physical properties.
With respect to a dressing that contains silver, it is important that the solubility of the silver is low, i.e. it does not solubilize into the wound in a short time but slowly, over a period of days, to provide a sustained release and prolonged activity. In this way there will be no bolus dosing that would possibly give rise to transient high tissue blood and urine levels, thus maximizing the systemic toxicity (i.e. unwanted side-effects) risks.
It is also important that there is no substantial chemical reactivity of the silver with wound exudate in order to achieve sustained antibacterial activity in the wound. The detailed pharmacology of silver, including SSD, has been detailed in reviews by Fox (1985) and by standard textbooks (Dollery, 1999). The antibacterial activity in vitro has been reviewed by Hamilton-Miller et al (1983), and the clinical efficacy has been reviewed by Hoffman (1984) and Wright et al (1999).
The critical factor in bactericidal action in the wound is the local concentration of drug required and the possibility of achieving this level by either systemic or topical application. If local blood supply is compromised, such as in ischaemic limbs, tissue oedema, and thermal coagulation, and in the presence of eschar and/or lipodermatosclerosis, the chances of systemic therapy achieving therapeutic concentrations is greatly reduced. Drugs dosed systemically, as opposed to those delivered topically, must separate freely from the plasma proteins to which they may bind, diffuse into the area of infection and, after reacting with amino acids, proteins and electrolytes in the wound, still maintain a bactericidal concentration.
MODE OF ACTION OF SILVER
The antibacterial effects of silver are usually attributed to the possible mechanisms listed in Table 1 (Thurman and Gerba, 1989). Details of these mechanisms have been published in an extensive review by Russell and Hugo (1994).
There is evidence that wounds treated with silver nitrate and SSD heal rapidly (Margraf and Covey, 1977; Kjolseth et al 1994); however, there are some contradictions (Stern, 1989).
In order to clarify the effects of silver on wound healing, Lansdown et al (1997) compared silver nitrate and SSD on intact and wounded rat skin. He found that both agents enhanced wound healing, possibly by the local enhancement of key trace elements zinc and calcium. This, it is postulated, is attributable to the preferential binding of silver to metallothionine, releasing zinc for metabolic functions and the formation of metalloenzymes. While this work has not been reproduced in human wounds, the evidence suggests that silver has both bactericidal and healing benefits when dosed at appropriate levels.
SAFETY AND TOXICITY
Silver compounds may react with environmental pollutants to form the black silver sulphide. When this occurs to topical or systemically applied silver medicaments the result is a grey discolouration (argyria) of the skin, sclerae, nails and mucous membranes (Gettler et al, 1927; Buckley, 1963; Pariser, 1968; Lansdown, 1995). This is particularly evident after prolonged topical and systemic use of silver nitrate (Marshall and Schneider, 1977) but rarely after SSD application (Dupuis et al, 1985). There are no reports of argyria after the use of any of the modern wound dressings mentioned later in this article.
In a review of 650 cases of children treated with topical SSD 1% for burns and scalds over a 5-year period, Lockhart et al (1983) found four instances of neutropenia and two of erythema multiforme rash. All were attributed to the sulphadiazine moiety. Urinalysis showed a mean urinary concentration of sulphadiazine of 31.8mg/l. This reflects the absorption of the active through the treated skin area and is testimony to the apparent lack of observed toxicity to silver (Boosalis et al, 1987). In a similar study on 45 severely burned patients, Kulick et al (1985) found evidence of sulphadiazine sensitization in the form of circulating IgG antibodies. There was no reference made to toxicity to silver although any evidence of systemic and cutaneous silver toxicity was sought.
Kernicterus has been associated with the topical use of SSD, which is also attributable to the sulphonamide. Accordingly, SSD should be avoided during pregnancy, on premature infants or those under 2 months of age (Ward and Saffle, 1995).
Silver nitrate topical and systemic dosage forms have given rise to toxicity to the intestine (Monafo and Moyer, 1968) and to new skin cells (Demling and DiSanti, 2001). This toxicity has been attributed to the nitrate moiety, which is a potent oxidizing agent, and not to the silver.
FORMULATIONS AND COMPOUNDS OF SILVER
Silver protein (argyrol) or mild silver protein
This is a mixture of silver nitrate, sodium hydroxide (an alkali) and gelatin for internal use. Such products are promoted as essential mineral supplements, and for the treatment of such diverse diseases as cancer, diabetes, AIDS and herpes (Fung and Bowen, 1996) although there is no theoretical or practical justification for their use (Osol and Farrar, 1960; Food and Drug Administration (FDA), 1995).
Silver zinc allantoinate
Also known as AZAC cream, this is the combination of an antibacterial (silver), a factor in wound healing (zinc) and allantoin, an agent that stimulates debridement and tissue growth (Margraf and Covey, 1977). In a
clinical trial on patients with chronic wounds, 339 out of 400 (85%) wounds healed with AZAC 1% treatment (Margraf and Covey, 1977). However, despite this promising preliminary data no further trials have been published and no product containing AZAC has found its way into routine clinical use.
This was first formulated as an ointment and an aqueous cream in 1967 (Fox, 1983). Although primarily intended for the treatment of burns, SSD has been used successfully in the treatment of leg ulcers (Margraf and Covey, 1977; Blair et al, 1988; Wunderlich and Orfanos, 1991; Bishop et al, 1992) and fingertip injuries (Buckley et al, 2000). In a recent systematic review of antimicrobial agents for chronic wounds, evidence was found supporting the use of SSD as a topical antimicrobial in the management of infected wounds (O'Meara et al, 2001).
RECENT SILVER-BASED WOUND DRESSINGS
Most recently, the interest in wound care, combined with concerns regarding sensitivity and resistance to topical antibiotics, has focused attention on to topical antiseptic and antibacterial agents (White et al, 2001). The requirements for a formulation that would provide a sustained release of a non-toxic agent has led to the development of numerous dressings containing silver.
A number of wound dressing products containing silver have been developed in the last decade. These are intended for use on colonized or infected wounds or as a prophylactic measure in at-risk patients. The rationale behind these products is: first, the need for a safe and effective topical antibacterial that provides a sustained effect over days; second, as resistance is such a problem with current antibiotics, the antibacterial should have a low or zero potential to select for resistant strains. The characteristics of the ideal silver-containing dressing are listed in Table 2.
Arglaes is manufactured by Maersk Medical. This transparent film, marketed in the UK since 1996, contains 10% w/w silver polymer which releases ions at a constant rate (Williams, 1997).
Silver-coated cloth (Acticoat, manufactured by Smith & Nephew Healthcare) is a high density polyethylene dressing coated with nanocrystalline silver. It has been evaluated in vitro and found to be effective against a variety of clinical isolates. In a comparative study in patients with burns, Acticoat was found to be more effective than silver nitrate and SSD in vitro (Yin et al, 1999) and clinically superior to silver nitrate 0.5% solution in respect of reduced wound sepsis and secondary bacteraemia (Tredget et al, 1998). It is also claimed to be unaffected in mode of action by the presence of proteins in wound exudate (Wright et al, 1998).
Actisorb Silver 220 (manufactured by Johnson & Johnson Medical), originally known as Actisorb Plus, is a combination of activated charcoal cloth impregnated with silver and enclosed within a porous nylon sleeve (Williams, 1994). The dressing adsorbs bacteria on to the charcoal cloth where they are exposed to the antibacterial activity of the silver (Furr et al, 1994). When compared with a charcoal cloth dressing and a chlorhexidine dressing in patients with leg ulcers, Actisorb Silver 220 was found to be the most effective for odour control, reduced frequency of dressing changes and overall improvement in ulcer condition (Millward, 1991).
Actisorb Silver 220 has also been found to be effective in venous leg ulcers (Wunderlich and Orfanos, 1991). The combination of a large surface area of odour-absorbent charcoal and bound elemental silver antiseptic is non-toxic and stimulates wound healing (Furr et al, 1994; Lansdown et al, 1997).
Silver has also been incorporated into a hydrophilic polyurethane foam dressing (Avance and Avance A adhesive, manufactured by SSL International UK). This dressing is intended for exuding wounds such as leg ulcers and pressure ulcers to help prevent cross- and self-infection. There is, however, no clinical data to substantiate its effectiveness.
The history of the use of silver and its compounds covers the last two millennia. The value of silver as an antibacterial has not, however, been fully understood or exploited clinically until relatively recently. Evidence suggests strongly that the true value of silver is as a topical antibacterial for the prophylaxis and treatment of wound infections and in infection control.
The bacterial colonization and infection of wounds can be treated topically, systemically, or a combination of both (White et al, 2001). Prophylactic treatment also involves the same principles. The advantages of topical therapy are listed in Table 3.
There is substantial evidence that silver and its compounds can achieve these functions although much of this evidence currently relates to SSD in cream formulation. The recent development of alternative dressings and delivery systems shows considerable promise for antibacterial activity, and particularly the adjunctive performance features of wound deodorization (where charcoal/carbon is included) and exudate control (where an absorptive component is included).
There is considerable evidence that topical silver, as the metal and colloidal forms, and in SSD formulation, is very safe.
Bishop JB, Phillips LG, Mustoe TA et al (1992) A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J Vasc Surg 16: 2517
Blair SD, Backhouse CM, Wright DD et al (1988) Do dressings influence the healing of chronic venous ulcers? Phlebology 3: 12934
Boosalis MG, McCall JT, Arenholtz DH, Solem LD (1987) Serum and urinary silver levels in thermal injury patients. Surgery 101: 403
Buckley WR (1963) Localized argyria. Arch Dermatol 88: 5319
Buckley SC, Scott S, Das K (2000) Late review of the use of silver sulphadiazine dressings for the treatment of fingertip injuries. Injury 31: 3014
Demling RH, DiSanti L (2001) The role of silver technology in wound healing. Wounds 13(1): A 5A15
Dollery C (1999) Therapeutic Drugs. 2nd edn. Churchill Livingstone, London
Dupuis LL, Shear NH, Zucker RM (1985) Hyperpigmentation due to topical application of silver sulfadiazine cream. J Am Acad Dermatol 12(6): 111214
Fakhry SM, Alexander J, Smith D (1995) Regional and institutional variations in burn care. J Burn Care Rehabil 16: 8690
FDA (1995) Health Fraud Bulletin No 19 and Promotional Materials from Manufacturers of Products. Non-traditional Drug Compliance Branch, Center for Drug Evaluation and Research, FDA, Rockville, Maryland
Fox CL (1983) Topical therapy and the development of silver sulfadiazine. Surg Oncol Obstet 157(1): 828
Fox CL (1985) The human pharmacology of silver sulphadiazine. J Burns Inc Therm Injury 11(4): 3067
Fung MC, Bowen DL (1996) Silver products for medical indications: risk-benefit assessment. Clin Toxicol 34(1): 11926
Furr JR, Russell AD, Turner TD, Andrews A (1994) Antibacterial activity of Actisorb Plus, Actisorb and silver nitrate. J Hosp Infect 27: 2018
Gettler AO, Rhoads CP, Weiss S (1927) A contribution to the pathology of generalized argyria with a discussion on the fate of silver in the human body. Am J Pathol 3: 63151
Hamilton-Miller JM, Shah S, Smith C (1983) Silver sulphadiazine: a comprehensive in vitro assessment. Chemotherapy 39: 4059
Halstead WS (1895) The operative treatment of hernia. Am J Med Sci 110: 1317
Hoffmann S (1984) Silver sulfadiazine: an antibacterial agent for topical use in burns. Scand J Plast Reconstr Surg 18: 11926
Hugo WB (1992) In: Russell AD, Hugo WB, Ayliffe GAJ, eds. Principles and Practice of Disinfection, Preservation and Sterilization. 2nd edn. Blackwell Scientific, Oxford: 36
Klasen HJ (2000a) Historical review of the use of silver in the treatment of burns. Early uses. Burns 26: 11730
Klasen HJ (2000b) A historical review of the use of silver in the treatment of burns. Renewed interest for silver. Burns 26: 1318
Kjolseth D, Frank JM, Barker JH et al (1994) Comparison of the effects of commonly-used wound agents on epithelialization and neovascularization. J Am Coll Surg 179: 30512
Kulick MI, Wong R, Okarma TB, Falces E, Berkowitz RL (1985) Prospective study of side- effects associated with the use of silver sulfadiazine in severely burned patients. Ann Plast Surg 14(5): 40718
Lansdown ABG (1995) Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions. Crit Rev Toxicol 25(5): 397462
Lansdown ABG, Sampson B, Laupattaraksem P et al (1997) Silver aids healing in the sterile skin wound: experimental studies in the laboratory rat. Br J Dermatol 137: 72835
Lawrence JC, Payne MJ (1984) Wound Healing. The Update Group, London: 1520
Lockhart SP, Rushworth A, Azmy AAF, Raine PA (1983) Topical silver sulphadiazine: side-effects and urinary excretion. Burns 10: 912
MacLeod CEA (1912) Electric metallic colloids and their therapeutical applications. Lancet 3 February: 3223
Margraf HW, Covey TH (1977) A trial of silver-zinc-allantoinate in the treatment of leg ulcers. Arch Surg 112: 699704
Marshall CR, Killoh GB (1915) The bactericidal action of collosols of silver and mercury. Br Med J 16 January: 1024
Marshall JP, Schneider RP (1977) Systemic argyria secondary to topical silver nitrate. Arch Dermatol 113: 10779
Millward P (1991) Comparing treatment for leg ulcers. Nurs Times 87(13): 702
Monafo W, Moyer C (1968) The treatment of extensive thermal burns with 0.5% silver nitrate solution. Ann NY Acad Sci 150: 93745
Montes LF, Muchinik G, Fox CL (1986) Response to varicella-zoster virus and herpes zoster to silver sulfadiazine. Cutis 38(6): 3635
Moyer C, Brentano L, Gravens DL, Margraf HW, Monafo WW (1965) Treatment of large human burns with 0.5% silver nitrate solution. Arch Surg 90: 81267
O'Meara SM, Cullum NA, Majid M, Sheldon TA (2001) Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 88: 421
Osol A, Farrar GE (1960) The Dispensary of the United States of America. 25th edn. Lippincott, Philadelphia: 12339
Pariser RJ (1968) Generalized argyria. Arch Dermatol 114: 3737
Russell AD, Hugo WB (1994) Antimicrobial activity and action of silver. Prog Med Chem 31: 35170
Stern HS (1989) Silver sulphadiazine and the healing of partial-thickness burns: a prospective clinical trial. Br J Plast Surg 42: 5815
Thurman RB, Gerba CP (1989) The molecular mechanisms of copper and silver ion disinfection of bacteria and viruses. CRC Critical Reviews in Environmental Control 18(4): 29515
Tredget EE, Shankowsky HA, Groenvald A, Burrell R (1998) A matched-pair, randomized study evaluating the efficacy and safety of Acticoat silver-coated dressing for the treatment of burn wounds. J Burn Care Rehabil 19(6): 5317
Ward RS, Saffle JR (1995) Topical agents in burn and wound care. Phys Ther 75(6): 52638
White RJ, Cooper R, Kingsley A (2001) Wound colonization and infection: the role of topical antiseptics. Br J Nurs 10(9): 56378
Williams C (1994) Actisorb Plus in the treatment of exuding infected wounds. Br J Nurs 3(15): 7868
Williams C (1997) Arglaes controlled release dressing in the control of bacteria. Br J Nurs 6(2): 11415
Wright JB, Lam K, Burrell RE (1998) Wound management in an era of increasing bacterial antibiotic resistance: a role for topical silver treatment. Am J Infect Control 26(6): 5727
Wright JB, Lam K, Hansen D, Burrell RE (1999) Efficacy of topical silver against fungal burn wound pathogens. Am J Infect Control 27(4): 34450
Wunderlich U, Orfanos CE (1991) Behandlung der ulcera cruris venosa mit trockenen Wundauflagen. Phasenubergreifende Anwend- ung eines silber-impragnierten Aktivkohle-Xerodressings. Hautarzt 42: 44650
Yin HQ, Langford R, Burrell RE (1999) Comparative evaluation of the antimicrobial activity of Acticoat antimicrobial barrier dressing. J Burn Care Rehabil 20(3): 195200