VOL: 103, ISSUE: 09, PAGE NO: 48
Alan Lansdown, PhD, FRCPath, is senior lecturer, Imperial College Faculty of Medicine, London
Angela Williams, MSc, RN, is vascular nurse specialist, Cardiovascular Surgery, Charing Cross Hospital, London
Human skin is colonised by an array of micro-organisms, some of which are liable to become opportunist pathogens in the event of trauma and can contribute to the indolence and non-healing of chronic wounds (Ovington, 2003; Davies et al, 2001).
Metallic silver, silver nitrate and silver sulphadiazine have been used as broad-spectrum antibiotics especially for controlling infections associated with burns and chronic skin wounds (Klasen, 2000). While there is a common belief that ‘bacteria are unable to develop resistance to silver ions’, clinical microbiologists are aware that silver-resistant bacteria can occur in a variety of circumstances and environments (Gupta et al, 1999; Gupta and Silver, 1998; Lowbury, 1975). These include chronic wounds and burns, dentistry, occupational silver exposure and water systems (Davis et al, 2005; Pruitt et al, 1998; Haefeli et al, 1984; Modak and Fox, 1981). True silver resistance is developed through mutational change - and may not be as common as believed (Gupta and Silver, 1998).
Clinical evidence for silver resistance
Using serial dilutions of silver nitrate in nutrient agar, Bridges et al (1979) recorded inhibition of bacterial growth. Some silver-resistant strains of Pseudomonas aeruginosa were identified, but the silver resistance was unstable - the bacteria became sensitive again on repeated subculture.
Lowbury (1972) found 0.5% silver nitrate controlled Pseudomonas aeruginosa in patients with burn injuries, reducing infections from 70% to 3% and reducing mortality. However, the prophylactic effectiveness of both silver nitrate and silver sulphadiazine declined with the emergence of resistant variants such as Proteus spp., Enterobacter cloacae and miscellaneous Enterobacteriaceae.
Definitive evidence that a bacterium is resistant to silver is provided by the presence of a mutagenic change within the bacterial genome (Silver et al, 2000). True silver resistance is stable within a bacterial population and transmissible to sensitive recipient strains by conjugation or transformation in vitro (Starodub et al, 1990; McHugh et al, 1975). Evidence of silver resistance in wound bacteria was provided from the US (McHugh et al, 1975). Burn patients were treated with 0.5% silver nitrate; sequential swab cultures revealed persistent Salmonella typhimurium infections that were clinically resistant to silver nitrate. Silver resistance was transmissible to susceptible strains of Escherichia coli and Salmonella typhimurium.
A stable silver-resistant strain of Acinetobacter baumannii (BL88) had been identified (Deshpande and Chopade, 1994) and resistance was transferable to Escherichia coli in plate culture.
Molecular and genetic features of bacterial resistance to silver
Bacterial resistance to silver can arise as an intrinsic, natural property or through mutation or acquisition of plasmids (independent pieces of DNA) or transposons (segments of DNA that can self-replicate and migrate to a new position on the same or another chromosome, plasmid or cell) (Silver et al, 2000). Alternatively, silver resistance may be attributable to epigenic mechanisms (a change in a cell that does not have a genetic cause).
Silver resistance depends upon a complex regulation of ion binding and efflux (occurs when silver ions are pumped out of the cells) (Gupta and Silver, 1998). Gupta et al (1999) propose that this pattern of silver resistance might be employed more widely and serve as a basis for molecular and biochemical studies in the epidemiology of silver-resistant organisms in a clinical setting where wounds are treated with silver antimicrobial agents or dressings. However, this prospect will be limited by a lack of routine access to facilities for conducting reverse transcription-polymerase chain reaction and appropriate primers for sil-gene identification (Gupta et al, 2001). A sil-gene is a gene complex that controls the metabolism of silver within bacterial cells, leading to silver resistance.
Biofilms are assemblages of microbial cells that are associated with a surface and enclosed within a polysaccharide matrix that may contain minerals, blood components, tissue debris and environmental contaminants. They may be attributable to one bacterium but more commonly represent mixed populations. They can form on a variety of surfaces including living tissues but their greatest clinical importance is seen in association with indwelling medical devices and prostheses.
Multi-species biofilms are highly resistant to most antimicrobial agents including silver and the transfer of resistance via plasmids is widely recognised (Donlon, 2002). Silver, silver oxide and silver sulphadiazine have been incorporated in materials used for constructing medical prostheses or have been incorporated in hydrophilic coatings. Although some clinical and in vitro studies provide evidence that silver ions limit bacterial adhesion, changes are frequently negligible or statistically insignificant (Bong et al, 2003).
Epigenic mechanisms of resistance
Epigenic mechanisms for silver resistance in wound bacteria are not well researched. Recent studies emphasise the extensive biological activity of silver ions and their propensity to complex with inorganic anions and proteins in a wound bed or in nutrient agar to form stable precipitates. This silver is ‘unavailable’ as an antibacterial agent.
While experimental and clinical evidence is available to show that bacterial growth under stressful conditions can select for resistance and the emergence of resistant strains, the mechanisms involved are imperfectly understood. Despite occasional references to silver-resistant bacteria in burn wounds, waste effluents and water systems, it must be concluded that true bacterial resistance to silver confirmed by genetic studies and the presence of silver-resistance plasmids is rare. This lack of evidence may be attributable to:
- The low propensity of bacteria in wounds and elsewhere to mutate or manifest resistance plasmids;
- Silver-resistant mutants not regularly being sought in clinical therapy or wound clinics through a lack of equipment or technical expertise.
It is conceivable that where an apparent lack of antibacterial activity has been reported in wounds treated with silver nitrate, silver sulphadiazine or a silver dressing, resistance is largely attributable to epigenic mechanisms - that is, insufficient free silver ions available to inhibit or kill bacteria. Although silver is highly reactive in its ionised (or hydroactivated) form and is expected to kill most bacteria at concentrations as low as 60ppm, stable binding of the free ions to albumins, macroglobulins, host cell membrane proteins and inorganic anions in the microenvironment leave insufficient ions available for bactericidal action.
Case study: controlling infections with silver dressings
Bacteria isolated from 31 patients attending a vascular clinic concurrently were cultured on nutrient agar plates enriched with serial dilutions of silver nitrate to identify phenotypic silver resistance (Cason et al, 1966).
All bacteria tested were inhibited by 1.0mM silver nitrate, apart from a strain of Enterobacter cloacae isolated from one patient. This bacterium was further subjected to genetic analysis in a commercial laboratory and the presence of the sil-gene complex was confirmed by polymerase chain reaction.
From the limited information presently available from studies at Charing Cross Hospital, there is no evidence that exposure to sustained silver-releasing dressings for at least three months predisposed patients to the emergence of silver-resistant bacteria. The bacterial infections in leg ulcers of the 30 patients studied were reduced in the presence of sustained silver-releasing dressings but the strains of bacteria isolated were of a similar type. In one patient coliform bacteria seemed to be less responsive to silver prophylaxis. Our observations confirm that silver dressings do control wound infections and achieve the appropriate bacterial balance as recommended in chronic leg ulcer therapy.
- This article has been double-blind peer-reviewed.
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