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      The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concern?

      Journal of Antimicrobial Chemotherapy
      Anti-Infective Agents, chemistry, pharmacology, Bacteria, drug effects, Drug Resistance, Microbial, Humans, Infection, drug therapy, microbiology, Microbial Sensitivity Tests, Silver Compounds

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          Abstract

          Silver first gained regulatory approval for use as an antimicrobial agent in the early 20th century, but its usage diminished with the introduction of antibiotics in the 1940s. Recently, however, topical silver has gained popularity once again, principally in the management of open wounds. This has been largely due to the spread of methicillin-resistant Staphylococcus aureus and the resultant reduction in first-line antibiotic prescribing. The increase in the use of topical silver has raised issues concerning silver resistance, together with questions about the standardization of antimicrobial testing methods for silver. Issues related to silver product testing include a failure to establish standard procedures for determining MIC values, an absence of recognized breakpoints, a lack of conformity in the way different products release silver and variations in the effects of microbiological media on silver release and the measurement of inhibitory activity. The clinical incidence of silver resistance remains low, and emergence of resistance can be minimized if the level of silver ions released from products is high and the bactericidal activity rapid.

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          Bacterial silver resistance: molecular biology and uses and misuses of silver compounds.

          Resistance to silver compounds as determined by bacterial plasmids and genes has been defined by molecular genetics. Silver resistance conferred by the Salmonella plasmid pMGH100 involves nine genes in three transcription units. A sensor/responder (SilRS) two-component transcriptional regulatory system governs synthesis of a periplasmic Ag(I)-binding protein (SilE) and two efflux pumps (a P-type ATPase (SilP) plus a three-protein chemiosmotic RND Ag(I)/H+ exchange system (SilCBA)). The same genes were identified on five of 19 additional IncH incompatibility class plasmids but thus far not on other plasmids. Of 70 random enteric isolates from a local hospital, isolates from catheters and other Ag-exposed sites, and total genomes of enteric bacteria, 10 have recognizable sil genes. The centrally located six genes are found and functional in the chromosome of Escherichia coli K-12, and also occur on the genome of E. coli O157:H7. The use of molecular epidemiological tools will establish the range and diversity of such resistance systems in clinical and non-clinical sources. Silver compounds are used widely as effective antimicrobial agents to combat pathogens (bacteria, viruses and eukaryotic microorganisms) in the clinic and for public health hygiene. Silver cations (Ag+) are microcidal at low concentrations and used to treat burns, wounds and ulcers. Ag is used to coat catheters to retard microbial biofilm development. Ag is used in hygiene products including face creams, "alternative medicine" health supplements, supermarket products for washing vegetables, and water filtration cartridges. Ag is generally without adverse effects for humans, and argyria (irreversible discoloration of the skin resulting from subepithelial silver deposits) is rare and mostly of cosmetic concern.
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            Silver as biocides in burn and wound dressings and bacterial resistance to silver compounds.

            Silver products have been used for thousands of years for their beneficial effects, often for hygiene and in more recent years as antimicrobials on wounds from burns, trauma, and diabetic ulcers. Silver sulfadiazine creams (Silvazine and Flamazine) are topical ointments that are marketed globally. In recent years, a range of wound dressings with slow-release Ag compounds have been introduced, including Acticoat, Actisorb Silver, Silverlon, and others. While these are generally accepted as useful for control of bacterial infections (and also against fungi and viruses), key issues remain, including importantly the relative efficacy of different silver products for wound and burn uses and the existence of microbes that are resistant to Ag+. These are beneficial products needing further study, although each has drawbacks. The genes (and proteins) involved in bacterial resistance to Ag have been defined and studied in recent years.
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              Molecular basis for resistance to silver cations in Salmonella.

              Here we report the genetic and proposed molecular basis for silver resistance in pathogenic microorganisms. The silver resistance determinant from a hospital burn ward Salmonella plasmid contains nine open reading frames, arranged in three measured and divergently transcribed RNAs. The resistance determinant encodes a periplasmic silver-specific binding protein (SilE) plus apparently two parallel efflux pumps: one, a P-type ATPase (SilP); the other, a membrane potential-dependent three-polypeptide cation/proton antiporter (SilCBA). The sil determinant is governed by a two-component membrane sensor and transcriptional responder comprising silS and silR, which are co-transcribed. The availability of the sil silver-resistance determinant will be the basis for mechanistic molecular and biochemical studies as well as molecular epidemiology of silver resistance in clinical settings in which silver is used as a biocide.
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