Letters to the Editor: Silver: Clarifying the Claims

Dear Editor,

    While we applaud Mr. Brett’s intention (A discussion of silver as an antimicrobial agent: alleviating the confusion. Ostomy Wound Manage. 2006;52[1]:34–41), “the fine line between info-mercial and information”¹ may have been crossed.

The literature reviews and data presented do not always support the claims and observations offered, compromising the strength and reliability of the information. For example, Wright et al² is used to reference silver availability from a silver-containing Hydrofiber® dressing into sodium thiosulphate solution. Hydrofiber® dressing was not commercially available in 1998; plus, the silver was released from two dressings (Arglaes®, Medline Industries, Mundelein, Ill; and and Acticoat™, Smith & Nephew, Largo, Fla ) into water. In addition, suggesting that thiosulphate is a representative medium for wound exudates (it is used as a neutralization agent for silver in microbiological assays) is illogical.

    Also, although the author implies that relevant, reliable, and independent data were used, many of the references (>45%) are more than 10 years old and principally related to the electrical generation of silver; only 32% are related to “modern” silver-containing wound care products, of which more than 60% are related to one particular product. Nanocrystalline silver product has been available for a long time but persistent reference to only one product crosses “the information line”.¹

    Opportunities to provide clarity and alleviate confusion were missed. The author uses amount and concentration interchangeably, yet these two terms have different meanings. The best illustration is in the discussion of silver sulfadiazine cream delivering “in excess of 3,000 parts per million (ppm) of silver ion (Ag⁺) over 24 hours.” The inference is that this concentration of silver ions (ppm is a concentration in solution, alternatively written as µg/mL) is immediately generated in the wound environment. However, what was expressed was the total amount of silver (in the un-ionized form of the complex with sulfadiazine) contained in the cream (µg/g). It is highly improbable that this amount of silver could be ionized, released from the cream, and sustained in the wound environment at the concentration suggested.³ Following the author’s discussion of Le Chatelier’s principle and the effect of chloride on silver ion concentration, the reader can conclude that, in an environment containing significant levels of chloride (such as a wound), silver ion concentration would be further reduced subsequent to wound chemistry. Therefore, because the in vivo situation is complex and many effects need to be considered, in vitro experiments should be performed in the most representative test medium possible — certainly not in water.

    Regarding bacterial resistance to silver, the author implies that “sublethal” doses of silver are more likely to induce resistance than an “adequate level” that is “delivered rapidly”; however, none of these values are defined or substantiated. It is well-accepted scientifically that ionic silver is microbicidal at very low concentrations^4-6 and that as previously indicated (and acknowledged by the author)⁷ ionic silver levels will be strongly influenced by the wound environment. Therefore, it must be emphasized that the goal of “advanced” dressings is to achieve and maintain the highest concentration of ionic silver the wound environment will allow. The use of “high dose” levels from more traditional treatments to support this argument is simply confusing and not reflective of the mechanism of some of those advanced dressings. Genetic resistance to silver occurs sporadically in bacteria; two strains of Enterobacter cloacae (one isolated in Hong Kong, the other in London, UK) have been identified as resistant to silver at concentrations in excess of those provided by any existing silver dressing or cream, irrespective of test environment. However, no reported evidence exists of transfer of genetic resistance to common wound pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Percival et al⁸ discuss the topic in a review article comparing the propensity of antiseptics (eg, silver) and antibiotics to induce resistance.

    We wholeheartedly agree with the author on the need for well-researched and presented pre-clinical and clinical data that enables clinicians to provide evidence-based care. Regrettably, the author’s implication that one silver-based antimicrobial dressing is supported by the review of the literature neither alleviates confusion nor fairly presents an unbiased and comprehensive review of the available clinical and scientific evidence.

    David Parsons, PhD
    Michael Walker, PhD
    Philip G. Bowler, MPhil
    ConvaTec Wound Therapeutics™, Global Development
    Centre, Deeside, UK.

References
1. van Rijswijk L. The fine line between info-mercial and information (Editor’s Opinion). Ostomy Wound Manage. 2003;49(8):6–7.
2. Wright JB, Hansen L, Burrell RE. The comparative efficacy of two antimicrobial barrier dressings: in-vitro examination of two controlled-release silver dressings. WOUNDS. 1998;10(6):179–188.
3. Hamilton-Miller JMT, Shah S, Smith C. Silver sulfadiazine: a comprehensive in vitro reassessment. Chemotherapy. 1993;39:405–409.
4. Demling RH, De Santi L. Effects of silver on wound management. WOUNDS. 2001;13(suppl A):4–15.
5. Russell AD, Hugo WB. Antibacterial activity and action of silver. Prog Medicinal Chem.1994;31:351–370.
6. Clement JL, Jarrett PS. Antibacterial silver. Met Based Drugs. 1994;1:467–482.
7. Lansdown ABG, Sampson B, Laupattarakasem P, Vuttivirojana A. Silver aids healing in the sterile skin wound: experimental studies in the laboratory rat. Br J Dermatol. 1997;137:728–735.
8. Percival SL, Bowler PG, Russell D. Bacterial resistance to silver in wound care. J Hosp Infect. 2005;60:1–7.

Reply

    With regard to the comments made relating to the intent of the paper, I respectfully disagree. Two of the authors sited in Parsons et al’s letter support views expressed in the original article. Parsons et al’s comments relate mostly to in vitro, laboratory-based data. The clinical benefits of dressings containing nanocrystalline silver are supported by in vivo models — eg, use in burns to help reduce infection rate and use in chronic wounds to achieve a significant reduction in total bacterial counts.¹ No other modern silver-containing dressing offers this consistent evidence-based support from the laboratory to the patient as demonstrated by the hierarchy of evidence associated with randomized trials, prospective audits, and a plethora of case materials presented at many global wound healing symposia.

    In an economic climate of limited and increased demand for healthcare, clinical professionals, policy planners, and budget holders require convincing, comprehensive data in addition to the traditional outcome of medical efficacy. Hierarchies of evidence ranging from randomized trials, patient audits, and case studies will be required to demonstrate consistency in outcomes. Price² summarizes these using the three elements of efficacy (healing), efficiency (amount of wasted effort in terms of ease of application, time involved or numbers treated), and effectiveness (economic benefit, health-related quality of life, and patient-centered outcomes). It is important for all new technologies to have consistent bench-to-bedside evidence in terms of performance and this has been demonstrated with the emergence of medical devices containing nanocrystalline silver.

    Laboratory comparisons are only one important piece of the evidence pathway.²

    In addressing concerns over the citations, the references are relevant and to infer otherwise is to suggest that research in the area of silver over the last 30+ years is fundamentally flawed. The age of the references is irrelevant — silver physics/chemistry affecting the solubility of silver compounds, for example, has not changed over the years. In addition, a thorough literature review should include historic works, not just the more recent papers in support of newer product technologies. Many of the references quoted in the review were published by authors who studied silver for the sole purpose of learning before the current “silver dressing era,” making them more objective and potentially more reliable from an educational standpoint and more helpful in alleviating some of the confusion around silver. With respect to the Wright paper, this was an unfortunate error; during the editing process a change was overlooked. The thiosulfate data actually came from Coloplast. Fortunately, this minor bookkeeping error has no impact on the validity of the points made in the paper.

    With respect to the point about 60% of 32% of the references used in the paper as focusing on a single product, I partially agree. Most of these references are comparative studies to other silver dressings and do not actually address a single dressing. The vast amount of literature supporting the efficacy of nanocrystalline silver is partially due to the length of time the dressings have been available to the clinician; using the selected 10 references to address the general topic of the cytotoxicity of silver with specific focus on the nanocrystalline form was intentional.

    Although Parsons et al³ used deionized water for silver extractions, the silver release data should not be used as the sole measure of efficacy. To clarify, the fact that different test media have been used by different researchers has confused many clinicians. The goal of the Silver Dissociation (Release) section of the review was to demonstrate that clinicians should not depend on silver release data alone to gain insight into the antimicrobial efficacy of a given silver dressing. This is better demonstrated by the speed of kill and longevity of a given dressing as determined via log- reduction testing or time-kill kinetic assays.

    To reiterate, different strains can require different levels of silver for kill as evidenced in the literature^3,4 and in industry-generated promotional materials. The rate of kill also must be considered. Given enough time, low levels of silver can accumulate within a given pathogen and have an effect. The question is, How long can a clinician afford to wait for an antimicrobial dressing to take effect?

    I respectfully and wholeheartedly disagree with the implication that the review is about a single dressing and biased. Less than 10% of the sited references refer to a single dressing; hopefully, the intention has been clarified. Much of the literature sited deals with silver as a chemical entity and the chemistry governing its activity, not a particular dressing. The silver compound used, the mechanisms by which silver is made available, and the antimicrobial activity of that silver are rooted in the science of silver. These aspects will ultimately determine the clinical efficacy of a given dressing. The literature certainly does not support a single dressing; rather, it shows that bactericidal activity is required from topically applied silver dressings and indicates that dressings capable of providing rapid and sustainable antimicrobial activity are better able to meet the clinical need within different timeframes. Parsons et al³ have demonstrated these differences between silver dressings via bacterial colony reduction studies. Basically, bactericidal effectiveness and the consistency in evidence-based support from the laboratory to the patient is variable. The review demonstrates that literature on this subject is abundant and viewpoints from both industry and academic sources are plentiful and diverse. The goal of the review was to present these different viewpoints and offer potential explanations to enable clinicians to align data in terms of consistency in order to alleviate confusion. The reader should understand that the efficacy of any antimicrobial is rooted in safety, speed of activity, sustained activity, broad spectrum activity (numerous strains), and protection against microbial invasion into the wound.

    Dave Brett, MS, BS

References
1. Fong J, Wood F, Fowler B, et al. A silver-coated dressing reduces the incidence of early burn wound cellulitis and associated costs of inpatient treatment: comparative patient care audits. Burns. 2005;31:562–567.
2. Price PE. The challenge of outcome measures in chronic wounds. J Wound Care. 1999;8:306–308.
3. Parsons D, Bowler PG, Myles V, Jones S. Silver antimicrobial dressings in wound management: a comparison of antibacterial, physical and chemical characteristics. WOUNDS. 2005;17(8):222–232.
4. Ovington LG. The truth about silver. Ostomy Wound Manage. 2004;50(9A suppl):1S–10S.