Letters to the Editor

Jenny Hurlow, GNP, CWOCN; D. W. Brett; Marcia Nusgart, RPh; Lia van Rijswijk, RN, MSN, CWCN

Silver is still confusing

    Dear Editor,
    Despite the title, the article Brett DW, A discussion of silver as an antimicrobial agent: alleviating the confusion (Ostomy Wound Manage. 2006;52[1]:34–41) only added to the confusion.

    If greater silver delivery decreases the risk for impending silver resistance, why is most current resistance related to silver sulfadiazine (SSD), which delivers in excess of 3,000 ppm of Ag+ in 24 hours?

    I understand 1) the silver ion (Ag+) is the active, antimicrobial agent and provides antiseptic action; 2) there is a difference in cidal activity between an antiseptic and an antibiotic; 3) Ag+ must be protectively stored in the dressing because it likes to bind with other material; 4) wound fluid contains sodium (Na+) and chloride (Cl-) ions and the antimicrobial activity of Ag+ may be inactivated by binding with Cl-; and 5) Ag+ also may kill a fibroblast cell instead of doing any of the above. But in the wound, which action(s) take precedence? Also, some dressings store Ag+ by binding it to Cl-. Wound drainage breaks this bond, releasing the Ag+. Once released, will the Ag+ bind again with Cl- in the exudates (a liquid state)? In vitro versus real-world considerations….

    With regard to Le Chatelier’s Principle, time-kill kinetic method, and different strains of methicillin-resistant Staphylococcus aureus (MRSA): Are some strains of MRSA killed with one Ag+ ion while other strains take two or three?

    The article’s implications only stimulated more questions. Plus, I am not certain the scientific criticism of Aquacel Ag (ConvaTec, a Bristol-Myers Squibb Company, Princeton, NJ) was sound; I have good results with this product. Perhaps in vivo data would help?
    Jenny Hurlow, GNP, CWOCN
    Memphis, Tenn

Reply
    At times, SSD is misused, allowing low levels of silver to reside in the wound. The high level of silver may last only for a short while (due to complexation by wound fluid components). Also, it has been shown in vitro (by Hoosier Microbiological Laboratories, Muncie, IN) and in vivo1 that some strains of bacteria are not affected by SSD, highlighting the need for an adequate level of silver for a prolonged period of time. Because this is not achieved with SSD, frequent re-application is necessary. However, the level of silver provided by SSD may explain why more resistant strains have not emerged. In addition, silver resistance mechanisms may be effective regarding other heavy metals and antibiotics (and vice versa).2

    Clearly, low levels of silver can promote resistance.3–5 Hopefully, clinicians will make wise decisions in their use of silver dressings and silver resistance will never become more widespread. However, never before in the history of wound care has the use of dressings that supply low levels of silver been as prominent. Researchers who have spent careers studying heavy metal resistance mechanisms, creating a vast body of literature, have shared their concerns. Some have found that low levels of silver promote resistance; hence, it may be wise to err on the side of caution.

    The complexation of Ag+ and Cl- occurs in vitro and in vivo, the low solubility of AgCl accounting for the low level of silver made available when using dressings that employ AgCl as the “active” agent.
Le Chatelier’s principle was used to explain how different test solutions can yield different results (eg, when examining silver release data) and to provide scientific explanation for the confusion in the literature regarding this issue. However, understanding “release” information is not necessary because it is not always relevant to the antimicrobial efficacy of a given dressing.

    The important issue is the amount of antimicrobially active available silver as demonstrated by the dressing’s antimicrobial efficacy. But confusion exists in this area as well. Different strains require different levels of silver for kill, which explains why much of the kill curve data (for a wide variety of dressings) look similar. If a dressing that supplies 1 ppm of silver is tested against a strain that is susceptible to 1 ppm of silver, the data will show efficacy. However, if that same dressing is tested against a strain that requires a higher level, the data will demonstrate lower efficacy. Peer reviewed literature6,7 and industry marketing materials are rife with such evidence. Low and high levels of silver will have an affect on silver-susceptible strains. Hence, silver-susceptible strains are likely to provide similar data for a variety dressings tested in a given experiment; whereas, less susceptible strains are more likely to show the true differences between dressings with respect to antimicrobial efficacy. Knowing which strains are in a given wound is not likely. Higher levels of silver are required to address the more robust strains — much more than the 2 ppm or 3 ppm mentioned. Maple8 demonstrated that 60.5 ppm of silver was required to kill all of the ~80 known strains of MRSA.

    The time-kill kinetic assay demonstrates that speed of kill is equated to efficacy; it has been demonstrated that kill quickly correlates with clinical outcomes.9–11 Several in vitro assays are used in microbiology; the time-kill assay provides the best insight into in vivo activity.12

    With respect to the product query, it may be more productive to ask whether success using silver-containing dressings is due to the promotion of a moist wound environment afforded by the hydrofibers or to the added silver. Higher levels of active silver are synonymous with greater antimicrobial efficacy. The original article details this issue.

    Although many in vivo silver studies have been conducted,13-24 more are undoubtedly needed.
    D. W. Brett

References
1. Hendry AT, Stewart IO. Silver-resistant Enterobacteriaceae from hospital patients. Can J Microbiol. 1979;25:915–921.
2. Silver S. Bacterial silver resistance: molecular biology and its uses and misuses of silver compounds. FEMS Microbiology Reviews. 2003;27:341-–53.
3. Starodub ME, Trevors JT. Mobilization of Escherichia coli R1 silver-resistance plasmid pJT1 by Tn5-mob into Escherichia coli C600. Biol Metals. 1990;3:24–27.
4. Gadd GM, Laurence OS, Briscoe PA, Trevors JT. Silver accumulation in Pseudomonas stutzeri AG259. Biol Metals. 1989;2:168–173.
5. Li X-Z, Nikaido H, Williams KE. Silver-resistant mutants of Escherichia coli display active efflux of Ag+ and are deficient in porins. J Bacteriol. 1997;179(19):6127–6132.
6. Ovington LG. The truth about silver. Ostomy Wound Manage. 2004;50(9A suppl):1S–10S.
7. 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.
8. Maple PA, Hamilton-Miller JMT, Brumfitt W. Comparison of the in-vitro activities of the topical antimicrobials azelaic acid, nitrofurazone, SSD and mupirocin against MRSA. J Antimicrob Chemother. 1992;29:661–668.
9. Barry AL, Graig WA, Nadler H, Reller LB, Sanders CC, Swenson JM. Methods for Determining Bactericidal Activity of Antimicrobial Agents. Approved Guideline. NCCLS document M26-A (ISBN 1-56238-348-1); 1999.
10. Susceptibility tests: special tests. In: Stratton CW, Cooksey RC. Manual of Clinical Microbiology, 5th ed. 1991:1153–1165.
11. Jackson CG, Riff LJ. Pseudomonas bacterimia: pharmacologic and other bases for failure of treatment with gentamicin. J Inf Dis. 1971;124:S185–S191.
12. Chandrakekar PH, Crane LR, Balley EJ. Comparison of the activity of antibiotic combinations in vitro with clinical outcome and resistance emergence in serious infection by P. aeruginosa in neutropenic patients. J Antimicrob Chemother. 1980;19:321–329.
13. Tredget EE, Shankowsky H, Groeneveld A, Burrell R. 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. 1998;19(6):531–537.
14. Honari S, Gibran NS, Engrav LH, Carlson AR, Heimbach DM. Clinical benefits and cost effectiveness of Acticoat for donor sites. J Burn Care Rehabil. 2001;3:74–78.
15. Perlov CD, Barton R, Corley R, Shack RB. Managing difficult donor sites with silver-impregnated dressings. Poster presentation at the Symposium on Advanced Wound Care. Las Vegas, Nev. April 30–May 3, 2001.
16. Hanna MK, Slugocki GMJ, Hickerson WL. A prospective study comparing the efficacy and patients satisfaction of Xeroform gauze dressings versus Acticoat silver-coated dressings for the treatment of skin graft donor sites. Abstract Presented at John A. Boswick, M.D. Burn and Wound Care Symposium. Maui, Hawaii. February 2001.
17. Strohal R, Schelling M, Takacs M, Jurecka W, Gruber U, Offner F. Nanocrystalline silver dressings as an efficient anti-MRSA barrier: a new solution to an increasing problem. J Hosp Infect. 2005;60(3):226–230.
18. Voigt DW, Paul CN. The use of Acticoat and silver-impregnated Telfa dressings in a regional burn and wound care center: the clinicians view. WOUNDS. 2001;13(supplB2):11–20.
19. Demling RH, De Santi L. The rate of re-epithelialization across meshed skin grafts is increased with exposure to silver. Burns. 2002;28:264–266.
20. Dunn K, Edwards-Jones V. The role of Acticoat with nanocrystalline silver in the management of burns. Burns. 2004;(1suppl30):S1–S9.
21. Yin HQ, Langford R, Tredget EE, Burrell RE. Effect of Acticoat antimicrobial barrier dressing on wound healing and graft take. J Burn Care Rehabil. 1999;Jan/Feb:S231.
22. DeLang BG, Sutherland JM, Peace LVN. Combination therapy using human fibroblast-derived dermal substitute and silver-impregnated dressing for chronic infected lower extremity diabetic ulcers. Poster presentation. Department of General Vascular Surgery, University of North Texas Health Science Center, Ft. Worth, Tex;2002.
23. Sibbald RG. A single centre, open-label pilot study to determine the effects of application of Acticoat™ 7 antimicrobial barrier dressing in the treatment of chronic venous leg ulcers. Oral presentation. Second World Union of Wound Healing Societies’ Meeting. Paris, France. July 2004.
24. Sibbald RG, Brown AC, Coutts P, Queen D. Screening evaluation of an ionized nanocrystalline silver dressing in chronic wound care. Ostomy Wound Manage. 2001;47(10):38–43.

Product classification

Dear Editor,
    In the January 2006 OWM editorial, “A New Year: A Therapeutic Future for Wound Care”, the author speaks of “jettisoning the 20th century product classification which has stifled progress.” The Coalition of Wound Care Manufacturers welcomes an open public policy information exchange about procedural improvements to the current regulatory classification systems used by the Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS). We would like to clarify some misunderstandings presented in the editorial regarding the clinical research, development, and marketing of medical devices in the US.
Although we agree there are ways to improve the current classification systems and processes, it is important to note that the FDA and CMS processes and systems have allowed patient access to significant advances in the range of products available for the management of wounds that have been made over the past 30 years. Recent examples include antimicrobial dressings, bioengineered human tissue, negative pressure wound therapy, and platelet-derived growth factor gel. The wound care research and product development arenas have experienced explosive progress. Research and development progress has not been stifled.

    First, the author states that classifying wound products according to the main ingredients in reimbursement categories hampers progress in patient care. It should be noted that device manufacturers and their products are bound by specific regulatory classification systems established by Congress, the FDA, and the CMS. These systems are used for different purposes than what the author is focusing on (educating clinicians on the appropriate selection of wound dressing based on the patient and the wound) — rather, the CMS uses the Healthcare Common Procedure Coding System (HCPCS) to classify surgical dressings, historically employing complex criteria (including components, materials, and structural features of the product) as the basis for decisions regarding new HCPCS codes.

    Second, some of the author’s statements regarding the FDA approval process need clarification. Surgical dressing manufacturers submit evidence of safety, effectiveness, and other clinical data to the FDA before—and in some cases after—marketing a new or changing an existing product. Class I devices, exempt from the 510(k) process, are not exempt from FDA safety and effectiveness requirements. The FDA has determined that safety and effectiveness for many Class I devices are adequately ensured with general controls provided in the law and regulations. These include premarket requirements (device listing, establishment registration, and labeling requirements), postmarket surveillance controls (Good Manufacturing Practices and Medical Device Reporting regulations), and ISO 10993 standards for device safety testing (cytotoxicity, sensitization, irritation, and systemic and subchronic toxicity).

    Third, the author suggests that clinicians are asked to select products based on a main ingredient or physical characteristic rather than their function. It is the Coalition’s understanding that clinicians are not asked to make selections based on a regulatory classification; rather, they have the ability to use their best clinical judgment for the appropriate patient care. Most clinicians would not and should not use a regulatory classification system such as the FDA or HCPCS coding systems to determine which surgical dressing to use for their patients; the purpose for the design of this system is not based on clinical selection of the dressing for the patient. Furthermore, the design of the FDA and CMS classification systems was not intended to prescribe or limit the practice of medicine.

    Fourth, we agree that clinical data help facilitate the choice of product used and support the author’s endorsement of clinical studies. Manufacturers provide clinical data for their products related to the physical properties of the dressing. However, manufacturers are prohibited from making any claims related to superior clinical effect or faster wound healing.

    Finally, regarding the author’s claim that clinical trials may not be required for the possible reclassification of dressings containing silver as Class II medical devices, if the FDA reclassifies such dressings, manufacturers would still require submission through the FDA 510(k) substantial equivalence process in order to demonstrate product safety and effectiveness. Data to support such submission may include clinical trials depending on the types of claims being made and the risk associated with the device.

    Physicians and clinicians play a vital role in helping device manufacturers develop the next generations of wound products. For the continued advancement of wound management and treatments, clinicians must continue to communicate and collaborate with manufacturers concerning the needs of their patients. Clinician input on what is important to them and to their patients provides valuable insights into manufacturer research and development plans for new products that will advance patient care.
    Marcia Nusgart, RPh
    Executive Director
    Coalition of Wound Care Manufacturers

Reply
    It is encouraging that the manufacturer’s coalition 1) agrees improvements in wound care product classifications are needed and 2) endorses clinical studies. However, suggesting that clinical data “help facilitate the choice of product used” is an understatement. Clinicians must provide evidence-based care and are unable to do so without clinical outcomes data. To that end, as originally stated, the FDA does not require submission of clinical safety and effectiveness data for products that are Class I exempt (which includes most dressings) and may or may not require clinical data for silver-containing dressings. Hence, in the editorial, clinicians were reminded about their important role in the postmarketing surveillance control process described by Ms. Nusgart and encouraged to report adverse events.

    Manufacturers do not ask clinicians to make selections based on the regulatory or reimbursement classifications of their products — they never have. However, matching the needs of a wound and its expected outcome with the correct product remains an unnecessarily arduous process, especially for the non-expert clinician.1 Some believe wound care would be much simpler if a product were chosen based on what it does (eg, facilitates re-epithelialization, granulation tissue formation, and other processes), not according to its ingredients.1-4 Clinicians do not prescribe tablets containing polymers, corn starch, or agents derived from a particular bacterial strain nor is that how they are classified.

    It is encouraging that the Coalition requests the input of clinicians. We look forward to our readers joining the discussion.
    Lia van Rijswijk, RN, MSN, CWCN
    Clinical Editor

References
1. Baranoski S. Wound assessment and dressing selection. Ostomy Wound Manage. 1995;41(7A,Suppl):7S–14S
2. Ovington L, Peirce B. Wound dressings: form, function, feasibility, and facts. In: Krasner DL, Rodeheaver GT, Sibbald RG (eds). Chronic Wound Care: A Clinical Source Book for Healthcare Professionals, 3rd ed. Wayne, Pa: HMP Communications; 2001:311–319.
3. van Rijswijk L, Beitz J. The traditions and terminology of wound dressings: food for thought. JWOCN. 1998;25:116–122.
4. van Rijswijk L. Ingredient-based wound dressing classification: a paradigm that is passé and in need of replacement. J Wound Care. 2006;15(1):11–14.