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FEATURES: CLINICAL MANAGEMENT EXTRA

Update: Topical Antimicrobial Agents for Chronic Wounds

Sibbald, R. Gary MD, DSc (Hons), MEd, BSc, FRCPC (Med)(Derm), FAAD, MAPWCA; Elliott, James A. MSc, BSc; Verma, Luvneed MAcc, BSc, MDc; Brandon, Alisa MSc, BSc; Persaud, Reneeka MD; Ayello, Elizabeth A. PhD, RN, ACNS-BC, CWON, ETN, MAPWCA, FAAN

Author Information
doi: 10.1097/01.ASW.0000524471.28441.b9

Abstract

INTRODUCTION

As the population ages, chronic wounds represent an increased burden to patients, healthcare professionals, and healthcare systems. These chronic wounds (present for >6–12 weeks) take longer to heal than regular wounds and are often not treated effectively. Worldwide, annual estimates of chronic wounds include 4.5 million pressure injuries, 9.7 venous leg ulcers (VLUs; although there are many other leg ulcer etiologies), and 10 million diabetic foot ulcers. Diabetes incidence is growing worldwide, and healthcare systems are going to be challenged to effectively manage diabetic foot ulcers to prevent lower-limb amputations.

Critical colonization that can be treated topically and deep and surrounding infections are complications of chronic wounds that delay healing and increase associated healthcare costs.1 Wound-related bacterial damage occurs in the surface compartment and can be treated topically; infections of the deep and surrounding compartments require systemic treatment.

To help illustrate the difference between infection in the superficial and deep tissue compartments, consider the analogy of a thin layer of soup in a bowl. The bottom of the bowl is a continuous compartment, with the sides representing the deep and surrounding compartments of a wound. The thin layer of soup represents the superficial critical colonization and changes on the wound surface that can be altered by topical therapy.

This article focuses on the superficial compartment and the appropriate use of topical antimicrobial therapies. The authors examined recent literature for the use of topical antimicrobials in chronic wounds. Topical antibiotic agents popular in the past such as mupirocin present several potential complications for patients with chronic wounds including bacterial resistance with a single mutation, contact allergy, inability to provide moisture balance or moisture reduction, and the lack of autolytic debridement. The last 40 years have seen the introduction of new classes of antiseptic dressings for critically colonized wounds.

Wound Classification for Healability

The wound bed preparation paradigm provides a comprehensive approach to chronic wound care that requires treatment of the wound cause and addressing patient-centered concerns (Figure 1).2

Figure 1.
Figure 1.:
WOUND BED PREPARATION PARADIGM 2015© WoundPedia, reprinted with permission.

As part of the initial assessment, the ability of the wound to heal needs to be determined (Table 1). Classification of the wound as healable, maintenance, or nonhealable will impact the provider’s specific choices for local wound care including topical antimicrobials and determining whether anti-inflammatory drugs may be beneficial.

Table 1.
Table 1.:
WOUND HEALABILITY, DEBRIDEMENT, INFLAMMATION/INFECTION MANAGEMENT, AND MOISTURE BALANCE

Most patients can have the wound cause corrected and have adequate blood supply to heal (healable wound). However, not all wounds are healable because of systems or patient limitations. Patients may not be able to afford protective footwear or wear them at all times. Similarly, a patient with a VLU may not wear compression bandages or be unable to afford compression stockings to prevent recurrence.

With corrective interventions, a maintenance wound may be reclassified as healable, or maintenance therapy will aim to prevent wound deterioration. A patient with a major illness, inadequate or uncorrectable vascular ischemia, or multiple comorbidities (eg, cancer, uncontrolled autoimmune disease, or immunosuppressive drugs that may interfere with healing) can render a wound nonhealable.

NERDS

Five clinical signs, known as NERDS, can be used to identify critical bacterial colonization. A validation study confirmed that a wound possessing any 3 of the 5 NERDS criteria (73.3% sensitive, 80.5% specific) would be an indication to prescribe a topical antimicrobial agent (Figure 2).3

Figure 2.
Figure 2.:
THE CONCEPT OF NERDS AND STONEES SUPERFICIAL CRITICAL COLONIZATION VERSUS DEEP AND SURROUNDING INFECTION© WoundPedia, reprinted with permission.

Each of the letters in the NERDS mnemonic represents a clinical sign:

  • Nonhealing is a measure of the length × width that did not get smaller or increase in size over a 4-week period, indicating that the proinflammatory environment on the wound surface has prevented healing but that bacteria have not invaded the sides of the wound.
  • Exudate is increased as a sign of irritation on the surface of the wound. The exudate may macerate the surrounding skin if the dressing cannot handle the increased discharge.
  • Red friable tissue on the wound surface indicates that vascular endothelial growth factor will produce more blood vessels than needed for mature granulation tissue. This is often bacterially stimulated and leads to a loose exuberant granulation tissue that may rise above the wound surface and will leave a blood stain when a dressing is removed. This tissue is different from firm pink granulation at a level surface with the wound edge that would promote re-epithelialization.
  • Debris on the wound surface (often yellow, brown, or black loose slough) is a result of surface cell death from local hostile conditions for viable cell growth and proliferation.
  • Smell is the result of proliferation of gram-negative bacteria and anaerobes.

STONEES

By a similar analogy, a wound that presents with any 3 of the 7 STONEES criteria indicates the potential need for systemic therapy. Four of these criteria come from the marginal surface of the wound:

Size is increasing,

Temperature of the surrounding skin by infrared thermometry is greater than 3°F compared with the same area on the opposite side of the patient’s body,4

Os is the Latin word for bone—probing or exposited—and increased Exudate or Smell as outlined above in the NERDS criteria.

New areas of breakdown with small satellite areas of breakdown in the wound margins, and

Erythema (often difficult to determine in brown or black skin) and/or

Edema of the surrounding skin (otherwise known as cellulitis).

Three criteria are derived from the deep wound compartment:

New or localized wound-related pain is an additional symptom that acts as supporting evidence to the clinical signs criteria for critical colonization or deep and surrounding infection.

RECENT LITERATURE ON TOPICAL ANTIMICROBIAL DRESSINGS

The authors searched MEDLINE (PubMed), the Cochrane Library, University of York Centre for Reviews and Dissemination database, and Google Scholar for systematic reviews, health technology assessments, high-quality randomized controlled trials (RCTs), and narrative review articles published from January 2012 to June 2017. Hand referencing was utilized. Burn, acute, traumatic, and postsurgical wound literature was excluded from this review. For topical antimicrobial therapies, where no high-quality studies could be found, lower-quality evidence was used to supplement findings along with expert knowledge. Search strings used are outlined in Table 2. This search was supplemented by landmark articles as per author judgment and a process similar to guideline synthesis.

Table 2.
Table 2.:
SEARCH STRINGS UTILIZED

TOPICAL ANTIMICROBIALS FOR HEALABLE WOUNDS

The following sections will discuss categories of topical antimicrobial therapies. Particular attention will be given to chemical composition, form, function, and clinical application. When there is not high-quality (RCT) evidence for an agent, this will be stated; however, the Cochrane reviews advise that “the lack of reliable evidence means that it is not possible to recommend discontinuation of any of the agents reviewed.” Based on this, the authors have indicated the current logical best practices for each of the following commonly used topical antimicrobial agents: polyhexamethylene biguanide (PHMB), silver, iodine, methylene blue/crystal violet (MB/CV), and honey.

Polyhexamethylene Biguanide

In wound dressings, PHMB is a positively charged polymer with a hydrophobic backbone and cationic groups separated by hexamethylene chains.5 This structure allows PHMB to bind to the negatively charged bacterial cell wall. When PHMB attaches to the acid membrane elements of the bacteria, the bacteria subsequently lose fluidity, causing separation of the individual membrane lipids and dissolution of the bacterial cell. This bactericidal mechanism means there are no residual organisms left alive to facilitate resistance.

Polyhexamethylene biguanide has been combined in gauze and foam dressing formats. Polyhexamethylene biguanide foam dressings are best utilized for healable surface wounds with exudate. Polyhexamethylene biguanide gauze packing is appropriate for a deep exudative wound that would benefit from antibacterial action. These dressings do not release the PHMB; rather, bacteria are killed in the compartment above the wound in the dressings. The effect is microbicidal for a broad spectrum of bacteria, yeast, and viruses.

One high-quality systematic review by Canadian authors6 supports PHMB use in chronic wounds. A recent low-quality narrative review covers practical advice, suggesting that while PHMB is effective in preventing critical wound colonization it may not be effective in destroying the biofilm of colonized wounds.7

In a 4-week, 45-patient RCT, a nonrelease PHMB foam was compared with foam alone. Surrogate outcomes favored the use of PHMB foam.5 The PHMB foam dressing was a significant predictor of reduced wound superficial bacterial burden (P = .016) at week 4 as compared with the foam alone. Pain reduction was also statistically significant at week 2 (P = .0006) and at week 4 (P = .02) in the intervention group. Polymicrobial organisms were recovered at week 4 in 5.3% of the PHMB foam dressing group patients versus 33% in the control group (P = .04). Subjects randomized to the PHMB foam dressing also had a 35% median reduction in wound size by week 4, compared with 28% in the control group, but this result did not reach statistical significance because of the small sample size of patients.

Additional supporting evidence is tabulated in Table 3.

Table 3.
Table 3.:
RECENT EVIDENCE ON POLYHEXAMETHYLENE BIGUANIDE TOPICAL DRESSINGS

Silver

Silver is ideally suited to healable wounds with critical colonization. It is an antibacterial agent in an ionized form that requires an aqueous environment. Ionized silver can attack at least 3 cellular components: cell membranes, cytoplasmic organelles, and DNA, so resistance is uncommon. Silver is most often combined with calcium alginates, hydrofibers, foams, and hydrogels and used as a coating on mesh-type structures with the appropriate moisture balance chosen for sustained release and exudate management to avoid periwound maceration. Topical silver can be combined with foam dressings so that the ionized silver can be released slowly in response to wound exudate. For nonhealable or maintenance wounds where moisture reduction is the target, silver is not indicated because silver cannot remain in an ionized state on a dry surface.2

Topical silver dressing studies were extensively reviewed by Leaper9 in an international consensus published in 2012, which concluded that silver dressings may be effective at reducing bacterial burden in critically colonized wounds.

Münter et al10 reported surrogate wound outcomes in a 4-week trial of 619 patients comparing silver foam versus local best practices. The silver foam had a significantly higher median reduction in ulcer area compared with the control group (47.1% vs 31.8%; P = .0019). The silver group also had significantly improved (P <.05) exudate handling, ease of use, odor reduction, and pain control.

Carter et al11 in 2010 conducted a systematic review of 10 leg ulcer RCTs with 38 to 619 patients in each of the studies. This review found some evidence that silver-impregnated dressings improved the short-term healing of leg ulcers, especially in the first 4 weeks; however, the longer-term effectiveness requires more study.

The more recent publications on silver as a topical antimicrobial agent, summarized in Table 4, emphasize the gaps in current knowledge and the need for further studies. There are also recommendations for decision makers that cost-effectiveness and patient preference should be key elements for dressing selection.

Table 4.
Table 4.:
RECENT EVIDENCE ON SILVER-BASED DRESSINGS

Iodine

Iodine is a natural, nonmetallic element that is essential for the production of thyroid hormone. Iodine has several antimicrobial actions including blocking bacterial cell efflux pumps, interfering with cellular respiratory processes, changing DNA structure, and denaturing cellular proteins and enzymes. Patients on iodine for large wounds or extended periods should have thyroid function tests at regular intervals as hypothyroidism or hyperthyroidism can be induced by iodine wound dressings.2

Iodophors, developed in the 1950s, are safer, slow-release iodine delivery systems.18 The 2 most commonly used iodophors in modern wound dressings are povidone iodine (PVP-I) and cadexomer iodine. Povidone iodine is a chemical complex of polyvinylpyrrolidone and elemental iodine. It is available as a slow-release dressing (knitted viscose mesh) in some regions (eg, Canada and Europe), along with 7.5% to 10% solution formats, creams, ointments, and sprays. Cadexomer iodine is an absorptive polysaccharide that absorbs exudate and provides autolytic debridement along with a slow release of iodine into the wound bed.18

In a recent review of iodine, the following concluding statement summarized the literature review19:

“Although it has been speculated that iodine delays healing and is cytotoxic, there is substantial evidence to suggest that the commonly used low-concentration, slow-release iodophors improve healing rates and are effective as highly potent antimicrobials with a broad spectrum of activity, including antibiotic-resistant strains such as MRSA [methicillin-resistant Staphylococcus aureus]. It is unfortunate that the concerns about iodine are based on studies that are so varied in method and design that it is difficult to draw reliable comparisons and conclusions…. but it is now widely accepted that slow-releasing iodophor antimicrobials are safe and have minimal detrimental impact on wound healing.”

The recent evidence summarized in Table 5 adds further support for cadexomer iodine for the improved healing of VLUs and the utility of PVP-I for nonhealable or maintenance wounds.

Table 5.
Table 5.:
RECENT EVIDENCE ON IODINE

Methylene Blue and Crystal Violet Foam Dressings

This product is a relatively nonrelease foam dressing with 2 agents, MB and CV, which produce a redox (oxidation-reduction) environment inhibiting the growth and survival of bacteria. There are 2 foam formats. The original polyvinyl alcohol foam needs to be partially hydrated to bind surface slough and provide autolytic debridement. The foam structure facilitates wicking and moisture retention/moisture balance. The more traditional polyurethane dressing is similar to most other foam products in its fluid-handling characteristics without autolytic debridement.2

Recent evidence on MB/CV is outlined in Table 6.

Table 6.
Table 6.:
RECENT EVIDENCE ON METHYLENE BLUE AND CRYSTAL VIOLET

Honey

Honey has been used in wound care for centuries because of its antibacterial and anti-inflammatory properties. Its acidic pH (3.2–4.5) and high sugar content (osmolality) make the local wound environment hostile to bacteria. Hydrogen peroxide released by honey is antibacterial; however, this action can be neutralized by blood, serum, and wound exudate. Manuka trees and some other Leptospermum genus plants have bee-derived honey that also contains methylglyoxal, an additional and more stable antimicrobial component. Honey may lose its antibacterial action when diluted with wound exudate, but this may not increase the incidence of bacterial resistance.2

Medical-grade honey should be used instead of honey from food sources. This is because bacterial spores, including Clostridium species, can persist in honey and have the potential to cause disease if activated.

Recent literature is summarized in Table 7. The following quote best summarizes the evidence on the use of honey in chronic wounds: “Current evidence does not support the routine use of honey. However, the lack of reliable evidence means that it is not possible to recommend the discontinuation of any of the agents reviewed.”12

Table 7.
Table 7.:
RECENT EVIDENCE ON HONEY

There may still be a role for honey in specialized patients where autolytic debridement is required for hard, fibrous surfaces or in wounds that need an increased moisture content.25

WOUND-PACKING MATERIALS

Wound-packing materials are required for deeper wounds (eg, Stages 3 and 4 pressure injuries). When packing a wound, clinicians need to match form to function. The packing materials listed in Table 8 are related to their key properties. Dry gauze will absorb exudate, but it is not antibacterial, and bacteria can grow in the gauze and contaminate the wound surface. Moist saline gauze will donate moisture to the wound surface, but again, it is not antibacterial and may facilitate wound contamination. With low host resistance, contamination can lead to critical colonization, then potential deep and surrounding infection.

Table 8.
Table 8.:
THE PROPERTIES OF COMMON WOUND-PACKING MATERIALS

Both PHMB gauze and iodine-saturated ribbon gauze are antibacterial. The PHMB gauze will sterilize the compartment above the wound by killing bacteria that penetrate the gauze. This mechanism relies on host resistance to clear the bacteria on the wound surface with a decreased number of contaminating organisms. Iodine-saturated ribbon gauze will deliver iodine to the surface of the wound, as long as there is an orange color in the gauze. There is probably less toxicity from PVP-I on the wound surface than predicted by in vitro studies.19 As soon as critical colonization is reversed, PHMB ribbon gauze may prevent surface bacterial contamination and relies on host resistance to prevent the return of critical colonization.

TOPICAL ANTISEPTIC AGENTS

Topical antiseptic agents are often used in maintenance and nonhealable wounds where tissue toxicity may not be as important as the agents’ antibacterial properties.

Chlorhexidine is related to PHMB and is available in antiseptic preparation solutions for the operating room or minor surgeries; mouthwash formulations with aqueous bases that will not burn or sting open skin; and petrolatum-type tulle dressings that have a nonrelease format to minimize bacteria in the compartment above the wound.

Polyhexamethylene biguanide is often used as a preservative in eye and ear preparations, which adds indirect evidence to its low toxicity. It is a large molecule, so percutaneous penetration is minimal.

Povidone iodine may also be used to paint around the edge of a maintenance wound or an area of gangrene. The infection of the deep and surrounding tissue will usually begin at the proximal edge of the gangrene, and this is where it is more important to paint the PVP-I to minimize bacterial invasion.

Compresses with diluted acetic acid (0.5%–1%) can lower wound pH and create a hostile environment for Pseudomonas and other bacteria that prefer an alkaline environment. Pseudomonas can often be treated topically, preferably with 2 agents (eg, acetic acid compresses and PVP-I or cadexomer iodine). If gram-positive and other bacteria are treated systemically, it is often not necessary to use oral agents against Pseudomonas, even for diabetic neurotrophic foot infections.27 More recently, hypochlorous acid has been utilized in some clinics in a similar fashion.

Other antiseptic agents in the red categories of Figure 3 have higher tissue toxicity and are not currently recommended for routine use in chronic wounds.

Figure 3.
Figure 3.:
SELECT ANTISEPTIC AGENTS LISTED BY INCREASING CYTOTOXICITYNB: Agents are color-coded by safety profile and antiseptic action. Green = low toxicity potential; yellow = no antibacterial effect; red = high toxicity potential.

CONCLUSIONS

Topical antiseptic agents are recommended for critically colonized chronic wounds. Patients should be carefully monitored every 2 to 4 weeks, and if the critical colonization persists, deep and surrounding infection, inadequate treatment of the cause, or patient-centered concerns should be reassessed. For all wounds, cleansing with agents that lower surface pH (into the acidic range) may aid in bacterial reduction, especially for gram-negative bacteria including Pseudomonas.

For healable wounds, moisture balance can be complemented with local care for critical colonization. Clinical options include silver dressings, slow-release iodine, medical-grade manuka honey, nonrelease PHMB, or MB/CV dressings. Additional criteria for dressing selection may be based on formulary availability, cost-effectiveness, and patient preference.

Nonhealable or maintenance wounds are best served with moisture reduction and topical antiseptics that may include PVP-I or chlorhexidine (or its derivative PHMB). Each patient must be considered individually, and wounds assessed for pain, local wound fragility, and tissue viability in order to make the best choice for local wound care utilizing the wound bed preparation paradigm.

PRACTICE PEARLS

  • Topical antimicrobial use should be based on 3 or more NERDS signs.
  • Silver is anti-inflammatory but needs an aqueous base, not a dry environment.
  • Iodine is effective in aqueous and dry environments and penetrates biofilms because of its proinflammatory properties.
  • Polyhexamethylene biguanide is a nonrelease antimicrobial agent that provides bacterial action above, but not on the surface of, wounds.
  • Honey is antibacterial and provides oncolytic debridement, but more evidence is required to support routine chronic wound usage.
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        Keywords:

        antimicrobial agents; iodine; polyhexamethylene biguanide; silver; topical agents; wound healing

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