Dressings have a major part to play in the modern management of wounds, whether they are closed, sutured wounds of surgical origin, or open wounds of various aetiologies, healing by secondary intention. Since George Winter described the value of the prevention of scab formation to promote the epithelialisation of experimental superficial wounds by using a moist wound environment (Winter, 1962), there has been a progressive exponential increase in the numbers and types of dressings available in clinical practice.
Progress and development has been considerable during the subsequent 40 years from the introduction of passive through to active dressings with sophisticated additional therapies (Leaper et al. 2002). Hydrocolloids, polyurethane films and foams and hydrogels were introduced for their exudate handling and ability to promote auto-debridement, and alginates and collagen-based dressings for an alleged promotion of granulation tissue (Cullen et al. 2002). Active dressings are now also available which allow the removal of cytokines and proteases, and this is most effectively achieved by topical negative-pressure (vacuum assisted closure) therapy (Thomas and Banwell, 2004), which is beginning to find a niche in wound management.
The basic tenet of keeping open wounds moist by use of dressings has not been challenged clinically and is still widely observed, but wounds should be kept neither too moist nor too dry (Fletcher, 2003). Management of wounds with dressings must be combined with optimal local wound care and systemic care, such as attention to holistic medicine and general nutrition, although the value of the latter is also unproven.
A major factor, common to all wound care, is the prevention of infection. However, infection control is a contentious issue, particularly against a background of the continuous and expanding number of resistant organisms. Systemically administered antibiotics should be reserved for treating invasive infection, and topical antibacterials used for superficial, local management of an open wound surface (European Wound Management Association, 2006). By contrast, topical antibacterials have been used for centuries and are still in widespread practice. Concerns about toxicity, or development of resistance to their antimicrobial qualities, have limited the use of some, but povidone-iodine, for example, is available in many different presentations for use as a topical antimicrobial (Teot, 2004) and is still to this day commonly used in the treatment of human wounds. In veterinary wound management it is less popular, but antimicrobial dressings are now being seen, which include silver and polyhexamethylene biguanide (PHMB)-impregnated dressings, as well as a resurgence in popularity of manuka honey as a topical antimicrobial dressing.
Antibacterial strategies
The evolution of antibiotic resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) and the clinical challenge they pose to wound management has been well publicised (Guyot and Layer, 2006). Resistance is an inevitable consequence of the widespread use of an antibiotic as selective evolutionary pressures are placed on those organisms that are resistant to its action. In human hospitals MRSA is most prevalent in surgical wards and long-term care facilities where indwelling devices are used (Coia et al. 2006).
Antibiotics were originally defined as naturally occurring antibacterial compounds produced by microorganisms such as fungi, although some are now chemically synthesised. An alternative is the use of purely synthetic antimicrobial agents that differ in mode of action from antibiotics and do not appear to generate resistance. A number of agents such as silver (Thomas and McGubbin, 2003) and iodine (Selvaggi et al. 2003) have been incorporated into wound dressings and other devices such as urinary catheters (Davenport and Keeley, 2005) for prophylaxis against urinary tract infection. Both iodine and silver have a long history as antibacterial agents with Egyptians implanting silver plates into skulls, with surgery. In ancient Greece and Rome, people used silver containers to keep liquids fresh. When settlers moved across the American West in the 1800s, they would purify a container of water by putting a silver dollar in it overnight, and silver dollars were used to keep milk from spoiling.
What is infection?
Infection is the main cause of delayed healing in primarily closed (surgical) wounds, traumatic and burn wounds. The recognition of a surgical site infection (SSI) is relatively easy when an incised wound presents with an extended, raised inflammatory margin (cellulitis) around the wound, sometimes associated with lymphangitis, raised local or systemic temperature and local pain. It is not so easy to define in open, wounds healing by secondary intention (Gardner et al. 2001; Cutting and Harding, 1994).
This overexpressed, inappropriate and uncoordinated inflammatory response relates to invasion of microorganisms through the normally intact resistant skin barrier. The bacteria release toxins and proteases, depending on their pathogenicity, which facilitates their spread. The host response, locally and systemically, may be overwhelmed, particularly in immunosuppressed patients, leading to bacteraemia, systemic inflammatory response syndrome, sepsis, organ failure or death. Infection may also be contained, as suppuration, or completely resolved depending on host response, bacterial load and virulence.
Silver dressings
Although silver has been used for centuries in water recycling and sanitisation, in complementary health care and to inhibit bacteria in food, the introduction of silver into wound care as an antibacterial, particularly in burns, is relatively recent.
There are a growing number of silver dressings (Figure 1), which are already available and are presented as creams, foams, hydrogels, hydrocolloids and polymeric films and meshes (e.g. Silvercel Ag (Systagenix), Acticoat (Smith and Nephew)). Each preparation claims different advantages, the common effect to all perhaps being the antibacterial action of silver. This latter characteristic is also being exploited in other medical devices (Furno, 2004), e.g. central (jugular) catheters.
Elemental silver (Ago) appears to have no antibacterial action or ionic charge, whereas its cation (Ag+) is highly reactive (Wright et al. 1998a). Unlike antibiotics, silver is toxic to multiple components of bacterial cell metabolism. These include causing damage to the bacterial cell wall, and altering membrane permeability leads to gross cellular structural changes, causing blockage of transport and enzyme systems such as the respiratory cytochromes, alteration of proteins and binding of microbial deoxyribonucleic acid and ribonucleic acid to prevent transcription and division. Like other antiseptics, silver is soon inactivated by protein binding, but this inactivation can also be caused by tissues and anions such as chloride, phosphate and sulphide. It is probable that the presentation of an immediate large bolus of silver with sustained release promotes the speed of bacterial kill (Ovington, 1999) and that rapid or sustained release of silver ions gives a wide spectrum of activity (Wright et al. 1998b). Dressings that can sustain release of silver do not need to be changed so often therefore their use is beneficial to both patient and owner.
Organisms do vary in their susceptibility to silver, but there is good evidence that silver has activity against the common pathogens, Staphylococcus aureus and Pseudomonas spp., which are commonly encountered in chronic wound care. The newer dressings present silver ions differently from silver nitrate and silver sulphadiazine (SSD) (Lansdown and Williams, 2004). These include forming unique Ag+/ Ago complexes by the use of nanocrystalline technology, or a high silver availability (Ag+) through other means, to give a large and effective sustained bolus delivery (Wright et al, 1998). The development of resistance is unlikely, as it is with other antibacterials such as povidone-iodine, as the antiseptic actions affect at least three bacterial cell systems (Ovington, 1999). Repeated exposure to low levels of silver may make resistance possible (Warriner and Burrell, 2005), and there is some in vitro evidence that this can occur (Li et al. 1997).
Systemic toxicity, argyria (a skin condition caused by improper exposure to chemical forms of silver), is unlikely as absorption from dressings is so small and probably depends on wound size (Lansdown et al. 2005). Nevertheless, argyria may theoretically result when there is a very large open wound and when dressings that release large amounts of silver ions are used.
Honeyww
The use of honey to treat wounds dates back to 2000 BC (Forrest, 1982). Numerous reports document the efficacy of honey in wound healing, and several studies even indicate that honey appears to be superior to many modern methods of treatment (White et al. 1963; White, 1966; Molan, 1999; Cooper and Molan, 1999).
Honey has been used for cleansing and accelerating the healing of wounds for centuries; however, the scientific basis for its success was not elucidated until the 20th century. Honey is currently used worldwide to treat human patients with contaminated wounds or infected body cavities. The use of honey to treat wounds on animals has been slow to come into acceptance.
Mechanisms associated with wound cleansing and healing properties of honey include decreased inflammatory oedema, attraction of macrophages to further cleanse the wound, accelerated sloughing of devitalised tissue, provision of a local cellular energy source, and formation of a protective layer of protein over the wound and a healthy granulation bed (Kamat, 1993). Honey also has a deodorising action; this may be due to its rich supply of glucose, which would be used by the infecting bacteria in preference to amino acids, resulting in the production of lactic acid instead of malodorous compounds (White, 1966).
Honey also has antibacterial properties that have been attributed to its high osmolarity, acidity, and hydrogen peroxide (H2O2) content (White, 1966). The effect of osmolarity in contaminated wounds is based on the low water content (or high osmolality) created in the wound (Chirife et al. 1982). As the high osmolarity of honey draws lymph from a wound, dissolved nutrients within the lymph provide nutrition for regenerating tissue (Molan, 1999).
The antibacterial factor inhibine has been isolated from honey produced from several different plant sources (White et al. 1963). Inhibine, which was determined to be H2O2, is produced by the natural glucose oxidase in honey. Glucose oxidase produces gluconic acid (which is the principal acid in honey) and H2O2 from glucose. Although H2O2 is primarily responsible for the antibacterial properties of honey, it is present at harmlessly low levels. H2O2 is continuously produced by the activity of the glucose oxidase enzyme, which is only activated when diluted (White et al. 1963). The concentration of H2O2 that accumulates in 1 hour is approximately 1000 times less than that found in the H2O2 solution (3%) that is commonly used as an antiseptic (Cooper and Molan, 1999), which means it does not damage tissues.
Honey is an excellent cellular energy source, provides a viscous barrier to wound invasion, and has a hygroscopic effect, which reduces oedema. Honey also has high levels of antioxidants, which protect wound tissues from oxygen radicals that may be produced by the H2O2 (Hyslop et al. 1995). H2O2 has been shown to be more effective against bacteria when it is continuously generated (Hyslop et al. 1995). The generation of low levels of H2O2 stimulates angiogenesis and the growth of fibroblasts. This increased angiogenesis increases oxygen delivery to tissues, which is a limiting factor for tissue generation (Molan, 1999). Topical acidification of wounds has been shown to promote healing (Kaufman, 1985); honey's low pH (3.6 to 3.7) will accelerate healing as well as increase antibacterial effects.
Most honey used in wound management is manuka honey (Figure 2) and there are a number of dressings containing manuka honey (Figure 3) (e.g. Activon (Dechra), Manuka ND and Manuka AD (Kruuse UK). The unique antimicrobial properties of manuka honey have been attributed in large part to the presence of methylglyoxal (MGO), which has been shown to originate from the high levels of dihydroxyacetone present in the nectar of manuka flowers (Adams et al. 2009; Mavric et al. 2008). MGO was found to be present in 100-fold higher concentrations in manuka than in other honeys (Mavric et al. 2008) and was confirmed as a significant bactericidal component of manuka honey (Kwakman et al. 2011).
Polyhexamethylene biguanide (PHMB) dressings
Antimicrobial peptides
Naturally occurring antimicrobial peptides (AMPs) were discovered about 25 years ago and have been found to be produced by the majority of living organisms. About 600 different AMPs have been identified. These AMPs have a broad spectrum of activity against bacteria, viruses and fungi and have been suggested as therapeutic alternatives to antibiotics (Hancock and Sahl, 2006). AMPs are positively charged molecules that bind to bacterial cell membranes and induce cell lysis by destroying membrane integrity; in effect rupturing the bacterial cell membrane meaning the bacteria can no longer survive. This mechanism of cell killing is similar to that found with antibiotics such as the penicillins and cephalosporins, which act by interfering with cell wall synthesis to cause cell fragility and lysis. They can be produced by many cells at the wound site, such as keratinocytes and inflammatory neutrophils, where they are considered to play a role in protection against infection (Sorensen et al, 2003).
A number of synthetic compounds with the antimicrobial activity of AMPs have been produced as alternatives to conventional antibiotics. One of these — PHMB — has a chemical structure similar to AMPs. This allows it to insert into bacterial cell membranes and kill bacteria in the same way as AMPs. PHMB has been demonstrated to block Pseudomonas aeruginosa-induced infection and prevent its degradation of wound fluid and skin proteins in vitro (Werthen et al, 2004).
Resistance and infection control
PHMB can be considered an antiseptic rather than an antibiotic. As mentioned, antiseptics have multiple targets of action, which means bacteria are less likely to generate resistance mechanisms (Gilbert, 2006). However, bacteria can protect themselves by pumping some antiseptic agents out of the cell using ‘efflux pumps’. PHMB acts to kill bacteria by integrating into the cell membrane and reorganising the membrane structure (Gilbert, 2006). This structural change prevents the cell from pumping PHMB out of the membrane and bactericidal concentrations are maintained in the cell.
PHMB in wound management
PHMB has been incorporated into a range of wound management products from several companies (Figure 4). The AMD range of infection control dressings (Tyco Healthcare, Basingstoke) is impregnated with 0.2% PHMB. The product range includes Telfa AMD non-adherent wound dressings, Kerlix AMD gauze dressings and AMD Foam dressings, another range of PHMB dressings is Suprasorb X + PHMB (Activa Healthcare) which contains 0.3% PHMB.
Conclusion
Resistant bacteria pose a continual problem in veterinary medicine, as much as human medicine. Healthcare professionals need to seek alternatives to the administration of antibiotics to patients, for their own health, as well as their patient's. The availability of antimicrobial dressings means there is now a first line alternative to antibiotics in the treatment of wounds, and the variety available means there are options for every stage of wound healing in veterinary patients. Topical antimicrobials should be used as first line in wound management in veterinary patients.
Key Points
- The basic tenet of keeping open wounds moist by use of dressings has not been challenged clinically and is still widely observed.
- A number of synthetic compounds with the antimicrobial activity of antimicrobial peptides have been produced as alternatives to conventional antibiotics.
- Antiseptics have multiple targets of action which mean bacteria less likely to generate resistance mechanisms.
- Honey has antibacterial properties that have been attributed to its high osmolarity, acidity, and hydrogen peroxide (H2O2) content.
- Infection is the main cause of delayed healing in primarily closed (surgical) wounds, traumatic and burn wounds.
- Unlike antibiotics, silver is toxic to multiple components of bacterial cell metabolism.
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