Topical Antimicrobials in the Control of Wound Bioburden—Part 2
Commonly Used Antiseptics
Iodine. Iodine (particularly in the safe, modern, formulations of the iodophor povidone iodine [polyvinylpyrrolidone iodine complex, or PVP-I] and cadexomer iodine) is a useful bacteriostatic and bactericidal agent shown to be effective against MRSA and other pathogens in in vitro and clinical studies.73-75
The slow release from the iodophor and cadexomer versions is intended to optimize activity and reduce toxicity. The use of PVP-I as a pre-surgical skin antiseptic is unquestioned76 although its value in wound antisepsis is subject to debate.56,57,75,77-79
Dressings containing iodine in slow-release formulations are considered safe and effective.68,80 The FDA maintains that PVP-I in 5% to 10% solutions does not adversely affect healing,81 although a later review of published data by Kramer82 disputes this view; specifically, evidence exists of toxicity in vitro. Lineaweaver83 states that povidone iodine at a concentration of 0.001% is bactericidal and non-cytotoxic to fibroblasts in vitro.
Iodine as the PVP-I iodophor is available in a range of concentrations as medicated dressings, solutions and ointments, powders and sprays, and incise drapes. The cadexomer is a polysaccharide starch lattice containing 0.9% elemental iodine that is released on exposure to exudate57 and has antimicrobial activity for up to 3 days.73 It has been extensively evaluated in a variety of acute and chronic wounds and found to be safe and effective80 in reducing bioburden.
The PVP-I and cadexomer-containing dressings provide sustained release of low levels of free iodine in the presence of moisture. Consequently, for best effect, modern iodinated dressings should only be used on exuding wounds. Iodine is also available as Iodoform and as an alcoholic tincture. Neither is regarded of clinical value in wound management due to stinging pain from alcohol.
Silver. Silver and silver compounds have been routinely used as antimicrobials for more than a century. Silver is generally recognized as a safe, broad-spectrum agent with minimal adverse effects. Only irritation and skin discoloration (argyria) have been reported.84
Silver acts as a heavy metal by impairing the bacterial electron transport system and some of its DNA functions.85,86 This occurs only when the active agents —silver ions Ag+ — are bioavailable (ie, able to enter the cell) at the correct concentration in solution.87 Although debate continues over the level of silver ions required to kill bacteria, the literature supports the oligodynamic property of activity at very low levels (parts per million). Silver ions at parts per billion (10-9mol/L or nanomolar) have been shown in vitro to be bactericidal88 and able to destabilize biofilms of S. epidermidis.44
Silver nitrate was probably the first silver compound used on wounds with an astringent and irritating effect. As a result, it is rarely used today except to occasionally reduce hypergranulation. The esterification (chemical bonding) of silver with a sulphonamide antimicrobial —SSD — has resulted in a safe, broad-spectrum agent for topical use. Silver is released slowly from the oil-in-water cream formulation in concentrations that have been shown in clinical and pre-clinical studies to be selectively toxic to micro-organisms such as bacteria (MRSA, gentamicin-resistant Pseudomonas spp. and Enterococcus spp.) and fungi.47 The 1% cream of SSD has been a mainstay of topical burn therapy89 and has been used successfully in acute90 and chronic wounds91 to treat infection. Resistance to SSD has been reported92 but is rare.
A variety of topical silver preparations has been evaluated on chronic wounds93,94 in controlled trials with favorable results. Recently, a number of silver-containing dressings have become available.84,95-98 In any formulation, the way silver is incorporated and how it interacts with micro-organisms over time (ie, its bioavailability in solution) are critical in determining the product’s antimicrobial efficiency and safety.87 Although the delivery systems vary from one dressing to another, the mode of action principle is the same in each case. The silver ion Ag+ is the antimicrobially active entity.99 Currently, few if any clinical evidence study results are available to support specific silver products (no randomized, controlled studies exist on the use of silver-containing dressings in the treatment of diabetic foot ulcers100 or other wounds). A study101 currently underway at the University of Sheffield, UK, is investigating the cost effectiveness of a variety of silver antimicrobial dressings in the treatment of venous leg ulcers. The rationale is based largely on in vitro studies,95,96 non-comparative trials, and case studies. Preliminary findings from microcalorimetry102 suggest that not all silver products can be expected to be equally effective. Products that can sustain the interaction of silver with micro-organisms in the exuding wound are likely to be more effective in controlling infection. The dressing may have an ancillary action, such as exudate uptake, that will help differentiate it for the practitioner. Recently, silver dressings based on hydrocolloid and foam,103 alginate,104 and hydrofiber97,105 have been marketed.
Chlorhexidine and polyhexanide compounds. Chlorhexidine (a biguanide) has been used clinically for about 50 years.106 Proven to be a useful antiseptic for skin, it is a highly effective hand-washing and surgical scrub. Chlorhexidine binds to the stratum corneum and remains active for at least 6 hours after application.63 The acetate form of chlorhexidine is intended for wound irrigation; the gluconate form of chlorhexidine is active against Gram-negative organisms such as P. aeruginosa and Gram-positive organisms such as S. aureus and Escherichia coli, although MRSA resistance has been recorded.107 Although toxicity and use on wounds has not been established categorically (thorough human in vivo research is not available), chlorhexidine may be a useful therapeutic agent for topical use.108 Dental studies on perioperative use of chlorhexidine rinse have shown that it reduces microbial complications.109 While chlorhexidine currently appears to have few adverse effects on healing, judgment should be reserved regarding long-term safety and efficacy.
Polyhexanide, a fast-acting biguanide compound (polyhexamethylene biguanide PHMB), has been found to be effective in in vitro and clinical studies against a broad spectrum of micro-organisms including human immunodeficiency virus (HIV).110 Its structure and mode of action are similar to antibacterial peptides that function by disrupting microbial membranes. No known resistance to polyhexanide has been reported, most likely due to rapid and non-specific bactericidal activity.111 Polyhexanide has been evaluated in wounds in a comparative clinical trial.112
Other topical antimicrobial agents.
Honey. The use of honey in wound care is largely confined to wounds healing by secondary intent; historically, generic honeys have been used in this context for thousands of years. Recently, a resurgence of interest in honey has occurred, prompted mainly by the ability to differentiate honeys according to their antimicrobial effects.113,114 One particular honey, obtained from the blossom of a Leptospermum or New Zealand Tea Tree (commonly known as Manuka honey) has been demonstrated to be antibacterially and clinically effective in a wide variety of acute and chronic wounds,115,116 although this is not the only honey exhibiting these properties. The published clinical evidence on honey in wound management has been reviewed elsewhere.71 Recent regulatory approval of Medical Device-grade honey dressings in Europe also has increased interest and usage.
Potassium permanganate. Potassium permanganate is an oxidizing agent used in weak solution (1 part in 5,000 to 1 part in 10,000) as a soak to cleanse and deodorize eczematous wounds and leg ulcers.117 Although favored by some dermatologists, only anecdotal reports support its use.118,119 Any perceived clinical value may be derived from its astringency, which produces a transient localized vasoconstriction leading to a reduction of exudate.
Sodium hypochlorite. The value and use of sodium hypochlorite has been debated for years; healthcare professionals have been polarized into a majority that vehemently oppose its use under any circumstances120 and a minority that still regard it as useful. In the UK in particular, the use of hypochlorites such as EUSOL or Dakin’s solutions is controversial.121 Similarly, the damaging effects of hypochlorites on endothelial cells, fibroblasts, and neutrophils in vitro have been reported.83,122,123 The consensus on hypochlorites, especially among nurses, is that they have no place in wound care, regardless of the concentration used.124 This view is based on evidence that they are rapidly deactivated in the presence of pus, painful to the patient, and delay healing by damaging cells and capillaries.125 However, recent developments in the form of a modified hypochlorite126 and that of a hypochlorous acid agent may have overcome many of the safety objections to traditional hypochlorite solutions.59
Acetic acid. Weak solutions of acetic acid have been used to eliminate Pseudomonads from wounds. Such use stems from the known sensitivity of these organisms to a slightly acid pH.127 However, available data do not support the use of acetic acid, particularly in comparison with other antimicrobial agents.128
Antibiotics. Although appropriate systemic antibiotics are considered to be essential for the treatment of clinically infected wounds,6,7,129 the use of topical antibiotics is not justified for the routine treatment of colonized or infected wounds.130 Topical antibiotics can provoke delayed hypersensitivity reactions131 and superinfections132 and, more importantly, select for resistance.133 This is particularly evident with antibiotics used both topically and systemically (eg, gentamicin, metronidazole, sodium fusidate, chlortetracycline). Antibiotic resistance has become a serious problem for those involved in wound care. In the US, the situation has been called a “crisis”134 and an “epidemic.”135 Routine use of topical antibiotics in the management of clinically infected leg ulcers has been shown to be of no benefit136 and some evidence shows it may be harmful because it encourages colonization by resistant organisms.137
Topical antibiotics might overcome the target site delivery issue but the general argument against using them in this way is a concern that resistance selection might be worse than for systemic administration.49
Therefore, antibiotics also used for systemic administration tend to be retained for that use only. Mupirocin can be used as a non-systemic (topical) antibiotic. Another disadvantage of topical antibiotic use is the frequent occurrence of contact allergy; neomycin and framycetin are particular examples.138
For these reasons, the topical use of antibiotics in open wounds is generally no longer recommended, with certain exceptions for particular indications — most notably, metronidazole for malodorous fungating wounds.139 Administering systemic antibiotics for soft tissue clinical infection remains the gold standard therapy129 with or without topical antiseptics.6 The route of administration is predominantly dependant on the speed required to achieve therapeutic levels at the target site in the context of the clinical severity of the case. Clinical severity suggesting the need for parenteral administration includes cellulitis that has extended beyond the immediate local wound area and is continuing to spread and any sign of a systemic host reaction to the wound infection such as pyrexia or confusion.129 In some cavity wounds, particularly sacral pressure ulcers, deep wound extension may present without cellulitis; this may be considered a sign of severity, necessitating intravenous antibiotics.
The detailed reviews conducted by O’Meara et al93,94 and the Scottish Intercollegiate Guidelines Network140 have found little evidence to support the routine use of systemic antibiotics in patients with chronic wounds, although a small, randomized controlled study141 showed benefit in reducing complications in diabetic foot ulcers. However, acute, spreading infections in chronic wounds should be treated with systemic antibiotics.7
Mafenide. Mafenide is a sulphonamide antibiotic marketed as mafenide acetate cream for topical application. It has been widely used for the treatment of burns for more than 30 years142,143 and recently used in chronic wounds.144,145 However, as with the application of any cream formulation to a wound, the risk of maceration from the water content and allergic contact dermatitis, both from the active and the excipients (inactive ingredients), is present,131,146,147 particularly in patients with leg ulcers.138,148,149
Mupirocin. Nasal carriage infection is a consideration for S. aureus infections.150 Mupirocin, a narrow-spectrum, topical application-only antibiotic, was developed to eradicate MRSA carriage,151 although low-level resistance (mupirocin is still effective when applied in clinical quantity) is now common and high-level resistance also has been documented.152 Studies have shown that clinically significant reductions in the rate of nosocomial S. aureus infections (P = 0.06) are achieved following use of mupirocin153; it has not been studied in wounds.
Fucidin/fusidic acid. Fucidin/fusidic acid is a narrow-spectrum agent effective against S. aureus. Its good bone penetration makes it useful in the treatment of osteomyelitis.154 Fusidic acid resistance in S. aureus isolates, resulting from use of topical preparations, has been noted in the UK.155,156
Neomycin, polymyxin, and bacitracin. The over-the-counter (OTC) triple antibiotic ointment (TAO) containing neomycin, polymyxin, and bacitracin is widely used in the US. It has been found to inhibit coagulase-negative Staphylococci, P. aeruginosa, and Enterobacteriaceae; S. aureus resistance to TAO is only 5%, rare after extensive OTC use, and not adversely influenced by decades of parenteral aminoglycoside use. The triple antibiotic maintains a wider spectrum of activity compared with mupirocin and is active in vitro against mupirocin-resistant Gram-positive strains.157 However, the benefits of these antibiotics must be balanced by the well-known risks of sensitization, particularly when using neomycin158 and bacitracin.159
Wound Cleansing
Wounds are cleansed to remove excess exudate, foreign bodies (including dressing residues), necrotic tissue, loose slough, and wound edge crusting (fibrinous material, dehydrated exudate, and dressing residue), some of which are mediums for bacterial overgrowth. Cleansing that does not achieve any of these aims is unlikely to be of value and is more likely to cause harm by damaging fragile new tissue and inhibiting growth; thereby, delaying healing.112 Cleansing the wound and keeping it moist will help ensure that promotion of healing will progress unhindered.112
If wound cleansing includes the periwound skin, removal of exudate and dressing adhesive residues should reduce the likelihood of maceration. Maceration not only may delay healing, but it also can increase wound size. Similar outcomes may be expected if periwound skin is excoriated from exudate, enzymes, bacterial toxins, and skin pH disturbance.160
The ideal cleansing method depends on individual circumstances. Some patients may require rapid surgical/sharp debridement under anaesthesia; others need a more conservative approach. (Although debridement is technically cleansing, it is usually discussed as a separate issue.) Cleansing is usually provided via fluid irrigation or mechanically with a moistened wipe. For wounds healing by secondary intention, sterile normal saline (isotonic) may be used; however, this is expensive in comparison to tap water, which is often considered the fluid of first choice, provided the local supply is suitable for drinking. Studies on traumatic wounds by Hall Angeras et al161 suggest tap water presents no quantifiable infection risk. Tap water makes cleansing convenient — it can be performed in a sink under running water, in the bath or preferably shower, or in a bucket for leg ulcer ablution — with the added advantage of ease of cleaning surrounding skin. In a study of surgical wounds (1,200 head and neck wounds), Chrintz et al162 demonstrated no increase in wound infection rate when patients showered postoperatively.
Pressurized irrigation can be achieved with commercially available aerosol spray formulations. The pressure should be sufficient to dislodge loose debris and slough without causing tissue damage or by driving debris into the tissue. Whirlpool baths, for example, may cause damage to tissues in leg wounds.163 Spray cans deliver a pressurized stream of saline at 8 lb/square inch (55 k Pa) and it is reasonable to conclude that such delivery onto the flat surface of most wounds has the potential to generate airborne residue and subsequently increase the risk for cross-contamination of the practitioner and surrounding environment. Therefore, it would be ill-advised for use anywhere but the home (avoids nosocomial infection risk) while wearing suitable protective clothing. A disposable splashguard would make aerosol devices more viable.
Non-ionic surfactants in dilute solution as wound cleansers are an alternative to using water. They have been shown in vitro to have the advantage of not harming fragile tissue or compromising natural healing processes.50 Physiologically balanced surfactants are compatible with the normal pH of the skin.
Microbial colonization of open wounds is inevitable; cleansing can lower the bioburden transiently. The effect of wound cleansing solutions and techniques has been the subject of a major systematic review by Moore and Cowman.164 No studies comparing cleansing of the wounds to not cleansing were found. A difference between cleansing solutions was observed in one comparative study (Bellingeri et al 2004 cited by Moore and Cowman164); a statistically significant improvement in pressure ulcer healing was found for wounds cleansed with a saline spray containing aloe vera, silver chloride, and decyl glucoside compared to wounds cleansed with isotonic saline solution. However, the review concludes that “there is no good trial evidence to support use of any particular wound cleansing solution or technique for pressure ulcers.”164
Wound Dressings
In addition to contamination and cross-contamination benefits mentioned earlier, the use of modern dressings in infection control shows great promise. Medicated (silver and iodine complexes) dressings can be useful in the local control of bacterial bioburden provided the active agents — silver ions and elemental iodine — are available in solution at an appropriate concentration over time. Such dressings may, in turn, assist in infection control by reducing the numbers of wound pathogens available for cross-infection.
Malodor, common in chronic wounds, has been found to be associated with aerobic and anaerobic bacteria colonizing or infecting the wound.165 Odor-controlling dressings such as those containing charcoal can be very helpful.166 While odor control alone may not eradicate infection or alter bacterial growth, it offers substantial patient quality-of-life benefits and, therefore, should be an adjunct to any topical and/or systemic antibacterial therapy.167
The role of dressings containing antibiotics in wound treatment is generally diminishing primarily because of resistance and sensitization. However, a case can be made for the use of topical metronidazole gel in the palliative treatment of malodorous malignant (fungating) wounds where odor is a major problem and, because of the terminal nature of the underlying condition, antibiotic resistance is not an issue.168
Discussion
Antimicrobial agents limit the growth of susceptible strains but eventually resistant strains are likely to emerge. These agents do not induce the formation of resistant genes; they merely provide an environment in which sensitive species are curtailed and resistant species flourish. At one time, the development of resistance to antiseptics and disinfectants was considered remote but such thinking has been proven incorrect.46 Certain species such as bacterial spores, mycobacteria, and Gram-negative bacteria possess intrinsic resistance but plasmid-mediated acquired resistance to antiseptics and disinfectants in several bacteria also has been observed.46
The emergence of wound pathogens with patterns of multiple antibiotic resistance has serious consequences in the hospital environment,168 nursing homes,169 and the community.170 This “crisis”134 involves all skin wounds including leg ulcers171 and is compounded by the increasing costs of searching for new antimicrobials and the decreasing rate of discovery of new agents.45
The presence of different species of micro-organisms in the wound has been linked to delayed healing and wound odor. In a study of qualitative and quantitative microbiology of leg ulcers, Trengove et al172 found a significantly greater chance of impaired healing when four or more species were present. Although the definition of wound infection is not accepted unanimously,173,174 the consensus is that the essential signs are suppuration, cellulitis, lymphangitis, and bacteraemia. Many texts refer to >105 organisms per gram of tissue as a criterion for infection,175 although the relevance of this figure recently has been critically reconsidered1 — ie, this growth density, in isolation, has no confirmed connection to the threshold or degree of immune response or to healing176 and none at all if sampling is inaccurate.177
In critical colonization, the number of organisms and species is postulated to increase above the levels found in the colonized wound. Clinical signs for critical colonization (most notably, delayed healing3,178) are apparent, although this primarily complex microbiological phenomenon may become apparent retrospectively only once infection is diagnosed.179 Evidence supports the fact that delayed healing or the failure to heal in a chronic wound that has no signs of clinical infection, suggestive of critical colonization, is directly related to the microbial bioburden, notably hemolytic streptococci and anaerobes.180 In this clinical study involving detailed microbiology of chronic leg ulcers, colonized wounds had been present for longer, were larger, and had a significantly delayed healing time when compared with ulcers where no bacterial growth was found. One potential implication of these findings is that early and appropriate intervention using silver- or iodine-containing dressings in particular16 can avoid progression to critical colonization and infection; thus, potentially improving healing rates and reducing the risk of cross-contamination.
Antiseptics and disinfectants have been the cornerstone of effective infection control and prevention of hospital-acquired infections. At this time and in the absence of clinical data the following can be suggested:
The use of topical silver and iodine-containing, sustained-release formulations on infected and critically colonized wounds can be supported as part of a holistic approach. A topical antiseptic sustained-delivery system (dressing, cream, or ointment) may be indicated if:
• one or more overt signs of infection or any less obvious signs such as increased exudate levels are present
• local pain is increased
• healing is delayed.
The use of appropriate topical products also helps reduce odor and local bioburden; thus, reducing the risks of cross-infection.
The use of topical creams and ointment formulations of antimicrobial agents, including antibiotics, always must be justified on clinical grounds. Highly effective agents such as metronidazole and mupirocin have restricted indications and should not be used indiscriminately. Emulsion formulations of SSD are of proven value in the treatment of burns but not in chronic wounds.94 It is important to remember that when using topical SSD cream in addition to the 1% active agent, 99% excipients are being applied, including potential sensitizers and water that could exacerbate maceration.
Optimal bioburden control with antimicrobial agents requires accurate assessment of wound status, careful and justified selection of treatment, and appropriate duration in order to maximize cost-efficacy and minimize toxicity.
Conclusion
This literature review suggests the following implications for practice: Topical antimicrobials, used discriminately, are a viable option in wound care. All wound management regimens should include wound assessment at each dressing change. Where wounds are static or exudate levels high, critical colonization or infection should be suspected. Wounds that require cleansing should be irrigated with tap water or saline to remove pus, tissue, and dressing debris. Irrigating wounds with antiseptic solutions is of debatable clinical value. Pre-treatment of the skin with appropriate antiseptics is effective in reducing the risk of surgical site infection. Topical antibiotics are of limited value in treating infected wounds or as prophylaxis; they should be used only where absolutely no alternative is available. Systemic antibiotics, dosed appropriately, are indicated for overt infection with signs of spreading cellulitis. Dressings and other delivery systems that provide sustained doses of effective antimicrobials have been shown to be valuable in the treatment of critical colonization and infection and enhance optimal wound management.
The literature also indicates that research is needed to establish when topical antiseptics should be used in order to avoid delayed healing and the development of wound infection.
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