Topical Antimicrobials

T he clinician treating chronic wounds is faced with the dilemma of when to use topical agents - either antibiotics or other antiseptic agents - and when to use systemic antibiotics or related antibacterial compounds. When a patient with a chronic wound has increased bacterial burden (see Figure 1),1 the clinician must decide whether the harmful bacteria is superficial and can be managed with local wound care or is deep and requires a systemic approach. Assessing Host Factors The invading microbial organism is only one part of the equation leading to infection.2 Infection = Number of bacteria x virulence/Host resistance In this equation, host resistance is the most important factor. Chronic pressure ulcers are most likely to have Staphylococcus aureus, Streptococcus, or Pseudomonas aeruginosa as significant invading organisms that produce potentially destructive and virulent tissue destroying factors.3 Although S. aureus and P. aeruginosa usually require >10⁵ colony forming units per gram of tissue to cause significant damage, Streptococcus in any concentration may be implicated in wound infection.2 A number of host resistance factors must be examined as part of the assessment of the infection. Systemic vascular disease or decreased local perfusion will result in tissue hypoxia and stress. Local perfusion can be compromised by sustained local pressure (as seen in pressure ulcers). Any decrease in oxygen favors microbial organisms and, in particular, anaerobes that are common and underrecognized copathogens in many infected wounds.4 A synergy exists between anaerobic organisms and the aerobic organism S. aureus.5 Tissue oxygen concentrations above 30 mm Hg are necessary for cell division.6 Uncontrolled edema also will influence cellular trafficking and create further stress on the local blood supply. Malnutrition leads to decreased albumen levels; albumen is necessary to manufacture protein. Individuals with immunodeficiency are also more prone to infections and opportunistic organisms - immunodeficiency may be secondary to diabetes mellitus, alcoholism, or drugs such as systemic corticosteroids (usually over 20 mg of prednisone per day) or immunosuppressive agents used for organ transplants and cancer chemotherapy. Some individuals also have inherited defects in the immune system such as neutrophil defects or gammaglobulin deficiency. Clinical Features of Infection Lindholm's article in this document addresses the clinical features of infection; additional issues as may need to be considered. Grayson et al7 demonstrated that a simple clinical test of probing to bone was predictive of osteomyelitis with a sensitivity of 66%, specificity of 85%, positive predictive value of 89%, and negative predictive value of 56%. When neuropathy is present with bony re-absorption, x-ray and specialized scans may be less reliable. Also, until infection is adequately treated, pain control must be managed. This may include medication before procedures such as surgical debridement or dressing removal. Alternatively, continuous pain must be controlled using the World Health Organization ladder for pain medication (acetaminophen, mild and strong narcotics, plus or minus adjuvants). Patients with deep constant pain should be given pain medication until deep infection has been adequately controlled. Topical Therapy Topical therapy must address the three components of local wound care: debridement, bacterial balance, and moisture balance. Slough (often loose and yellow in color) or necrotic debris (often brown or black) serves as an excellent source for bacterial colonization and subsequent infections.4 Debridement. Debridement can be accomplished by several means: sharp surgical, autolytic with dressing, enzymatically, mechanically, or with biological agents. Sharp surgical debridement with a scalpel is a fast and effective way to remove debris.8 It is important to remove all devitalized tissue, converting a chronic wound into an acute wound within a chronic wound and decreasing the surface bacterial burden. Autolytic debridement is facilitated by a number of modern classes of moist interactive dressings such as hydrogels, hydrocolloids, alginates, and transparent films. The action of these dressings with protolytic autolysis is often apparent within 24 to 72 hours; if not, another form of debridement should be used. If the wound surface is firm and dry, the wound can be scored with a scalpel to develop superficial grooves within the tissue. A grid is formed that should cause minimal bleeding and facilitate the autolytic process.1 Enzymatic debridement is accomplished using topically applied proteolytic agents to facilitate the removal of nonviable tissue.1 Mechanical debridement has largely been replaced by other modalities. In the simplest form, saline wet-to-dry gauze is nursing time-intensive, painful, and may remove healthy granulation tissue when the dry gauze is lifted from the wound base. The gauze can be integrated into the granulation bed. If small pieces of gauze are left behind, they act as a sequestrum, lowering the bacterial concentration required to produce infection.9 Some practitioners also have used irrigation, pulsatile lavage, and whirlpool therapy.10 Moist environment. A moist wound environment may accelerate wound healing. Animal studies indicate that rate of healing in a moist wound may increase as much as 50% compared to a dry wound.11,12 In the extreme, overhydration of wounds is equally damaging. Wet-to-dry saline dressings are not considered moist and should only be used very selectively for debridement.13 Selecting a moist dressing for the wound is also important. Moist dressings include: * foams - maximum absorption for a moist surface * calcium alginates - moderate absorption and control of bleeding * hydrogels - limited absorption (70% to 90% water with increased viscosity) * hydrocolloids - absorption is limited by longer wear time and ability to maintain a seal * adhesive films - retain moisture but cannot be used if fluid accumulates below the surface. Chronic wounds are constantly evolving and re-evaluation is the key. Depending on the characteristics of the wound base, an appropriate moisture control category needs to be selected. Topical Antibacterials: Antibiotics Topical antibacterials (see Table 1) can be used when the surface component of the wound bed is out of bacterial balance. These agents should be re-evaluated at frequent intervals (eg, every 2 weeks). If a response is not obtained, clinicians should look for resistant organisms or signs and symptoms that the deeper wound bed is out of balance. Three general rules apply to the use of topical agents: 1. Do not use agents that are used systemically because of the ability to breed resistant organisms. For this reason, topical use of gentamycin and tobramycin is avoided. 2. Do not use agents that are common allergens (eg, neomycin). An extremely common allergen, neomycin is among the top five cutaneous sensitizers. Neomycin contains two allergens: the neosamine sugar and the deoxystreptamine backbone. The neosamine sugar is the same allergen found in framacetin. The deoxystreptamine backbone is also present in the aminoglycoside antibiotics: gentamicin, amikacin, and tobramycin. Other common sensitizers include lanolin, often present in tulle dressings. Bacitracin recently also has been identified as a common allergen. It is available as a topical antibiotic ointment and is often present in combination products in ointment base. It is not soluble in cream base combinations that are the preferred combination products at the present time (provided they do not contain neomycin). 3. Do not use agents that have a high cellular toxicity in healable wounds (eg, povidone iodine, chlorhexidine, and hydrogen peroxide). One agent that meets the above criteria is silver sulfadiazine cream (Silvadene, Monarch Pharmaceuticals, Bristol, Tenn.; and Flamazine, Smith and Nephew, Canada). The mainstay of therapy in burn units for years, this agent has broad-spectrum antibacterial coverage against Gram-positives, Gram-negatives, and anaerobes as well as yeast and some viruses. Silver sulfadiazine has been shown to preserve viable dermal tissue with the formation of pronounced granulation tissue and an abundance of myofibrobasts in a pig burn model,14 although it may delay re-epithelialization. The European Pressure Ulcer Advisory Panel recommends that systemic antibiotics not be required for pressure ulcers that have only clinical signs of local infection.15 A period of 2 weeks would be reasonable trial with these agents before considering systemic treatments or re-examining the treatment of the cause or the ability of the ulcer to heal. Topical Antiseptics and their Safety Topical antiseptics have well documented toxicity in the literature.9,16 This includes injury to granulation tissue with povidone iodine, chlorhexidine, and similar agents. These agents are toxic due to the concentrations delivered to the tissue. If a wound does not have the ability to heal, antimicrobial action is more important than cellular toxicity; these agents may be used to dry the surface of the wound and to discourage further local bacterial proliferation. This may help an area of gangrene to demarcate and prevent proximal tissue invasion. Non-healability may be due to systemic factors (as previously mentioned) or local factors. Local factors that may impair wound healing include a large wound area, increased depth, and degree of chronicity. Anatomical locations such as the perineal area (no collateral blood supply) or a distal extremity are less likely to heal. The presence of a foreign body, including a sequestrum as simple as retained dressings like gauze, may lower the amount of bacteria needed to cause infection. The presence of necrotic tissue or other forms of external wound contamination also may decrease healability. If a wound does have the ability to heal, antimicrobial agents such as heavy metals have been combined with advanced wound care dressings. As outlined by Burrell,17 nanocrystalline silver has excellent antimicrobial properties. The nanocrystalline silver affects DNA, cytoplasmic organelles, and enzymes. Multiple mutations are necessary to cause resistance. These silver products have a low sensitization potential.18 Nanocrystalline silver. Nanocrystalline silver dressings were evaluated through an uncontrolled, prospective study of a case series of 29 patients with a variety of chronic, nonhealing wounds.19 The four arms of the study included nine patients with foot ulcers, six patients with venous stasis ulcers, two patients with pressure ulcers, and 12 patients with miscellaneous wounds. All wounds were assessed for the usual signs of clinical infection (most parameters were measured and recorded). Microbiologically, bacterial load was determined via quantitative biopsies and semi-quantitative swabs. In general, the results showed a marked clinical improvement for the majority to which the dressing was applied. Decreased exudate and decreased purulence were some of the improved clinical parameters documented in this study. The quantitative bacterial biopsies did not show any decreased in organism numbers, although the semi-quantitative swabs indicated a decreased in the wound surface bacterial loading. Complexity of Bacterial Chronic Wound Interaction Chronic wound bacterial interaction can be divided into superficial and deep, but all chronic wounds contain bacteria (see Figure 2). Contamination exists from organisms on the surface of a wound. When those organisms are attached to the tissue and multiply, colonization is established. Colonization may exist in the form of biofilms - microcolonies of bacteria protected by a glycocalyx of their own synthesis. This glycocalyx provides less exposure to antimicrobial agents, forming a physical barrier to contact with the bacterial cell membrane. In a biofilm, cells are in a resting state and the genes targeted for antimicrobial action by usual agents are not active or effective.20-22 An altered gene expression in other bacteria also may be present so that the cells are active but not susceptible to the agent. Periodically, biofilms release planktonic (single) cells that may be responsible for recurrent infections within chronic wounds. Conclusion The concept of preparing the wound bed helps in the approach to bacterial burden in chronic wounds. The clinician must first decide whether the wound is in balance. If bacterial balance exists, antimicrobial agents are not necessary. Host factors are all that is necessary, both systemically and locally, to keep the bacteria in check. If, however, signs and symptoms of superficial bacterial imbalance are evident, topical agents may be necessary. Newer, modern topical agents may combine properties of debridement, bacterial balance, and moisture balance all in the same product and help adequately prepare the wound bed for healing. Despite adequate wound bed preparation, some wound beds do not heal. Once healability has been re-ascertained and the cause of delayed healing corrected, biological agents (growth factors, acellular dermis components, viable cells), skin grafting, or adjunctive therapies may be considered. These modalities will more likely be successful if bacterial balance has been obtained.

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