Topical Antimicrobials in the Control of Wound Bioburden—Part 1

  Intact skin provides a physical barrier to the ingress of micro-organisms. When skin is wounded, micro-organisms from the surrounding skin, other body sites, or exogenous sources have access to a warm, moist environment. Whether organisms survive and multiply depends on 1) their ability to evade the body’s immune system and 2) whether essential chemical and physical requirements are met.

  Wound microbial contaminants may not persist,¹ but it has been shown that species that flourish may establish the states described as colonization, critical colonization, or wound infection as outlined in the wound infection continuum.² What follows depends on the interplay among complex host and microbial factors.³ The size, position, and duration of a wound; local perfusion (dissolved oxygen levels); and host immunocompetency are balanced against the number and type of invading microbial species and the presence of foreign bodies (including necrotic tissue and eschar).⁴

  The presence of micro-organisms in a wound is not unusual but not all wounds support the same range and number of species.^5-7 Elective (ie, surgical) wounds are usually subject to preoperative antiseptic measures and aseptic surgical techniques, minimizing the risk of infection and allowing healing to proceed within expected timeframes. Traumatic wounds are more likely to contain devitalized tissue and debris and to be contaminated with micro-organisms from environmental sources; consequently, infection rates are higher.

  Chronic wounds (ie, 6 weeks’ duration⁸) such as leg ulcers or pressure ulcers, are inevitably colonized with a mixture of species, many of which are potential pathogens.⁶ The development of infection in chronic wounds is considered to reflect host susceptibility.⁹ Colonization per se usually does not influence wound healing because a review of the literature suggests that most colonized chronic wounds heal — ie, all chronic wounds that heal will do so in the colonized state.¹⁰ Although clinical studies have not been conducted and a consensus has not been reached either on the impact of specific micro-organisms on the healing process or the definition of critical colonization, clinicians agree that the development of infection causes serious delays in healing as a result of the expression of bacterial virulence factors.^11,12 These factors are believed to damage the wound bed through a variety of mechanisms:
  • Micro-organisms consume nutrients and oxygen required for wound repair
  • Protease virulence determinants (eg, elastase) damage the extracellular matrix (ECM)
  • White cell function is impaired through the release of short-chain fatty acids produced by anaerobes. Endotoxins stimulate production of interleukins: tumor necrosing factor (TNF) and then matrix metalloproteases (MMPs)
  • Free oxygen radical production increases imbalances that occur between MMPs and tissue inhibitors of metalloproteases (TIMPs)
  • Fibroblast production is decreased or delayed, collagen disorganized, and scar strength is decreased.

  Additional consequences for the patient may be increased pain and discomfort, inconvenience, and life-threatening illness. Adverse consequences for the healthcare system may be extended hospital stay and increased treatment costs in terms of extra antibiotic and dressing usage, as well as extra staff costs.

  Wound infection prevention and management are clinical priorities. The continued and often inappropriate use of systemic and topical antibiotics over the last 50 years has contributed to the emergence of antibiotic-resistant strains. Colonized and infected wounds act as reservoirs of potential pathogens that may contribute to increased risks of cross-contamination or infection. As chronic wounds, and all those left to heal by secondary intent, become contaminated or even colonized with micro-organisms, the host immune system often will restrict the development of infection. Thus, not all colonized wounds will, by necessity, become infected. Healthcare professionals are increasingly concerned about the risks associated with the presence of micro-organisms in wounds: Do they represent a real risk for cross contamination and cross-infection? Should antimicrobial agents be used? If so, when and how? What is the evidence to support their use? The purpose of this literature review is to explore these questions to place use of topical antimicrobials into a contemporary context.

  Definitions of commonly used terms in the field of infection control are provided to ensure consistency of language and understanding between authors and readers (see Table 1^13-23).

Antimicrobial Goals by Wound Type

  Chronic wounds. Chronic wounds such as pressure ulcers, diabetic foot ulcers, and ulcers of the lower leg can persist for many months or years. Despite advances in care, their prevalence is likely to escalate with an increasing elderly population in the western world. Studies have shown that chronic wounds are usually colonized with multiple species and although bacteria may proliferate many of these wounds are successfully resolved through careful management.²⁴ If colonization has progressed to infection, the goal is to restore a balance between the bioburden and the local immune system. In theory, the role of antimicrobials in this restorative process is to provide bactericidal or bacteriostatic action which, indirectly (by these actions) will prevent the byproducts (eg, bacterial proteases) from further damaging the wound bed.

  Surgical wounds. Clean surgery carries a small risk (1% to 5%) of postoperative wound infection; “dirty procedures” (eg, involving the large intestines) have a much higher risk (up to 27%).²⁵ Minimizing the incidence of infection in surgical wounds relies on adequate asepsis, antisepsis, and preservation of local host defenses.²⁶ Asepsis involves effective infection control to minimize exogenous contamination during surgery. Antisepsis involves the use of skin antiseptics and prophylactic antibiotics before surgery.²⁷ Guidelines have been published on the prevention of surgical site infection²⁸; most emphasize the role of rapid perfusion because ischemic tissue heals poorly and is easily infected.²⁹ Healing and resistance to infection improve with increased local blood supply and tissue oxygenation. The delivery of antibiotics, systemically dosed, to the infected wound also depends on perfusion. Antibiotics given at the time of injury will reduce but not eliminate the risk of infection.

  In one third of surgical wound infections, bacteria cultured from the wound are susceptible to the prophylactic antibiotic provided. The key factors to the development of infection are hypoxia and local perfusion problems.²⁹ In such instances, it is easy to make a case for prophylactic and therapeutic antiseptics, particularly those providing sustained dosing from medicated dressings. In cases where ischemia and hypoxia are present, systemic antibiotic therapy should be augmented with local topical antimicrobials.

  The American Study of the Effect of Nosocomial Infection Control (SENIC), in defining risk assessment for surgical wounds, examined the effect of nosocomial infection.³⁰ In order to develop a comprehensive overview, the results of this study and other risk factors have been summarized by Kingsley,² and include:
  • Three or more diagnoses at operation
  • Abdominal surgery
  • More than 2 hours spent in surgery
  • Contaminated/dirty operation
  • Inadequate antibiotic prophylactic
  • Inadequate skin preparation
  • Peri-operative hospitalization
  • Hair removal (particularly shaving)
  • High ASA score
  • Lack of supplemental peri-operative oxygen
  • Loss of peri-operative normothermia
  • Inadequate analgesia
  • Malnutrition

  A recent audit conducted in the UK and review of the literature found great variations in skin preparation methods used. The authors of this study concluded that research-based evidence on this topic is limited and offer recommendations for best practice.³¹

General Preventive Measures

  Measures to prevent wound infection and delayed healing are based on currently accepted tissue viability principles.
  • Identify the etiology of the wound
  • Remove any continuing intrinsic and extrinsic causative factors such as venous hypertension and shearing pressure
  • Eliminate or reduce any factors that may impair healing such as malnutrition, hyperglycemia, and anemia
  • Initiate the most effective therapy at the outset; do not use holding or wait-and-see treatments just because they are more convenient
  • Use universal infection control precautions to prevent cross-contamination of the wound
  • Remove necrotic and foreign material
  • Allow drainage of wound exudate/pus, particularly from the sinuses. This does not preclude use of occlusive dressings; it helps determine dressing frequency, depending on the absorbency of the individual product
  • Observe the wound closely for signs of change at all dressing changes, particularly changes representing a delay in healing or infection control
  • Construct a management plan that details expected progress so delays can be detected at the earliest opportunity
  • Use a framework to guide decision making for undesired events^22,23

  Modern moist wound healing dressings have been shown to be valuable in controlling infection. They form part of the non-microbiological approach to control the wound bioburden.

The Role of Dressings

  Some occlusive dressings, such as hydrocolloids, have bacterial and viral barrier properties. These dressings can be used to prevent contamination of the wound and reduce the spread of pathogens and cross-infection.³² Hydrocolloids also have been shown to reduce the airborne distribution of organisms at dressing change when compared with dry dressings.³³ In general, occlusive dressings are associated with a lower overall wound infection rate than non-occlusive dressings.³⁴

  Dry dressings, such as gauze, stick to the wound.³⁵ On removal, the trauma of detachment has been demonstrated to facilitate the airborne spread of bacteria,³⁶ a likely factor in hospital clinics. No evidence that traditional dry dressings have any role in infection control exists — they even may lead to an increased rate of infection.³⁵

  A hydrofiber dressing has been found to sequester or bind bacteria, thereby containing the spread of pathogens. In a study using an in vitro wound model seeded with Staphylococcus aureus, Bowler and colleagues³⁷ compared a number of fibrous dressings. Results show hydrofiber dressings to be most effective in sequestering or binding the bacteria (P <0.001), followed by alginates. Subsequent in vitro research has demonstrated how viable bacteria interact with and are sequestered by hydrofiber dressing fibers.³⁸

Therapeutic Influences

  Patient risk status. Logically, steps that should be taken to reduce colonization or counteract infection depend on the nature of the wound, status of the patient, and pathogenicity of the organism(s) involved. An organ transplant patient threatened with methicillin-resistant S. aureus (MRSA) infection in a surgical wound is at greater risk because immunosuppressed status puts the patient at higher risk of life-threatening infection than the patient with a long-standing leg ulcer known to be colonized but with minimal host reaction.

  Bioburden. The level/degree of bacterial loading (bioburden) of the wound does not in itself indicate if a wound is infected,¹ but it is reasonable to conclude that it may influence the healing rate and is a particularly important factor in patients known to be at risk (eg, known to have compromised healing or host response, diabetes, or ischemia).

  Biofilm. Wound bacterial biofilm has been postulated^39-41 to exist in wounds left to heal by secondary intention. Biofilms are likely but not proven to be implicated in a majority of infections.⁴² In vivo and in vitro research has demonstrated that two widely-used topical antimicrobial agents — ionic silver and cadexomer iodine — are effective against biofilms.^43,44 This mode of action is believed to be important in the control of wound infection when using some antiseptic agents.

  Antimicrobial agents. Antimicrobial agents have been applied to wounds for thousands of years⁴⁵ but the relentless emergence of resistant strains has forced the continued search for novel agents. As each new type of antimicrobial agent has been introduced into clinical practice, changes in microbial sensitivity have been observed. Initially, some strains are not inhibited by a new agent (ie, possess intrinsic resistance), while some species are susceptible.

  Antiseptics. Antiseptics destroy or inhibit the growth of micro-organisms and have been used on wounds for more than a century to prevent or treat infection. Unlike antibiotics that act selectively on a specific target, antiseptics have multiple targets with a broad spectrum of activity. Several different types of antiseptics exist, including alcohols (ethanol, isopropanol), anilides (triclocarban), biguanides (chlorhexidine, polyhexanide), bisphenols (triclosan), halogen compounds (polyvinyl pyrrolidone-iodine [PVP-I]), sodium hypochlorite in the form of EUSOL (Edinburgh University Solution of Lime, an extemporaneous formulation of hypochlorite) and Dakin’s solution, heavy metals (silver compounds — silver nitrate, silver sulphadiazine [SSD], ionic silver), peroxygens (hydrogen peroxide), and quaternary ammonium compounds (benzalkonium chloride, cetrimide).⁴⁶ Until recently, the most commonly used products in clinical settings were PVP-I, alcohol, acetic acid (vinegar), hydrogen peroxide, sodium hypochlorite, silver nitrate, and SSD.⁴⁷ These agents have been available for many years and were not developed according to newer exacting standards⁴⁸; some newer dressings that contain these agents have been microbiologically assessed retrospectively.⁴⁹

  However, some antiseptics have been found to be cytotoxic in vitro both to micro-organisms and the host’s own cells in a concentration-dependent manner.⁵⁰ Such in vitro findings do not necessarily translate to the in vivo situation and should be interpreted with caution. Although the usefulness of antiseptics on intact skin is well established, the use of antiseptic solutions on open wounds remains controversial. Two official guidelines have been released concerning antiseptic use on wounds. Povidone iodine has been approved by the US Food and Drug Administration (FDA) for short-term treatment of superficial and acute wounds,⁴⁹ having been found to neither promote nor delay wound healing. On the other hand, guidelines for the treatment of pressure ulcers by the US Department of Health and Human Services^51,52 strongly discourage the use of antiseptics (as solutions) and promote the use of normal saline for cleansing pressure ulcers.

  Arguments against the use of antiseptics on wounds. Some clinicians are not in favor of using antiseptics in wound care.⁵³ Although not clear why, some considerations include overzealous interpretation of research findings, misuse or unrealistic expectations of antiseptics, peer pressure, and locus of control.⁵⁴

  For many, the use of antiseptic solutions in wound care is influenced by the bad press related to sodium hypochlorite (Dakin’s solution, EUSOL).⁵⁵ Iodine compounds also have attracted criticism.⁵⁶ The potential for cell toxicity of antiseptics in solution form is the main argument against their use.⁵⁷ This toxicity is related to formulation, concentration, and exposure⁵⁰ compared to untreated controls.⁵⁵ A balance between potentially harmful effects on newly dividing cells and the need to control bioburden must be achieved. Antiseptic toxicity is clearly evident in vitro but less obvious in vivo.

  When considering use of topical antiseptics on wounds, the first thought should be dosage form. Solutions have been shown to have more disadvantages than the new sustained-release antiseptic dressing systems.⁵⁴ A major concern in clinical practice is safety. Agents that are cytotoxic or delay wound healing must be used with caution. The strongest in vitro argument for not using antiseptics has been provided by Wilson et al⁵⁰ who demonstrated resultant cytotoxicity to cells essential to the wound healing process (eg, fibroblasts, keratinocytes, and leukocytes). However, cytotoxicity has to be interpreted in the context of the chemical nature of the antiseptic, concentration used, and duration of use, as well as the tissue types present in the wound at a particular time. For example, cytotoxicity to fibroblasts and keratinocytes is of minor concern in a wound in the inflammatory stage with slough and necrotic tissue present. In this example, the important issue is whether the antiseptic kills bacteria and if it will help debride slough and necrotic tissue or whether it will kill or hinder the leukocytes and regenerating tissues. Even agents believed to be relatively non-toxic have been shown to delay cell growth in vivo when used at high concentrations.⁵⁰ Generally speaking, solutions of antiseptics should not be used to irrigate wounds because cell toxicity risk is high and no added benefit over saline has been noted.^52,58

  Antiseptics in solution form have not been formulated for use on wound tissues — they are strong, concentrated solutions developed to kill bacteria and remove necrotic tissue. This antiquated approach is no longer clinically acceptable in modern wound management. However, recent developments may change this position.⁵⁹ Another reason antiseptics are not used on open wounds is that their efficacy is inhibited in vivo by exudate components, serum, or blood present in the wound. However, in practice, several bacteriological studies and reviews^60,61 have shown that antiseptics can decrease bacterial counts within wounds, which may be a vital consideration for patient outcomes.

  Topical dressings, creams, or ointments that provide adequate sustained delivery of an antiseptic agent (eg, silver or iodine) may be useful. The use of povidone iodine in solution as a routine chronic wound cleanser is not justified,^10,62 although it is useful in irrigating acute (traumatic) wounds.⁶³ Solutions used as antimicrobial rinses do not have sufficiently long contact time to have much effect.⁶⁴
Cleansers that rely on pressure, such as normal saline aerosol sprays or sprays containing biocompatible surfactants, may be helpful in removing devitalized material but infection control measures must be carefully considered before use.

Arguments for Antiseptic Use on Wounds

  It is well known that infection will delay wound healing and that every wound, even surgical wounds created under aseptic conditions, are soon colonized by micro-organisms.⁶⁵

   The severity of infection depends both on the pathogenicity and density of the colonizing microbes. However, the risk of infection diminishes as host defense mechanisms increase. Rather than relying on host defense mechanisms or just debriding and cleansing the wound, additional therapeutic strategies are commonly applied in an attempt to prevent infection.

   Antiseptic use in wound infection may be preferable to antibiotic use with regard to development of bacterial resistance. In addition, problems with the antibiotic reaching the site of infection in sufficient quantity (especially in ischemic wounds and those with surrounding edema) lead to subtherapeutic dosing and an increased risk for development of resistance. Antiseptics in vitro generally have been shown to have broader spectrum of activity than antibiotics.⁴⁶

  Careful and objective review of the literature suggests that the use of many antiseptics in wound management must be subject to a risk-benefit assessment of possible local toxicity and beneficial antibacterial action⁵⁵; balancing the beneficial antimicrobial effects and bioavailability with possible cellular toxicity before use is advised.⁵⁰ In solution form, antiseptics often are used for pre-operative skin preparation and to irrigate or cleanse wounds — ie, a short period of contact with tissues. Therefore, solutions are usually concentrated in order to have this desired effect, increasing the likelihood of tissue toxicity and delayed healing when used for an extended period of time.^66,67 Antiseptic agents incorporated into dressings are in contact with the wound bed for much longer than antiseptics applied in solution, allowing them to be more dilute and less toxic in order to exert a prolonged antimicrobial effect. However, little information on systemic absorption is available, making it difficult to determine unfavorable side effects. Wilson et al⁵⁰ identified the difficulties of translating in vitro findings into clinical practice. They also note the dynamic nature of wound repair and how in vitro investigations are unable to mirror these events. Wilson and colleagues⁵⁰ conclude that these issues compound the variables generated in clinical practice, which include the dwell time of the cleanser, the current phase of healing when the cleanser is applied, and repeat applications.

  The newer antiseptic dressings, particularly those with slow- and sustained-release characteristics, are not generally regarded as harmful. These dressings satisfy current US and EU regulatory requirements for safety.⁶⁸ For this reason, broad-spectrum antimicrobial agents such as iodine (as PVP-I and cadexomer iodine dressings), silver, and honey, have been widely used on acute and chronic wounds.^3,69-71

The Optimal Antiseptic Dressing

  The potential disadvantages of traditional antiseptics led to the development of a new generation of antiseptics that offer antimicrobial capabilities without the potential disadvantages of more traditional antiseptic formulations. Current opinion suggests that the ideal wound antiseptic is believed to have the following key attributes⁷²:
  • Effective against likely contaminants and pathogens
  • Fast-acting with prolonged residual activity after a single dose
  • Inexpensive
  • Incapable of promoting bacterial resistance
  • Minimal systemic absorption
  • Non-carcinogenic and non-teratogenic to host cells
  • Non-toxic
  • Widely available

  Currently, the ideal antiseptic does not exist. Such a product would be dressing-based rather than a solution for irrigation and have the advantages of topical therapy over systemic therapy — ie, only the wound and immediate tissues would be exposed to the active ingredient rather than the whole body, as is the case with systemic treatment, and the active agent would be delivered directly to the wound bed rather than indirectly through the vascular system, which might be compromised due to ischemia.

  Results of a review of the literature⁶¹ support the use of sustained-release antiseptics in wound care and demonstrate that the majority of modern antiseptic dressings have not been found to impede healing. Additional findings state that the recently developed silver products, together with cadexomer iodine, may play an important role in wound care management.