Connecting Wound Bed Preparation 2024, Therapeutic Index, and Covert and Overt Infection

INTRODUCTION The concept of therapeutic index is introduced in the Clinical Management Extra article, “Therapeutic Indices of Topical Antiseptics in Wound Care: A Systematic Review” in this issue of Advances.1 In this Practice Points article, the authors seek to connect widely accepted concepts around wound bed preparation (WBP) with ongoing research in bacterial bioburden and therapeutic index. The WBP framework has evolved considerably in the past 25 years since the report of the first Canadian advisory board in 1999.2 Through international consensus panels, the most recent iteration in 2024 (Figure 1) is the eighth update. It includes 10 statements and new sub-statements for application in resource-limited settings.3 These settings include many parts of rural, remote communities in North America, including Indigenous peoples.Figure 1.: WOUND BED PREPARATION AS THE BASIS FOR AN APPROACH TO WOUND INFECTION©WoundPediaDetermining the ability to heal has become an established element of the WBP framework.3 Generally, chronic wounds fall into one of three categories: healable, maintenance, and nonhealable. However, wound status may change over time. Healable: The underlying cause has been addressed and the wound has sufficient blood supply to heal. Typically, two-thirds of wounds in the community are healable. Maintenance: The wound has adequate blood supply to heal but the patient either cannot or will not adhere to the plan of care. In addition, the healthcare system may not have appropriate resources. This type may account for a quarter of chronic wounds. Nonhealable: The wound has an inadequate blood supply and/or a cause that cannot be corrected. Approximately 5% to 10% of chronic wounds cannot be healed because of inadequate blood supply or advanced chronic disease. For patients with nonhealable wounds, the paramount points of care to address are pain, infectious complications, exudate, odor control, and activities of daily living. Chronic wounds result from a failure to progress through the expected four phases of healing (hemostasis, inflammation, proliferation, and remodeling) in a timely manner. A major factor contributing to impaired wound healing is bacterial bioburden. Open wounds are susceptible to colonization by bacteria from the patient’s skin microflora and the surrounding environment (above the wound compartment). The presence of bacteria does not necessarily cause tissue damage or indicate an infection. The number of bacteria and their proliferation (colonization) can vary from bacterial balance to bacterial tissue damage. Bacterial imbalance occurs when increasing bacterial burden leads to local covert or overt infection. The local bacterial infection (covert infection) can then spread to the deep and surrounding compartment (overt infection). The International Wound Infection Institute’s Wound Infection Continuum (IWII-WIC) consensus classifies wounds into five categories of escalating bacterial bioburden.4 The five conceptual stages described by their continuum are: (1) contamination; (2) colonization; (3) local infection (covert and overt stages); (4) spreading infection; and (5) systemic infection. Among the wound infection assessment tools described are NERDS and STONEES.4,5Figure 2 uses a soup bowl analogy to illustrate the approaches for different wound compartments. Wounds can be categorized into compartments: the superficial compartment, comprising a thin layer of surface cells, and the deep and surrounding component. An analogy of the wound as a soup bowl with a thin layer of soup explains this concept of a superficial compartment around a deep and surrounding tissue compartment (Figure 2). The thin layer of soup signifies the covert infection (previously designated as superficial critical colonization/local infection) and can be treated with topical antiseptics. The soup bowl represents the sides and bottom of the deep and surrounding wound compartment that requires systemic antimicrobials.Figure 2.: WOUND COMPARTMENTS, NERDS/STONEES CRITERIA, AND TREATMENT TO REDUCE BACTERIAL BIOBURDENCriteria shown in red are common to both NERDS and STONEES so additional criteria are needed to differentiate. Increased local wound-related pain is a symptom and not a sign, but increased pain may count as a criterion sign if there is no other reason for the increased pain.Abbreviation: PHMB, polyhexamethylene biguanide.© WoundPediaWounds in bacterial balance should be cleansed with normal saline (0.9% sodium chloride) or potable water. Apply topical antiseptics to help reduce surface contamination (above the wound compartment) with surface bacterial counts. These agents should be used to reduce wound contamination but need to be balanced against tissue toxicity. The ability of a wound to heal is determined by the patient’s host resistance to prevent bacterial damage. In nonhealable or maintenance wounds, the cytotoxicity of an antiseptic agent is often less critical than its antimicrobial effect. Local covert wound infection can be classified when three or more NERDS criteria are met. Treatments include topical antiseptics and/or antimicrobial wound dressings, as noted in Figure 2. Consider deep and surrounding wound infection when three or more STONEES signs are present. In addition, pain is a symptom that may substitute for one sign if it is present locally without another cause. Most deeper infections contiguous with the skin and soft tissue that involve bone may be treated with oral therapy as evidenced by the oral versus IV antibiotics (OVIVA) trial.6 The multicenter UK OVIVA study demonstrated that oral antimicrobials were not inferior to IV administration for the majority of patients with osteomyelitis.6 These oral antibiotic options may include cephalexin 500 mg to 1 g QID; cefuroxime 500 mg to 1 g BID; Augmentin (USAntibiotics,) is a combination of clavulanic acid and amoxicillin; trade name Clavulin [GlaxoSmithKline LLC]in Canada) 500 mg TID or 875 mg BID; moxifloxacin 400 mg OD; or levofloxacin 500 or 750 mg OD. A systematic review submitted for publication will extend our understanding of the evidence concerning the use of oral antibiotics to treat deep and surrounding (overt) wound infection (Siddhartha Sood, HBSc, et al, unpublished data, December 2024). Bacteria growing on two different surface viscosities within a wound environment favor biofilm formation. Biofilms support bacterial proliferation, and the outer glycocalyx protects against eradication by the host immune system and the administration of antimicrobial treatment. Biofilms warrant special consideration. In this issue of Advances, the article by Geng, Sibbald, and student assistants, with senior author the late Dr Gregory Schultz,1 examined the therapeutic index of common wound bacterial pathogens. Therapeutic index is defined as: Therapeutic index=mean cytotoxic concentration in mammalian cellsmean minimum bactericidal concentration of bacterial species However, the therapeutic index value for different topical antiseptics is not the only factor that should determine the selection of the most appropriate topical treatment for cleansing a patient’s chronic wound (compress, soak, or irrigation) during the entire course of treatment. The optimal topical cleansing antimicrobial treatment selected in the early stage of wound treatment may have a lower therapeutic index value than other antimicrobial agents. However, it would be selected because it has a superior minimum bactericidal concentration value against the dominant bacterial species isolated from a wound and considered a probable pathogen. In other words, deciding which antimicrobial agent to select for initial treatments is a balance between rapidly and effectively reducing the bacterial bioburden in the wound at the cost of killing some wound cells. In later stages, once the bacterial bioburden has been effectively reduced, the selection of a cleansing agent may revert to saline or potable water. If an antiseptic is still required, an agent with a higher therapeutic index value that causes less potential host cellular damage may be preferred to reduce harm to human cells but still maintain a lower bacterial bioburden. The choice of antiseptic should be individualized to the patient, with consideration for patient characteristics and the stage of wound healing. Topical antiseptics with a higher therapeutic index offer greater potential safety and clinical effectiveness. The results calculated by Geng et al1 identified hypochlorous acid as having the highest therapeutic index values against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. Polyhexamethylenebiguanide (PHMB) has the highest therapeutic index values for methicillin-resistant S aureus. The diagnosis of infection is made clinically by assessing the wound bed, deeper structures, and surrounding skin. Differentiating bacterial burden from potential contamination above the wound to covert superficial infection and the spread to the deep and surrounding compartment can aid in the choice of neutral or antiseptic cleansers, topical antimicrobial wound dressings, or moisture management choices, along with the need for systemic antimicrobials.3,4 CONCLUSIONS This Practice Points enabler positions the WBP paradigm as the basis for an approach to wound infection, building on NERDS and STONEES through the soup bowl analogy. Topical antiseptics with a higher therapeutic index offer greater safety and clinical effectiveness. Further, WBP 2024 also provides an opportunity to link education to improved patient outcomes and healthcare system change.

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