Pharmacology of Wound Care

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Introduction   

Wound care is a very dynamic segment of health care that is not without its challenges. Antimicrobial resistance (AMR) is one of the top global public health concerns that was responsible for approximately 1.3 million deaths in 2019 (10). By 2050, AMR is predicted to be responsible for 10 million deaths a year, equating to the death of one person every three seconds (2, 10). This will exceed the deathrate of cancer (10). This trend, if left unchecked, will result in a world where many infectious diseases have no cure and no vaccine (8). 

The World Bank predicts that AMR could result in $1 trillion additional healthcare costs by 2050, and $1 trillion to $3 trillion in gross domestic product (GDP) losses by 2030 (8, 9). This would continue to contribute to the fiscal inequality among countries because those countries with lower incomes would suffer the greatest, thus widening the gap (8). AMR affects patients in every country, of every race and economic level (9). It also makes treatments such as surgery, cesarean sections, and cancer chemotherapy much riskier, and it unravels the good that advancements in modern medicine have achieved.  

AMR affects many organisms including those that are the catalyst for disease and illness in humans, such as E. coli, S. aureus, K. pneumoniae, and C. auris. Drug resistance has also been shown in human immunodeficiency disease (HIV), tuberculosis (TB), malaria, leprosy, and several tropical diseases (9). 

Wound care products are instrumental in the treatment of wound infection. The global wound care products market is expected to reach almost $19 billion by 2027, up from $12 billion in 2020 (3). This is why it is important for nurses to understand the most effective product options for specific wounds, which can help decrease the financial burden of wound management. 

A collaborative and holistic approach is paramount to the prevention, diagnosis, assessment, and treatment of wound infection. 

Definition 

A healthy individual’s immune system is capable of destroying microbes that cause infection. However, wound infection occurs when a wound is invaded by microorganisms to a level that provokes a systemic response in the patient (10). Microorganisms then multiply within the wound, causing a release of toxins and biofilms that delay wound healing. A prolonged inflammatory response then delays collagen synthesis and tissue epithelialization, leading to wound infection. It is important for the nurse to remember that even though all wounds become colonized and contaminated with microorganisms, not all wounds become infected (10).  

Patients become susceptible to wound infection when their immune systems are not able to combat opportunistic pathogens. The number of microbes in the wound overwhelms the patient’s defenses, and the species of microbe present causes increased virulence and synergistically combats the patient’s immune system (10). 

There are five stages of wound infection development (10): 

1. Contamination: Microorganisms are present in the wound, there is no host reaction, and no delay in wound healing is observed. Phagocytosis is active, in which the host’s defenses are working to destroy the microorganisms. 
2. Colonization: The microorganisms proliferate, but virulence is low. There is no host reaction and no delay in wound healing is observed. The microorganisms may be exogenous in nature or occur as a result of environmental exposure. 
3. Local infection: The microorganisms continue to proliferate, causing a response in the host and a delay in wound healing. The infection is contained within the wound and periwound. The patient’s signs and symptoms are most likely very subtle and not yet recognized as early signs of infection. These early signs of infection are hypergranulation, bleeding or friable granulation, epithelial bridging and pocketing in the granulation tissue, increased exudate, and delayed wound healing beyond expectations. These early signs can progress into more pronounced signs of infection, such as erythema, swelling, warmth, purulent discharge, wound enlargement, increasing pain, and malodor. 
4. Spreading infection: This stage includes cellulitis when the surrounding wound tissue is invaded by microorganisms, causing signs and symptoms that extend beyond the wound border. These signs and symptoms include lymphangitis, crepitus, extending induration, dehiscence, and erythema that extends greater than two centimeters from the wound edge. This spreading can involve deep tissue, muscle, fascia, organs, and body cavities. 
5. Systemic infection: The infection spreads from a local wound via the vascular and lymphatic systems throughout the body. System signs and symptoms of infection are lethargy, malaise, anorexia, pyrexia, severe sepsis, septic shock, organ failure, and death.  

As a quick review, the types of open wounds are abrasion, laceration, puncture, burn, and avulsion, and the phases of wound healing are hemostasis (clot formation), inflammatory (cleaning), proliferative (wound stabilization), and remodeling (scar tissue formation) (6). The stages of pressure ulcers are Stage 1 (skin intact), Stage 2 (break in epidermis and dermis), Stage 3 (fatty tissue involvement), and Stage 4 (muscle, tendon, ligament, bone involvement). 

Assessment and Diagnosis 

The patient’s host characteristics, the environment, and the etiology of the wound all influence the type of infection and how quickly it spreads (10). Therefore, it is imperative that nurses conduct a holistic assessment that is continuous and accurate. It is also important for nurses to recognize that no single sign or symptom confirms the presence of a wound (10). 

There are several assessment tools available to help identify the presence of wound infection, including (10): 

• ASEPSIS: Uses a point system to identify characteristics of surgical wounds like Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of the deep tissues, Isolation of bacteria, and Stay duration (inpatient time duration). 

• Clinical Signs and Symptoms Checklist (CSSC): Includes signs and symptoms of general infection and wound infection, as well as secondary signs and symptoms of wound infection in various types of wounds. 

• Infection Management Pathway: Is used for all wound types and provides a treatment plan depending on the signs and symptoms of infection that are present. 

• IWGDF/IDSA System: Is used for diabetic foot ulcers and defines the severity of foot infection according to four levels. 

• IWII Wound Infection Continuum (IWII-WIC): Uses a conceptual model and teaching tool to identify the wound infection stages in various types of wounds. 

• NERDS and STONES: Helps assess superficial (NERDS) and deep (STONES) chronic wound infections. 

• Therapeutic Index for Local Infections (TILI) Score: Includes six criteria for local wound infections and three direct indications for acute and hard-to-heal wounds. The tool is available in multiple languages. 

• Wound Infection Risk Assessment and Evaluation (WIRE) tool: Is used to assess the risk of infection in community-based wounds. It detects early wound infection based on the wound’s clinical presentation. 

• WOUND: The nurse should determine What happened?, Oxygenation and perfusion of the tissue, Underlying factors, Nutritional status, and Diseases and drugs that affect the patient. 

Additional assessment tools include The Infection Management Pathway, T.I.M.E. Clinical Decision Support Tool, The Adult Burns Patient Concerns Inventory, Wound Healing Strategies to Improve Palliation, Universal Model for the Team Approach to Wound Care, TIMERS, and Wound Bed Preparation 2021 (10). 

While infection related to acute wounds (trauma-related, surgical, burns) is easily recognized by nurses, chronic wound infection is more difficult to determine since it depends on subtle signs and symptoms that can be masked in immunocompromised and older patients, or those with poor vascular perfusion (6, 10). Nurses need to be able to determine the difference between acute and chronic wound infection to establish effective management goals, prevent serious complications, and make appropriate referrals (10). Additionally, many nurses are apt to encounter patients with chronic wounds since this type of wound affects 2% of the global population in developed countries (1). Studies indicate that diabetic foot ulcers are prevalent in 6.3% of the population while chronic leg ulcers affect 1% of the adult population (1). 

The wound’s etiology and patient’s risk for wound infection are important determinants for the presence of wound infection and the manner in which the wound may present (6, 10).  

There are several factors that put patients at risk for developing wound infection and chronic wounds. These patient risk factors include (6, 10): 

• Diabetes/hyperglycemia 
• Peripheral neuropathy 
• Neuropathic arthritis 
• Immune disorders 
• Hypoxia/tissue perfusion disorders 
• Connective tissue disorders 
• Corticosteroid use 
• Chemotherapy/radiation therapy 
• Obesity/malnutrition 
• Alcohol/tobacco/illicit drug use 
• Inadequate hand hygiene 

Additional factors that can contribute to acute and chronic wound infections are (6, 10): 

• Hematomas 
• Traumatic injuries 
• Foreign bodies (drains, sutures) 
• Ineffective hair removal 
• Surgical factors (hypothermia, blood transfusion, prolonged surgery) 
• Wound location near a “dirty” body site (perineum, scrotum) 
• Impaired tissue perfusion 
• Wounds over bony prominences 
• Tendon, muscle, joint, bone involvement 
• Increased wound moisture (poorly managed exudate) 
• Necrotic or sloughy wound tissue 

While assessing patients, the nurse should remember to ask about comorbidities and their management, nutritional status, psychosocial wellbeing, and any factors that can affect the patient’s immune status and tissue healing (6, 9, 10). 

The following table provides information about how to assess wound infection in specific wound types (10). 

Table 1. How to assess wound infection in specific wound types (10) 

In surgical patients, wound edge color (redness) and induration are not reliable indicators of wound infection. Sepsis is not common in diabetic foot ulcers; however, diabetic foot ulcers can have deep infection that is not identifiable without deep probing or surgery. Predictors for chronic leg ulcers are anticoagulant use, chronic pulmonary disease, and depression. In patients with skin tears, tetanus vaccinations or boosters may be required (10). 

To diagnose wound infection, the nurse should only collect a wound sample if clinical signs and symptoms of infection are present. A wound culture can help identify the causative microorganisms and guide antimicrobial treatment after diagnosis is confirmed. The types of wound specimen include tissue biopsy or curettage, wound fluid aspirate, wound swab, and wound debridement. Research indicates that using the Levine technique versus the Z-swab technique is more effective when collecting a wound sample via swabbing (10).  

Osteomyelitis and abscesses can be confirmed via x-ray, bone scan, magnetic resonance imaging (MRI), computerized tomography (CT), fluorodeoxyglucose positron emission tomography (PET), leukocyte scintigraphy, and ultrasound. Bloodwork includes complete blood count (CBC), white blood cell count (WBC), c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and blood cultures (10).  

Advanced diagnostic techniques include DNA sequencing that more precisely identify microbial species in a wound specimen, fluorescence imaging that directly identifies bacteria density on a wound surface, and wound blotting that uses wound staining to map biofilms in a wound (6, 10). 

Products and Medications 

Treatment for wound infection occurs when acute or chronic wound infection is suspected of spreading or becoming systemic, infected wounds have not responded to antimicrobial treatment, and the presence of infection would negate a surgical procedure, such as the presence of infection prior to skin grafting surgery. The goals of wound management are to decrease the wound’s microbial burden, promote an optimal wound environment for healing, and optimize the patient’s response by minimizing risk factors and other barriers to effective care (10). Today, nurses must consider not only products that are optimal for wound bed healing, but also those that treat the peri-wound skin and wound edge (3). 

“Antimicrobial” is a general term that is used to describe agents that inhibit the growth of, and/or kill, microorganisms. Disinfectants, antiseptics, antivirals, antifungals, antiparasitics, and antibiotics are all considered antimicrobials (9, 10). Antimicrobial resistance occurs when these organisms no longer respond to these medications, increasing the risk of disease, disability, and death (6, 10). AMR is a natural process that occurs over time due to the genetic changes in pathogens, but human activity like the misuse and overuse of antimicrobials to prevent and treat infections in plants, animals, and humans causes an acceleration in AMR. AMR is a global concern because it not only impacts the health of animals and plants, but it also reduces farm productivity, threatens clean water, and causes food insecurity (5, 9). 

The foundational wound care product is an effective cleanser. Wound cleansers include (10): 

• Sterile water 
• Sterile normal 0.9% saline 
• Surfactant wound cleansers (octenidine dihydrochloride [OCT] or polyhexamethylene biguanide [PHMB]) 
• Super-oxidized solutions containing hypochlorous acid and sodium hypochlorite 
• Povidone iodine 
• Other antimicrobial agents 

Topical antiseptics work by disrupting the effect of bacteria, fungi, parasites, and viruses, and since they have multiple sites of antimicrobial action on target cells, they have a low risk of bacterial resistance (10). Antiseptics include gels, liquids, pastes, and impregnated dressings. Hydrogen peroxide, traditional sodium hypochlorite (Dakin’s solution), and chlorhexidine are no longer recommended for use in open wounds since they cause tissue damage (10).  

Table 2. Most popular topical antimicrobials and distinguishing characteristics (10) 

When topical antimicrobials are not effective, topical antibiotics and topical antifungal therapies can be implemented. Topical antibiotics are not toxic to human cells, but they can kill bacterial cells. Topical antibiotics and antifungals come in gels, creams, and impregnated dressings. However, many healthcare institutions do not support the use of topical antibiotics due to the high likelihood of antibiotic resistance (2, 5).  

Topical antifungals can reduce infection in fungal wounds, particularly when the specific fungus is identified and targeted. Chronic wounds that have fungal biofilm require an individualized treatment approach, especially since many antifungals are not capable of penetrating the biofilm (10). 

Wound dressings maintain a humid environment and promote oxygen permeability, which helps with wound healing (3).  There are currently over 3,000 types of wound dressings on the market with films, hydrogels, and polymers being the most popular (3).  

Table 3. Wound dressings commonly used today (3, 6) 

Table 4. Types of dressings used for specific wounds (3, 6). 

Bioengineered skin substitutes are composed of biomaterials, cells, and growth factors that mimic normal skin and enhance regeneration by providing a protective semi-permeable barrier around the wound. These are used to repair partial and full thickness wounds, chronic ulcers, and burns. Epidermal, dermal, and epidermal-dermal skin substitutes are available and include the brand names Alloderm, Dermagraft, Integra, Matriderm, and Transcyte (3). 

New antibiofilm agents are emerging, including nanomaterials, antimicrobial peptides, and bacteriophages. Nanoparticles’ small diameter allows them to penetrate cell membranes and biofilms, and thus emit bactericidal properties. Wound dressings, encapsulated drugs, and microneedle injection systems deliver nanoparticles directly under the skin. The advantages to nanoparticles are improved bioavailability, half-life, and penetration of the drugs into bacterial biofilms (3). Nanomaterials include not only nanoparticles, but also nanogels, nanofibers, nanoemulsions, micelles, liposomes, nanosheets, ethosomes, solid-lipids, quantum dots, carbon nanotubes, and magnetics (3). 

Bacteriophages are found to destroy S. aureus, P. aeruginosa, and E. coli, and are being used in fibers, hydrogels, and films (5, 10). The bacteriophagic endolysin proteins can target specific bacteria with little damage to the surrounding microbiome and are responsible for a new class of antimicrobial agents called “enzybiotics” (5).  

Additional newer therapies include stem cell therapy, bioprinting, platelet-rich plasma (PRP), and cold plasma. Stem cell therapy is very effective in healing chronic wounds by utilizing growth factors, regulating inflammatory processes, and stimulating immune processes for accelerating vascularization and re-epithelialization. Autologous stem cells are well-tolerated by patients and carry minimum adverse reactions (3). The types of stem cells used in wound therapy are embryonic stem cells, mesenchymal stem cells, and pluripotent stem cells. Bone marrow-derived stem cells are effective in treating acute and chronic full thickness wounds and chronic diabetic wounds. Adipose-derived stem cells are used to treat chronic diabetic wounds and chronic full thickness burn wounds. Hair follicle stem cells treat acute full thickness excisional wounds, chronic venous leg ulcers, and acute full thickness wounds. Induced pluripotent stem cells are effective in managing acute full thickness wounds, chronic diabetic ulcers, and chronic burn wounds (3). 

Three-dimensional (3D) bioprinting fabricates biocompatible artificial skins by precisely layering living cells, biomaterials, biomolecules, and growth factors. The advantages of this advancement include faster and less expensive fabrication; improved wound innervation, pigmentation, and vascularization; deposition of the biomaterials in different positions; and large-scale fabrication with successful plasticity (3). Bioprinting is being enhanced with bio-inks that help improve wound closure and re-epithelialization (3). 

Platelet-rich plasma accelerates wound healing by supplying growth factors to the wound. Platelets have a hemostatic function that promotes cell proliferation and tissue expansion. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor beta 1 (TGF-β1), insulin growth factor-1 (IGF-1), keratinocyte growth factor (KGF), and vascular epithelial growth factor (VEGF) act as signaling molecules that influence cellular metabolism that leads to wound healing (3). 

Cold atmospheric plasma (CAP) is an ionized room-temperature gas that consists of electrons, diverse reactive oxygen, nitrogen, and ultraviolet (UV) irradiation that inactivates microbes, enhances growth factors, remodels fibroblasts, and promotes angiogenesis (3). 

Research indicates that there is excessive over-prescribing of antibiotics in patients with non-healing wounds (5, 10). Antibiotic therapy is frequently prescribed without addressing the etiology of the wound, thus leading to prescriptions that are not clinically justifiable or beneficial. Antiseptics have been shown in the research to be safer and more effective in the long-term than antibiotic use (10). Research also indicates that early detection of infection combined with improved wound hygiene practices reduce the need for antimicrobial dressings (10). 

Indications of Use 

Topical antimicrobial products typically complete wound healing in 8-12 weeks, improve wound bed tissue, reduce the clinical signs and symptoms of wound bed infection, and reduce microorganisms and biofilm as confirmed by laboratory diagnostics (10). The duration of use is individualized to the patient and is based on regular wound assessment. However, most antimicrobial products require use for two to four weeks to see effective results. Many nurses find that rotating topical antiseptic treatment, in conjunction with cleansing and debridement, helps improve wound healing (10). 

When selecting which topical antiseptic to administer, the nurse should ask themselves the following questions (10): 

• Is the antimicrobial action broad-spectrum or confirmed for specific microorganism use? 

• Is the substance toxic-free or have low toxicity? 

• Is the substance fast-acting and long-lasting? 

• Does the substance have a history of being bacterial resistant? 

• Will the substance help reach the clinical goals of the patient? 

• Does my facility approve the use of this product? 

Antimicrobial resistance is a serious consideration that is affected by inappropriate use, and over-use, of antimicrobials, inadequate infection prevention and control, and lack of knowledge surrounding antimicrobial use (10). 

To ensure effective wound care and prevent infection, the nurse should follow these steps (10): 

• Review the patient’s medical history, diagnosis, treatment goals, current wound condition and treatment regimen, and preferences. 

• Explain the procedure to the patient and obtain consent to change the wound dressing. 

• Conduct a pain assessment and administer analgesia, as indicated. 

• Wipe down the work area with disinfectant. Remove pets (if applicable). Turn off fans and air conditioning (if possible) to decrease the spread of pathogens. 

• Collect the necessary equipment: hand sanitizer, personal protective equipment (PPE), wound cleanser, dressing kit, measuring tape, wound device supplies (if applicable), and camera (for wound photography). 

• Prepare and position the patient, promoting comfort, privacy, and safety. 

• Perform hand-hygiene and don non-sterile gloves. 

• Moisten the existing dressing, remove, and discard. 

• Remove and discard non-sterile gloves. 

• Open the sterile dressing pack/kit onto the cleansed work surface. 

• Perform hand hygiene and don sterile gloves. 

• Remove the primary dressing using the sterile forceps. The forceps are now considered dirty. 

• Cleanse and debride the wound using sterile equipment. The equipment is now considered dirty. 

• Take wound measurements and photographs. After measuring the wound, remove sterile gloves and perform hand hygiene. 

• Select the dressing based on amount of wound exudate, wound condition, type of infection, frequency that dressing will be changed, and patient preference. 

• Perform hand hygiene and don sterile gloves. 

• Cut and apply the new dressing.  

• Discard waste. 

• Document the wound treatment. 

However, the American Nurses Association (ANA) advocates for slightly different measures (7): 

• Research does not indicate a difference in wound infection rates when using clean versus sterile techniques. Therefore, sterile technique is not always warranted. 

• Hydrofiber and alginate dressings are not interchangeable. Alginates are created from naturally occurring seaweed or algae and can absorb up to 20 times their weight. Conversely, hydrofiber is created in a lab and can hold 30 times its weight. Hydrofibers are preferred in managing wounds with excessive drainage since they present less of a risk for maceration than alginates. There are dressings that use both alginate and hydrofiber, but these have not been found to be more effective than the individual products. Hydrofibers cost more than alginates, but they also last longer. 

• Negative pressure wound therapy (NPWT) should be used for fistulas in open wounds if the fistula exhibits potential for closure and no bowel is present. If wound healing is not possible, NPWT is not recommended. Fistula management should commence with a pouching system, and NPWT should only be implemented if pouching fails. 

• The Bates-Jensen Wound Assessment Tool should be utilized instead of the Braden Scale, Norton Scale, and Waterlow Scale, which were developed over thirty years ago, and thus don’t reflect current evidence-based research or knowledge.  

• If wound care does not consider the patient’s comorbidities and nutritional status, it is not an effective treatment plan. 

Reducing the patient’s individual risk factors for wound infection is the priority step in prevention, followed by the use of topical antimicrobials (10).  

Research Findings 

As much as 80% of chronic wounds contain biofilm in contrast to 6% of acute wounds. This is an area of interest to researchers because it is not completely understood why biofilms are more present in chronic wounds; however, scientists state that biofilms are tolerant or resistant to antibiotics, antiseptics, and the host’s defenses, thus making them difficult to treat (10). It is known that microorganisms exist on both the wound surface and within the extracellular matrix beneath the surface of the wound bed.  

Biofilm has also been shown to be present on both healthy skin and acute epidermal wounds, indicating that biofilm may be established prior to being introduced to a wound. Some wounds that appear to be healthy to the unaided eye actually contain biofilm. This is why it is important for nurses to suspect the presence of biofilm in wounds that are chronically inflamed and fail to heal at the expected rate. Debridement is considered the gold standard treatment for reducing biofilm (10). 

Antimicrobial stewardship is a concept that entails the supervised and organized use of antimicrobial agents to decrease the spread of infections by multidrug resistant organisms and improve clinical outcomes by promoting the effective use of antimicrobials. Global organizations that promote antimicrobial stewardship include the World Health Organization (WHO), Transatlantic Task Force on Antimicrobial Resistance (TATFAR), Global Antibiotic Resistance Partnership (GARP), Global Health Security Agenda (GHSA), Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), Food and Agriculture Organization of the United Nations (FAO), and the World Organization for Animal Health (OIE). The WHO coordinates an annual event, World Antimicrobial Awareness Week, to increase antimicrobial resistance awareness (10). 

Researchers encourage healthcare institutions to establish guidelines, formularies, and clinical decision pathways via antimicrobial stewardship committees to ensure a multidisciplinary and multifaceted approach to antimicrobial use. 

Conclusion

Nurses, regardless of their specialty, are likely to encounter patients with infected wounds since this condition is on the rise. It is important for nurses to remember that wound care is constantly evolving; therefore, relying on outdated treatments and techniques is not advised. With the increasing phenomena of antimicrobial resistance and the dry pipeline of new drug development, clinicians and researchers are tasked with relying on wound care techniques that incorporate bioengineered skin substitutes, stem cells, bioprinting, growth factors, and other therapies. Additionally, considering the holistic patient, including their comorbidities and nutritional status, is paramount to a successful wound management program. 

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