Innovations in Infection Prevention and Treatment

Abstract

Background:

Patients with large, acute burn injuries are a major challenge for clinicians. The loss of skin barrier protection against micro-organisms combined with the induced immunosuppression after burn injury makes this population especially vulnerable to infection. For burn-injured patients who survive immediate management considerations and burn resuscitation after acute injury, sepsis remains the primary cause of death. The purpose of this article is to describe current strategies and innovations in burn sepsis prevention and management.

Methods:

This work reviews the current understanding of the systemic inflammatory response to burn injury and burn sepsis as well as current strategies in insolation and infection prevention, newer burn unit design strategies in the context of infection prevention, and novel therapies being considered in topical antimicrobial wound care management.

Results:

A review of burn sepsis is key to understanding current paradigms and innovation in burn management and prevention. Key management principles begin from the time of injury and persist throughout the patient's hospital course. This includes use of personal protective equipment, burn unit design considerations, and knowledge of critical care principles such as central venous catheter management strategies. Innovations on wound dressing types, forms, and use have been key to better controlling burn wound sepsis and improving wound healing. Products incorporating nanotechnology, novel anions, oxygen, and even light have been key to introducing previously unconsidered methods to fight or prevent infection.

Conclusion:

Understanding the pathophysiology and source identification of sepsis from burn wounds has been a key contributor in developing innovative prevention and therapeutic strategies in burn management. The emergence of drug-resistant pathogens and the difficulty of systemic antibiotic agents to reach poorly vascularized wounds have further reinforced the need to anticipate management strategies moving forward. A proactive, multidisciplinary approach is necessary to minimize the morbidity and mortality associated with infection control.

Among the 400,000 patients who receive some form of burn injury treatment annually, approximately 40,000 patients require hospitalization and more than 3,000 patients die because of burn-related complications [1]. Infection remains the largest contributor to burn-related morbidity and mortality and the risk of infection increases with burn injury size [2,3]. The recognition of septicemia as a major driver of burn-related complications and identification of its source in burn wounds has impacted the management of burn injury profoundly. Elucidation of the pathophysiologic mechanisms underlying burn sepsis has been a key driver in developing burn sepsis prevention and management strategies. The emergence of drug-resistant pathogens and the difficulty of systemic antibiotics to reach poorly vascularized wounds have further reinforced the need for innovative approaches to burn wound infection and sepsis. A collaborative approach involving the burn surgeon and a multidisciplinary team that includes an infectious disease physician and pharmacist is key to ensuring current infectious management paradigms are being met [4].

Pathophysiology of Systemic Infection in Burn Patients

The physiologic changes that follow burn injury and eventually sepsis represent a dysregulation in mechanisms intended to restore homeostasis. This begins with macrophage attraction to burn-injured tissue for bacterial pathogen and damage-associated molecular patterns recognition. This then signals leukocyte and fibroblast arrival to isolate infectious sources and promote wound healing. The inflammatory response that ensues produces key cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) to mediate inflammatory induced cell signaling [5,6].

With mild burn injury, cytokine levels remain relatively low and contained to the injury site. However, as burn injury size increases, cytokines spill into the circulation to induce a systemic inflammatory response that affects multiple organ systems. The hypothalamus, for example, recognizes the cytokine surge and redirects hormone production while the adrenal gland induces a catecholamine and glucocorticoid surge that clinically manifests as tachycardia and tachypnea. The body's metabolic rate concurrently increases, leading to increases in body set point temperature and fevers, while the liver produces acute phase reactants such as C-reactive protein [6,7]. Capillary beds start to leak and endothelial exposure leads to coagulation factor consumption, platelet adhesion, and eventually disseminated intravascular coagulopathy [8,9]. End organs detect a hypoxic state and stimulate nitric oxide release from cells, resulting in decreased vascular resistance, intravascular hypovolemia, and hypotension that worsens end organ perfusion [6].

As this process continues, additional organs may fail. Inflammatory fluid shifts into the alveoli to interfere with capillary oxygen transfer and eventually leads to acute respiratory distress syndrome. The combination of a low flow state and circulating toxic molecules result in acute tubular necrosis (ATN) of the kidneys. Damage to the liver manifests with transaminitis and hyperbilirubinemia while exhausted intracellular calcium stores decrease myocardial contractility, resulting in decreased cardiac output and further exacerbating end organ perfusion [10,11]. The result of this sepsis-induced massive physiologic process is multiorgan failure and represents the primary cause of death after burn injury [6].

The loss of the skin barrier creates a unique continuous systemic inflammation that lasts as long as burn wounds remain open. As burn injury increases in size, the inflammatory response becomes large enough to result in a sustained hypermetabolic response that increases normal set points for body temperature, heart rate, respiratory rate, and clinical laboratory measures [6]. As a result, standard definitions of systemic inflammatory response syndrome and sepsis are difficult to apply in this population. The American Burn Association consensus guidelines on sepsis detail unique parameters to consider when identifying sepsis in burn injured patients. Guidelines are summarized in Table 1 [12].

Table 1.

American Burn Association Consensus Guidelines to Establish Burn Sepsis

Temperature	>39°C or <36.5°C
Heart rate	Tachycardia >110 beats/min
Respiratory rate	Tachypnea >25 breaths/min
Minute ventilation	Minute ventilation >12 L/min
Platelet count	Thrombocytopenia <100 k/mcL 3 days post-burn
Glucose control	Hyperglycemia in absence of diabetes; Untreated plasma glucose >200 mg/dL; intravenous insulin requirement >7 U/h, insulin resistance
Enteral feeding	Enteral feeding intolerance >24 h; distention, uncontrolled diarrhea, increased residuals
Identification/treatment	Source of infection identified by culture or pathologic tissue; Clinically responds to antimicrobial

Prevention Strategies To Minimize Contamination following Burn Injury

Burn patients are both susceptible to and a source of infection. Practices to prevent contamination and burn sepsis begin from the time of injury and should be pursued at facility presentation. Receiving hospitals must have dedicated burn unit facilities separate from the general hospital population with exclusive equipment, burn wound and dressing care capability, visitation flow considerations, and close proximity to operating rooms [13]. Personal protective equipment such as a scrub hat, mask, gown, gloves, and shoe covers are essential and must always be used during patient care [2].

Burn unit design must consider both endogenous and exogenous sources of infection when caring for the burn injured patient. Endogenous sources of infection are generated from the patient whereas exogenous sources originate from the environment. Endogenous sources remain the primary source of infectious outbreaks in the burn unit and can be found on patients' skin flora, open burn injuries, and aerosolized respiratory secretions [3]. Exogenous factors are multiple and varied. Hospital providers, medical equipment, and cleaning staff may inevitably encounter objects such as medical equipment, room furniture, or even door handles that further circulate concerning sources. Additional vectors such as ventilation systems, visitors, or even stationary objects such as uncleaned patient televisions should also be considered for spread [2].

Advanced monitoring devices such as electrocardiograms and pulse oximetry devices are also potential sources of infectious spread. Probes and cables used for these monitoring devices can harbor bacteria and should ideally be disposable to eliminate shared use between patients. If this is not possible, regular meticulous cleansing of non-disposable cables can be incorporated into room cleaning processes. Stationary and portable devices such as radiograph or ultrasound machines should be cleaned thoroughly prior to entering patient rooms, covered in plastic during use, and be cleaned again after leaving patient rooms [2]. Sinks and toilets in particular have been identified as previous sources for burn unit bacterial outbreaks and must be thoroughly cleaned regularly [14]. Wash tubs are difficult to clean and can be a source of bacterial proliferation. Newer tub designs provide inner lining removal to be changed between patient use. Hydrotherapy may need to be considered only in smaller wounds and more stable patients to minimize this risk [2].

Non-contact room decontamination systems have become a useful way to minimize infectious spread of multi-drug–resistant organisms between patient stays. Hydrogen peroxide functions to lyse DNA, lipid membranes, and various other cell components through reactive hydroxyl radicals [15]. Two types of hydrogen peroxide room disinfection systems include aerosolized hydrogen peroxide (aHP) systems and hydrogen peroxide vapor systems. The aHP systems typically combine 5%–7% hydrogen peroxide with Ag cations for a process time of approximately two to three hours whereas vapor systems use 30%–35% hydrogen peroxide and range from 2.5 to eight hours of disinfection process time. Both systems have shown efficacy in reducing organism contamination in species such as methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter spp, and vancomycin-resistant enterococci (VRE) [16]. Additional excellence in sporicidal activity, as well as efficacy in inactivating viruses such as human adenovirus type 1, severe acute respiratory virus, and feline calicivirus has been shown [17]. Comparison of hydrogen peroxide systems have overall shown a reduction of contaminated surfaces to 0% in most studies, or at least 5% or less in all studies [16]. Direct comparison of aerosolized versus vapor systems have shown superior biologic spore and microbial load inactivation with vapor systems [18,19].

Common Septic Sources in Burn Injured Patients

Burn-injured patients themselves are frequently colonized or at risk to multi-drug–resistant pathogens, fungal infections, and even viral infections [6]. Burn wound colonization typically occurs within one week of injury and is predominantly gram-positive organisms. This is eventually replaced over time by gram-negative organisms. Continually open wounds provide a nidus for resistant organisms, yeast, and fungi to proliferate. Larger burn sizes, full-thickness burn sizes, and delayed burn care represent the highest risks for infection and eventual spread [3]. Although early excision and grafting is known to decrease bacterial wound load and the incidence of sepsis and wound infection, practices such as meticulous and frequent dressing changes, oral hygiene, pulmonary toileting, early nutrition, topical antimicrobial dressings, targeted intravenous antibiotic use, early mobility, and appropriate contact isolation precautions help stem infection risk [2,20,21].

Data suggest pneumonia as a leading cause of infectious complication in burn-injured patients, but other sources include general bacteremia, burn wounds, cellulitis, and line-associated infections [11,22]. Because of the onset of early burn eschar excision with early skin grafting and topical antibiotic use, burn wounds are not usually the initial source of infection [11]. Invasive lines are required in long-term burn injury management and includes indwelling urinary catheters, central venous catheters, arterial monitoring catheters, and endotracheal intubation. These place patients at risk for in central line-associated blood stream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and ventilator-acquired pneumonias [4].

Studies examining central line infections in burn injury have tried to optimize frequency of line changes and exchanges resulting from bacterial milieu incited by burn injury. One study established the utility of frequent central venous catheter changes to minimize the risk of catheter-related blood stream infections by changing lines over guidewire every six days and new site placement on day 12 [23]. Peripherally inserted central catheter (PICC) lines were also notably at risk of infection and increasingly so with severe burn injury and longer hospital stays [24]. Further still, higher central venous catheter (CVC) infection rates were seen in catheters inserted near or directly through a burn wound, or those inserted through the femoral vein [25].

Overview of Topical Wound Management and Current Standards

Topical wound care has been an important factor in the management of acute burn injury and for wound healing. Wounds have a variety of types and sizes and each has their own requirements to optimize wound healing. Acute wounds are tissue injuries expected to heal within 12 weeks with minimal scarring whereas chronic wounds are expected to heal beyond 12 weeks and can often recur [26]. Superficial wounds involve the level of the epidermis only. Partial thickness wounds involve the epidermis, dermis, and associated dermal structures such as blood vessels, sweat glands, and hair follicles. Full thickness wounds occur after injury that reaches the subcutaneous fat and deeper tissues [27]. There is no single dressing that fulfills all characteristics needed to heal a wound [28]. Previous topical wound care strategies focused on coverage that would prevent infection. This included materials such as plant fibers, honey, and animal fat as well as drier materials such as cotton, wool, lint, and gauze to dry wound exudate and prevent bacterial spread into a surrounding wound environment [29]. Important characteristics in an ideal wound dressing include affordability, prevention of infection, and aesthetics [30]. Examples of product availability for various dressing types are summarized in Table 2.

Table 2.

Examples of Available Products for Various Dressing Types

Dressing type	Products available
Polymeric materials	Tegaderm™ (3M, St. Paul, MN)
Polymeric materials	Superabsorber (McKesson, Irving, TX)
Foam dressings	Mepilex^® Ag, Mepitel^® (Molnlycke Health Care AB, Gothenburg, Sweden)
Foam dressings	Allevyn (Smith and Nephew, London, UK)
Hydrocolloids/hydrogels	Hydrocolloid dressing (McKesson, Irving, Texas, USA)
Oxygen delivery dressings	OxyBand™ (Oxyband Technologies, St. Louis, MO, USA)
Light-based dressings	LED, OLED, QLED
Nanocrystalline products	Acticoat™ (Smith and Nephew, London, UK)
Nanocrystalline products	Silverlon™ (Silverlon, Geneva, IL, USA)
Gold nanoparticles	Remains experimental
Hypochlorous acid	Vashe^® Wound Solution (Urgo Medical, Fort Worth, TX)
Biologics	Cultured epithelial autografts
	Recell^® Noncultured autologous cell suspension (Avita Medical, Valencia, CA)
	MatriDerm^® (Medskin Solutions, Billerbeck, Germany)
	EZ Derm^® (Molnlycke Health Care AB, Gothenburg, Sweden)
	AlloDerm™ (Allergan, Dublin, Ireland)
	Biobrane^® (UDL Laboratories, Rockford, IL)
	Xeroform (Convidien, Mansfield, MA)

LED = light emitting diode; OLED = organic light emitting diode; QLED = quantum light emitting diode.

Newer Biomaterials

Polymeric materials

There are several types of polymeric materials used as wound dressings to aid in wound healing [28]. Passive synthetic dressings include gauze and tulle and serve to help restore function. These are usually non-occlusive in nature and are built with synthetic polymers that take the form of films, hydrogels, or hydrocolloids to provide a barrier against bacterial penetration of a wound [31]. Polymer films encourage a moist wound environment by trapping exudate. Components such as polyurethane serve multiple functions by providing a barrier to bacterial contamination and liquids while remaining permeable to moisture vapor and air. Because of the non-absorbent nature of these dressings, exudate may accumulate underneath, causing a breakage in the dressing environment and allowing exposure to outside elements [28]. One comparison of polyurethane films to control dressings with Tegaderm™ (3M, St. Paul, MN) showed thinner scabbing, decreased inflammatory cell infiltration, earlier granulation tissue formation, and better epithelial cell organization in polyurethane films [32].

Foam dressings

Although wet environments help facilitate faster wound healing, occlusive dressings are eventually unable to manage the exudate built up over time. In comparison, foam dressings allow the ability to absorb exudate while maintaining a moist environment for wound healing [30]. Foam dressings are ideal because they provide absorption, can be left in place for several days, do not shed particles, and minimize or eliminate maceration [33]. Factors that affect dressing performance include dressing thickness, porosity, density, the capacity to retain fluid or exudate, and antimicrobial properties such as silver-releasing foam dressings [34,35].

Hydrocolloids

Hydrocolloids originate from several plant-based ingredients such as agar, alginate, carrageenan, and pectin, and are usually used in a gelatin form derived from animal protein collagen for wound care [28]. Hydrocolloids can be occlusive, absorbent, or semi-permeable. Production involves the generation of a gel agent that is mounted onto a flexible and water-resistant layer. This helps maintain a moist, hypoxic environment that contours to a wound and facilitates wound healing. Fluid from the wound is then absorbed by the dressing while the gel provides a moist environment conducive to wound healing. Dressings are semi-permeable and can allow swimming and bathing without dressing change, thus decreasing the needed frequency of dressing changes [28]. Synthetic or natural dressings utilizing polymers with hydroxyl groups to create a hydrophilic environment utilize the occlusive hypoxic environment to facilitate liquefactive necrosis and autolytic debridement [36, 37]. This dressing is thought to encourage antimicrobial behavior by increasing leukocyte infiltration into wounds [38].

Hydrogels

Hydrogels are made from hydrophilic cross-linked polymers that swell once in contact with water. The release of macromolecules is controlled by its hydrophobicity [39]. Macromolecules such as silver hydrogels have been developed as dressings and shown to be effective in topical antimicrobial control [40].

Polymer films

Alginate dressings are a porous sheet designed for draining or exudating wounds. This dressing design allows for ion exchange and fluid absorption once in contact with a draining wound [41]. These dressings are additionally used to provide hemostasis, with zinc-containing alginates having the highest hemostatic ability [42].

Oxygen-delivering bandages

Oxygen plays a large role in infection prevention, angiogenesis, collagen syntheses, and wound healing. Animal studies have shown that decreased wound oxygen levels can impair fibroblast proliferation and collagen deposition while increasing rates of wound infection [43 –46]. Several animal models have shown improvements in wound size, epithelialization, and time to wound closure with topically applied oxygen [47,48]. Hyperbaric oxygen has been introduced as a method to provide supranormal levels of oxygen to patients with chronic wounds, but requires trained personnel, available facilities, and risks systemic oxygen toxicity [49]. Oxygen diffusion dressings have been developed to harness the benefit of oxygen delivery in a more manageable form. Designed as multilayered dressings prefilled with high levels of oxygen between layers, the topmost layer is a protective barrier designed to withhold oxygen from escaping the dressing and the bottom layer is a transfer layer to facilitate oxygen delivery to the wound. This non-adherent dressing provides the wound with continuous oxygen delivery to healing wounds [49]. A study comparing oxygen diffusion dressings on burn patient donor site wounds found a substantially reduced time to healing, lower pain scores, but no differences in cosmetic outcomes post-operatively compared with xeroform [49].

Light-based dressings

Medical applications of light therapy is a burgeoning field with demonstrated effectiveness in chronic pain, inflammation, and tissue regeneration [50,51]. The number of studies examining light applications in wound healing has seen substantial growth [52,53]. Called photobiomodulation (PBM), this method of wound therapy uses light to stimulate cellular function toward intended beneficial clinical effects. It has been described as a minimally invasive treatment strategy involving the use of bulky light sources such as laser or light-emitting diode (LED) arrays [54]. A recent study on photobiomodulation of dermal analogue tissue, for example, showed use of 660-nm wavelength of light induced transcription of cytokines IL-1β and IL-6 mRNA while decreasing IL-8 [53].

Despite this, wound dressing application and considerations remain paramount to widespread use. A bulky, expensive dressing would be difficult to efficiently deploy for general use. Organic light-emitting devices (OLEDs) were thought to be an ideal candidate because of their unique thin, flexible, and lightweight properties while maintaining luminescence over large areas. However, general LEDs in comparison are able to maintain brighter wavelengths in the deeper red regions necessary for deeper tissue penetration and to maintain molecular excitation [54]. Recently developed quantum light emitting devices (QLEDs) possess many of the positive properties of OLEDs while maintaining the deep red illumination required for effectiveness. An in vitro study examining the use of QLED-based photodynamic therapy showed effective eradication of MRSA [55]. Development of tunable and flexible photodynamic therapy remains promising and represents a potential minimally invasive therapy in burn infection treatment.

Nanocrystalline silver products

Silver has an extensive history in the use of disinfection and antimicrobial use [56]. Silver as an antibiotic has broad-spectrum coverage and serves antiseptic, antimicrobial, and anti-inflammatory roles [57 –59]. Silver cations produce their antimicrobial effect by blocking the function of bacterial membranes to prevent cellular respiration. By binding to proteins in the cellular membrane, structural changes and bacterial DNA denaturation eventually lead to cell death [60 –62]. Nanocrystalline silver products such as Acticoat^TM (Smith and Nephew, London, UK) are examples of new technologies that further improve the application of topical antimicrobial care in burn wounds in innovative ways.

Utilizing nanotechnology, clusters of small and reactive silver particles are slowly released in small concentrations, resulting in approximately 30 times less silver cation release compared with other silver-based dressings such as silversulfadiazine cream or 0.5% silver nitrate solution [63]. Size factors in smaller particles of silver allow for greater wound contact, bioactivity, and solubility [64]. This in turn alters the wound inflammatory milieu, reduces wound infection, and promotes wound healing [63]. Additional moistening will cause controlled release of further silver product and allows a moist environment to facilitate wound healing further [56,65]. Human studies in burn patients have shown decreased dressing change frequency and decreased incidence of wound sepsis in nanocrystalline silver dressings [60]. Some studies have also shown decreased pain levels for wounds treated with nanocrystalline silver dressings [66].

Modern military operations require efficient management and stabilization of acute burn injury in the battlefield. Despite the availability of modern topical antimicrobial solutions and ointments commonly used in the civilian setting, the concern for shelf life and need for continued dressing changes make this a challenge in the combat setting. One strategy is the use of silver-coated nylon fibers called Silverlon™ (Argentum Medical, Geneva, IL) that contour to the burn wound and allow the sustained release of silver ions upon regular application of water at set intervals. This allows sustained antimicrobial coverage while obviating the need for frequent dressing changes [67 –70]. These dressings are simple, shelf stable, and cost effective, making them ideal combat scenario dressings [68,69]. A recent 10-year retrospective analysis of silver nylon dressings showed decreased wound infection rates compared with other topical antimicrobial agents and no significant differences in burn-related complications [71].

Gold nanoparticles

Additional metals other than silver have been tested for antimicrobial properties and effectiveness in topical wound care. Gold nanoparticles have been shown to be chemically stable, easy to synthesize, and possess both antimicrobial and wound healing properties [72,73]. These nanoparticles bind to bacterial cell walls and DNA such as silver and can additionally block the formation of reactive oxygen species [74,75]. One recent mouse burn model demonstrated healing promotion and inhibition of microbial colonization with the use of gold nanoparticles [73].

Hypochlorous acid

Whereas agents such as mafenide may protect against infection, it has also been shown overall to be toxic to cells and may have a detrimental effect on wound healing and may cause allergic reactions [76 –78]. Hypochlorous acid (HOCl) is a topical antimicrobial recently thought to carry many of the positive aspects of mafenide while minimizing associated complications. Normally produced by neutrophils as part of the respiratory burst pathway, HOCl is thought to work through inhibition of bacterial plasma membrane proteins involved in ion transport [79,80]. Hypochlorous acid has a large range of antimicrobial coverage, including resistant organisms such as MRSA and VRE [81]. There have been no reports of microbial resistance to HOCl as yet. One recent preliminary randomized control trial showed equivalent efficacy and safety compared with mafenide solution in post-operative burn wound skin graft dressings [78].

Biological skin substitutes

As satisfactory survival rates continue to improve, attention has now shifted toward long-term form and function [82,83]. Timely restoration of protective skin function has been identified as a key pillar of successful burn wound management, but this may be challenged in the setting of larger and more severe burn sizes. Skin substitutes have been identified as an important tool that can help with wound coverage, closure, and skin function through either temporary or permanent coverage [82,84]. Skin substitutes come in biologic or synthetic variants and each come with their own characteristics. Biologic skin substitutes, for example, may allow more natural dermal construction and epithelialization whereas synthetic substitutes can serve specific functions such as control over scaffold composition [82]. Ideal skin substitutes provide replacement of dermal and epidermal function and can to resist infection, prevent water loss, or provide better conformity [85]. Skin substitutes are sourced from a number of areas, including naturally occurring substances, synthetic and tissue engineered materials, animals, and human cadavers [86]. Modifications to these substitutes have also been made to improve antimicrobial properties during temporary coverage. Xenografts, for example have been recently modified to include aldehyde cross-linking and silver ion impregnation to better maximize their antimicrobial coverage [84].

Conclusions

Burn-injured patients are a unique group of patients with sustained inflammatory responses and an overall immunocompromised state that places them at increased risk for infection. Newer prevention initiatives and innovations burn sepsis management have been key drivers to improving morbidity and mortality in this patient population.

Footnotes

Authors' Contributions

The authors have made equal contributions to the conception, design, analysis, interpretation, drafting, and revision of the article for this study.

Funding Information

There was no funding received in the creation of this article.

Author Disclosure Statement

No competing financial interests exist.

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