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Previous Article | Next Article 
Clinical Microbiology Reviews, April 2006, p. 403-434, Vol. 19, No. 2
0893-8512/06/$08.00+0 doi:10.1128/CMR.19.2.403-434.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Division of Microbiology, Calgary Laboratory Services,1 Departments of Pathology & Laboratory Medicine,2 Surgery,3 Critical Care, Calgary Health Region and University of Calgary, Calgary, Alberta, Canada4
SUMMARY INTRODUCTION HUMAN SKIN—A MAJOR HOST DEFENSE BURN INJURY IN CIVILIANS Magnitude and Risk Factors of Civilian Burn Injury Pathogenesis and Etiology of Burns Thermal injury. Chemical injury. Extent and Location of Burn Injury Inhalation Injury Early Excision and Burn Wound Closure IMMUNOLOGICAL RESPONSE TO BURN INJURY Systemic Response to Burn Injury Inflammatory response to burn injury. Anti-inflammatory response to burn injury. Innate Immune System Response to Burn Injury Adaptive Immune System in Response to Burn Injury Altering the Immunologic Response to Burn Injury EPIDEMIOLOGY OF BURN WOUND INFECTIONS Impact of Patient Demographics and Burn Severity Impact of Changes in Burn Wound Care PATHOGENESIS OF BURN WOUND INFECTIONS Pathogenesis Biofilm Formation Microbial Etiology Virulence Factors and Tissue Invasion CLASSIFICATION OF BURN WOUND INFECTIONS Types of Burn Wound Infection Burn wound impetigo. Burn-related surgical wound infection. Burn wound cellulitis. Invasive infection in unexcised burn wounds. MICROBIOLOGICAL ANALYSIS OF BURN WOUND INFECTIONS Best Approach for Burn Wound Infection Surveillance Burn Wound Sampling Techniques Superficial wound samples. Tissue biopsy. Sampling techniques for other microbial pathogens. Specimen Transport Analysis of Burn Wound Specimens Gram stain. Surface swab culture. Quantitative tissue culture. Histological analysis. Distinguishing Burn Wound Colonization from Infection Antimicrobial Susceptibility Testing Antimicrobial resistance and burn units. Burn unit antibiogram. Other Types of Infection Fungal infections. Viral infections. OTHER TYPES OF INFECTION IN BURN PATIENTS Sepsis and Toxic Shock Syndrome Pneumonia Urinary Tract Infections Catheter Infections and Suppurative Thrombophlebitis Myonecrosis PREVENTION OF BURN WOUND INFECTIONS Topical Antimicrobial Therapy Silver nitrate. Silver sulfadiazine. Mafenide acetate. Acticoat A.B. dressing/Silverlon. Mupirocin (Bactroban). Nystatin. Other topical antimicrobials. Prophylactic Systemic Antibiotics Selective Bowel Decontamination Prevention of Tetanus Infection Control in the Burn Unit FUTURE DIRECTIONS IN MICROBIAL BURN WOUND SURVEILLANCE REFERENCES
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| INTRODUCTION |
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The survival rates for burn patients have improved substantially in the past few decades due to advances in modern medical care in specialized burn centers. Improved outcomes for severely burned patients have been attributed to medical advances in fluid resuscitation, nutritional support, pulmonary care, burn wound care, and infection control practices. As a result, burn-related deaths, depending on the extent of injury, have been halved within the past 40 years (7, 252, 320, 369, 373, 439). In patients with severe burns over more than 40% of the total body surface area (TBSA), 75% of all deaths are currently related to sepsis from burn wound infection or other infection complications and/or inhalation injury (15, 20, 24, 32, 140).
This review focuses on modern aspects of the epidemiology, diagnosis, management, and prevention of burn wound infections and sepsis. Recent factors contributing to the development of burn wound infection are also discussed, including the nature and extent of the burn injury itself and the secondary immunosuppression resulting from thermal injury. The prevention of burn wound infection is reviewed in the context of newer therapeutic strategies employed by specialized burn care facilities.
| HUMAN SKIN—A MAJOR HOST DEFENSE |
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Figure 1 provides a schematic representation of the skin layers in relation to the depth of burn injury (96, 113, 369). The skin is derived from ectoderm and mesoderm and has two anatomic layers: the epidermis or outermost nonvascular layer consists of several layers of epidermal cells that vary in thickness over various body surfaces, and the dermis or corium is largely made of collagen and contains the microcirculation, a complex vascular plexus of arterioles, venules, and capillaries. The two skin layers are bound together by a complex mechanism that is essential for normal function. Epidermal appendages are distributed throughout the dermis layer, including the sweat glands, sebaceous glands, and hair follicles. The dermal layer is capable of producing new epithelial cells to replace those lost from the epidermis by burning or other injury to the skin because the shafts of these appendages are lined with epithelial cells. Nerve endings occur throughout both skin layers, and the connective tissue of the dermis also provides a firm structural base for the skin. Burn injury is a very painful form of trauma because of the multitude of pain receptors and nerves that traverse the skin layers. Beneath the skin lie the subcutaneous tissues, muscle, and bone.
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13 and 22 lbs). The average adult skin surface area is 1.5 to 2.0 square meters, in contrast to that of a newborn, whose skin surface area is only 0.2 to 0.3 square meter. The two skin layers together are up to several millimeters thick, but both epidermal and dermal thickness varies depending on the body site. The epidermis is the thinnest (0.05 mm) over the eyelid but thicker (up to 1 mm) over the soles of the feet (114, 369). The dermis is thickest on the back. Males generally have thicker skin than females. General skin thickness peaks in midlife and gradually thins as part of the aging process (113, 114, 216, 217, 369). Infants, young children, and elderly adults have a much thinner dermal layer to their skin, resulting in an increased propensity for deeper burn injury. Epidermal cells are constantly being shed and replaced every month through a process that continually pushes new cells to the surface. This natural process is designed to continually replenish and heal breaches in the outermost protective skin barrier, be it from the microtraumas sustained as part of daily living or from overt injury. The epidermis therefore heals itself after superficial injury. Several important physiological functions of the skin are altered by thermal injury. Survival of the severely burned patient requires immediate access to a specialized burn care unit. Modern emergency burn resuscitation and ongoing treatment are designed to alleviate the systemic changes that result from acute disruption of a large part of the skin barrier. Meticulous attention is given to the replacement and prevention of fluid loss, the maintenance of body temperature homeostasis within a constant normal range, the easing of severe pain, and the prevention of infection.
| BURN INJURY IN CIVILIANS |
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Adult burn injury may also result from an industrial or work-related accident or occur as a result of suicide attempts, assault, and unintentional injury due to alcohol and/or drug use (32, 211, 265, 332, 368). A significant proportion of adult burn patients also suffer from a high degree of mental illness (344). Since legal action is taken in many of these cases, it is important to document the etiology and extent of the burn injury.
Burn injuries incur a significant cost to the health care system in North America and worldwide. In the United States and Canada there are currently 167 centers specializing in burn care, with over 2,000 beds (369). Although the overall hospitalization rates from less-serious burn injuries have declined by 50% since 1971, the proportion of patients admitted to burn centers has increased (7, 369). Recent estimates in the United States show that 45,000 patients are admitted to acute-care hospitals annually with burn injuries, and in approximately 50% of these cases the extent of thermal injury is severe enough to warrant admission to a specialized burn center (7, 68-70, 369). Burn care centers in North America currently admit an average of more than 200 patients per year, whereas other hospital units admit an average of fewer than five burn patients per year (7, 369).
Initial hospitalization costs and physicians' fees for specialized care of a patient with a major burn injury are currently estimated to be US$200,000 (292, 318, 369). Overall, costs escalate for major burn cases because of repeated admissions for reconstruction and rehabilitation therapy. In the United States, current annual estimates show that more than US$18 billion is spent on specialized care of patients with major burn injuries (292, 318, 369).
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Chemical injury. Chemical interaction may also damage protein structures. A classification system that was described in 1974 and remains in use groups chemicals according to their mode of action (Table 1) (9, 56, 57, 74, 223, 305).
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Subjective clinical methods have historically been used to determine the depth of burn injury. Body diagrams provide an estimate of the percentage of total body surface area (%TBSA) of the burn exposure and injury and document a patient's initial and clinical ongoing assessment in this regard (202, 369). Areas of partial and full-thickness burn injury are described, noting areas of circumferential involvement and burn injury across joints. Figures 3 and 4 outline a schematic assessment of %TBSA for adult and pediatric burn patients, respectively, using the rule of nines. A Berkow's percentage chart can also be used to obtain a more accurate estimate of %TBSA (40).
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The pathogenesis of pulmonary injury from smoke inhalation has been well described (99-102, 201, 203, 433). Direct heat injury is restricted to the upper airway above the glottis and is manifested by rapid swelling with the threat of obstruction. Steam inhalation is the only type of heat that damages the lower respiratory tract. However, inhalation of smoke and products of combustion and destruction of the tracheobronchial respiratory epithelium cause chemical injury. Inhalation injury progresses during the first few days following a burn and results in edema and sloughing of the respiratory tract mucosa and impairment of the normal mucociliary clearance mechanism. Damage of the mucociliary lining of the respiratory tract decreases the clearance of invading microorganisms. Pulmonary edema results from direct microvascular injury and the release of oxygen free radicals and inflammatory mediators. Cast formation due to aggregates of mucus and cellular debris causes obstruction of moderate-size airways when the mucosa sloughs. Disruption of endothelial and epithelial integrity results in exudation of protein-rich plasma into terminal airways, which, in combination with atelectasis, leads to bacterial growth and the subsequent development of pneumonia. Smoke inhalation also destroys type II pneumocytes, which results in impaired surfactant production (15, 251, 411).
Advances in respiratory resuscitation support in trauma intensive care units have improved the prognosis for burn patients with inhalation injury (15, 104, 139, 275). Inhalation injury should be suspected if the patient was burned in an enclosed space, has facial burns, and/or develops progressive hoarseness or stridor or a cough productive of carbonaceous sputum. The clinical effects of thermal inhalation injury typically become manifest within a few hours after injury, whereas chemical injury of the lower respiratory tract progresses more slowly (e.g., 1 to 2 days) (101, 322). Stridor that develops immediately after heat injury associated with an increased respiratory rate, worsening hypoxemia, and trouble expectorating secretions are signs of worsening edema of the upper airway (e.g., glottis), and immediate airway intubation is required to maintain patency (15, 95, 275). Similar signs of impending respiratory failure also develop in burn patients with a smoke inhalation injury and require immediate respiratory resuscitation. Intubation and mechanical ventilation as well as intensive tracheobronchial care (e.g., regular airway suctioning and therapeutic bronchoscopy) are required to assist clearance of bronchial mucus and debris (275, 312). High-frequency ventilation may also be beneficial in the clearance of secretions and also stabilizes collapsed and diseased lung segments (104, 275).
Patients with inhalation injury have greater fluid requirements than those who have only sustained a cutaneous injury. More fluid must be given in the immediate period following thermal injury in patients with inhalation injury (208, 369). Various agents have been administered, including inhaled heparin along with bronchodilators or free-radical scavenging agents such as dimethyl sulfoxide or N-acetylcysteine, in the treatment of inhalation injury in order to decrease cast formation and small-airway obstruction (15, 61, 229, 275). Nitric oxide is a potent vasodilator that has recently been administered as inhalation therapy to burn patients with acute respiratory distress syndrome due to lung injury in order to reduce ventilation-perfusion mismatch by dilating blood vessels perfusing lung alveoli (15, 122).
Although early surgical excision and grafting have been repeatedly attempted in the 20th century, the outcomes were initially poor (218, 219, 295, 296). However, an improved understanding of the pathophysiology of burns allowed the advancement of multiple intra- and postoperative medical and surgical techniques that has resulted in gradual decreases in morbidity and mortality (66, 87, 127, 181, 196, 200, 470). Medical support to maintain hemodynamic and respiratory function within the trauma intensive care unit and operating theater, the provision of early adequate nutrition, and the use of surgical techniques that minimize blood and heat loss allowed this approach to become the standard of care for large thermal injuries in modern burn centers.
Early burn wound excision now occurs within the first few days after burn injury and has resulted in improved survival (30, 127, 170, 185, 196, 200, 253, 334, 390, 429). Full-thickness and deep partial-thickness wounds are excised as soon after injury as possible once the patient has been hemodynamically stabilized. An appropriate burn care plan that includes a surgical timeline for wound closure must be developed based on the age of the patients and their clinical condition and extent of burn injury. A more conservative surgical approach may be required for patients with severe inhalation lung injury on ventilator support, the elderly, and those with underlying medical conditions that increase the risk of operation (202, 217, 457).
The primary aims of early excision are removal of the dead tissue that stimulates an overwhelming systemic inflammatory response syndrome and prevention of infection by temporary or permanent closure of the burn wound. Furthermore, shortening the period of wound inflammation, which in turn reduces the development of hypertrophic scarring, may optimize the outcome in terms of function and appearance (12, 97, 398). This is achieved by early removal of necrotic tissue (e.g., eschar) and wound closure with autograft, allograft, or skin substitutes in selected patients (15, 66, 196, 286, 390, 470).
Surgical excision of the burn wound may be carried out in a variety of ways, but the two most common methods are excision to fascia and tangential excision, whereby the eschar is removed in layers until viable tissue is reached (195, 286, 295, 296). The extent of excision at any one operation is limited by factors such as blood loss and temperature control. Usually no more than 20% of the burned area is excised during any single procedure (66, 195, 286, 297, 351, 369, 430). The open wound is usually covered with autograft, fresh allograft, or frozen allograft, in descending order of preference (297, 369). In otherwise healthy adults with burns, this process is repeated during several successive operative procedures until the entire burn wound has undergone debridement and secondary covering with new skin grafts. However, skin substitutes may be used for resurfacing in burn patients who have limited skin graft donor sites because of the extent of the injury (52, 53, 198, 225, 230, 293, 460).
Biobrane, a bilaminar temporary skin substitute, has been used in burn treatment centers since the early 1980s (28, 98, 231). Biobrane has recently been shown to be as effective as 1% silver sulfadiazine topical antibiotic therapy in the treatment of pediatric partial-thickness burns. Application of Biobrane in the immediate (e.g., 24 h after injury) postburn period decreased the children's pain, pain medication requirements, wound healing time, and length of hospital stay. However, older wounds and those with large areas of full-thickness injury may not be suitable for Biobrane treatment.
| IMMUNOLOGICAL RESPONSE TO BURN INJURY |
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Host defense against infection can be divided into innate and adaptive immune responses. The innate immune response acts immediately after the integument system is breached and relies on a phylogenetically ancient system for microbial recognition in which germ line-encoded receptors (pattern recognition receptors) recognize structural components of microorganisms and viruses (pathogen-associated molecular patterns) (412). The adaptive immune response often takes longer, especially if it involves exposure to new antigens. However, the adaptive immune response is a more efficient system for dealing with recurrent infections, relying on immune cell memory, antigen recognition, and clonal proliferation. The immunosuppression associated with burn injuries has effects on both of these systems.
Many in vitro and in vivo studies have been conducted to characterize the immune responses and the relationships between various cell types and inflammatory mediators. Several reviews have been written on the topic, discussing the findings of original works in more detail (82, 173, 194, 244, 412). This review is a synthesis of summarized data and original research that have contributed to our current understanding of the immune response following burn injury.
Inflammatory response to burn injury.
Increased serum levels of proinflammatory cytokines characterize the systemic response to burns. Interleukin-1ß (IL-1ß) and tumor necrosis factor alpha are produced by a wide variety of cells in response to injury, of which leukocytes are key players. Both of these cytokines contribute to the production of fever, acute-phase proteins, and an overall state of catabolism. They also up-regulate the production of prostaglandin E2 (PGE2), IL-6, and platelet-activating factor by endothelial cells and macrophages (80, 454). Levels of IL-6 are increased after injury through its production by a number of different cells (1, 42). Like IL-1ß and tumor necrosis factor alpha, IL-6 induces fever and the production of acute-phase reactants that contribute to T-cell activation (471). Levels of IL-6 peak approximately 1 week after injury (178), and high levels have been associated with increased rates of morbidity and mortality, for which it is likely a marker of disease severity rather than an etiologic factor. Gamma interferon (IFN-
) is another proinflammatory cytokine, produced by NK cells and Th-1 cells in response to injury. It has an important role in macrophage activation and the differentiation of CD4+ T cells into Th-1 cells while inhibiting their differentiation into Th-2 cells (167). Cell types that are important in facilitating a proinflammatory response to injury are proinflammatory macrophages and CD4+ T helper cells.
Anti-inflammatory response to burn injury. The anti-inflammatory response and the subsequent immunosuppression following burn injury are characterized by a set of opposing cell types and cytokines. The production and release of monocytes/macrophages are decreased following burn injury and sepsis (151). Under these circumstances, macrophages produce increased amounts of PGE2 and decreased amounts of IL-12, which have a cooperative effect on T-cell differentiation (82, 166). T helper cells begin to preferentially differentiate into Th-2 cells, which produce the anti-inflammatory cytokines IL-4 and IL-10 (107, 167).
The exact sequence of events that result in immunosuppression after burn injury remains unknown; however, biochemical changes that may affect the immune system include those to the endocrine system, the arachidonic acid cascade, and the cytokine network. Following severe burn injury, there is an increase in the levels of vasopressin, aldosterone, growth hormone, cortisol, glucagon, and catecholamines (362, 454). Elevated levels of glucocorticoids inhibit the production of IFN- and IL-2, but not IL-4 and IL-10 (132, 353, 454). Similarly, norepinephrine released early after injury inhibits Th-1 cell function, but not that of Th-2 cells (376). Increased production of PGE2 by inhibitory macrophages has been observed after severe injury (454). PGE2 may have an important role in secondary immunosuppression, as it has been shown to decrease lymphocyte proliferation, to decrease the levels of the proinflammatory cytokines IL-1ß and IL-2, to diminish the response to IL-2, to inhibit the activity of NK cells, and to activate suppressor T cells (4, 167). Many of the changes in cytokine levels represent alterations of the adaptive immune system following burn injury, more specifically within the T-lymphocyte population.
Before a pathogen can establish invasive infection within the host it must break through the natural barriers of the skin or mucosa. For example, there is a loss of barrier function of the gastrointestinal epithelium in burn patients, which may be induced by up-regulation of the nitric oxide synthetase gene and the overproduction of nitric oxide (311); postoperative changes, such as decreased intestinal motility and mucus secretion; and increased exposure to endotoxin (4). The development of multiple-organ dysfunction syndrome in critically ill patients has also been associated with a derangement in intestinal permeability (109). As a result, higher rates of bacterial translocation and endotoxin absorption through the gastrointestinal mucosa may contribute to the inflammatory response seen in burn patients.
The cellular elements of the innate immune system have important roles in antimicrobial killing and in coordinating the immune response. Decreased macrophage and natural killer cell activation results in reduced levels of IFN- following burn injury (88, 187). The function of NK cells is diminished following significant injury (362). Neutrophil dysfunction after significant thermal injuries has also been reported (44, 137, 175, 242). Endothelial adherence of neutrophils is initially decreased after injury and then increases (374); however, the site of endothelial adhesion may not be at the point of injury, and this misguided neutrophil adhesion and activation contribute to neutrophil-mediated endothelial injury, which may play a significant role in the pathogenesis of systemic inflammatory response syndrome and multiple-organ dysfunction syndrome.
Neutrophil chemotaxis and intracellular killing are impaired following major burns (1, 173, 174). Diminished cytotoxic activity follows from a surge of degranulation early after injury and a subsequent inability to replenish intralysosomal enzymes and defensins (173, 362). Macrophages also demonstrate diminished phagocytic capacity following severe injury (5, 381). Lower levels of major histocompatibility complex class II expression and antigen presentation disrupt their roles in coordination of the immune response (362, 413). They also produce larger quantities of PGE2, resulting in the suppression of B- and T-cell reactivity (281). Increased levels of IL-4 and IL-10 inhibit macrophage antigen presentation, decrease the production of proinflammatory cytokines such as IL-1ß, and suppress bactericidal and fungicidal activity (110, 130, 138, 186, 329, 442, 447).
The complement cascade represents an important humoral component of the innate immune system. Following significant burn injuries, the alternative pathway of the complement cascade is primarily depressed, while there is little effect on the classical pathway (150). Complement levels fall in proportion to injury severity and then rise to supranormal levels (150). Activation of the complement cascade by thermal injury (39) increases levels of C3a and C5a, which may result in changes in blood pressure, vascular permeability, and leukocyte function (214, 473). Small amounts of C5a have been shown to stimulate leukocyte function; however, large amounts lead to suppression of activity (453). Membrane attack complexes may target normal cells near the site of injury, contributing to reactive cell lysis, which may induce end-organ damage (194). Lastly, increased levels of C3b may be directly immunosuppressive, as they have been shown to decrease phagocytosis and contribute to lymphocyte dysfunction (4).
These alterations to the innate immune system have the combined effect of increasing the burn patient's exposure to pathogens and decreasing the natural defenses that are responsible for counteracting them. Exposure to pathogens occurs via the burn wound, invasive monitoring devices, and the gastrointestinal tract, which loses some of its capacity to act as an effective barrier to bacterial translocation. The effects of an anti-inflammatory cytokine milieu on NK cells, neutrophils, and macrophages impair the eradication of these pathogens by the innate immune system. Furthermore, the activation of complement following burn injury may be directly immunosuppressive. As a result of these phenomena and subsequent alterations to the adaptive immune system, burn patients are more susceptible to wound infections, severe sepsis, and multiple organ failure.
by monocytes (133, 463). The production of immunoglobulin G (IgG) in response to T-cell-dependent antigens is also impaired after serious injury; however, no impairment of antibody formation to T-cell-independent antigens has been observed (325). There is a decreased ratio of CD4+ T helper cells to CD8-positive T suppressor cells (67, 327). After an initial proinflammatory phase, injury results in a loss of Th-1 cells associated with depressed levels of IL-1ß and IFN-. Concomitantly, Th-2 lymphocytes are present in increased numbers along with higher levels of the anti-inflammatory cytokines IL-4 and IL-10, which may inhibit Th-1 cell activation by suppressing antigen presentation (167). A correlation between increased levels of IL-10 and septic events has been reported (256, 395). It remains uncertain whether the relative predominance of Th-2 cells over Th-1 cells represents a phenotypic change or an increase in the rate of apoptosis of Th-1 cells (244). Alterations in the balance between T suppressor lymphocytes and T helper lymphocytes and the ratio of Th-1 to Th-2 cells appear to be important etiologic factors in the suppression of the adaptive immune response.
Immune function in burn patients can only be restored through intensive resuscitation and support. Early excision of burn eschar and prompt wound coverage remove a significant inflammatory stimulus and restore the barrier function of the skin. Providing adequate analgesia and maintaining adequate tissue perfusion, ambient temperature, and blood volume help optimize the oxidative killing capacity of neutrophils (235). Early and adequate nutritional support is also important in restoring protein synthesis and normal immune function. Research efforts have focused on the topic of immune-modifying diets, such as glutamine-enriched diets, and their clinical benefits (155). However, there is insufficient evidence to support the use of such diets in burn patients at this time.
| EPIDEMIOLOGY OF BURN WOUND INFECTIONS |
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Burns in the elderly constitute more severe injuries than in the general population and result in a higher number of fatalities. A recent review of adult patients admitted to a burn center over a 7-year period showed that 221 of 1,557 (11%) were >59 years of age and a higher proportion were women (279). Most elderly burn patients had one or more existing medical conditions and impaired judgment and/or mobility. Approximately one-third of the elderly patients in this study also sustained smoke inhalation injury. Substance abuse was a factor in some elderly patients, because toxicology screening showed that 10% had used alcohol and almost one-third tested positive for other drugs. Mortality was highest in elderly patients who had more severe burns and/or smoke inhalation injury that had existing underlying disease.
A recent study also assessed the factors affecting burn mortality in the elderly and analyzed changes that occurred over the past three decades (252). The study included 201 patients 75 years of age of older that had been admitted to a university-based burn center between 1972 and 2000. Almost half of these patients died (95, or 47.3%), and the severity of the burn injury as measured by TBSA and the abbreviated burn severity index were both strongly correlated with mortality. Due to improved burn care, however, the elderly are much less likely to die from burns now than in the 1970s unless they have an inhalation injury. Mortality increased significantly with inhalation injury despite advances in intensive respiratory support.
Children have a much higher risk of being burned than adults (344). In the United States in 2001 to 2002, an estimated 92,500 children aged 14 years and under required emergency care for burn-related injuries, and approximately 500 of these children died (320). Approximately two-thirds of these children sustained thermal injuries, while children <4 years of age are particularly prone to scald injury (320). Male children have a higher risk of burn injury and burn-related death than females, and obese boys represented a disproportionate number of the patients admitted to a pediatric burn center from 1991 to 1997 (26). Children who show failure to thrive (e.g., height and/or weight <5% of that expected by age) also have a higher risk of burn injury, perhaps due to the combined effects of malnutrition and neglect or abuse (26, 344).
Most of our understanding of the epidemiology of burn wound infections has been gleaned from studies carried out in the 1950s through 1990 during the preexcision era of burn care (273). It is not surprising that the overall morbidity and mortality of burn wound infections, tissue invasion, and secondary sepsis were extremely high during this time period because the growth of bacteria on the burn wound surface was controlled but not eradicated. Case fatality rates were 40% or higher depending on the extent of the burn injury (272, 285, 340, 341). Immediate colonization by the patient's normal skin flora (i.e., Staphylococcus aureus and Streptococcus pyogenes) occurred following injury (23, 164, 249, 259, 333). Subsequent colonization by the patient's own gut flora added to the complex microbial ecology on the burn wound surface shortly thereafter (106, 248, 266, 267, 269, 371).
Nosocomial transmission of microorganisms to the burn wound also occurred by transfer from the hands of health care personnel and through immersion hydrotherapy treatment (73, 273, 450, 468). Burn unit outbreaks of infection were attributed mainly to contaminated Hubbard hydrotherapy tanks or water but in other cases to contaminated surfaces such as the patient's mattress (126, 274, 280, 397, 436). Despite the recognized infection risk of immersion hydrotherapy treatment in burn units, this was standard practice in many specialized burn centers until the 1990s. In a survey of burn centers in North America in 1990, 81.4% still used immersion hydrotherapy regardless of the size of the burn wound, and most centers also continued this therapy throughout hospitalization on all patients (385). Aside from microbial contamination of the tank water, aerators and agitators in hydrotherapy tubs were difficult to clean (280, 436) Hydrotherapy water continued to be cross-contaminated between patients despite the removal of these devices from the tanks (436). Sodium hypochlorite and chloramine-T disinfectants added to the hydrotherapy tank water decreased the microbial load on the burn wound surface and health care workers' hands (73, 414). However, the hydrotherapy water irritated the mucosal surfaces (e.g., conjunctiva and nares) of the patient and health care personnel, although this practice was effective in eliminating gram-negative microorganisms from burn wounds after several days of treatment (73).
Showering with a hand-held sprayer has gradually replaced hydrotherapy for cleansing and debridement of the burn wound. This practice decreases the transfer of bacteria on surfaces to the patient's burn wound. However, outbreaks related to shower hydrotherapy have also recently been reported. Pseudomonas organisms were recovered from the hydrotherapy tank used to initially remove the patient's adherent dressings in one outbreak (436), and another outbreak was caused by contamination of the shower hand grip and showering stretcher by methicillin-resistant Staphylococcus aureus (MRSA) (126). Performing local wound care in the patient's room has controlled burn unit outbreaks due to immersion hydrotherapy.
| PATHOGENESIS OF BURN WOUND INFECTIONS |
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Although burn wound surfaces are sterile immediately following thermal injury, these wounds eventually become colonized with microorganisms (129, 469). The nature and extent of the thermal injury along with the types and amounts of microorganisms colonizing the burn wound appear to influence the future risk of an invasive wound infection (29, 129, 268, 315). Gram-positive bacteria that survive the thermal insult, such as staphylococci located deep within sweat glands and hair follicles, heavily colonize the wound surface within the first 48 h unless topical antimicrobial agents are used (6, 129, 164). Eventually (after an average of 5 to 7 days), these wounds are subsequently colonized with other microbes, including gram-positive bacteria, gram-negative bacteria, and yeasts derived from the host's normal gastrointestinal and upper respiratory flora and/or from the hospital environment or that are transferred via a health care worker's hands (6, 129, 267, 268, 356, 449, 450, 468).
Over the last several decades, gram-negative organisms have emerged as the most common etiologic agents of invasive infection by virtue of their large repertoire of virulence factors and antimicrobial resistance traits (84, 92, 162, 358, 360, 363, 388, 401, 404, 436). If the patient's host defenses and therapeutic measures (including excision of necrotic tissue and wound closure) are inadequate or delayed, microbial invasion of viable tissue occurs, which is the hallmark of an invasive burn wound infection (see "Histological analysis" under Analysis of Burn Wound Specimens, below).
Although biofilms are best known for their role in foreign device-related infections, recent studies have confirmed the importance of biofilms in the pathogenesis of burn wound infections (434). In animals with experimentally inflicted partial-thickness cutaneous burns, mature biofilms develop in 48 to 72 h, while in vitro experiments with Pseudomonas aeruginosa strains recovered from human burn wounds demonstrate that mature biofilms can form in about 10 h (184). Factors delaying the formation of biofilms in vivo may be related to the need for microbial nutrient replenishment, exposure to killing by the immune system, and immediate wound cleansing (184).
Bacteria within a biofilm typically undergo a phenotypic change whereby microbial virulence factor production is altered and metabolic rate and motility are reduced (118, 419, 421). Channels formed within the protective environment of the biofilm facilitate the transport of nutrients and microbial waste products (118, 184, 419, 421). Intercellular signaling molecules produced by bacteria within the biofilm are able to traverse these channels and influence the overall growth pattern and behavior of the biofilm in response to various host and environmental factors (258, 350, 419, 421). Persister cells within the biofilm are the cells that have remained within the biofilm after treatment with antimicrobial agents and antiseptics (434). These persister cells temporarily disable their inherent mechanisms of programmed cell death in the presence of harsh environmental conditions and help in repopulating the biofilm, often leading to failure in biofilm eradication (419, 421).
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The emergence worldwide of antimicrobial resistance among a wide variety of human bacterial and fungal burn wound pathogens, particularly nosocomial isolates, limits the available therapeutic options for effective treatment of burn wound infections (6, 84, 120, 148, 190, 358). MRSA, methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci, and multiply resistant gram-negative bacteria that possess several types of beta-lactamases, including extended-spectrum beta-lactamases, ampC beta-lactamases, and metallo-beta-lactamases, have been emerging as serious pathogens in hospitalized patients (84, 92, 126, 152, 190, 241, 358). Fungal pathogens, particularly Candida spp., have increasingly become important opportunistic pathogens due to the use of broad-spectrum topical and systemic agents when infection occurs in the burned patient and have demonstrated increasing degrees of antifungal drug resistance (10, 19, 233, 302).
Staphylococcus aureus also has a diverse array of virulence factors that facilitate adherence to host tissues, immune system evasion, and destruction of host cells and tissues, including coagulase, protein A, leukocidins, hemolysins, and superantigens (142). Resistance to methicillin in Staphylococcus aureus, and more recently emergence of resistance to glycopeptides and oxazolidinones, also complicate the treatment of burn wound infections and sepsis caused by this highly virulent organism (183, 288, 309, 391).
| CLASSIFICATION OF BURN WOUND INFECTIONS |
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Burn wound infections were previously classified based on changes in the burn wound and/or eschar appearance, time of occurrence, and associated mortality into distinct conditions, including impetigo, cellulitis, and invasive infection. Due to the advent of early excision therapy, new classifications for burn wound infections related to surgical wound infection at the excision site(s) have been developed by a subcommittee of the Committee on the Organization and Delivery of Burn Care of the American Burn Association (273, 331, 369). Each of these distinct clinical conditions that make up the spectrum of burn wound infections is described briefly below. Burn wound impetigo may or may not be associated with systemic signs of infection, but fever (temperature of >38.4°C) or leukocytosis (white blood cell count of >10,000 cells/mm3) and/or thrombocytopenia is present in all of the other types of burn wound infections outlined. The development of burn wound cellulitis or invasive burn wound infection may also be heralded by bacteremia or septicemia.
In addition to burn wound surface and/or tissue cultures, patients with signs of systemic infections should have a complete septic workup that includes blood and urine cultures as well as burn wound sample cultures. Effective treatment of burn wound infections combines an increased frequency of burn wound dressing changes with optimization of the patient's antimicrobial therapy regimen according to microbiology culture and susceptibility results from burn wound cultures.
Burn-related surgical wound infection. Surgical wound infections in burn patients include both excised burn and donor sites that have not yet epithelialized. The wound has purulent exudate that is culture positive. Surgical wound infections in open areas of the burn show loss of synthetic or biological covering of the wound, changes in wound appearance (such as hyp
