Burn infection, sepsis, and antimicrobial management

Overview

Infection is the dominant late-phase threat to a severely burned patient. Septicemia is the most frequent cause of death in patients with severe burns; sepsis is the commonest cause of death following burn injury, and infections remain the leading cause of death after major burns across multiple decades of literature [12, 13, 14, 15]. Loss of the cutaneous barrier, persistent immune dysregulation, and prolonged ICU exposure together create a sustained infection risk that does not fully resolve until the wound is closed. Significant thermal injury induces a state of immunosuppression that predisposes burn patients to infectious complications ^[16]. Early excision of the eschar has substantially decreased the incidence of invasive burn wound infection and secondary sepsis, but most deaths in severely burn-injured patients are still due to burn wound sepsis or complications due to inhalation injury ^[16].

Three infection compartments matter at the bedside: the wound, the bloodstream, and the lung. Wound colonization is universal; invasive wound infection is the dangerous subset where bacteria cross from eschar into viable tissue. Bloodstream infection (BSI) commonly originates from the wound or from central venous access. Pneumonia, particularly ventilator-associated pneumonia (VAP), remains a major source of morbidity and mortality after severe burns [57, 59]. These infections range from cellulitis that requires systemic antibiotic agents to invasive burn wound infection that requires prompt treatment with antibiotic agents and surgical intervention ^[40].

The downstream physiology is the same regardless of compartment: burn injury triggers a complex inflammatory cascade in which the interplay between pro- and anti-inflammatory mediators determines recovery or progression to sepsis, VAP, or multi-organ dysfunction ^[73]. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in burn patients, driven by smoke inhalation, pneumonia, and the systemic inflammatory process ^[18]. Multiple organ failure (MOF) is one of the major causes of death in patients with severe burns and is the dominant cause of late mortality after the first 48 hours [19, 20].

Epidemiology

There are few systematic data on the epidemiology of burn wound infections from the era of early excision and closure; data are needed on infection rates for excised and closed wounds and the etiologies of remaining infections ^[17]. What is established: the patient cohorts most at risk are large-TBSA injuries with delayed closure, mechanical ventilation, central venous access, and prolonged ICU stays. In a modern Dutch national cohort, the most common cause of late mortality (>48 hours, in 60 of 88 patients, 68.2%) was multiple organ failure (38.3%) ^[20]. In children, the cutoff burn size for mortality, sepsis, infection, and multiple organ failure was approximately 60% TBSA, and in modern burn care setting adults over 40% TBSA and children over 60% TBSA remain at high risk for morbidity and mortality even in high-volume units ^[21].

The microbiology of the burn unit is dominated by Pseudomonas aeruginosa, which is the leading cause of nosocomial infections in burn centers reporting longitudinally [22, 23]. Pseudomonas aeruginosa remains a cause of serious wound infection and mortality in burn patients ^[24]. Pseudomonas in adult burn populations historically carried mortality near 40% in unprotected cohorts; the New Delhi arm of the early polyvalent Pseudomonas vaccine trial reported a reduction from 40.6% (13/32) in unvaccinated adults to 6.6% (2/30) in vaccinated adults ^[1]. Outbreak control measures (eliminating shared hydrotherapy facilities, cohorting carriers, environmental decontamination) reduced overall mortality, eliminated mortality from Pseudomonas sepsis, decreased nosocomial Pseudomonas infections, and lowered aminoglycoside resistance ^[24]. Carbapenem-resistance has emerged in Pseudomonas, and multidrug-resistance in Acinetobacter has increased to 47% in some series [36, 37].

Candida is the next most common burn pathogen after bacteria. Candida organisms were cultured from 452 of 1,513 hospitalized burned patients over 6 years in one large series, and untreated Candida burn wound infection carried a mortality near 100%, dropping to 91.6% even with aggressive medical-surgical therapy in historical cohorts ^[25]. The incidence of Candida colonization (26.7% vs 15.6%), infection (21.3% vs 10.0%), and sepsis (12.2% vs none) was reduced significantly with nystatin prophylaxis in pediatric burn patients ^[26]. Patients with bacterial or fungal burn wound infection had massive injury, with burn size averaging greater than 50% TBSA, and the factors that markedly reduced bacterial burn wound infection (isolation, topical chemotherapy, early excision) did not appear to reduce fungal infection comparably ^[28].

Risk factors for nosocomial infection and mortality in burn ICU patients include advanced age, high TBSA, and underlying disease ^[36]. Allogeneic blood transfusion is independently associated with wound infection (OR 13.5, 95% CI 1.7-107), sepsis (OR 8.3, 4.2-16.3), and other infectious complications after adjustment for injury severity ^[100]. The elderly carry a higher rate of pneumonia, cellulitis, urinary tract infection, central line infections, and burn wound infections, driven by pre-existing comorbidity ^[101].

Pathophysiology

Burn injury triggers a complex inflammatory cascade. The interplay between pro- and anti-inflammatory mediators determines whether the patient recovers, develops VAP, develops MOF, or progresses to sepsis ^[73]. Significant thermal injury induces a state of immunosuppression that predisposes burn patients to infectious complications ^[16]. The mechanisms span loss of the cutaneous barrier, suppression of cell-mediated immunity, neutrophil and monocyte dysfunction, and a hypermetabolic-hyperdynamic state that obscures clinical sepsis recognition.

The wound itself is a launchpad. Burn wound-associated biofilms act as a launchpad for bacteria to establish deeper, systemic infection and ultimately bacteremia and sepsis ^[74]. Biofilm formation in the burn wound site is a major contributing factor to the failure of burn treatment regimens and to mortality from burn wound infection ^[74]. Even the act of treating the wound translocates organisms: wound cleaning and staged early excision produced 50 documented instances of induced bacteremia or fungemia, with burn wound infection contributing significantly to both spontaneous and induced bloodstream events ^[69].

The host-defense compartment is suppressed in parallel. Endogenous translocation of gut organisms occurs in animal models of burn-plus-sepsis, with disseminated infection from Proteus, Enterococcus, and Streptococcus involving lungs, liver, blood, and subeschar space when burn and sepsis coexist. Burn sepsis drives monocytosis and granulocyte dysfunction; propranolol reverses burn sepsis-induced monocytosis and simultaneously increases granulocyte counts and enhances inflammatory potential of granulocytes and inflammatory monocyte subsets ^[81].

The clinical translation matters for diagnosis. Burn patients, by definition, already have systemic inflammatory response syndrome ^[2]. Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making those definitions less applicable to the burn population ^[2]. The diagnostic difficulty in burn sepsis is structural, not stylistic; it is the reason the field developed dedicated criteria sets.

Classification

Sepsis in the burn population has been defined by three frameworks in active use.

ABA 2007 criteria. The American Burn Association published diagnostic criteria in 2007 to standardize the definition of sepsis in these patients ^[3]. The consensus conference goal was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population ^[2]. The original criteria require three of six clinical triggers (temperature, heart rate, respiratory rate or minute ventilation, thrombocytopenia, hyperglycemia, enteral feeding intolerance) plus a documented infection.

Mann-Salinas criteria. Mann-Salinas et al. developed a derived predictor set targeted at the day-before-blood-culture window, reporting a logistic-regression model AUC of 0.775 versus an ABA AUC of 0.619 in their cohort ^[4]. The ABA criteria were significantly different on the day before culture positivity (P = 0.004), but their usefulness was limited to that immediate pre-culture window ^[4].

Sepsis-3 criteria. Sepsis-3 anchors diagnosis to infection-attributable organ dysfunction quantified by Sequential Organ Failure Assessment (SOFA) score change. In a head-to-head burn cohort, the American Burn Association, Mann-Salinas, and Sepsis-3 criteria were positive in 59%, 28%, and 85% respectively of suspected-sepsis events, with Sepsis-3 the most predictive followed by ABA and Mann-Salinas ^[5]. Severe burn patients face diagnostic challenges in distinguishing sepsis from systemic inflammation using Sepsis-3 criteria ^[7]. A "Burn SOFA score" and a "3 H's of burn sepsis" framework have been proposed on the basis of past developments and the current update of the Surviving Sepsis Campaign guidelines ^[8]. An international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes; the committee developed sixty statements within fourteen topics to guide the early treatment of sepsis in burn patients ^[102]. Current Sequential Organ Failure Assessment validation studies focus on composite scores and neglect subsystem-level analysis in burn-specific pathophysiology; subsystem-specific SOFA analysis identifies creatinine elevation and thrombocytopenia as key sepsis indicators in burns, and these specific organ systems appear to be the principal contributors to SOFA score in burn-related sepsis [6, 7].

Burn wound infection categories. Wound-side infection is classified along a clinical-histologic axis. Surface colonization is universal in the open wound. Invasive burn wound infection is the diagnosis of consequence: bacterial penetration into viable tissue beneath the eschar, established histologically. Most burn-infection categorization systems also recognize cellulitis (peri-wound inflammation requiring systemic antibiotic) and burn impetigo as distinct entities, with the spectrum running from cellulitis that requires systemic antibiotic agents to invasive burn wound infection that requires prompt antibiotic and surgical intervention ^[40].

Bloodstream and pulmonary infection categories. Bloodstream infection in burn patients is partitioned by source: primary bacteremia, catheter-related, wound-related, and gut-translocation-derived. Infectious complications were observed in 92 patients (68.7%) of 134 ICU burn patients in a pan-European cohort, of whom 76 (56.7%) met the criteria for infection of the burned area, 26 (19.4%) for bloodstream infection, and 21 (15.7%) for pneumonia ^[104]. Pulmonary infection is partitioned into community-acquired, hospital-acquired, and ventilator-associated pneumonia; VAP remains a major source of morbidity and mortality after severe burns and is the subject of a dedicated ABA practice guideline [57, 59].

Assessment

Diagnosis of invasive burn wound infection

Surface swabs and surface cultures correlate poorly with invasive infection. Only 62.5% of patients with a positive surface culture showed signs of clinical sepsis, while 87.5% of patients with a significant bacterial count on biopsy culture showed signs of clinical sepsis ^[55]. Wound surface cultures, though the simplest method, gave poor indication of the organisms invading into the burn wound ^[55].

Quantitative biopsy culture is more reliable. Careful daily clinical evaluation and serial quantitative burn wound biopsy cultures provide the most effective means of establishing an early diagnosis of wound sepsis ^[56].

Histology is the diagnostic standard for invasive infection. In matched specimens, agreement of 96.1% was found between negative cultures (fewer than 5 logs/g) and histologic absence of invasive infection ^[54]. In sharp contrast, histologic invasion occurred in only 36% of specimens with positive cultures ^[54]. Low tissue counts are essentially synonymous with negative histologic findings, but quantitative microbiology is not a diagnostic substitute for histologic examination because high tissue counts do not reliably equate to invasion ^[54]. Wound monitoring is typically done at least twice weekly by either surface swab or quantitative biopsy ^[97]. A 4-method comparison of bacterial count determination in burn wounds found significant correlation between surface swab and gauze-pad methods but no significant correlation between either surface method and the deeper burn wound biopsy technique ^[98].

Diagnosis of bloodstream infection

Blood cultures remain the reference for BSI documentation; early evaluations demonstrated that serial blood cultures performed by older techniques were of limited value in early recognition of bacteremia ^[56]. Overall 3.2% of central venous catheters in pediatric burns were associated with sepsis (10.9% by Centers for Disease Control definition), and catheter sites were used for a mean of 15.6 days without an increased rate of line sepsis when replaced by guidewire one to three times ^[61].

Diagnosis of pneumonia and VAP

Ventilator-associated pneumonia in burns is reviewed in a dedicated 2009 ABA practice guideline whose purpose was to review the available published literature on VAP as it pertains to the burn patient and to provide an evidence-based framework for prevention, diagnosis, and treatment ^[57]. The guideline is designed to assist healthcare providers caring for adult burn patients with suspected VAP ^[57]. Bronchoalveolar lavage (BAL) and protected specimen brush sampling are the diagnostic surfaces for VAP in burns; VAP remains a major source of morbidity and mortality across burn cohorts, and the use of BAL eliminated unnecessary antibiotic treatment for 21% of patients in the BAL time period of one burn-unit comparison and was associated with a lower VAP rate ^[96]. Patients with severe burns are at increased risk of developing MRSA VAP ^[58]. Mechanical ventilation duration was not different between patients who did not develop pneumonia and those who developed early-onset, community-acquired, or late-onset hospital-acquired pneumonia in one prospective comparison of in-line heat-moisture exchangers ^[60].

Biomarkers

Procalcitonin (PCT) is the best-characterized serum biomarker for burn sepsis. Serum PCT is a useful biomarker (AUC=0.92) for early diagnosis of sepsis in burn patients ^[67]. A meta-analysis showed PCT may be considered as a biomarker with a strong diagnostic ability to discriminate septic from non-septic burn patients ^[68]. PCT was the biomarker with the largest AUC and effect size (AUC=0.71) in a multibiomarker comparison ^[95]. Cabral et al. concluded procalcitonin was the best of the biomarkers studied for an early diagnosis of sepsis and positioned it as a candidate adjunct in antimicrobial stewardship programs in burn units ^[95].

Mid-regional pro-adrenomedullin (MR-proADM) adds an early-warning surface. In patients who went on to develop sepsis (n=27, 64.3%), MR-proADM and PCT levels were significantly higher on days categorized as septic than on days categorized as nonseptic (P<0.001); MR-proADM levels demonstrated an increase one day earlier than PCT, with PCT displaying higher specificity and sensitivity and MR-proADM more suitable for early recognition ^[92]. The optimal sensitivity-specificity relationship for MR-proADM detected sepsis at an increase of 31% and at least 0.015 nmol/L (AUC 0.76); for PCT the corresponding threshold was an increase >39% and at least 0.15 µg/L (AUC 0.83) ^[92]. MR-proadrenomedullin values are elevated after thermal injury but are not affected by hemodynamic changes; mean MR-proADM during resuscitation was 3.51 ± 2.30 nmol/L in non-survivors versus 1.28 ± 1.10 nmol/L in survivors (p = 0.0001) ^[93].

Presepsin and neutrophil CD64 are additional candidate biomarkers. Sepsis time points differ significantly from non-sepsis in presepsin (p < 0.0001), PCT (p = 0.0012), and CRP (p < 0.0001) levels, with AUC-ROC values of 83.4% for presepsin, 84.7% for PCT, 81.9% for CRP, and 50.8% for WBC; plasma presepsin levels have comparable performance in burn sepsis ^[70]. Neutrophil CD64 is highly efficient at diagnosing burn infection in the populations studied ^[94]. IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients ^[90]. The predictive value of PCT and CRP for burn sepsis prognosis was low, while BNP was better in one cohort ^[91].

Management

Source control through early excision

Source control is the highest-yield infection-control intervention in the modern burn unit. Excised patients had shorter hospitalizations and lower rates of burn wound sepsis and serious burn wound contamination, and used fewer potentially toxic antibiotics, than patients managed conservatively ^[71]. Mortality from burns without inhalation injury was significantly decreased by early excision from 45% to 9% in patients aged 17 to 30 years (p < 0.025) ^[72]. A modern propensity-matched cohort of 6,158 burn patients found a decreased risk of wound infection when excision occurred within 0-3 days (37.84%) compared to 4-7 days (42.48%), p < 0.05, and a lower risk of mortality at 0-3 days (3.84%) versus 8-14 days (6.09%), p < 0.05 ^[103].

Early excision of the eschar has substantially decreased the incidence of invasive burn wound infection and secondary sepsis, although most deaths in severely burn-injured patients are still due to burn wound sepsis or complications due to inhalation injury ^[16]. As early burn wound excision and wound closure became the focal point of burn wound management, and as units shifted from immersion hydrotherapy to showering hydrotherapy, the rate of burn wound infection fell substantially ^[17].

The act of excision itself transiently increases the risk of bacteremia. Induced bacteremia or fungemia was documented in 50 of 112 instances of wound cleaning and staged early excision; 31 cases of bacteremia or fungemia occurred after wound cleaning alone, and burn wound infection contributed significantly to both spontaneous and induced bacteremia or fungemia ^[69]. Perioperative antibiotic coverage during excision is a separate question (see below).

Infection-control program

Infection-control discipline is the second highest-yield lever. A comprehensive infection control strategy based on hand hygiene, education and training in antibiotic prescribing, environmental cleaning, contact precautions, good antibiotic stewardship, and active surveillance reduces burn-unit MRSA prevalence ^[40]. The best approach to decreasing wound infections is prevention; practices that have been beneficial include isolation rooms, handwashing, appropriate wound care, early excision and grafting, and antibiotic stewardship ^[42]. Outbreak history demonstrates the cost of lax infection control: an outbreak of R-factor-mediated carbenicillin resistance in Pseudomonas aeruginosa was followed by a second outbreak six months later, with a single R-factor type maintained in the unit between outbreaks ^[63]. Control of MRSA is particularly difficult in burn units, which are often cited as sources of hospital-wide MRSA outbreaks; an MRSA control program including surveillance culturing, clinician feedback, flexible site-specific isolation, and a list of known carriers is associated with a low rate of nosocomial MRSA ^[64].

Multidrug-resistant Klebsiella pneumoniae outbreaks in burn ICUs cluster around patients with larger burns (32% vs 18% TBSA) who are older (55 vs 42 years) and have full-thickness injury (53% vs 22%); colonized patients had higher illness severity scores, more days of mechanical ventilation, and longer critical-care stays, and the dominant risk factors were head-and-neck burns (OR 4.81) and higher injury severity scores ^[83]. Control of outbreaks was achieved by enforcing contact precautions and extensive cleaning ^[83].

CLABSI prevention

Central-line-associated bloodstream infection has been driven to and held at zero in modern burn ICUs that implement bundle care. A unit-level implementation-science intervention reduced CLABSI rates from 15.5 per 1,000 central-line days to zero with a sustained rate of zero CLABSI infections in the burn ICU ^[66]. Topical mupirocin at the CVC insertion site significantly reduces both bacterial colonization at CVC tips (RR=0.316, p=0.001) and CLABSI incidence (5.3 vs 29.1 per 1000 catheter days, p<0.001); mupirocin is effective in the prophylaxis of CLABSI ^[65]. CDC guidelines for prevention of intravascular catheter-related infections position antimicrobial-coated catheters as one option for decreasing the risk of catheter-related bloodstream infection ^[62].

VAP prevention and treatment

The 2009 ABA practice guideline on VAP in burns provides an evidence-based framework for prevention, diagnosis, and treatment of VAP in adult burn patients ^[57]. Nosocomial pneumonia is a major source of morbidity and mortality after severe burns; a trace-element supplementation trial demonstrated reduction of nosocomial pneumonia, which occurred in 16 (80%) versus 7 (33%) patients, and of VAP from 13 to 6 patients ^[59].

Empirical antimicrobial choice

Empirical antibiotic selection at the time of suspected sepsis is driven by recent surveillance cultures and unit ecology, not by standing protocol. Raz-Pasteur et al. concluded that, when there is clinical suspicion of sepsis, appropriate empirical systemic antibiotic therapy is broad spectrum and relies on the susceptibility of the organisms from recent cultures of the burn wound surface, until blood culture results are completed ^[53]. On suspicion of sepsis, empirical antibiotic treatment combining piperacillin, oxacillin, and gentamicin can be proposed until identification of the causative microorganism is available ^[52]. Multidrug-resistant infection patterns impact the choice of empiric antibiotics in critically ill burn patients ^[41]. Dodd et al. observed that early burn sepsis therapy targets gram-positive organisms, while infection later in the course raises suspicion of nosocomial pathogens such as Pseudomonas aeruginosa or other resistant gram-negatives ^[33].

Treatment of MRSA in burn wounds includes topical agents. Mupirocin is highly effective in controlling MRSA burn wound infection in the cited literature, with topical 24-hour application ^[30]. Brain abscesses and MRSA infection remain major problems in the treatment of burns ^[29]. Topical antimicrobial sensitivity is decreased for MDROs compared to non-MDROs, with smaller zones of inhibition; even MDRO Acinetobacter remained sensitive to most topicals, but with reduced potency for silvadene, neomycin, and polymyxin combinations ^[89].

Treatment of VRE is more constrained. All antimicrobials screened against VRE were either ineffective or of limited effect; preliminary data support chloramphenicol therapy when a VRE burn wound infection is encountered or suspected ^[31].

Systemic prophylaxis

The evidence on systemic antibiotic prophylaxis is contested but converging. A systematic Cochrane review concluded that systemic antibiotic prophylaxis in non-surgical burn patients was evaluated in three trials (119 participants) with no evidence of an effect on rates of burn wound infection, and perioperative systemic antibiotic prophylaxis had no effect on any of the outcomes of the review ^[44]. Earlier work concluded systemic antibiotic prophylaxis is of no value in controlling burn wound sepsis and might even favor the growth of P. aeruginosa in the burn wounds ^[42]. A separate systematic review reported that trials assessing systemic antibiotic prophylaxis given for 4 to 14 days after admission showed a significant reduction in all-cause mortality (risk ratio 0.54, 95% CI 0.34-0.87) ^[43]; perioperative non-absorbable or topical antibiotics alone did not significantly affect mortality ^[43]. Prophylactic antibiotic use may improve 28-day in-hospital mortality in mechanically ventilated patients with severe burns but not in those who do not receive mechanical ventilation ^[86]. One pediatric cohort concluded prophylactic antibiotic use is unnecessary and that antibiotic use should be guided on a case-by-case basis according to symptoms ^[45]. Prophylactic empiric pharmacologic treatment is reserved for patients highly at risk for invasive burn wound infection only ^[99].

Perioperative coverage during excision is a narrower question and has the strongest signal. Statistically significant increases in donor-site infections occurred when patients did not receive perioperative antibiotics, when excisions were large, and when delay between injury and excision was longer, and perioperative antibiotics decrease the risk of these infections ^[46]. Patients with acute deep burns treated with autografts may benefit from systemic perioperative antibiotic prophylaxis, as antibiotics seem to be associated with increased autograft survival rate ^[47].

Selective digestive tract decontamination (SDD)

Selective decontamination of the digestive tract has been shown to reduce the risk of infections and improve survival in mechanically ventilated adult ICU patients ^[50]. In burns specifically, treatment with SDD reduces mortality and pneumonia incidence in patients with severe burns ^[48]. There is evidence that selective digestive tract decontamination reduces mortality and infectious episodes in major burns ^[49]. Most infections in critically ill burn patients, as in other critically ill patients, are preceded by colonization of the digestive tract; preventative measures include selective digestive decontamination and hygienic measures ^[49].

Adjunctive therapies

Low-dose hydrocortisone reduces vasopressor administration in burn patients with severe shock ^[75]. Prophylactic intravenous immune globulin (IVIG-B) is associated with a reduction in the incidence of septic episodes and decreased hospital length of stay following major thermal injury ^[79]. Supplementation of multiple vitamins, calcium, and magnesium reduced the risk of wound infection and sepsis, shortened hospitalization, and is a candidate adjunct in major burns ^[80]. Propranolol reverses burn sepsis-induced monocytosis and simultaneously increases granulocyte counts and enhances the inflammatory potential of granulocytes and inflammatory monocyte subsets ^[81]. Local application of probiotic bacteria prophylaxes against burn wound Pseudomonas aeruginosa infection in animal models, with probiotic-treated animals showing dramatically lower mortality than Pseudomonas-only animals ^[82].

Nutritional source-control adjunct

Early enteral feeding is the dominant nutritional adjunct. Early enteral feeding may decrease intestinal permeability, preserve the intestinal mucosal barrier, and have a beneficial effect on the reduction of enterogenic infection ^[76]. Patients fed early had shorter ICU length of stay (adjusted hazard ratio 0.57, 95% CI 0.35-0.94) and reduced wound infection risk (adjusted OR 0.28, 95% CI 0.10-0.76) ^[77]. Early enteral nutrition has been demonstrated safe with no increase in complications and a lower rate of wound infections and shorter ICU length of stay ^[77]. In a meta-analysis of early enteral nutrition versus non-EEN, the EEN group had significantly lower mortality (OR = 0.39, 95% CI 0.20-0.74) and shorter wound healing time ^[78].

Complications

The dominant complication patterns of burn infection and sepsis are organ-system failure and treatment-driven toxicity.

Acute kidney injury. AKI is a common and morbid complication after severe burn, with incidence and mortality as high as 30% and 80% respectively ^[10]. In a prospective exploratory cohort of major burns, AKI incidence among major burns was 0.11 per 100,000 people per year, and 24% of 127 patients developed AKI (12% Risk, 8% Injury, 5% Failure); age, TBSA, and full-thickness extent were higher in patients who developed AKI, and pulmonary dysfunction and systemic inflammatory response syndrome were present in all of the patients with AKI and developed before AKI itself ^[87]. Variability in fluid resuscitation and difficulty recognizing early sepsis are major barriers to preventing AKI after burn injury ^[9]. During initial hospitalization, AKI was associated with increased pulmonary failure, mechanical ventilation, pneumonia, myocardial infarction, length of stay, cost, and mortality, and lower likelihood of discharge home ^[9]. Mortality is unacceptably high in burn patients who develop AKI requiring renal replacement therapy and is presumed to be even higher when combined with septic shock ^[11].

ARDS and other pulmonary failure. ARDS is a leading cause of mortality in burn patients ^[18]. Smoke inhalation, pneumonia, and the inflammation process are the major causes of ARDS in burn patients ^[18]. Patients with severe burns are at increased risk of developing MRSA ventilator-associated pneumonia ^[58].

MOF. Multiple organ failure is one of the major causes of death in patients with severe burns; clinically, MOF cases develop organ failure and most die between 3 and 7 days postburn ^[19].

Late mortality. The most common cause of late mortality (>48 hours) was MOF in the largest published modern Dutch cohort (38.3% of late deaths) ^[20].

Treatment-associated nephrotoxicity. Use of colistin in the management of imipenem-resistant Acinetobacter baumannii outbreaks was associated with renal outcomes in univariate analysis; after adjustment using machine-learning analysis, IR-AB outbreak episodes were associated with increased kidney events that appear to be driven by colistin use ^[84].

Resistance emergence. The problematic increase in carbapenem-resistance highlights the need for new antimicrobial stewardship policies and antibiotic prescribing protocols ^[38]. The carbapenem resistance of P. aeruginosa has decreased in some recent series, whereas that of A. baumannii has increased to a prevalence of 94% in some single-center series ^[36]. The lowest resistance rate observed in A. baumannii and P. aeruginosa was to colistin (21% and 27% respectively in pooled estimates), and the highest rate of resistance was to cefepime ^[85].

Special considerations

Pediatric burn sepsis. Children with burns over approximately 60% TBSA cluster at high mortality and high infection rates ^[21]. Body mass index ≥85th percentile altered the post-burn acute phase and catabolic response but did not increase the incidence of sepsis, MOF, or mortality in pediatric burn patients in one prospective cohort ^[88].

Elderly burn sepsis. Pre-existing conditions are common in the elderly and contribute to a higher rate of pneumonia, cellulitis, urinary tract infection, central line infections, and burn wound infections ^[101].

MDR epidemiology in resource-limited and mass-casualty settings. Antibiotic-resistant bacteria isolated in burn-unit settings include vancomycin-resistant Enterococcus faecium, MRSA, MDR Pseudomonas aeruginosa, MDR Vibrio sp, and other XDR organisms ^[34]. Within ≤7 days after admission, gram-positive bacteria are mainly Staphylococcus aureus, while gram-negative bacteria are mainly Klebsiella pneumoniae and Stenotrophomonas maltophilia; with extension of time after admission, dominant strains shift to Acinetobacter baumannii and Pseudomonas aeruginosa ^[35].

Fungal infection in immunocompromised burn cohorts. Mortality of untreated Candida burn wound infection was 100%, and with aggressive medical-surgical therapy 91.6% ^[25]. With early recognition of burn wound invasion by routine biopsies, wound swabs, and early amphotericin therapy, the mortality was reduced to 14% compared to 60-90% reported in other series ^[27]. Prophylactic empiric pharmacologic antifungal treatment is reserved for those highly at risk for invasive burn wound infection only ^[99].

Outcomes

Mortality data are heavily TBSA- and age-stratified. In one modern Dutch cohort, MOF accounted for 38.3% of late deaths (>48 hours), with sepsis-related mortality dominating in many other cohorts ^[20]. In children, the cutoff burn size for mortality, sepsis, infection, and multiple organ failure was approximately 60% TBSA; in modern burn care setting adults over 40% TBSA and children over 60% TBSA remain at high risk for morbidity and mortality even in high-volume units ^[21]. AKI requiring renal replacement therapy carries unacceptably high mortality in burn patients and is presumed even higher when combined with septic shock [9, 10, 11]. Early excision drove mortality reductions across multiple historical cohorts, with one series reporting a drop from 45% to 9% mortality in 17-to-30-year-olds ^[72]. The polyvalent Pseudomonas vaccine trial in the New Delhi arm reduced adult mortality from 40.6% (13/32) to 6.6% (2/30) and pediatric mortality from 20.8% (5/24) to 4.8% (1/21) ^[1].

ICU length of stay tracks infection burden. Patients fed early had shorter ICU length of stay (adjusted hazard ratio 0.57) and lower wound infection rates ^[77]. Trace-element supplementation reduced nosocomial pneumonia incidence from 80% to 33% and reduced VAP burden ^[59].

Controversies and Evidence Gaps

Best sepsis-definition framework. No single sepsis-criteria set is fully validated for burns. ABA, Mann-Salinas, and Sepsis-3 criteria were positive in 59%, 28%, and 85% respectively of suspected-sepsis events in one direct comparison, with Sepsis-3 the most predictive ^[5]. Severe burn patients face diagnostic challenges in distinguishing sepsis from systemic inflammation using Sepsis-3 criteria ^[7]. The ABA trigger for sepsis did not correlate strongly with bacteremia in a retrospective chart review of severe burn patients, with an ROC AUC of 0.638 (95% CI 0.573-0.704) for meeting >3 ABA criteria ^[3]. Usefulness of the ABA criteria to predict sepsis is limited to the day before blood culture is obtained ^[4]. SOFA-based scoring requires burn-specific subsystem calibration; subsystem-specific SOFA analysis identifies creatinine elevation and thrombocytopenia as key sepsis indicators in burns ^[7]. A "Burn SOFA score" and a "3 H's of burn sepsis" framework have been proposed ^[8].

SIRS criteria. Traditional SIRS criteria do not aid diagnosis of sepsis in burn centers ^[33]. Burn patients, by definition, already have systemic inflammatory response syndrome ^[2].

Systemic antibiotic prophylaxis. The literature is split. A Cochrane review concluded no evidence of an effect on burn wound infection rates in non-surgical patients, and no effect of perioperative prophylaxis on the review's outcomes ^[44]. A separate systematic review reported a significant all-cause mortality reduction with 4-to-14-day systemic prophylaxis (RR 0.54, 95% CI 0.34-0.87) ^[43]. Prophylactic antibiotics may improve 28-day in-hospital mortality in mechanically ventilated severe burn patients but not in non-ventilated patients ^[86]. The signal is heterogeneous across population, duration, and route.

SDD. SDD reduces mortality and pneumonia in burn patients in the cited cohorts [48, 49, 51]. The intervention has not been universally adopted because of antimicrobial-resistance and selection-pressure concerns; the evidence is broadly favorable but contested.

Biomarkers. PCT is the best-characterized burn-sepsis biomarker but the literature on whether PCT changes outcomes (rather than diagnostic accuracy) is thin [67, 68, 95]. The predictive value of PCT and CRP for burn sepsis prognosis was low in some series, while BNP was better ^[91]. MR-proADM may rise earlier than PCT and may be more suitable for early recognition ^[92]. None of these biomarkers has been shown to reduce mortality on its own; their role is in earlier recognition and stewardship support.

Empirical antibiotic timing. Empirical antibiotic selection at the time of suspected sepsis is driven by recent surveillance cultures and unit ecology; there is no validated single empirical regimen across burn centers [52, 53, 41].

Antifungal prophylaxis. Prophylactic empiric pharmacologic antifungal treatment is reserved for those highly at risk for invasive burn wound infection only ^[99]. Whether broader prophylaxis confers benefit in massively burned patients is unsettled.

Mass-casualty and resource-limited settings. Antimicrobial-resistant bacteria reported in burn-unit settings include vancomycin-resistant Enterococcus faecium, MRSA, multidrug-resistant Pseudomonas aeruginosa, and Vibrio sp ^[34]. Risk factors for imipenem-resistant P. aeruginosa acquisition in the burn unit have been identified through case-control analysis ^[37].

References

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