Necrotizing soft-tissue infections (NSTIs) are potentially life-threatening medical emergencies that encompass a devastating and rapidly spreading destruction of soft tissue with associated systemic toxicity.
NSTI is a rare diagnosis with a wide spectrum of presentations in the emergency department (ED). The most significant challenge associated with NSTI is establishing an early diagnosis. Skin may not be involved initially, which may delay treatment in a patient who may appear healthy. During the first stages, NSTIs may be confused with cellulitis or other superficial skin infections.
The infectious process can be located anywhere in the body, with a characteristic rapid progression of the infection site and hyperacute systemic deterioration of the patient.
The spread of the infection can lead to limb amputation, and the mortality risk has been estimated to be 15%-20%. [1, 2, 3, 4] The rapid clinical course is assumed to be related to microbial virulence, and many studies show that most cases are polymicrobial as opposed to monomicrobial with an organism such as group A beta-hemolytic Streptococcus or Streptococcus pyogenes. 
The lack of universal terminology used to define NSTIs and similar infections makes nomenclature confusing. Definitive treatment remains early and aggressive surgical intervention, and delay often results in increased risks of morbidity and mortality. [4, 5]
The etiology of necrotizing soft-tissue infections (NSTIs) is not always obvious. Pathogens can gain entry with a small site of inoculation, blunt trauma, cutaneous infections, post-surgical complications, blunt trauma, hematogenous spread, burns, childbirth, or idiopathic causes. 
Individuals with multiple comorbidities are at an increased risk for NSTI. Among the risk factors include intravenous drug use, diabetes, steroid use, immunocompromise, peripheral vascular disease, obesity, liver disease, chronic renal failure, and alcohol use. Nonetheless, healthy people without these risk factors may also be susceptible. [7, 8]
NSTIs can be defined as life-threatening infections of any of the layers within the soft-tissue compartment that are associated with necrotizing changes. NSTIs can range from skin and subcutaneous necrosis to muscle and fascial involvement, but classification is less important than the general principles. [7, 9, 10]
NSTI is pathophysiologically characterized by effects of bacterial toxins and enzymes (eg, hyaluronidase) that enable horizontal extension through the fascial planes, leading to intravascular thromboses and ischemic necrosis with disturbance of the host’s humoral and cellular immune response.  The infection is usually polymicrobial. Typical pathogens include group A beta-hemolytic Streptococcus, Staphylococcus aureus (including community-associated methicillin-resistant S aureus [CA-MRSA]), Enterococcus, Enterobacteriaceae, Bacteroides, and clostridia.
Some of the clinical manifestations of NSTI include rapidly evolving signs of systemic compromise and devastating infection with signs of tissue destruction, skin manifestations of blistering, and hemorrhage with crepitus.
Necrotizing fasciitis can be a misleading term used to describe an aggressive infection of subcutaneous tissue and the superficial fascia. Histologically, the necrosis of the fascia can manifest with or without polymorphonuclear infiltrates or bacteria. Surgical findings include presence of foul-smelling “dishwater” pus and gray, friable necrotic fascia that does not resist blunt dissection.  The infection primarily does not affect musculature, but the prolongations of the deep fascia reach the surroundings of the skeletal muscle; progression to intermuscular fascia involvement and myonecrosis are signs of late-stage disease and indicate a poor prognosis. [13, 14]
Fournier gangrene is a fulminant necrotizing fasciitis of the genitourinary tract. It is a well-defined urological emergency that rapidly progresses to the entire perineum and abdominal wall. A handful of studies have described several scoring systems for Fournier gangrene, such as Fournier’s Gangrene Severity Index (FGSI), surgical Apgar score (sAPGAR), and Uludag Fournier's Gangrene Severity Index (UFGSI), to predict the likelihood of mortality. 
Myonecrosis is a rare, potentially lethal condition that refers to necrotic infection of the muscle. The terms gas gangrene and clostridial myonecrosis have been used to refer to necrosis of the muscle tissue caused by toxin-producing Clostridia. Other bacteria are also capable of producing gas, and nonclostridial organisms have been isolated in 60%-85% cases of NSTIs with subcutaneous gas, and the term gas gangrene has been used to describe any gas-forming soft-tissue infection. 
Spontaneous gangrenous myositis (also known as spontaneous streptococcal gangrenous myositis, group A streptococcal necrosis, or streptococcal myonecrosis) is very rare. It is characterized by rapidly progressing necrotizing S pyogenes infection of skeletal muscle, usually preceded by influenzalike symptoms.
Epidemiology and Microbiology
The Centers for Disease Control and Prevention (CDC) monitors specific infections in the United States, including necrotizing fasciitis, with a special system called Active Bacterial Core surveillance (ABCs), based on causal organism. Each year in the United States, approximately 650-850 cases of necrotizing fasciitis caused by group A Streptococcus are reported, although this figure is probably low because of underreporting. 
The incidence of necrotizing soft-tissue infections (NSTIs) is approximately 500-1500 cases per year, with a recent increase thought to be related to increased microbial virulence and antibiotic resistance. 
NSTI can be classified based on microbial etiology. Type I infections are the most common and are polymicrobial. [1, 6] Type II NSTI is monomicrobial in etiology and is associated with streptococci, staphylococci, and clostridia. Staphylococcal NSTI is increasing in prevalence owing to more cases of MRSA infection and association with intravenous drug use, particularly the use of black tar heroin.
Classification of NSTIs based on microbiology is as follows:
Type I - Polymicrobial etiology (most common)
Type II - Monomicrobial etiology ( Streptococcus, Staphylococcus, Clostridium); ; Staphylococcal NSTI is increasing in prevalence owing to more cases of MRSA infection and association with intravenous drug use, particularly the use of black tar heroin
Type III - V vulnificus (associated with seawater exposure, in individuals with underlying cirrhosis)
Presentation and Diagnosis
NSTIs describes necrosis that involves subcutaneous fat, fascia, or muscle. It can present with a wide variety of clinical findings, and objective confirmation becomes difficult during the early stages of the infection. 
Necrotizing fasciitis is a rapidly progressive, highly destructive bacterial infection that can initiate as an apparently benign skin infection with an area of painful erythema and edema. Findings in more advanced necrotizing fasciitis include dusky skin and yellowish to red-black fluid-filled bullae that rapidly progresses to a demarcated area of necrosis resembling a third-degree burn, evolving to frank cutaneous gangrene with penetration along deep fascial planes and myonecrosis. Other manifestations include thrombophlebitis in the lower extremities, bacteremia, septic shock, and hypotension with rapid death. [19, 20]
Myonecrosis, which is characteristically associated with clostridial infection, may result in a bronze color, followed by hemorrhagic bullae, dermal gangrene, and, finally, crepitus. Nonclostridial infections are usually associated with erythema, pain, and swelling but are frequently initially identical to simple cellulitis. An apparent superficial cellulitis that fails to respond to standard antibiotic therapy and that progresses rapidly, resulting in systemic toxicity, should raise suspicion for necrotizing soft-tissue infection (NSTI).
A seroma with partial or complete dehiscence of a recent operative incision are potentially suggestive of necrotizing infection. The patient should be returned to the operating room for tissue biopsy and thorough examination of all layers of the skin, subcutaneous tissue, fascia, muscle, and peritoneum.
Chronic edema resulting in venous stasis or peripheral vascular disease, as well as preexisting diabetic foot wounds, are associated with NSTIs. NSTIs occur more commonly in patients with comorbidities such as diabetes mellitus, chronic alcoholism, chronic renal disease, HIV disease, liver disease, and underlying malignancy. [21, 22]
In rare cases, necrotizing infections can occur in the retroperitoneum and have cutaneous manifestations on the abdominal wall as a complication of intra-abdominal infectious processes, perforated viscous, or severe pancreatitis complicated by abscess. [23, 24]
NSTIs can be difficult to diagnose early in the disease course, as initial signs and symptoms can be typical of cellulitis. As mentioned above, the classic examination finding of pain out of proportion to examination or pain extending beyond the border of infection are both concerning for NSTI. Hemorrhagic bullae, ecchymosis, and crepitus are later findings.
It is common for patients with NSTI to present with signs of systemic toxicity due to a systemic inflammatory response caused by cytokine release. However, some patients with underlying chronic illness may be relatively immunosuppressed and demonstrate a less-dramatic presentation.
Some patients present with “la belle indifference” and, despite a severely infected extremity, seem inappropriately unbothered, which may be a result of local ischemia causing the skin to become insensate.
One European study identified the presence of initial visible skin necrosis as an independent predictor of mortality. 
The most important discriminative information to be established in patients with soft-tissue infection is the presence of a necrotizing component. This will confirm NSTI and, by definition, identifies patients who require surgical debridement. The first and most important tool for early diagnosis of NSTI is a high index of suspicion. Unfortunately, true risk factors for NSTI have not been identified. 
See the images below.
When evaluating a patient for possible NSTI, the border of erythema should always be marked upon initial evaluation to assess for rapid advancement.
Radiographic studies can demonstrate subcutaneous emphysema, but this is late finding and should not be used to rule out NSTI; however, if present, it is associated with severe disease. 
MRI is superior to all other imaging modalities because of its remarkable soft-tissue capabilities. Intermuscular fluid collection and variable fascial thickening are useful findings; however, T2 hyperintensity in the deep muscular fascia is an important feature for diagnosis.  Nonetheless, MRI may be inappropriate for unstable patients or if it would delay surgical intervention. 
The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score can be used to increase suspicion for a necrotizing skin infection.  The LRINEC score includes 6 variables associated with NSTI and are used to calculate a score correlating to the risk of NSTI (see tables 1 and 2 below). Patients with an LRINEC score of 6 or higher are at highest risk for the presence of a necrotizing infection. However, an LRINEC score of 6 or less cannot be used to rule out the diagnosis completely. Patients still need a thorough evaluation to rule out the disease. Not included in the LRINEC score is a serum lactate level, which, if elevated, should also increase concern for NSTI. Patients with concern for NSTI can rapidly deteriorate and should be reevaluated frequently.
Table 1. LRINEC Score Parameters (Open Table in a new window)
|Laboratory Parameter||LRINEC Points|
|C-reactive protein (mg/L)|
|Total white blood cell count (µ L)|
Table 2. LRINEC Score and Risk of NSTI (Open Table in a new window)
|Risk Category||LRINEC Score, Points||Probability of NSTI, %|
|Low||< 5||< 50|
Emergency Department Management
Early recognition of necrotizing soft-tissue infections (NSTIs) is critical and requires a coordinated multidisciplinary approach. Patients with suspected necrotizing fasciitis must be promptly and aggressively treated to reduce the risk of morbidity and mortality. 
Obtain intravenous access in the unaffected extremity and begin fluid resuscitation with normal saline or lactated Ringer solution.
Administer adequate intravenous broad-spectrum antibiotics, as the etiology can be polymicrobial.
Consider supplemental oxygen and intubation in patients with hypoxia or altered mental status.
Electrolyte replacement is initiated as needed.
Immediate surgical consultation is indicated when necrotizing soft-tissue skin infection (NSTI) is suspected. A surgeon should be promptly consulted for definitive management. Tetanus status should be assessed and updated, if indicated.
Broad-spectrum intravenous antibiotic therapy should be initiated upon suspicion for possible necrotizing soft-tissue infection (NSTI). Antibiotic selection should cover gram-positive, gram-negative, and anaerobic organisms. The current Infectious Disease Society of America (IDSA) guidelines recommend broad-spectrum coverage (vancomycin or linezolid plus  piperacillin-tazobactam or a carbapenem or  ceftriaxone and metronidazole). 
Organism-specific management is as follows: 
Mixed infections: (1) Piperacillin-tazobactam 3.37 g IV every 6-8 h plus vancomycin 30 mg/kg/d in 2 divided doses, (2) imipenem-cilastin 1 g IV every 6-8 h IV, (3) meropenem 1 g IV every 8 h, (4) ertapenem 1 g IV daily, or (5) cefotaxime 2 g IV every 6 h plus metronidazole 500 mg IV every 6 h or clindamycin 600-900 mg IV every 8 h
Streptococcus and Clostridium species: Penicillin 2-4 million units IV every 4-6 h plus clindamycin 600-900 mg IV every 8 h
S aureus: Nafcillin 1-2 g IV every 4 h, oxacillin 1-2 g IV every 4 h, cefazolin 1 g IV every 8 h, vancomycin (resistant strains) 30 mg/kg/d IV in 2 divided doses, or clindamycin 600-900 mg IV every 8 h
V vulnificus: Doxycycline 100 mg IV every 12 h plus ceftriaxone 1 g IV qid, or cefotaxime 2 g IV qid
Aeromonas hydrophila: Doxycycline 100 mg IV every 12 h plus ciprofloxacin 500 mg IV every 12 h, or ceftriaxone 1-2 g IV every 24 h
Debridement and Definitive Surgical Management
Aggressive surgical debridement of all necrotic tissue is the definitive treatment of necrotizing soft-tissue infections (NSTIs). Although pus may be nearly absent, the wounds can discharge copious amount of tissue fluid. Antibiotic treatment alone without surgical intervention leads to progressive sepsis. Debridement is best accomplished by early and extensive incision of skin and subcutaneous tissue wide into healthy tissue, followed by excision of all necrotic fascia and nonviable skin and subcutaneous tissue.
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy (HBO) in necrotizing soft-tissue infection (NSTI) is controversial, as it has not been proven as a benefit for the patient and can delay resuscitation and surgical debridement. HBO involves the use of oxygen at 2-3 times atmospheric pressure with proposed benefits of bacteriocidal effects, improved polymorphonuclear lymphocyte function, and enhanced wound healing. There are few controlled clinical studies with conflicting results. HBO should be considered as a treatment adjunct and does not replace surgical debridement. [22, 32]
Intravenous Immunoglobulin Therapy
Intravenous immunoglobulin (IVIG) therapy is an experimental treatment for necrotizing fasciitis and is postulated to bind exotoxin produced by streptococcal and staphylococcal species, potentially delaying the onset of the systemic inflammatory response and sepsis. The use of IVIG has not been definitively established, but it can be considered on a case-by-case basis in hemodynamic unstable, critically ill patients. However, controlled trials are lacking. 
Consultations and Transfer
Obtain early surgical consultation for aggressive debridement in cases of suspected necrotizing soft-tissue infection (NSTI) without delay for results of laboratory or radiology studies. Consider surgical subspecialty consultation for necrotizing fasciitis involving specific anatomic areas such as urology in cases of Fournier gangrene. Consultation with an infectious diseases specialist may help guide initial empiric antibiotic therapy. If the current facility is not capable of handling the aggressive care, monitoring, and serial surgical debridement that these patients require, arrangements for transfer should be made. However, patients should not be considered for transfer until they remain hemodynamically stable.