Necrotizing Fasciitis

Necrotizing fasciitis is a rapidly progressive inflammatory infection of the fascia, with secondary necrosis of the subcutaneous tissues. The speed of spread is directly proportional to the thickness of the subcutaneous layer. Necrotizing fasciitis moves along the fascial plane.[1, 2]

Necrotizing fasciitis has also been referred to as hemolytic streptococcal gangrene, Meleney ulcer, acute dermal gangrene, hospital gangrene, suppurative fasciitis, and synergistic necrotizing cellulitis. Fournier gangrene is a form of necrotizing fasciitis that is localized to the scrotum and perineal area.

Necrotizing fasciitis may occur as a complication of a variety of surgical procedures or medical conditions, including cardiac catheterization,[4] vein sclerotherapy,[5] and diagnostic laparoscopy,[6] among others.[7, 8, 9, 10, 11, 12, 13] It may also be idiopathic, as in scrotal or penile necrotizing fasciitis.

The causative bacteria may be aerobic, anaerobic, or mixed flora.[14] A few distinct necrotizing fasciitis syndromes should be recognized. The 3 most important are as follows:

• Type I, or polymicrobial

• Type II, or group A streptococcal

• Type III gas gangrene, or clostridial myonecrosis

A variant of necrotizing fasciitis type I is saltwater necrotizing fasciitis, in which an apparently minor skin wound is contaminated with saltwater containing a Vibrio species.

Because of the presence of gas-forming organisms, subcutaneous air is classically described in necrotizing fasciitis. This may be seen only on radiographs or not at all.

The frequency of necrotizing fasciitis has been on the rise because of an increase in immunocompromised patients with diabetes mellitus, cancer, alcoholism, vascular insufficiencies, organ transplants, HIV infection, or neutropenia.

According to the Centers for Disease Control and Prevention, an estimated 700-1150 cases of necrotizing fasciitis caused by group A Streptococcus occur annually in the United States.[33]

The mean age of a patient with necrotizing fasciitis is 38-44 years. This disease rarely occurs in children. Pediatric cases have been reported from resource-poor nations where poor hygiene is prevalent. The male-to-female ratio is 2-3:1.

These infections can be difficult to recognize in their early stages, but they rapidly progress. (see Clinical and Workup). They require aggressive treatment to combat the associated high morbidity and mortality (see Treatment).

Images of necrotizing fasciitis are shown below.

Left upper extremity shows necrotizing fasciitis in an individual who used illicit drugs. Cultures grew Streptococcus milleri and anaerobes (Prevotella species). Patient would grease, or lick, the needle before injection.

Left lower extremity in a 56-year-old patient with alcoholism who was found comatose after binge drinking. Surgical drainage was performed to treat the pyomyositis-related, large, non–foul-smelling (sweetish) bullae. Gram staining showed the presence of gram-positive rods. Cultures revealed Clostridium perfringens. The diagnosis was clostridial myonecrosis.

Sixty-year-old woman who had undergone postvaginal hysterectomy and repair of a rectal prolapse has a massive perineal ulceration with foul-smelling discharge. Cultures revealed Escherichia coli and Bacteroides fragilis. The diagnosis was perineal gangrene.

Necrotizing fasciitis at a possible site of insulin injection in the left upper part of the thigh in a 50-year-old obese woman with diabetes.

Necrotizing fascitis of entire thoracolumbar posterior area in 20-year-old patient with chronic myelogenous leukemia and neutropenia (WBC count, 680/uL). Cultures revealed gram-negative Pseudomonas species and Bacteroides fragilis.

Historical background

Necrotizing fasciitis was first described by a Confederate Army surgeon, Joseph Jones, during the US Civil War.[15] In 1883, Fournier documented necrotizing fasciitis in the perineal and genital region.[16] Meleney later reported 20 patients he encountered in China in whom necrotizing fasciitis was caused by hemolytic streptococcus.[17] Wilson used the term necrotizing fasciitis without assigning a specific pathologic bacterium that caused the disease.[18]

Smith et al first classified soft tissue infections as either local or spreading.[19] Lewis later further classified soft tissue infections into either necrotizing or non-necrotizing.[20] He further subdivided these infections into either focal or diffuse.

Collective reviews

In 2010, a team of scientists and surgeons from the Legacy Emanuel Shock Trauma Center in Portland, Oregon, wrote a collective review on the diagnosis and treatment of necrotizing fasciitis. These scientists and surgeons found extensive wide debridement of all tissues that can be easily elevated off the fascia with gentle pressure should be undertaken. The use of adjunctive therapies, such as hyperbaric oxygen therapy (HBO), continue to receive considerable attention as a integral parts of the life-saving therapies.[21]

In 2011, Drs Rausch and Foca wrote an exciting report focusing on necrotizing fasciitis in a pediatric patient. At the end of the report, the authors pointed out that all pediatricians must be aware of the possibility of severe infections in pediatric patients with necrotizing fasciitis who had vascular lymphatic malformations.[22]

In 2012, a team of scientists and surgeons from Turkey wrote a comprehensive collective review on necrotizing fasciitis. At the end of their report, they emphasize that early diagnosis of necrotizing fasciitis may be life saving.[23]

At the Imperial College in London, United Kingdom, 5 scholars wrote a comprehensive 5-year review of necrotizing fasciitis. They emphasize that necrotizing fasciitis is a life-threatening disease that is often difficult to diagnose. The authors guide the readers to make the correct diagnosis as soon as possible in order to save lives.[24]

National Necrotizing Fasciitis Foundation (NNFF)

The cofounders of this distinguished foundation are necrotizing fasciitis survivors, Donna Batdorff and Jackie Roemmele.[25] In the years since these 2 women have teamed up to be leaders in this society, they have diligently worked in concert with a dedicated volunteer staff to fulfill the foundation’s mission to increase awareness about necrotizing fasciitis. Foundation activities include public speaking and outreach efforts regarding necrotizing fasciitis throughout the world to educate the medical community and to help save lives from this often misdiagnosed, rapidly fatal disease. See National Necrotizing Fasciitis Foundation.

Necrotizing fasciitis is characterized by widespread necrosis of the subcutaneous tissue and the fascia. It was once considered an uncommon clinical entity. In the 1990s, the media popularized the idea that this infection was caused by "flesh-eating bacteria." Although the pathogenesis of necrotizing fasciitis is still open to speculation, the rapid and destructive clinical course of necrotizing fasciitis is thought to be due to multibacterial symbiosis and synergy.[15]

Historically, group A beta-hemolytic Streptococcus (GABS) has been identified as a major cause of this infection. This monomicrobial infection is usually associated with an underlying cause, such as diabetes,[34] atherosclerotic vascular disease, or venous insufficiency with edema. GABS usually affects the extremities; approximately two thirds of the GABS infections are located in the lower extremities.[35]

During the last 2 decades, researchers have found that necrotizing fasciitis is usually polymicrobial rather than monomicrobial.[36, 37, 38] Anaerobic bacteria are present in most necrotizing soft-tissue infections, usually in combination with aerobic gram-negative organisms. Anaerobic organisms proliferate in an environment of local tissue hypoxia in those patients with trauma, recent surgery, or medical compromise.

Facultative aerobic organisms grow because polymorphonuclear neutrophils (PMNs) exhibit decreased function under hypoxic wound conditions. This growth further lowers the oxidation/reduction potential, enabling more anaerobic proliferation and, thus, accelerating the disease process.

Carbon dioxide and water are the end products of aerobic metabolism. Hydrogen, nitrogen, hydrogen sulfide, and methane are produced from the combination of aerobic and anaerobic bacteria in a soft tissue infection. These gases, except carbon dioxide, accumulate in tissues because of reduced water solubility.

In necrotizing fasciitis, group A hemolytic streptococci and Staphylococcus aureus, alone or in synergism, are frequently the initiating infecting bacteria. However, other aerobic and anaerobic pathogens may be present, including the following:

• Bacteroides

• Clostridium

• Peptostreptococcus

• Enterobacteriaceae

• Coliforms (eg, Escherichia coli)

• Proteus

• Pseudomonas

• Klebsiella

Bacteroides fragilis is usually noted as part of a mixed flora in combination with E coli. B fragilis does not directly cause these infections, but it does play a part in reducing interferon production and the phagocytic capacity of macrophages and PMNs.

A variant synergistic necrotizing cellulitis is considered to be a form of necrotizing fasciitis, but some authorities feel that it is actually a nonclostridial myonecrosis. This condition begins in the same manner as necrotizing fasciitis, but it progresses rapidly to involve wide areas of deeper tissue and muscle at an earlier stage than might be expected. Severe systemic toxicity occurs.

Anaerobic streptococci, occasionally seen in intravenous drug users, cause many forms of nonclostridial myonecrosis (see the image below). Some cases of necrotizing fasciitis can be caused by Vibrio vulnificus. This organism is seen more often in patients with chronic liver dysfunction, and it often follows the consumption of raw seafood. V vulnificus may cause subcutaneous bleeding.

Left upper extremity shows necrotizing fasciitis in an individual who used illicit drugs. Cultures grew Streptococcus milleri and anaerobes (Prevotella species). Patient would grease, or lick, the needle before injection.

Organisms spread from the subcutaneous tissue along the superficial and deep fascial planes, presumably facilitated by bacterial enzymes and toxins. This deep infection causes vascular occlusion, ischemia, and tissue necrosis. Superficial nerves are damaged, producing the characteristic localized anesthesia. Septicemia ensues with systemic toxicity.

Important bacterial factors include surface protein expression and toxin production. M-1 and M-3 surface proteins, which increase the adherence of the streptococci to the tissues, also protect the bacteria against phagocytosis by neutrophils.

Streptococcal pyrogenic exotoxins (SPEs) A, B, and C are directly toxic and tend to be produced by strains causing necrotizing fasciitis. These pyrogenic exotoxins, together with streptococcal superantigen (SSA), lead to the release of cytokines and produce clinical signs such as hypotension. The etiological agent may also be a Staphylococcus aureus isolate harboring the enterotoxin gene cluster seg, sei, sem, sen, and seo, but lacking all common toxin genes, including Panton-Valentine leukocidin.[39]

The poor prognosis associated with necrotizing fasciitis has been linked to infection with certain streptococcal strains. Community-acquired methicillin-resistant S aureus (MRSA) has also been associated with necrotizing fasciitis.[40]

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species. They may alter bacterial virulence; a single-nucleotide mutation in the group A Streptococcus genome was identified that is epidemiologically associated with decreased human necrotizing faciitis.[41]

It was found that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. It was speculated that a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis.

Severe myositis accompanying septic necrotizing fasciitis may be caused by a Panton-Valentine leukocidin–positive S aureus strain.[42] Immunostaining may document strong binding of the Panton-Valentine leukocidin toxin to necrotic muscle tissues.

Although necrotizing fasciitis most frequently develops after trauma that compromises skin integrity, it may rarely develop in a healthy person after minor trauma such as an isolated shoulder sprain that occurred without a break in skin barrier.[43]

Surgical procedures may cause local tissue injury and bacterial invasion, resulting in necrotizing fasciitis. These procedures include surgery for intraperitoneal infections and drainage of ischiorectal and perianal abscesses. Intramuscular injections and intravenous infusions may lead to necrotizing fasciitis.

Minor insect bites may set the stage for necrotizing infections. Streptococci introduced into the wounds may be prominent initially, but the bacteriologic pattern changes with hypoxia-induced proliferation of anaerobes.

Local ischemia and hypoxia can occur in patients with systemic illnesses (eg, diabetes). Host defenses can be compromised by underlying systemic diseases favoring the development of these infections. Illnesses such as diabetes or cancer have been described in over 90% of cases of progressive bacterial gangrene.

Of patients with necrotizing fasciitis, 20-40% are diabetic. As many as 80% of Fournier gangrene cases occur in people with diabetes. In some series, as many as 35% of patients were alcoholics. However, approximately one half of the cases of streptococcal necrotizing fasciitis occur in young and previously healthy people.

A study by Hung et al suggested that liver cirrhosis is an independent risk factor for necrotizing fasciitis. In a retrospective analysis of hospital data, the investigators determined the incidence of necrotizing fasciitis development in 40,802 patients with cirrhosis and 40,865 control patients, over a three-year follow-up period after each patient’s initial hospitalization. Necrotizing fasciitis occurred during follow-up in 299 patients with cirrhosis (0.7%) and in 160 control patients (0.4%), giving patients with cirrhosis a hazard ratio of 1.98 for necrotizing fasciitis. It was also found that the risk of necrotizing fasciitis was greater in patients with complicated cirrhosis than in those with the noncomplicated type (hazard ratio 1.32).[44]

Studies have shown a possible relationship between the use of nonsteroidal anti-inflammatory agents (NSAIDs), such as ibuprofen, and the development of necrotizing fasciitis during varicella infections. Additional studies are needed to establish whether ibuprofen use has a causal role in the development of necrotizing fasciitis and its complications during varicella infections. This has not previously been described.

Group A beta-hemolytic streptococci have historically been noted as a cause of necrotizing fasciitis, but Haemophilus aphrophilus and S aureus are also associated with the condition, and some patients have mixed infections involving multiple species of bacteria, including mycobacteria, as well as fungi.[45, 46]

A synergistic infection with a facultative anaerobic bacterium may be significant. In 1 patient, Phycomycetes appeared to be responsible for necrotizing fasciitis.

Streptococcus pneumoniae is a rare cause of necrotizing fasciitis.[45] In one patient, S pneumoniae serotype 5 was also isolated. This serotype 5 antigen is included in the polysaccharide 23-valent pneumococcal vaccine, highlighting the value of pneumococcal immunization.

In type I necrotizing fasciitis, anaerobic and facultative bacteria work synergistically to cause what may initially be mistaken for a simple wound cellulitis. A variant of type I necrotizing fasciitis is saltwater necrotizing fasciitis in which an apparently minor skin wound is contaminated with saltwater containing a Vibrio species.

In type II necrotizing fasciitis, varicella infection and the use of nonsteroidal anti-inflammatory drugs may be predisposing factors.

Type III necrotizing fasciitis is usually caused by Clostridium perfringens. When type III necrotizing fasciitis occurs spontaneously, C septicum is more likely to be the etiologic agent; these cases usually occur in association with colon cancer or leukemia.

Unusual causes include injection anthrax.[47] Rapidly progressive necrotizing fasciitis following a stonefish sting has been described in 2 patients.[48]

The reported mortality in patients with necrotizing fasciitis has ranged from 20% to as high as 80%.[49, 36, 38, 50] Pathogens, patient characteristics, infection site, and speed of treatment are among the variables that affect survival.

Poor prognosis in necrotizing fasciitis has been linked to infection with certain streptococcal strains. However, McHenry et al found that monomicrobial infection with S pyogenes was not associated with an increased mortality.[38]

A retrospective study by Hsiao et al found that Aeromonas infection, Vibrio infection, cancer, hypotension, and band form WBC count greater than 10% were independent positive predictors of mortality in patients with necrotizing fasciitis, while streptococcal and staphylococcal infections were not identified as predictors of mortality. Hemorrhagic bullae appeared to be an independent negative predictor of mortality. However, accuracy of these factors needs to be verified.[51]

A retrospective cohort study by Chang et al of patients with necrotizing fasciitis who underwent amputation reported that in those individuals in whom amputation was performed more than 3 days after admission, the mortality risk was higher when hemorrhagic bullae, peripheral vascular disease, or bacteremia was present or the laboratory risk indicator for necrotizing fasciitis (LRINEC) score was over 8. The investigators recommended that in cases in which any of these risk factors is present, amputation not be delayed more than 3 days postadmission.[52]

In another study, preexisting chronic liver dysfunction, chronic renal failure, thrombocytopenia, hypoalbuminemia, and postoperative dependence on mechanical ventilation represented poor prognostic factors in monomicrobial necrotizing fasciitis. In addition, patients with gram-negative monobacterial necrotizing fasciitis had more fulminant sepsis.[53]

Similarly, a retrospective study by Adachi et al reported that in patients with necrotizing fasciitis, renal dysfunction predicts fatal outcomes. Estimated glomerular filtration rate was a prognostic factor, the cutoff value being 20.6 mL/min.[54]

The mean age of survivors is 35 years. The mean age of nonsurvivors is 49 years.

A retrospective review by Cheng et al showed that upper extremity necrotizing fasciitis has a high mortality rate. In their review, about 35% of patients died. A state of altered consciousness and respiratory distress at initial presentation were found to be statistically significant factors for eventual mortality. Early diagnosis and referral for aggressive surgical treatment prior to the development of systemic toxic signs are essential for survival.[55]

In a retrospective review of craniocervical necrotizing fasciitis, Mao et al reported a survival rate of 60% for patients with thoracic extension (6 of 10) compared with 100% for those without thoracic extension. Lower overall survival for the patients in the thoracic extension group was attributed to older patient age, greater comorbidity, need for more extensive surgical debridement, and increased postoperative complications.

Better survival of the patients without thoracic extension was attributed to aggressive wound care and surgical debridement, broad-spectrum intravenous antibiotics, and care in the surgical intensive care unit.[56]

A study by Friederichs et al indicated that necrotizing fasciitis tends to have a worse outcome when acquired iatrogenically via injection or infiltration than it does when acquired in other ways, with higher mortality and amputation rates (67% and 73%, respectively) found. The study included 21 patients with injection- or infiltration-related necrotizing fasciitis and 134 patients who were infected with the condition through other means.[57]

In a study by Rouse et al, the overall mortality rate was 73% (20 of 27 patients). They indicated that prompt recognition and treatment of necrotizing fasciitis was essential: Of 12 patients whose treatment was delayed for more than 12 hours, 11 patients died.[36]

Similarly, McHenry et al reported that the average time from admission to operation was 90 hours in nonsurvivors of necrotizing soft-tissue infections; in survivors, this average time was 25 hours.[38] Early debridement of the infection was obviously associated with a significant decrease in mortality.

Necrotizing fasciitis survivors may have a shorter life span than population controls, owing to infectious causes such as pneumonia, cholecystitis, urinary tract infections, and sepsis.[58]

Necrotizing fasciitis has become sufficiently common in the United States that a National Necrotizing Fasciitis Foundation has been formed. The cofounders of this foundation are survivors of necrotizing fasciitis. The goals of this foundation are to increase awareness about necrotizing fasciitis, to educate the medical community, and to help save lives from this often misdiagnosed, rapidly fatal disease.

The foundation’s website has stories about survivors of necrotizing fasciitis with color photographs. The Foundation provides a list of journal articles as well as 8 brief reports on necrotizing fasciitis that can be downloaded at no cost.

Diagnosis of necrotizing fasciitis can be difficult and requires a high degree of suspicion. In many cases of necrotizing fasciitis, antecedent trauma or surgery can be identified. Surprisingly, the initial lesion is often trivial, such as an insect bite, minor abrasion, boil, or injection site. Idiopathic cases are not uncommon, however.

Olafsson et al indicate that the hallmark symptom of necrotizing fasciitis is intense pain and tenderness over the involved skin and underlying muscle.[59] The intensity of the pain often causes suspicion of a torn or ruptured muscle. This severe pain is frequently present before the patient develops fever, malaise, and myalgias.

In some cases, the symptoms may begin at a site distant from the initial traumatic insult. Pain may be out of proportion to physical findings. Over the next several hours to days, the local pain progresses to anesthesia.

Other indicative findings include edema extending beyond the area of erythema, skin vesicles, and crepitus. McHenry et al and others have noted that the subcutaneous tissue demonstrates a wooden, hardened feel in cases of necrotizing fasciitis.[38] The fascial planes and muscle groups cannot be detected by palpation.

A history of comorbid factors, including diabetes mellitus, should be sought in all cases of suspected necrotizing fasciitis. A retrospective, multicenter study by van Stigt et al of 58 patients with necrotizing fasciitis found cardiovascular disease to be the most common comorbidity (39.7% of patients).[49]

Physical findings may not be commensurate with the degree of patient discomfort. Early in the disease course, the patient may look deceptively well; unfortunately, this may interfere with early detection, which is key to a favorable outcome. Soon, however, the patient will usually begin to appear moderately to severely toxic.

Typically, the infection begins with an area of erythema that quickly spreads over a course of hours to days. The redness quickly spreads, and its margins move out into normal skin without being raised or sharply demarcated. As the infection progresses, the skin near the site of insult develops a dusky or purplish discoloration. Multiple identical patches expand to produce a large area of gangrenous skin, as the erythema continues to spread.

Iwata et al reported that 2 of 3 patients who lacked inflammatory signs such as redness and heat experienced fulminant progression of necrotizing fasciitis and death.[60]

The initial necrosis appears as a massive undermining of the skin and subcutaneous layer. If the skin is open, gloved fingers can pass easily between the 2 layers and may reveal yellowish green necrotic fascia. If the skin is unbroken, a scalpel incision will reveal it.

The normal skin and subcutaneous tissue become loosened from the rapidly spreading deeper necrotic fascia that is a great distance from the initiating wound. Fascial necrosis is typically more advanced than the appearance suggests.

Anesthesia in the involved region may be detected, and it usually is caused by thrombosis of the subcutaneous blood vessels, leading to necrosis of nerve fibers.

Without treatment, secondary involvement of deeper muscle layers may occur, resulting in myositis or myonecrosis. Normally, however, the muscular layer remains healthy red with normal bleeding muscle under the yellowish green fascia.

Usually, the most important signs are tissue necrosis, putrid discharge, bullae, severe pain, gas production, rapid burrowing through fascial planes, and lack of classic tissue inflammatory signs.

Usually, some degree of intravascular volume loss is detectable on clinical examination. Other general signs, such as fever and severe systemic reactions, may be present.

Local crepitation can occur in more than one half of patients. This is an infrequent finding, specific but not sensitive, particularly in cases of nonclostridial necrotizing fasciitis.

Fournier gangrene in males begins with local tenderness, itching, edema, and erythema of the scrotal skin. This progresses to necrosis of the scrotal fascia. The scrotum enlarges to several times its normal diameter. If the process continues beyond the penile-scrotal region to the abdomen or the upper legs, the normal picture of necrotizing fasciitis can be seen.

In males, the scrotal subcutaneous layer is so thin that most patients present after the skin is already exhibiting signs of necrosis. In 2-7 days, the skin becomes necrotic, and a characteristic black spot can be seen. Early on, this infection may resemble acute orchitis, epididymitis, torsion, or even a strangulated hernia.

In women, Fournier gangrene acts more like necrotizing fasciitis because of the thicker subcutaneous layers involving the labia majora and the perineum.

Complications

Complications may include the following:

• Renal failure

• Septic shock with cardiovascular collapse

• Scarring with cosmetic deformity

• Limb loss

• Sepsis

• Toxic shock syndrome

Metastatic cutaneous plaques may occur in necrotizing fasciitis. Septicemia is typical and leads to severe systemic toxicity and rapid death unless appropriately treated.

Laboratory tests, along with appropriate imaging studies, may facilitate the diagnosis of necrotizing fasciitis.[26, 27] Laboratory evaluation should include the following:

• Complete blood count with differential

• Serum chemistry studies

• Arterial blood gas measurement

• Urinalysis

• Blood and tissue cultures

Skin and superficial tissue cultures may be inaccurate because samples may not contain the infected tissue. Deeper tissue samples, obtained at the time of surgical debridement, are needed to obtain proper cultures for microorganisms. (See Biopsy, below.) New techniques include rapid streptococcal diagnostic kits and a polymerase chain reaction (PCR) assay for tissue specimens that tests for the genes for streptococcal pyrogenic exotoxin (SPE; eg, SPE-B) produced by group A streptococci.

B-mode and possibly color Doppler ultrasonography, contrast-enhanced computed tomography (CT) scanning, or magnetic resonance imaging (MRI) can promote early diagnosis of necrotizing infections.[61] In addition, these studies permit visualization of the location of the rapidly spreading infection. More importantly, MRI or CT scan delineation of the extent of necrotizing fasciitis may be useful in directing rapid surgical debridement.

However, when the patient is seriously ill, necrotizing fasciitis is a surgical emergency with high mortality. Therefore, laboratory tests and imaging studies should not delay surgical intervention.[62]

Most fluid collections in the tissue, especially in the musculoskeletal system, can be localized and aspirated under ultrasonographic guidance. Whether fluid is infected cannot be determined on the basis of its ultrasonographic characteristics; however, laboratory analysis of the aspirated fluid can help in identifying the pathogen.[63]

In a study of 13 patients with thoracic and abdominal wall infections, Sharif et al reported that CT and MRI were superior to sonography, scintigraphy, and plain radiography in providing useful information about the nature and extent of infections.[64] Furthermore, they point out that while CT compares favorably with MRI in accurate diagnosis of soft tissue infection, multiplanar MRI images can be obtained without ionizing radiation and the use of intravenous contrast agents.

Although the laboratory results may vary in a given clinical setting, the following may be associated with necrotizing fasciitis:

• Elevated white blood cell (WBC count), possibly to more than 14,000/µL

• Elevated blood urea nitrogen (BUN) level, possibly to greater than 15 mg/mL

• Reduced serum sodium level, possibly to less than 135 mmol/L

A study by Sandner et al indicated that the laboratory risk indicator for necrotizing fasciitis (LRINEC) is an effective tool for early detection of cervical necrotizing fasciitis. The investigators, who used a cutoff score of 6, reported that the LRINEC had a sensitivity and specificity for cervical necrotizing fasciitis of 94%, as well as a positive predictive value of 29% and a negative predictive value of 99%. The study included 16 patients with the disease and 595 patients with severe nonnecrotizing neck infections.[65]  A retrospective study by Narasimhan et al reported that an LRINEC score of 5 or above had a sensitivity of 76.3% and a specificity of 93.1% in the diagnosis of necrotizing fasciitis, with positive and negative predictive values being 95.5% and 88.1%, respectively.[66]

In contrast, however, a literature review by Fernando et al indicated that an LRINEC score of 6 or above has a sensitivity and specificity of 68.2% and 84.8%, respectively, in the detection of necrotizing soft tissue infection, while a score of 8 or above has a sensitivity and specificity of 40.8% and 94.9%, respectively.[67]

Nonetheless, a retrospective study by El-Menyar et al suggested that the LRINEC score is not only useful as a diagnostic tool but also as a prognostic one. In the study, patients with an LRINEC score of 6 or above had a greater tendency toward diabetes mellitus, Pseudomonas aeruginosa infection, and a higher Sequential Organ Failure Assessment (SOFA) score. They also tended to have a longer period of intensive care, a longer hospital stay, and higher septic shock and mortality rates.[68]

However, a retrospective study by Neeki et al indicated that the LRINEC score may prove inaccurate when used in the emergency department for necrotizing fasciitis risk stratification and the differentiation of cellulitis from necrotizing fasciitis. The investigators found that in emergency department patients with confirmed cellulitis, the LRINEC score had a high false-positive rate, classifying 10.8% of these patients as being at moderate or high risk for necrotizing fasciitis. In emergency department patients with confirmed necrotizing fasciitis, however, the LRINEC score had a high false-negative rate, classifying 63.8% of these patients as being at low risk for the disease. The study also found that in both the cellulitis and necrotizing fasciitis patients, the misclassification rate was higher for nondiabetic patients than for patients with diabetes. The results of the report indicate that a high index of clinical suspicion is warranted in the use of the LRINEC score in the emergency department.[69]

Radiographs

Plain radiographs, often obtained to detect soft-tissue gas that is sometimes present in polymicrobial or clostridial necrotizing fasciitis, are of no value in the diagnosis of necrotizing infections.[70] Indeed, nondiagnostic plain radiographs may even hinder the diagnosis of necrotizing infection.[61] In their study of 29 patients with necrotizing soft tissue infections, Lille et al reported that nondiagnostic radiographs correlate with a delay in operative intervention and consequent increased morbidity and mortality.[71]

The presence of subcutaneous gas in a radiograph does not necessarily indicate a clostridial infection, as Escherichia coli, Peptostreptococcus species, and Bacteroides species may produce gas under appropriate conditions. Misleading subcutaneous gas can also result from the undermining of tissue planes during surgical debridement. Perforations of the esophagus, the respiratory tract, or the GI tract related to endoscopy or chest tube insertion can result in the radiographic appearance of gas.

Ultrasonography

Bedside ultrasonography may be useful in patients with necrotizing fasciitis, as well as other soft-tissue infections, including cellulitis, cutaneous abscess, and peritonsillar abscess. It may be superior to clinical judgment alone in determining the presence or the absence of occult abscess formation.[72]

Sonography may reveal subcutaneous emphysema spreading along the deep fascia, swelling, and increased echogenicity of the overlying fatty tissue with interlacing fluid collections, allowing for early surgical debridement and parenteral antibiotics.[28]

Parenti et al retrospectively reviewed the ultrasonographic appearances of 32 pathologically proven cases of necrotizing fasciitis.[73] Ultrasonography revealed changes in the subcutaneous fat (28 of 32 patients), investing fascia (18 of 32 patients), and muscle (15 of 32 patients), which correlated well with histological findings. However, in some cases, ultrasonography missed histologically apparent inflammation in the subcutaneous tissues (3 of 32 patients) or muscle (8 of 32 patients).[73]

CT and MRI

CT scanning can pinpoint the anatomic site of involvement by demonstrating necrosis with asymmetrical fascial thickening and the presence of gas in the tissues. However, note that early on, CT scan findings may be minimal.

While no published, well-controlled, clinical trial has compared the efficacy of various diagnostic imaging modalities in the diagnosis of necrotizing infections, MRI is the preferred technique to detect soft tissue infection because of its unsurpassed soft tissue contrast and sensitivity in detecting soft tissue fluid, its spatial resolution, and its multiplanar capabilities.[29, 30]

The usefulness of MRI in the diagnosis of necrotizing fasciitis has been supported in a study by Rahmouni et al, who were able to differentiate nonnecrotizing cellulitis that would respond to medical treatment from severe necrotizing infections that required rapid life-saving surgery.[74] In necrotizing fasciitis, MRI can provide dramatic evidence of an inflammatory process infiltrating the fascial planes.[61]

Craig notes that the combined use of MRI and aspiration under ultrasonographic guidance is very useful in complicated infections (eg, septic arthritis and osteomyelitis) and that its role in the diagnosis of necrotizing fasciitis should be considered.[75] Early muscle necrosis may be apparent.

Absence of gadolinium contrast enhancement in T1 images reliably detects fascial necrosis in those requiring operative debridement. Combined with clinical assessment, MRI can determine the presence of necrosis and the need for surgical debridement. T2-weighted MRI may show well-defined regions of high signal intensity in the deep tissues. However, the sensitivity of MRI exceeds its specificity.[76]

The finger test should be used in the diagnosis of patients who present with necrotizing fasciitis.[31, 32] The area of suspected involvement is first infiltrated with local anesthesia. A 2-cm incision is made in the skin down to the deep fascia. Lack of bleeding is a sign of necrotizing fasciitis. On some occasions, a dishwater-colored fluid is noticed seeping from the wound.

A gentle, probing maneuver with the index finger covered by a sterile powder-free surgical double glove puncture indication system is then performed at the level of the deep fascia. If the tissues dissect with minimal resistance, the finger test is positive.

Tissue biopsies are then sent for frozen section analysis. The characteristic histologic findings are obliterative vasculitis of the subcutaneous vessels, acute inflammation, and subcutaneous tissue necrosis. If either the finger test or rapid frozen section analysis is positive, or if the patient has progressive clinical findings consistent with necrotizing fascia, immediate operative treatment must be initiated.

Excisional deep skin biopsy

Excisional deep skin biopsy may be helpful in diagnosing and identifying the causative organisms.[77] Specimens can be taken from the spreading periphery of the necrotizing infection or the deeper tissues, reached only in surgical debridement, to obtain proper cultures for microorganisms.

Avoid doing this procedure from the actual necrosis or granulating center, as many bacteria that neither cause nor add to the infection would be detected.

Uman et al recommended percutaneous needle aspiration followed by prompt Gram staining and culture for a rapid bacteriologic diagnosis in soft-tissue infections.[78] A needle aspirate should be taken on the advancing edge of the infection, where group A beta-hemolytic Streptococcus (GABS) is plentiful.[79]

The Gram stain usually shows a polymicrobial flora with aerobic gram-negative rods and positive cocci when polymicrobial infection is present. However, in many cases, a single organism (eg, GABS, methicillin-resistant Staphylococcus aureus [MRSA], Clostridium) may be causing the infection, while cultures, including blood cultures, may spuriously reveal a polymicrobial infection. The presence of plentiful cocci on the Gram stain is characteristic of necrotizing infection, whereas cocci are rarely identified in erysipelas.[79]

Polymicrobial infections are often associated with previous surgical procedures, pressure ulcers, penetrating trauma, perianal abscesses, and intravenous drug use. In the study by Andreasen et al, 71% of their patients had polymicrobial infections.[37]

Sections from necrotizing fasciitis tissue show superficial fascial necrosis with blood vessels occluded by thrombi. A dense infiltration of neutrophils may be observed in deeper parts of the subcutaneous tissue and fascia. Subcutaneous fat necrosis and vasculitis are also evident. Eccrine glands and ducts may be necrotic. Alcian blue or periodic acid-Schiff staining with diastase may show clusters of bacteria and fungi (see the image below).

Photomicrograph of Fournier gangrene (necrotizing fasciitis), oil immersion at 1000X magnification. Note the acute inflammatory cells in the necrotic tissue. Bacteria are located in the haziness of their cytoplasm. Courtesy of Billie Fife, MD, and Thomas A. Santora, MD.

Once the diagnosis of necrotizing fasciitis is confirmed, initiate treatment without delay.[27, 80] Because of the complexity of this disease, a team approach is best (see Consultations). Hemodynamic parameters should be closely monitored, and aggressive resuscitation initiated immediately if needed to maintain hemodynamic stability.

Because necrotizing fasciitis is a surgical emergency, the patient should be admitted immediately to a surgical intensive care unit in a setting such as a regional burn center or trauma center, where the surgical staff is skilled in performing extensive debridement and reconstructive surgery. Such regional burn centers are ideal for the care of these patients because they also have hyperbaric oxygen facilities.

A regimen of surgical debridement is continued until tissue necrosis ceases and the growth of fresh viable tissue is observed. If a limb or organ is involved, amputation may be necessary because of irreversible necrosis and gangrene or because of overwhelming toxicity, which occasionally occurs. Prompt surgery ensures a higher likelihood of survival.

Antibiotic therapy is a key consideration. Possible regimens include a combination of penicillin G and an aminoglycoside (if renal function permits), as well as clindamycin (to cover streptococci, staphylococci, gram-negative bacilli, and anaerobes).

While the literature appears to support the use of hyperbaric oxygen as an adjunctive treatment measure in patients with necrotizing fasciitis, transfer to a hospital equipped with a hyperbaric oxygen chamber should not delay emergency surgical intervention.

In a study of six patients with necrotizing fasciitis, Crew et al found that flow-through instillation with saline containing pure 0.01% hypochlorous acid (with no sodium hypochlorite impurity) may weaken bacterial toxins and the toxins released from damaged cells, as well as mitigate the immune dysfunction they cause.[81]

The following related guidelines have been published:

• Society of Critical Care Medicine -Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008

• Infectious Diseases Society of America -Practice guidelines for the diagnosis and management of skin and soft-tissue infections

Surgery is the primary treatment for necrotizing fasciitis. .Surgeons must be consulted early in the care of these patients, as early and aggressive surgical debridement of necrotic tissue can be life-saving.[17, 71, 82, 83, 84, 80] In addition, early surgical treatment may minimize tissue loss, eliminating the need for amputation of the infected extremity.[85, 86]

The authors recommend wide, extensive debridement of all tissues that can be easily elevated off the fascia with gentle pressure. Wide debridement of all necrotic and poorly perfused tissues is associated with more rapid clinical improvement.

Controversy exists regarding how much tissue should be initially excised because the skin may often appear normal. Andreasen et al examined the normal-appearing tissues microscopically and reported that the tissues had extensive early vascular thrombosis as well as vasculitis.[37] Their findings indicate that these tissues, though they have a normal appearance, have a high potential for full-thickness loss.

After the initial debridement, the wound must be carefully examined. Hemodynamic instability is usually present after surgery, and it may cause progressive skin necrosis. After debridement, the patient may return as often as necessary for further surgical debridement. The anesthesiologist is an important member of the operative team because continued resuscitative efforts are undertaken during the operative procedure.

The surgical regimen can be summarized as follows:

• Surgical incisions should be deep and extend beyond the areas of necrosis until viable tissue is reached

• The entire necrotic area should be excised

• The wound should be well irrigated

• Hemostasis should be maintained, and the wound should be kept open

• Surgical debridement and evaluations should be repeated almost on a daily basis

• The wound should be inspected in the operating room

Double gloving

During surgery, all operating room personnel should wear a powder-free double-glove hole indication system (ie, including an underglove with distinct color that becomes apparent when the outer glove is punctured in the presence of fluid). This protects the staff as well as the patient from exposure to potentially deadly blood-borne viral infections.[87]

The US Food and Drug Administration (FDA) only requires that the leakage rate of sterile surgical gloves does not exceed 1.5%. This high frequency of glove holes is an invitation to the spread of deadly blood-borne infections between operating room personnel and the patient.

Cornstarch in wounds has been well documented to potentiate the development of infection. Using powder-free gloves reduces this potentially serious complication. In addition, the cornstarch on latex gloves can carry the latex antigen and precipitate anaphylactic reactions in individuals who are allergic to latex.[88]

Dressings

Following each debridement of the necrotic tissue, daily antibiotic dressings are recommended.[89] Silver sulfadiazine (Silvadene) remains the most popular antimicrobial cream. This agent has broad-spectrum antibacterial activity and is associated with relatively few complications in these wounds.

The current formulation of silver sulfadiazine contains a lipid-soluble carrier, polypropylene glycol, which has certain disadvantages, including pseudoeschar formation. When this antibacterial agent is formulated with poloxamer 188, the silver sulfadiazine can be washed easily from the wound because of its water solubility, making dressing changes considerably more comfortable.

If the patient is allergic to sulfa, alternative agents include Polysporin, Bacitracin, and Bactroban. While these agents are relatively inexpensive, they may induce allergies.

Mafenide is an alternate agent that penetrates eschar more effectively than silver sulfadiazine. Consequently, it is frequently used on infected wounds that do not respond to silver sulfadiazine. Use mafenide with caution because it can induce metabolic acidosis.

The Acticoat brand of barrier dressings provides the beneficial antimicrobial properties of the silver ion by coating the dressing material with a thin, soluble silver film. This dressing appears to maintain antibacterial levels of silver ions in the wound for up to 5 days. Because Acticoat can remain on the wound for up to 5 days, the patient is spared the pain and expense associated with the dressing changes. Additional studies are now under way to determine the ultimate benefit of this product.

Soft-tissue reconstruction

Once all of the affected tissues have been debrided, soft tissue reconstruction can be considered. In the authors’ experience, this may take at least 2 debridements. When the debridement involves relatively small (< 25%) body surface areas, skin grafts and flaps can provide coverage. When donor-site availability is limited, alternatives to standard skin graft construction must be considered, including Integra artificial skin (Integra Life Sciences, Plainsboro, NJ) and AlloDerm (LifeCell Corporation, Blanchburg, NJ).[90, 91]

Empiric antibiotics should be started immediately. Initial antimicrobial therapy should be broad-based, to cover aerobic gram-positive and gram-negative organisms and anaerobes. A foul smell in the lesion strongly suggests the presence of anaerobic organisms. The maximum doses of the antibiotics should be used, with consideration of the patient's weight and liver and renal status.

Antibiotic therapy is a key consideration. Possible regimens include a combination of penicillin G and an aminoglycoside (if renal function permits), as well as clindamycin (to cover streptococci, staphylococci, gram-negative bacilli, and anaerobes).

A more specifically targeted antibiotic regimen may be begun after the results of initial gram-stained smear, culture, and sensitivities are available.

Although some necrotizing infections may still be susceptible to penicillin, clindamycin is the treatment of choice for necrotizing infections, for the following reasons[70] :

• Unlike penicillin, the efficacy of clindamycin is not affected by the inoculum size or stage of bacterial growth[92, 93]

• Clindamycin is a potent suppressor of bacterial toxin synthesis[94, 95]

• Subinhibitory concentrations of clindamycin facilitate the phagocytosis of GABS[61]

• Clindamycin reduces the synthesis of penicillin-binding protein, which, in addition to being a target for penicillin, is also an enzyme involved in cell wall synthesis and degradation[93]

• Clindamycin has a longer postantibiotic effect than β-lactins such as penicillin[95]

• Clindamycin suppresses lipopolysaccharide-induced mononuclear synthesis of tumor necrosis factor-α (TNF-α)[96]

Consequently, the success of clindamycin also may be related to its ability to modulate the immune response.[97]

Broad-spectrum beta-lactam drugs such as imipenem cover aerobes, including Pseudomonas species. Ampicillin sulbactam also has broad-spectrum coverage, but it does not cover Pseudomonas species; however, necrotizing fasciitis caused by Pseudomonas aeruginosa is unusual.[98]

If staphylococci or gram-negative rods are involved, vancomycin and other antibiotics to treat gram-negative organisms other than aminoglycosides may be required. The use of vancomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) may depend on the clinical situation. For example, use may depend on whether a nasocranial infection is present, or it may need to be avoided in patients who are likely to be carriers of MRSA (eg, those with diabetes, those who use illicit drugs, those undergoing hemodialysis).

For more information on antimicrobial therapy, see the Medscape Reference articles Necrotizing Fasciitis Empiric Therapy and Necrotizing Fasciitis Organism-Specific Therapy

Because of persistent hypotension and diffuse capillary leak, massive amounts of intravenous fluids may be necessary after the patient is admitted to the hospital. Nutritional support is also an integral part of treatment for patients with necrotizing fasciitis. This supplementation should be initiated as soon as hemodynamic stability is achieved. Enteral feeding should be established as soon as possible to offset the catabolism associated with large open wounds.

Successful use of intravenous immunoglobulin (IVIG) has been reported in the treatment of streptococcal toxic shock syndrome (STSS).[99, 100] In a multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of high-dose polyspecific IVIG as adjunctive therapy in 21 patients with soft-tissue STSS, mortality at 28 days was 3.6-fold higher in the placebo group.[101]

Norrby-Teglund et al successfully used high-dose polyspecific IVIG, along with antimicrobials and a conservative surgical approach, in 7 patients with severe group A streptococcal soft tissue infections.[102] However, Sarani et al indicate that this therapy has not been approved by the FDA for the treatment of necrotizing fasciitis.[103]

Once other modalities, including surgical debridement and antibiotic administration, have been used, hyperbaric oxygen therapy (HBOT) may be considered, if available.[104, 56, 105] The literature suggests that HBOT can reduce mortality when used as part of an aggressive treatment regimen for necrotizing fasciitis.[106, 61, 107, 70, 108]

A retrospective, single-center study by Mladenov et al, for example, found that the survival rate for patients with necrotizing fasciitis who underwent HBOT was higher than that for individuals who, despite having clinical indications for HBOT, were ineligible for the treatment owing to contraindications (73.5% vs 36.4%, respectively). The survival rate of the patients who received HBOT was comparable to that of persons with necrotizing fasciitis who did not require the therapy (75.5%).[109]

Well-controlled, randomized, clinical trials demonstrating a statistically significant benefit of HBOT are lacking, however, and consequently its use as an adjunctive therapy for necrotizing fasciitis remains controversial.[110, 111, 112] Transfer to a hospital equipped with HBOT should not delay emergency surgical intervention.

A team approach is the best method of treating this complicated disorder. Team members should include the following:

• Surgeon

• Infectious disease specialist

• Pathologist

• Microbiologist

Depending on the infection site, the team may also include a urologist; a specialist in plastic surgery; or an ear, nose, and throat surgeon in cases of infections of the cervical area.[113]

The specialists and subspecialists involved should discuss the patient's condition and determine a comprehensive plan of treatment.

Antibiotic therapy is a key consideration. Possible regimens include a combination of penicillin G and an aminoglycoside (if renal function permits), as well as clindamycin (to cover streptococci, staphylococci, gram-negative bacilli, and anaerobes).

Class Summary

Therapy must cover all likely pathogens in the context of the clinical setting.

Penicillin G (Pfizerpen)

Penicillin G interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Clindamycin (Cleocin)

Clindamycin is a lincosamide for treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). This agent inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer RNA (t-RNA) from ribosomes causing RNA-dependent protein synthesis to arrest. It is used as an alternative to penicillin G.

Metronidazole (Flagyl)

Metronidazole is an imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa. It is used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Metronidazole appears to be absorbed into cells of microorganisms containing nitroreductase. Unstable intermediate compounds that bind DNA and inhibit synthesis are formed, causing cell death.

Ceftriaxone (Rocephin)

Ceftriaxone is the drug of choice in initial treatment. It is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin-binding proteins.

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with both an agent against gram-positive organisms and one that covers anaerobes. It is not the drug of choice, but should be considered if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Adjust the dose based on creatinine clearance (CrCl) and changes in volume of distribution. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing). Peak level may be drawn 0.5 h after a 30-min infusion.

Chloramphenicol

Chloramphenicol binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.

Ampicillin

Ampicillin has bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to take medication orally. It may be added to the initial regimen if the Gram stain suggests that enterococci are present.

Imipenem and cilastatin (Primaxin)

This combination is used for treatment of infections due to multiple organisms in which other agents do not have wide-spectrum coverage or are contraindicated because of potential for toxicity.

Ampicillin and sulbactam (Unasyn)

This combination of ampicillin and a beta-lactamase inhibitor covers skin, enteric flora, and anaerobes. It is not ideal for treatment of nosocomial pathogens.

Vancomycin (Vancocin)

Vancomycin is an antibiotic directed against gram-positive organisms and active against Enterococcus species. It is useful in the treatment of septicemia and skin-structure infections. Vancomycin is indicated for patients who cannot take or whose conditions fail to respond to penicillins and cephalosporins or those with infections with resistant staphylococci.

To prevent toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, with samples obtained 0.5 h prior to the next dose. Use the CrCl to adjust the dose in patients with renal impairment.