NORD gratefully acknowledges Babak Sarani, MD, FACS, FCCM. Associate Professor of Surgery; Director, Trauma and Acute Care Surgery, George Washington University, for assistance in the preparation of this report.
Early symptoms of NF are often mistaken for the flu. They include high fever, sore throat, stomach ache, nausea, diarrhea, chills, and general body aches. Around the same time, patients may notice redness (erythema) and pain or tenderness around the red area. The red area often occurs at the infection point, which may include surgical sites, a cut, scratch, bruise, boil, site of medication or drug injection, or any small injury that could have occurred during daily life. The affected area may also spread from the infection point quickly, sometimes spreading at a rate of an inch an hour.
If NF progresses to show advanced symptoms, the patient will continue to have a very high fever (over 104 degrees Fahrenheit) or may become hypothermic (low temperature) and become dehydrated. The pain in the infected area becomes constant and piercing, much more severe than the original injury would dictate. The infected area may appear bright red, shiny, swollen, and very hot to the touch. As the infection progresses, the affected area will continue to swell, become purple or mottled (blotches of black, purple, and red), and may be accompanied by a rash of blisters and this is a sign of skin necrosis. The affected area may become hard due to the swelling/inflammation caused by the infection (induration). Although the pain becomes excruciating over the initial 12-48 hours, a very late sign of infection is sudden improvement in pain or lack of sensation in the affected area. This may occur as the nerves to the area begin to die. The patient may have extremely low blood pressure (hypotension) and a faint, rapid heartbeat (tachycardia), which results in dizziness, weakness, and confusion.
If NF progresses to show critical symptoms, the patient’s confusion and weakness will become pronounced and the patient may become delirious. S/he may repeatedly lose consciousness and the infected area will swell to several times the normal size. On occasion, the swollen area may split open and release large amounts of thin, cloudy drainage fluid. Large blisters (bullae) filled with a bloody or yellowish fluid and blackened necrotic lesions appear, causing the skin to break open. The pain, slowly subsides as nerves are destroyed, causing a lack of sensation (anesthesia). Urine output ceases (anuria), blood pressure drops severely, heart rate continues to be rapid and shallow, and breathing becomes rapid (tachypnea). Eventually, the patient’s vital organs (kidneys, liver, lungs, etc) shut down due to toxic shock. The skin and other tissues continue to blacken as they die and may shed from the body. Death is imminent.
NF is caused by a bacterium (monomicrobial NF) or several bacteria (polymicrobial NF) infecting the tissue just beneath the skin (subcutaneous tissue). The bacteria or bacterium enter into the body either via an external injury (surgical sites, a cut, scratch, bruise, boil, or any small injury) or via direct spread from a punctured / perforated internal organ (particularly the colon, rectum, or anus) or sexual organ. Upon infection, the bacteria or bacterium spreads via the fascia, producing endo-toxins (toxins released as the bacteria die and break apart or are lysed) and exo-toxins (toxins released by bacteria as waste) that restricts blood supply to tissue (tissue ischemia), digestion of cells by enzymes resulting in a lesion consisting of pus and the fluid remains of dead tissue, and often systemic illness (disease of any major organ system or any condition that ultimately affects the whole body). Because blood supply to these tissues becomes impaired, neither antibiotics nor the body’s own mechanisms to fight infection are able to reach these tissues. As such, treatment requires surgical debridement (surgical removal of dead and infected tissue).
Given the prevalence of all the bacteria that cause NF, it is important to ensure external wounds are kept clean to minimize infection. This can be done using alcohol, hydrogen peroxide, or by simply using soap and water.
The rest of this section highlights the different bacteria known to cause NF.
Group A Streptococci (Streptococcus pyogenes)
Group A Strep bacteria are among the most common causes of NF. These Gram-positive bacteria are commonly carried by humans in our noses, throats, and skin without showing any symptoms. There are over 100 types (serotypes) of Group A strep. Strep is the bacteria that causes strep throat. However, when it penetrates into the body, it can cause necrotizing fasciitis. When Group A Strep causes NF, it can occur together with Streptococcal Toxic Shock Syndrome (STSS), which accelerates the speed and deadliness of the infection.
Staphylococcus Aureus bacteria are becoming a more common cause of NF. Similar to Strep, these Gram-positive bacteria are commonly carried by humans on our skin or noses without showing any symptoms. Staph bacteria can cause boils and food poisoning. Methicillin-Resistant Staphylococcus Aureus (MRSA) is a strain of these bacteria that is a major source of hospital-acquired infections. Its resistance to antibiotics presents a concern during treatment, but second-line antibiotics are available to treat MRSA.
Klebsiella are Gram-negative bacteria commonly found in nature. They are known to cause pneumonia, urinary tract infections, as well as NF.
Escherichia coli are Gram-negative bacteria often found in the large intestine. Most are harmless, but have been known to cause food poisoning. Most strains are helpful for humans when confined to our large intestine (colon), as they provide vitamin K and prevent harmful bacteria from establishing in the intestines. However, E. Coli outside of the intestine can cause infection, including NF.
Bacteroides are anaerobic (can survive without oxygen) Gram-negative bacteria that are normally found in the mouth, intestines, and genitals. These bacteria are usually benefit humans by preventing serious pathogens from colonizing the gut. However, when bacteroides infect the fascia (e.g., via a perforated bowel), NF can result.
Clostridium are anaerobic Gram-positive bacteria that are commonly found in soil, as well as the intestines of humans and animals. Clostridium botulinum is a bacteria that causes botulism, but there are many other types of Clostridium, including Clostridium perfringens,
Clostridium histolylicum, Clostridium septicum, and Clostridium sordellii. These bacteria are not as common causes of NF, but have been known to cause NF and gas gangrene.
Pseudomonas are Gram-negative bacteria that are widespread in nature. They cause many infections, including skin infections and pneumonia. NF infections caused by Pseudomonas usually occur in patients with compromised immune systems.
Prevotella are Gram-negative bacteria that exist throughout the body, usually without causing symptoms. NF infections caused by Prevotella often occur together with other bacteria and usually target the mouth, jaw, neck, and face.
Conditions and behaviors that increase the prevalence of poly-microbial NF include obesity, chronic kidney failure, HIV, alcohol abuse, abscess, IV drug use, blunt or penetrating trauma, insect bites, surgical incisions, indwelling catheters, chicken pox, vesicles, and (rarely) perforation of the gastrointestinal tract (Sarani et al). However, everybody is susceptible to NF.
Diagnosing NF early and quickly is vital to improving survival. However, studies have shown that since it is so rare (on average, doctors see 2 cases of NF during their lifetime), misdiagnosis is common. As such, patients and doctors should have a high index of suspicion and ask to eliminate NF as a diagnosis as soon as possible.
Once at the hospital, patients will have laboratory testing performed. Often, patients will have white blood cell counts greater than 15,400 cells/mm3 or a sodium level lower than 135 mmol/L. While doctors and scientists have tried to develop Laboratory Risk Indicators for Necrotizing Fasciitis, they have yet to be validated in large scale studies. Patients may also be undergoing Toxic Shock Syndrome. If this is the case, immediate treatment is necessary to stabilize the patient.
Apart from clinical diagnosis based on presenting symptoms (i.e., doctor’s initial opinion based on his/her experience and observations), doctors have two options to help diagnose NF. The first is radiographic testing (e.g., X-Ray, CT scans, and MRIs). X-Rays tend to be a poor choice of diagnostic testing as it only shows air trapped under the skin (subcutaneous emphysema), which is only present in a small proportion of NF patients. CT scans are readily available and do a good job of helping doctors diagnose NF because it can show inflammatory changes, such as accumulation of fluid (edema), thickening, or collection of pus (abscesses) in the fascia, in addition to gas formation. MRIs are less available and often difficult to administer to patients in critical or unstable condition, often leading to a delay in diagnosis. However, they also effectively help doctors diagnose NF by showing soft-tissue or fascial thickening.
The second option is the gold standard in diagnosing NF i.e. exploratory surgery where it is common to find “dishwater” or foul-smelling discharge, necrosis or lack of bleeding, and loss of the normal resistance of the fascia to finger dissection. Intra-operative biopsy with Gram stain can be used in some cases but not necessary as findings from the exploratory surgery are often definitive.
Upon diagnosing NF, doctors will often perform tissue cultures on the infected tissue to determine the bacteria that is causing the infection. However, beginning NF treatment before the results of the cultures are available (often ~3 days after culture) is essential.
Upon arriving at the hospital, it is important for doctors to assess the situation and determine which treatments to begin first to best suit the patient. Patients may present with Toxic Shock Syndrome, which will require additional treatments including fluid management via IVs or use of vasopressors (to regulate blood pressure). Discussing treatments for additional complications (like TSS) from NF is beyond the scope of this document. This section will focus on describing therapies to treat NF specifically: surgical debridement, antibiotic therapy, hyperbaric oxygen therapy, and IV immune globulin (IVIg) therapy.
Surgical debridement is the cornerstone of treatment for NF. It is the removal of dead, damaged, or infected tissue to allow the remaining healthy tissue to heal more effectively. Many studies have shown that the timing and adequacy of the initial debridement has the biggest impact on mortality. Multiple debridements are often needed as the infection is rarely eliminated after a single surgery. On average, three debridements spaced 12 to 36 hours apart are needed to control the infection. Often, entire muscle groups are infected and must be removed by the surgeon. The surgeon must remove all tissues and structures that are dead or infected to control the infection and prevent spread of the infection to vital organs (usually in the torso), sometimes resulting in removal of significant amounts of tissue or even limbs.
After surgery, the wounds should be left open and treated with wet-to-dry dressings (or “packing”). There is little evidence that using enzymatic debriding agents or caustic solutions, such as dilute sodium hypochlorite (bleach), iodine solutions (eg, Betadine), or antibiotic solutions have any use in post-surgery care. Vacuum-assisted closure devices maybe useful in treating large wounds once infection is controlled, but there have not been significant studies in NF patients showing improvement in wound management or healing from use of these devices. Upon confirmation that no more surgeries are required, skin grafts and/or plastic surgery may be required to fully close the wounds.
Since antibiotics cannot penetrate into the necrotic infected tissue, surgical debridement is the first priority of treatment. However, antibiotic therapy is essential in helping to control sepsis and prevent the further spread of the infection. The recommended course of treatment is the use of vancomycin, linezolid, or daptomycin to treat MRSA and gram-positive bacteria, an agent to treat anaerobic bacteria (e.g., clindamycin), and an agent to treat gram-negative bacteria. Alternatively, anaerobic and gram-negative bacteria can be treated with one drug that covers both.
While there is increasing resistance to clindamycin, it should still be used as it inhibits production of bacterial endo- and exo-toxins. Quinolones, as well as piperacillin / tazobactam, imipenem, or meropenem are often used to cover gram-negative organisms also.
Although there have been no studies to determine the appropriate length of antibiotic therapy, current best practices continue antibiotic treatment until no additional surgical debridement is needed and the patient is no longer showing signs of systemic inflammation.
Common combinations of antibiotic therapies include:
1. Vancomycin, Clindamycin, and Piperacillin/ tazobactam
2. Linezolid and Piperacillin/tazobactam
Vancomycin may be replaced with daptomycin. Piperacillin/tazobactam may be replaced with imipenem or meropenem. Clindamycin is recommended because of its ability to inhibit toxin production in Streptococcal (gram positive) infections.
Hyperbaric Oxygen (HBO) Therapy
Use of HBO is controversial to treat NF and has not been proven using adequate large-scale clinical studies in humans. Use of HBO therapy for NF is based on animal and human studies showing that hyperbaric conditions inhibit infection and exo-toxin production by clostridia. Animal studies have shown mortality reductions with HBO in clostridial NF. While HBO may be an effective treatment for NF in conjunction with antibiotics and surgical debridement, it should be used with careful consideration of the risk-benefit proposition for the patient. Some considerations include the fact that Clostridial NF is not common, and use of HBO means moving a patient out of intensive care where emergency intervention can be provided safely and quickly (this is not the case during HBO therapy).
IV immune globulin (IVIg) therapy
Immune globulins are antibodies (proteins) that are found in blood or other bodily fluids of animals. They are used by the immune system to fight foreign objects like bacteria and viruses. IVIg therapy is not an FDA-approved therapy for NF and its use and effectiveness are controversial. Use of IVIg therapy is based on the theory that IVIg can bind to exo-toxins released by staphylococci and streptococci, limiting damage by these toxins. This has been confirmed in some small clinical trials, but these trials have not been extensively done in large populations. If used, IV immune globulin should be restricted to critically ill patients with either staphylococcal or streptococcal NF whose exo-toxins IVIg therapy may control.
Currently, clinical trials for off-patent antibiotics for uncomplicated skin and soft-tissue infections (SSTIs) are being planned with support of the National Institutes of Health. Future research efforts are needed to monitor ongoing changes in microbiologic cause and to enhance imaging and diagnostic techniques to improve the ability to detect and treat this disease in its earliest stages. There is currently a lack of well-designed trials comparing various imaging and diagnostic procedures for NF. In addition, clinical studies are needed to determine which current or future treatments can positively impact outcomes.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about necrotizing fasciitis:
Babak Sarani, MD, FACS, FCCM
Associate Professor of Surgery
Director, Trauma and Acute Care Surgery
George Washington University
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Krieg A, Röhrborn A, Schulte AEJ, et al. Necrotizing fasciitis: microbiological characteristics and predictors of postoperative outcome. Eur J Med Res. 2009;14(1):30-6.
Sarani B, Strong M, Pascual J, Schwab CW. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208(2):279-88.
Abrahamian FM, Talan DA, Moran GJ. Management of Skin and Soft-Tissue Infections in the Emergency Department. Infect Dis Clin North Am. 2008;22(1):89-116.
American Federation for Medical Research. AFMR: 2009 Southern Regional Meeting. Escherichia Coli Necrotizing Fasciitis in a Transplant Patient. http://www.afmr.org/abstracts/2009/SR2009_abstracts/37.cgi Accessed May 14, 2015.
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