The incidence of NSTIs in the United States has been estimated from large administrative databases and has been noted to have increased since the 1980s [3, 4]. Whether the increase represents a true rise in the number of infections or simply better identification and reporting of NSTIs is unclear. An analysis of medical claims data from 1997 to 2002 reported the incidence rate of NSTIs, or the probability of developing the disease over a specific period of time, as 0.04 per 1,000 person-years [5]. A review of more than 28 million patients in the Nationwide Inpatient Sample (NIS) database in the years 2001 and 2004 identified a total of 10,940 or 0.04% of hospitalized patients as having an NSTI [6]. Although rare, it is estimated that clinicians, whether surgeons or primary care physicians or specialists, will encounter at least one NSTI patient in their lifetime [7].

There are several methods for describing NSTIs, although there is no standard classification system. NSTIs can be described by their depth of invasion (Fig. 37.1); necrotizing fasciitis is characterized by pathological findings at the level of the subcutaneous fat (i.e., thrombosed vessels) and deep fascia (i.e., necrosis). NSTIs can also be classified by their anatomic location (i.e., Fournier’s gangrene for NSTIs of the perineum). Another method for describing NSTIs is based on their microbiology: Type I, II, or III. Type I NSTIs are the most common type, accounting for 55–75% of infections. They are polymicrobial and include organisms such as gram-positive cocci (i.e., Staphylococcus aureus), gram-negative bacilli (i.e., Escherichia coli), and anaerobes (i.e., Clostridium and Bacteroides species). They have been associated with multiple predisposing factors including surgical procedures, diabetes, and peripheral vascular disease. Type II NSTIs are caused by Group A beta hemolytic Streptococci with or without S. aureus. These infections are less common than Type I infections and can occur in young, healthy individuals. Type III NSTIs have been attributed to Vibrio species by some authors and to Clostridium species by other authors [8].

An alternative classification system was proposed by Bakleh et al. based on histopathologic findings [9]. They proposed three stages based on combinations of inflammatory response and gram-stain results. Grades of the inflammatory response were characterized by the degree of neutrophilic infiltration and presence of necrosis or microabscesses. The histopathologic stages correlated with mortality, although only unadjusted analyses were performed due to small sample size.

Although there are multiple risk factors for NSTIs that include medical comorbidities and other factors, NSTIs often develop in young, healthy hosts. Comorbidities include diabetes mellitus, peripheral vascular disease, obesity, chronic renal failure, cirrhosis, heart disease, acquired immunodeficiency syndrome (AIDS), and immunosuppression. Injection drug use and alcoholism are associated with NSTIs as well. Infections may develop as a result of insect bites, abscesses, recent trauma, or surgery [3, 10].

As previously described, NSTIs may be polymicrobial or monomicrobial depending upon the patient’s comorbidities, risk factors, and clinical setting. One study of patients from the late 1980s and early 1990s found an average of 4.4 organisms per infection [11]. Cultures may identify gram-positive and gram-negative bacteria, aerobic and anaerobic bacteria, and fungi. Historically, monomicrobial NSTIs were attributed to Group A Streptococcus (GAS), Clostridium species, and Vibrio species, but as described as follows, any number of microorganisms may cause monomicrobial NSTIs.

The two most common gram-positive cocci isolated from patients with NSTIs are Staphylococci and Streptococci [1, 11]. S. aureus is the most common pathogen present in serious soft tissue infections in North America, Latin America, and Europe [12]. Over time, its virulence and resistance has changed; there has been a concomitant decrease in infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and an increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) [13]. Furthermore, there has been an increase in the prevalence of community acquired MRSA (CA-MRSA), which was first described in the 1990s [14]. Initially CA-MRSA infections were primarily present only in specific sub-populations such as prisoners or sports participants, but now CA-MRSA is on its way to becoming the predominant strain of MRSA in hospitals [15]. Similarly, CA-MRSA was not previously common in patients with NSTIs [16]. In 2005, Miller et al. described 14 patients with NSTIs and positive cultures for CA-MRSA, 12 of who had monomicrobial infections [16]. These patients had risk factors that included medical comorbidities such as diabetes and hepatitis, history of injection drug use, homelessness, and prior MRSA infection. All of the infections were due to the USA300 clone and had similar genotypes including the presence of the Panton–Valentine leukocidin (pvl) gene, which encodes an exotoxin that causes leukocyte destruction. Several series of patients have reported high rates of MRSA NSTIs, although genotyping was not performed in all of the series [17–20]. In one case series, MRSA was the most frequent cause of monomicrobial NSTIs [18]. There is a suggestion that mortality may not be as high in patients with CA-MRSA, but because of its increasing prevalence, empiric coverage should be started in patients with suspected NSTIs [16–20].

Streptococcus pyogenes is a type of Group A beta-hemolytic Streptococcus (GAS) that can cause a spectrum of diseases from bacterial pharyngitis to necrotizing fasciitis and myositis to toxic shock syndrome. In a European population-based study, the crude rate of S. pyogenes infection was 2.79 per 100,000 population [21]. Eight percent (308 patients) of all of the cases were diagnosed with necrotizing fasciitis, of which 50% were associated with toxic shock syndrome (TSS). Streptococcal TSS has been reported to be an independent predictor of mortality [22]. Risk factors for GAS infections include comorbidities such as liver disease or underlying malignancy and behaviors such as injection drug use, but these infections can also occur in healthy immunocompetent patients as well [23]. GAS NSTIs have a predisposition for the lower extremities and tend to spread rapidly. These organisms have a number of factors that contribute to their virulence including M protein, which facilitates attachment to the host cells and prevents bacterial phagocytosis, enzymes that facilitate the spread of infection and that prevent the migration of neutrophils to the site of infection, and superantigens that stimulate a pro-inflammatory response [8].

Gram-negative rods have been associated with NSTIs including Klebsiella species, Enterobacter species, Pseudomonas and Aeromonas, Vibrio species, Acinetobacter species, Eikenella corrodens, and Citrobacter frundii [1, 11]. Liver disease is a risk factor for NSTIs due to gram-negative rods, particularly Vibrio, Klebsiella, and Aeromonas [24]. Furthermore, these gram-negative rod NSTIs appear to have a higher prevalence in Asian countries [24]. Vibrio infections occur in immunocompromised hosts such as those with cirrhosis, diabetes mellitus, adrenal insufficiency, and chronic renal insufficiency; they are associated with contact with seawater or ingestion of raw seafood [24–28]. These infections may have an atypical presentation; increased level of suspicion should occur in these patients, particularly when hemorrhagic bullae are present given an increased associated mortality [25, 26]. Klebsiella NSTIs are more common in Asia, but has been reported to have been acquired nosocomially in a patient with underlying malignancy in the Western hemisphere [29].

Clostridum is a genus of gram-positive bacteria that are obligate anaerobes. Multiple species including Clostridium perfringens have been identified in NSTIs [1]. Clostridial infections may cluster in areas with heavy injection drug use. For example, King County, Washington, has a high prevalence of drug users who inject heroin. In a review of 10 years’ of autopsies of patients who died due to NSTIs, clostridial infections were identified as being significantly associated with injection drug use of black tar heroin [30, 31]. Different species were noted including Clostridium sordellii. A retrospective review of patients treated in Seattle, Washington, similarly identified an association between clostridial infections and injection drug use. Furthermore, clostridial infections were significantly associated with an increase in mortality and limb loss [30]. NSTIs caused by Clostridium septicum are often associated with an underlying colonic malignancy [32, 33].

Fungi (i.e., Candida species) may also be found in both polymicrobial and monomicrobial NSTIs. There have been case reports of monomicrobial NSTIs due to Aspergillus [34, 35]. Zygomycotic NSTIs from Apophysomyces have been reported in trauma patients and in immunocompetent hosts [36–38]. Cryptococcocal NSTIs have also been reported, largely in immunocompromised patients [39, 40].

Spread of pathogens that cause NSTIs occurs through the production of a variety of endotoxins and exotoxins, many of which have already been mentioned. Toxins may cause tissue destruction, ischemia, and necrosis; endothelial damage, which results in increased tissue edema and impaired capillary blood flow; increased escape from host defenses such as phagocytosis and neutrophil infiltration at the site of infection; and activation of the coagulation cascade, which may cause vascular thrombosis and worsened tissue ischemia [3].