Necrotizing Soft Tissue Infections

Richard L. Gamelli

Joseph A. Posluszny Jr

Necrotizing soft tissue infections (NSTIs) include a spectrum of diseases ranging from necrotizing fasciitis to gas gangrene and Fournier’s gangrene. These infections occur within the soft tissue compartment from the dermis to the fascia and deep to the muscle layer, are associated with necrotizing changes, progress rapidly and can occur at any location in the body. Although many terms have been used to describe these infections, NSTI encompasses all necrotizing infections of the soft tissue compartment as they share common clinical, pathophysiologic, microbial, treatment, and outcome characteristics [1].

Most of the clinical information for NSTIs stems from large retrospective reviews [2,3,4,5,6]. Few prospective studies have
been performed given the high morbidity and mortality associated with these infections. However, these retrospective reviews have been surprisingly similar, each confirming previous data on risk factors, inciting events, microbiology, diagnosis, prognosis, and management while providing unique findings about their populations, NSTI, and its management.

Epidemiology and Risk Factors

Surveillance of NSTIs in the United States no longer occurs, but the incidence can be estimated from epidemiologic studies [7]. Using a statewide database, Mulla et al. estimated an incidence of NSTI of 1.3/100,000 people with a total of 216 patients in Florida treated for NSTI in 2001 [8]. Demonstrating the frequent occurrence of cellulitis and rare incidence of NSTI, using an insurance claims database in Utah, Ellis Simonsen et al. estimated an incidence rate of cellulitis of 24.6/1,000 person years with an incidence rate for NSTI of only 0.04/1,000 person years [9]. NSTI is found in all age groups but most commonly in adults [10].

NSTIs occur in a wide range of patients who almost always possess preexisting conditions. More than 80% to 90% of patients with NSTIs possess comorbidities [2,3,11], whereas 62% may have three or more preexisting conditions [11]. Diabetes is the most frequent preexisting condition. In two large retrospective reviews, diabetes was present in 56% and 70% of the patients, respectively [2,4]. Other common preexisting conditions include obesity, hypertension, cirrhosis/chronic liver failure, peripheral vascular disease, HIV, and immunosuppressive therapy [2,3,12,13]. Behaviors like intravenous drug abuse (IVDA) and alcoholism leading to chronic liver disease also increase the risk of developing a NSTI [2,6,11,14]. Preexisting disease is not only a risk factor for NSTI but also for mortality [15]. When totaling comorbidities, patients who died had an average of 1.5 comorbidities versus 1.0 for survivors [3]. Preexisting conditions that correlated with mortality include cardiac disease, pulmonary disease, carcinoma, malnutrition, and IVDA [4].

Although preexisting conditions may increase the risk of developing a NSTI and mortality from NSTI, time to surgical debridement is the main risk factor for mortality. Since 1985, we have known that both prompt and radical surgical debridement of all devitalized tissue improves mortality [16]. Since then, many studies have supported early and aggressive surgical therapy for NSTI. Bilton et al. showed that delay in therapy increased mortality (38% mortality) when compared with early and aggressive surgical debridement (4% mortality) [12]. McHenry et al. found an average time to debridement of 25 hours in survivors but 90 hours for nonsurvivors [5]. Elliott et al. showed an average time to debridement of 1.2 days for survivors and 3.1 days for nonsurvivors [4]. On multivariate analysis, Wong et al. found that a delay in surgery of more than 24 hours was the only variable to correlate with increased mortality [2].

Although the incidence of NSTI is relatively low, the mortality is high at approximately 25% [17,18]. Early and radical surgical debridement is the key to successful treatment.

Inciting Events

Many patients report an insect bite, blister, abscess, or the feeling of a pulled muscle several days prior to presenting with a NSTI. Although some (15% to 52%) cases of NSTI are idiopathic in origin, the remainder have an identifiable source [3,5,11,15]. Abscesses, foot ulcers, traumatic wounds, burns, surgical wounds, IVDA, decubitus ulcers, perforated viscus, and strangulated hernia were all identified as inciting events by Elliott et al. [4]. Endorf et al. also reported liposuction, an infected arteriovenous graft, invasive rectal cancer, a percutaneous gastrostomy tube site, and an enterocutaneous fistula as suspected causes of NSTI [3]. Anaya et al. found inciting events to include subcutaneous/IV injection, trauma, postoperative wound infection, boils, chronic wounds/ulcers, bites, and perirectal abscesses [11].

Pathophysiology

Regardless of the inciting event, the pathophysiology of NSTIs is quite similar. NSTIs are a specific disease process in which entry of organisms through a compromised skin barrier results in a soft tissue infection that rapidly spreads along the superficial fascia of the subcutaneous tissue but initially spares the overlying skin and underlying muscle [19]. The rapidly spreading infection causes thrombosis of penetrating vessels, which in turn causes necrosis of overlying tissues supplied by those vessels. Histologic examination reveals necrosis of the superficial fascia, thrombosis and suppuration of veins traversing the fascia and microorganisms proliferating in the destroyed fascia [2]. Systemic spread of infection causes overwhelming sepsis or toxic shock syndrome if associated with streptococcal exotoxin of group A streptococcus (GAS) [20,21]. When muscle is involved early, the pathogen is commonly a clostridial species [22].

Microbiology

The microbial causes of NSTIs can be polymicrobial or monomicrobial. The majority of NSTIs (53% to 85%) are polymicrobial [2,4,5]. Organisms in polymicrobial NSTIs include anaerobes and aerobes, Gram-positive and Gram-negatives and rarely fungi (< 5%) [3,4,5]. In Elliott et al., the organisms recovered from NSTIs included streptococci, staphylococci, enterococci, E. coli, Proteus, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter, Eikenella, Citrobacter, peptostreptococci, Bacteroides, clostridia, and fungal species [23]. In a similar analysis, Wong et al. identified streptococcal species, staphylococcal species, enterococci, Escherichia coli, Acinetobacter, Pseudomonas, and Klebsiella as the most common isolates with Bacteroides being the most frequent anaerobe [2]. In Elliott et al., four or more organisms grew from the initial wound culture almost 50% of the time [4].

Monomicrobial NSTI occurs in approximately 15% to 29% of cases and over 50% of these monomicrobial NSTI are attributable to GAS [2,4,5]. Occasionally, monomicrobial NSTIs are caused by clostridia species [22], methicillin-resistant Staphylococcus aureus (MRSA) [24,25,26,27,28], and even group B streptococcus [20]. Tissue cultures have been found to not yield any organisms in 9% to 18% of debrided tissue samples [2,3]. In cases in which no organism is cultured and GAS is suspected, polymerase chain reaction can be used to amplify the streptococcal pyrogenic exotoxin B gene in tissue samples [29]. Although this may not be necessary for immediate management, it may aid in subsequent antibiotic therapy, prophylaxis of other close personal contacts, and for epidemiologic studies.

Attempts have been made to classify NSTIs based on microbial characteristics and to correlate the infectious organism to an inciting event, risk factor, or anatomic location [2,30,31]. Given the lack of uniformity and consistency in this classification system and the need to still treat all NSTIs initially
with prompt diagnosis, early surgical debridement, broad-spectrum antimicrobials, adequate nutrition and critical care support, labeling an NSTI based on the type of organism present should be used only to guide later antimicrobial choice and for research purposes. Therefore, we supply a slightly modified table listing the historical classification of Type I (polymicrobial) and II (GAS ± additional organisms) NSTIs with an additional classification of Type III (community-acquired MRSA, Acinetobacter, Clostridial, and Vibrio species) to include emerging or unique pathogens which require consideration when NSTI is suspected (Table 153.1) [30,31]. These unique NSTI pathogens are discussed in more detail later. Although some classifications consider Type I to be polymicrobial and Type II to be monomicrobial, given the virulent nature and incidence of GAS, these infections remain as their own group.

Table 153.1 Microbial Classification of Necrotizing Soft Tissue Infections

Type I	Polymicrobial
Type II	Group A Streptococcus ± additional organisms
Type III	Unique and emerging pathogens (CA-MRSA, Acinetobacter, Clostridia, Vibrio)
CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus.

Diagnosis

The diagnosis of NSTI is not difficult when obvious signs of tissue necrosis are present. However, this is rare. Wong et al. found that only 14.6% of their patients eventually diagnosed with NSTI had the diagnosis of NSTI or a suspicion of NSTI on admission [2]. Most often, patients were diagnosed with cellulitis or an abscess. Hard clinical signs of NSTI (bullae, skin necrosis, crepitance, gas on radiograph) are present on admission for only 44% of patients with NSTI [14]. The difficulty with diagnosing NSTI is determining when NSTI is present before these obvious signs present as delay is detrimental to patient outcome. If distinguishing nonnecrotizing infection from NSTIs is not possible, then close monitoring of physical examination changes is required to avoid further progression of the disease process. Therefore, the majority of this section focuses the physical examination features common to NSTI and measures that can be employed to earlier diagnose NSTI and thus, prompt more expeditious treatment.

Physical Exam

Signs shared by both nonnecrotizing and necrotizing soft tissue infections include pain, erythema, induration, and swelling. The hard signs of NSTI which may help to differentiate it from nonnecrotizing infection include crepitus, blistering, and skin necrosis, all of which occur at later stages of the disease process. In Elliott et al., on admission, crepitus was present in 36% of patients, skin necrosis in 31% and blistering in 23% [4]. Similarly, Faucher et al. found an open wound in 39%, crepitus in 32%, and vesicles in 23% of patients on admission. However, symptoms common to nonnecrotizing and necrotizing soft tissue infections (pain 89%, edema 84% and erythema 74%) were predominant on admission [11]. If a patient presents with tenderness, erythema and warmth, the development of bullae may be the first sign leading to a higher suspicion of NSTI [2]. NSTI has also been described as having poorly defined and indistinct margins of tissue involvement, tenderness beyond the area of cutaneous involvement and pain out of proportion to physical findings [2,4]. In an attempt to earlier differentiate benign soft tissue infections from NSTI, Wang et al. developed a staging system for the progression of NSTI using only cutaneous manifestations. Stage 1 included tenderness to palpation beyond the apparent area of skin involvement, erythema, swelling, and calor. Stage 2 included blister or bullae formation and later, Stage 3 included crepitus, skin anesthesia, and skin necrosis with dusky coloration. By Day 4 of hospitalization, 68% of their patients with NSTI displayed Stage 3 cutaneous manifestations whereas only 5% did at time of admission. Although this system helps to describe the cutaneous manifestations of NSTI, absence of these cutaneous manifestations does not exclude NSTI [32]. Waiting for the presence of Stage 3 cutaneous manifestations may be detrimental to the patient.

Imaging

Plain radiography, ultrasound, CT and MRI have all been studied as adjuncts to physical exam in cases of suspected NSTI. Classically, air or gas between the muscle and soft tissue layer is diagnostic of NSTI and very often, clostridial NSTI. However, gas is found on x-ray in only a small percentage (16–19%) of cases [2,14]. The soft tissue changes seen with both complex cellulitis and NSTI are indistinguishable on plain radiograph. Therefore, plain radiography is only valuable in the rare cases in which air is present between the tissues. Ultrasound may benefit these patients in that it is quick, noninvasive and can be performed at the bedside. However, there are few studies on ultrasound use to distinguish NSTI from cellulitis [33,34]. Yen et al. showed that ultrasound had 88% sensitivity and 93% specificity for NSTI in a limb using diffuse thickening of the subcutaneous tissue accompanied by a layer of fluid accumulation more than 4 mm in depth along the deep fascial layer when compared with the contralateral limb [33]. Ultrasound is limited by the need for operator experience, the interpretation of the images, and its use in body areas aside from limbs. CT can be used as an adjunct to an equivocal physical exam. Similar to the findings on plain radiograph, gas in the subcutaneous tissues is characteristic of NSTI on CT. Since gas is not seen in all cases of NSTI, other features include thickened, asymmetrical fascia, fluid and gas collections along the deep fascial sheaths, and extension of edema into the intermuscular septa and muscles [35,36]. MRI has also been studied in the differentiation between NSTI and simple/complex cellulitis using fascial inflammatory changes as the indicator of NSTI [37,38]. MRI was found to have a sensitivity of 100% and specificity of 86% in a small cohort [37]. However, whether NSTI could have been diagnosed prior to MRI or if the delay needed for MRI altered patient outcome were not identified. If an imaging modality is deemed necessary to confirm NSTI due to equivocal physical examination findings, it may be prudent to start with the least invasive plain radiograph to look for gas and then progress to CT if necessary. Ultrasound can be used in centers if the technician and radiologist are comfortable with the exam and its interpretation. Operative debridement should not be delayed in cases in which NSTI can be confirmed on physical exam.

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