Necrotizing Soft Tissue Infections

Microbiology

Historically, two microbial subtypes of NSTI have been described. Type I, or polymicrobial, is the more common form, comprising 55–75% of all NSTIs [5,8–10]. On average, 4.4 organisms are isolated per culture, which include various combinations of gram-positive, gram-negative, and anaerobic bacteria [8]. These infections tend to occur in the perineal and trunk region and often afflict patients with known risk factors or immune compromise. Type II infections are monomicrobial and are caused by Group A Streptococcus (GAS), either alone or in association with Staphylococcus aureus, and as such can be associated with toxic shock syndrome. Despite their notoriety in the lay press as a product of “flesh-eating” bacteria, Type II infections are much less common. These infections classically occur on the extremities and are more likely to be diagnosed in young, otherwise healthy hosts. Group A Streptococcus can be an especially aggressive pathogen, causing rapidly progressive disease, because of its variety of unique virulence factors [11,12] (Table 1).

Equipoise persists regarding the classification of Type III NSTI. Some authors identify the marine species Vibrio as the causative organism, which produces infection via direct exposure through compromised skin or ingestion of contaminated seafood. These infections typically are fulminant, with a high mortality rate, and tend to occur in patients with underlying hepatic disease [13]. Others identify Clostridium spp., most commonly C. perfringens, as the cause of Type III infections. These gram-positive, anaerobic, spore-forming bacteria are ubiquitous and produce the classical clostridial myonecrosis or gas gangrene. The elaboration of α-toxin, a phospholipase C, contributes to the virulence of this organism, causing extensive tissue necrosis and cardiovascular collapse [14]. Despite its historical significance, C. perfringens is a rare cause of NSTI now, the likely consequence of improvements in public hygiene. Nonetheless, it should always remain in the differential diagnosis, especially when one encounters a patient with rapidly progressive disease.

An emerging cause of NSTI that is currently uncategorized but requires special mention is community-acquired methicillin-resistant S. aureus (CA-MRSA). Until recently, CA-MRSA was implicated only rarely as the causative organism in NSTI, but recent studies have demonstrated otherwise [15,16]. Miller et al. [15] reported that 29% of their necrotizing fasciitis cases were caused by CA-MRSA, and Lee et al. [16] reported an even higher prevalence of 39%. These rates are in stark contrast to a previous review demonstrating a meager 3% rate [8]. This observed change in microbial flora has important implications for the anti-microbial management of NSTI, as most currently recommended antibiotic regimens do not provide adequate coverage for MRSA. Whether MRSA continues to evolve as a clinically important pathogen in these cases remains to be seen.

Diagnosis

Establishing the proper diagnosis of NSTI in an expeditious fashion is required to institute appropriate life-saving treatment. However, extensive diagnostic evaluation should never delay operative debridement. Any clinical doubt should be settled in the operating room with exploration and rapid microbiological analysis. Foremost are a high index of suspicion and a low threshold for operative intervention. This perspective is particularly relevant in managing patients with known risk factors: Diabetes mellitus, intravenous drug use, human immunodeficiency virus infection, obesity, ethanol abuse, and recent trauma or surgery [17]. Bear in mind, however, that a substantial number of NSTIs occur in otherwise healthy, immunocompetent hosts with no discernable inciting event.

The key factor in the diagnosis of soft tissue infections is to identify the necrotizing component. This seemingly straightforward task actually can be rather difficult on the basis of clinical findings alone, as the external findings often are less extensive than the underlying tissue damage. Clinical findings suggestive of NSTI include pain out of proportion to the examination findings, tense edema, ecchymoses, bullae, crepitus, local anesthesia, systemic toxicity, and disease progression despite antibiotic therapy [18]. Radiographic imaging in the form of plain films, computed tomography, or magnetic resonance imaging should be obtained only if it can be performed expeditiously. These ancillary studies may reveal soft tissue gas, enhancement or thickening of involved fascia, or abscesses [19]. Employing routine laboratory studies, Wong et al. developed the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 2) [20]. This score has been validated as a reliable means of distinguishing NSTI from other soft tissue infections and may prove to be an invaluable tool as it becomes more widely utilized [21].

Antibiotic Therapy

Antibiotics are a vital adjunct to the source control afforded by operative debridement. Impaired delivery of antibiotics to necrotic infected tissue can limit their effectiveness locally, but they remain critical in restricting bacterial spread and ameliorating systemic sepsis. Knowledge of the common pathogens involved in NSTI is vital in guiding appropriate antibiotic therapy. As polymicrobial infections constitute the majority of NSTIs, empiric broad-spectrum antibiotic therapy directed against gram-positive cocci, gram-negative bacilli, and anaerobic bacteria should be instituted immediately. No single regimen has been advocated in the literature to date, and many single- and multi-drug regimens have been shown to be efficacious (Table 3) [8,17].

Special consideration should be given to antimicrobial coverage of GAS and MRSA. Many advocate the addition of clindamycin to any empiric regimen, especially for coverage of GAS [12,22–24]. Clindamycin is a macrolide with activity largely against gram-positive and anaerobic organisms. It exerts its antimicrobial effects by binding to the 50S ribosomal subunit, thereby inhibiting protein synthesis. This drug suppresses the production of GAS M protein, exotoxins, and superantigens, thereby enhancing phagocytosis, limiting toxin-mediated destruction, and inhibiting the systemic release of cytokines. In addition, unlike penicillin, which historically has been the drug of choice for GAS infections, clindamycin is unaffected by the bacterial growth phase or the size of the inoculum [22]. Furthermore, retrospective studies have demonstrated a lower mortality rate for patients with NSTI secondary to invasive GAS whose initial treatment included clindamycin [24].

The ability to inhibit protein synthesis, specifically toxin production, also makes clindamycin useful against other toxin-producing bacteria such as S. aureus and C. perfringens, although there are reports of increasing resistance of MRSA to this agent [16]. As MRSA appears to be evolving as a major pathogen in NSTI, empiric therapy should include one of vancomycin, daptomycin, or linezolid [17]. Vancomycin was long the preferred agent because of its low cost, safety, and efficacy profile, with one study reporting complete susceptibility of MRSA specimens [16]. However, recent studies suggest that linezolid is superior to vancomycin for complicated MRSA soft tissue infections [25]. As with clindamycin, linezolid is a protein synthesis inhibitor, and as such, has the theoretical added benefit of reducing bacterial virulence and toxin production.

Regardless of the initial regimen, antibiotic therapy should be tailored appropriately to the final microbiological speciation and antibiotic sensitivity findings. There is no evidence that prolonged antibiotic therapy provides benefit; therefore, current guidelines recommend continuing treatment until no further surgical debridement is necessary and the patient's physiology has normalized, typically a 10–14 day course [17].

Surgery

Risk factor analysis has demonstrated clearly that the most important determinant of survival in NSTI is prompt surgical intervention [4–7]. One study reported a significant decrease in the mortality rate for patients who underwent surgery within 24 h of admission compared with those who did not (6% vs. 24%) [5]. Radical excision of all devitalized tissue through a generous incision should be performed until healthy, bleeding tissue is encountered. Surgical findings consistent with NSTI include gray necrotic fascia, loss of resistance to blunt finger dissection (i.e., the “finger test”), lack of bleeding tissue, and the presence of foul-smelling “dishwater” fluid. Post-operatively, the site should be inspected frequently to assess tissue viability and progression of disease. Serial debridements spaced 12–36 h apart generally are the rule, as infections rarely are eradicated by the initial debridement. Amputation occasionally is required if there is joint involvement or rapid progression to the torso, or if extensive muscle damage renders an extremity useless. In addition, a temporary diverting colostomy may be considered in patients with extensive perineal infections in order to facilitate wound hygiene and dressing changes. Site management can be a challenge, as tissue loss often is extensive. Initially, as with all infected wounds, they should be left open and packed with wet-dry dressings. Once infection is controlled, the patient may benefit from Vacuum-Assisted Closure (V.A.C.®) therapy (Kinetic Concepts, San Antonio, TX) to assist with granulation and closure [26], although larger wounds ultimately may require skin grafting.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen (HBO) therapy has been proposed as an adjunct to operative intervention and antibiotics in the treatment of NSTI. The technique involves the administration of 100% oxygen at a pressure greater than 1 atm absolute (ATA), resulting in a dramatic increase in oxygen tension to support basic metabolic functions independent of hemoglobin [27]. Typical HBO therapy involves administration at 2 to 3 ATA for 90 min three times in the first 24 h, then twice daily, although no standard regimen has been established. With such therapy, an arterial oxygen tension of 300 mm Hg can be attained, which contrasts with 75 mm Hg under standard conditions. The proposed benefits of a hyperoxic environment include suppression of clostridial α-toxin production and generalized bacterial growth, enhancement of leukocyte-killing activity and antibiotic effects, promotion of tissue repair and wound closure, and bactericidal effects on anaerobic organisms [27]. Animal models of clostridial gas gangrene have demonstrated a clear reduction in the mortality rate when HBO was utilized in addition to aggressive debridement and antibiotics [28].

Despite the physiologic rationale behind its use, clinical studies are limited mostly to case series and retrospective analyses, and the data from these are inconsistent [29–34]. One compelling study in favor of HBO therapy found that its addition to standard therapy significantly decreased the mortality rate, from 66% to 23%, a finding especially remarkable in light of the fact that the HBO group was more seriously ill on admission [30]. In contrast, the most recently published retrospective analysis of 78 patients with NSTI did not reveal a significant difference in the mortality rate in the HBO and non-HBO groups (8.3% vs. 13.3%; p = 0.48) [33].

With such conflicting reports and the lack of randomized controlled trials, it is not possible to issue firm recommendations on the use of HBO. However, many authors cite the purported theoretical benefits and relatively few major risks, suggesting HBO use as an adjunct to standard therapy. This perspective may be particularly pertinent in cases of clostridial infections provided facilities are readily available and HBO does not interfere with or delay appropriate resuscitation and surgical therapy.

Intravenous Immunoglobulin

Intravenous immunoglobulin is another adjunctive measure that has been studied in patients with NSTI, primarily in those with GAS or staphylococcal infections. It also has been studied in a general population of critically ill adults with severe sepsis and septic shock, where it has been associated with a reduction in the mortality rate [35]. Intravenous immunoglobulin (IVIg) is a concentrated pooled product containing primarily IgG isotypes derived from multiple human donors. In addition to a generalized anti-inflammatory effect, IVIg contains broad-spectrum antibodies that enhance bacterial opsonization, neutralize virulence factors and toxins, and inhibit superantigen-elicited T-cell activation, all of which are believed to be crucial in the development of invasive streptococcal or staphylococcal disease [36]. In fact, recent data suggest that patients who develop invasive disease are deficient in antibodies recognizing streptococcal cell wall-attachment proteins, which theoretically would be replaced with pooled IVIg [11]. A mortality benefit from treatment with IVIg has been suggested in this patient population in a number of small case report series and retrospective studies [37–40]. The only randomized, placebo-controlled trial to date was terminated early because of slow patient recruitment resulting from the low incidence of disease. The study was underpowered (10 patients receiving IVIg and 11 placebo), but the data revealed a 3.6-fold higher likelihood of death in patients who received placebo compared with those who received IVIg [41]. Although it is difficult to form solid conclusions on the basis of the available evidence, many experts support the use of IVIg as a reasonable adjunct to surgery and antibiotics in critically ill patients with NSTI secondary to streptococcal or staphylococcal infections.

Extracorporeal Plasma Therapy

Necrotizing soft tissue infection often progresses to or presents with severe sepsis, septic shock, and multiple organ dysfunction syndrome. As such, adjunctive treatments for these conditions must be considered. Extracorporeal plasma therapies include hemofiltration, plasma exchange, and plasmapheresis. The aim is to attenuate the host inflammatory response by removing the circulating inflammatory mediators or toxins responsible for producing systemic illness. The data on the use of plasmapheresis in patients with NSTI currently consist of a single case report [42]. Hence, most evidence is generalized from the literature on patients with severe sepsis or septic shock. For example, Busund et al. [43] observed significant reductions in Acute Physiology and Chronic Health Evaluation (APACHE) II scores and a trend toward a reduced mortality rate (odds ratio 0.41, 95% confidence interval 0.15-1.19) for a cohort of patients with severe sepsis who received plasmapheresis. By contrast, other investigators have not observed improvements in these clinically relevant outcomes [44]. Similarly, the effectiveness in reducing markers of inflammation and circulating cytokines has been inconsistent. In part, this variability stems from the nearly limitless permutations by which these “blood purification” therapies are delivered. Further study is warranted to see if this therapy has any role as an adjunct in the treatment of NSTI, particularly in the presence of severe sepsis or septic shock.

Drotrecogin Alfa (Activated)

Drotrecogin alfa (activated (Xigris®) Eli Lilly and Co., Indianapolis, IN), or recombinant human activated protein C (rhAPC), is an agent with pro-fibrinolytic, anti-coagulant, and anti-inflammatory effects that currently is approved for use in patients with severe sepsis and a predicted high risk of death (APACHE II ≥ 25) [45]. In fact, it is the only U.S. Food and Drug Administration-approved pharmacologic intervention for the management of severe sepsis and septic shock. This recommendation is based largely on the results of the PROWESS trial, which demonstrated a significant reduction in the mortality rate in patients with severe sepsis, albeit at a higher risk of serious bleeding complications [46]. It is out of concern for this risk that surgeons should exercise caution in utilizing this drug in the context of NSTI, where multiple surgical debridements form the mainstay of therapy and thus predispose to the patient to hemorrhage. Thus far, only two single case reports have documented the use of rhAPC in the context of NSTI secondary to GAS infection, both of which reported patient survival and no increase in bleeding complications [47,48].

Conclusion

Relatively uncommon, NSTI threatens both life and limb in the majority of affected patients. Clearly, the major determinant of the outcome is the rapidity with which the disease is diagnosed and source control is obtained. Early, aggressive surgical debridement, broad-spectrum antibiotics, and resuscitation form the cornerstone of management. The interest in adjunctive therapies such as HBO, IVIg, plasmapheresis, and rhAPC stems from the desire to impact the high mortality rate still associated with NSTI despite advances in modern medicine. Unfortunately, further evidence likely will continue to appear primarily in the form of retrospective analyses and case reports, as the infrequency of NSTI limits the ability to perform properly powered, randomized, controlled trials. Nevertheless, when utilized in the appropriate context and after a thoughtful, patient-specific risk–benefit assessment, these novel therapies have demonstrated real promise and may carry the potential to improve outcomes substantially.