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The new journal of medicine

Review Article

Dan L. Longo, M.D., Editor Necrotizing Soft-Tissue

Dennis L. Stevens, Ph.D., M.D., and Amy E. Bryant, Ph.D.​​

ecrotizing is a surgical diagnosis characterized by From the Veterans Affairs Medical Cen­ friability of the superficial , dishwater-gray exudate, and a notable ter, Boise, ID; and the University of Wash­ ington School of Medicine, Seattle. Ad­ absence of . This and other necrotizing soft-tissue infections have dress reprint requests to Dr. Bryant at the N Veterans Affairs Medical Center, Infec­ multiple causes, risk factors, anatomical locations, and pathogenic mechanisms, but all such infections result in widespread tissue destruction, which may extend tious Diseases Section, 500 W. Fort St. (Mail Stop 151), Boise, ID 83702, or at from the epidermis to the deep musculature. ­amy​.­bryant@​­va​.­gov. Necrotizing infections can occur after major traumatic injuries, as well as after N Engl J Med 2017;377:2253-65. minor breaches of the skin or mucosa (e.g., tears, abrasions, lacerations, or insect DOI: 10.1056/NEJMra1600673 bites), varicella , nonpenetrating soft-tissue injuries (e.g., muscle strain or Copyright © 2017 Massachusetts Medical Society. contusion), or routine obstetrical and gynecologic procedures; they can also occur in postsurgical and immunocompromised patients (Table 1). Although necrotizing infections have common clinical features, various entities have been defined, such as progressive bacterial synergistic , synergistic necrotizing , streptococcal gangrene, (clostridial myonecrosis), and nonclostridial anaerobic cellulitis. Subtle differences may distinguish one entity from another, but the clinical approaches to diagnosis and treatment are similar. In this review, we describe the clinical and laboratory features of and other necrotizing soft-tissue infections. We also discuss diagnostic pitfalls and recommended treatment approaches, as well as the effect of delays in surgical intervention on mortality. (Details about pathogenic mechanisms are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Epidemiologic Features and Causes of Necrotizing Fasciitis Types I and II Infections Necrotizing fasciitis types I and II are distinguished largely by whether the cause is polymicrobial (type I) or monomicrobial (type II).1 The annual incidence of necrotiz- ing fasciitis ranges from 15.5 cases per 100,000 population in Thailand2 to 0.3 to 5 cases per 100,000 in other regions.3-5 The relative incidence of type I and type II infections varies considerably. In some studies, type II infections have accounted for 55 to 87% of all cases of necrotizing fasciitis,6,7 whereas type I infections have been more prevalent, by a factor of approximately 2, in other studies,8,9 and in some studies, the incidence of the two types of infection has been similar.10-12 Necrotizing fasciitis type I is a polymicrobial infection involving aerobic and anaerobic organisms. It is usually seen in the elderly or in those with underlying illnesses. Predisposing factors include diabetic or decubitus ulcers, hemorrhoids, rectal fissures, episiotomies, and colonic or urologic surgery or gynecologic pro- cedures. Type I infection is often associated with gas in the tissue and thus is

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Table 1. Factors Conferring a Predisposition to Specific Necrotizing Soft-Tissue Infections.*

Predisposing Factor Clinical Syndrome Etiologic Agent Major penetrating trauma: crush or deeply penetrating Gas gangrene perfringens, C. histolyticum, wound or C. novyi Minor penetrating trauma NF type II Freshwater laceration hydrophila Saltwater laceration vulnificus Minor nonpenetrating trauma: muscle strain, sprain, NF type II or streptococcal myonecrosis pyogenes or contusion Mucosal breach: mucosal tear (rectal, vaginal, urethral); NF type I Mixed aerobic and anaerobic organisms gastrointestinal, genitourinary or gynecologic surgery Skin breach Varicella lesions NF type II or streptococcal myonecrosis S. pyogenes Insect bites NF type II or streptococcal myonecrosis S. pyogenes Injection drugs Gas gangrene C. perfringens, C. histolyticum, C. novyi, or C. sordellii Immunocompromised state with peripheral vascular disease NF type I Mixed aerobic and anaerobic organisms and ingestion of raw oysters NF type II V. vulnificus Neutropenia Gas gangrene C. septicum In women: pregnancy, childbirth, abortion (spon­ NF type II, streptococcal myonecrosis, S. pyogenes, C. perfringens, or C. sordellii taneous or medically induced), gynecologic or clostridial myonecrosis ­procedures or surgery Occult factors: colonic lesions, including carcinoma Spontaneous gas gangrene C. septicum

* Gas gangrene is also known as clostridial myonecrosis.

difficult to distinguish from gas gangrene. Non- as progressive bacterial synergistic gangrene or clostridial anaerobic cellulitis and synergistic large phagedenic ulcer15 can follow surgery in- necrotizing cellulitis are type I variants. Both volving colostomy sites or wire sutures. Though occur in patients with diabetes and typically in- large ulcerations often develop, the process does volve the feet, with rapid extension into the leg. not involve the fascia. Though nonnecrotizing cellulitis is common in Necrotizing fasciitis type II is a monomicro- patients with diabetes, necrotizing fasciitis should bial infection (Table 1). Among gram-positive be considered in patients with systemic manifes- organisms, group A streptococcus remains the tations of sepsis, such as tachycardia, leukocyto- most common pathogen,2,4,7,11,16 followed by meth- sis, acidosis, or marked hyperglycemia. icillin-resistant (MRSA).17,18 Bacterial penetration into the fascial compart- Unlike type I infections, type II infections may ments of the head and neck may result in Lud- occur in any age group and in persons without wig’s angina (i.e., infection of the submandib­ any underlying illness. ular fascial spaces) or Lemierre’s syndrome Other pathogens include (thrombophlebitis of the jugular vein), with or and . Some experts have proposed without severe sepsis.13,14 Breach of the gastro- that infections with these microbes, and possi- intestinal or urethral mucosa may result in bly clostridial species, be classified as necrotiz- Fournier’s gangrene, which begins abruptly with ing fasciitis type III. Monomicrobial necrotizing severe pain and may spread rapidly from the fasciitis due to gram-negative pathogens (bacte- perineal region to the anterior abdominal wall, roides and ) has also been report- the gluteal muscles, and in males, the genitalia. ed,6,19-21 though these infections are typically Finally, an indolent polymicrobial infection known seen in immunocompromised, diabetic, obese,

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or postoperative patients or in those with pre- pain escalation sufficiently severe to require existing, chronic organ dysfunction and are not ketorolac or narcotics) may be present, and such typically classified as necrotizing fasciitis type II. pain prompts patients to seek urgent medical Resolution of these nomenclature issues requires care. Malaise, myalgias, diarrhea, and anorexia a consensus among international infectious dis- may also be present in the first 24 hours. Since ease physicians, surgeons, and intensive care cutaneous manifestations are absent initially, practitioners. the infection is often misdiagnosed or the cor- The classic clinical and histologic features of rect diagnosis is delayed,30 and as a result, the necrotizing group A streptococcal and clostridial mortality exceeds 70%.28 By the time ecchymoses infections are mediated by potent bacterial exo- and bullae develop, tissue destruction is exten- and by the host response. For details, see sive, and systemic toxicity and organ failure are the Supplementary Appendix. evident. Emergency surgery, including extensive débridement or multiple , is often Invasive Group A Streptococcal Soft-Tissue required to ensure survival and necessitates pro- Infections longed hospitalization.26,30-32 Erroneous diagnoses A 2005 report estimated that more than 18 mil- include severe muscle strain and deep-vein throm- lion people worldwide have invasive Streptococcus bophlebitis; because of the associated gastro­ pyogenes diseases,22 including postpartum infec- intestinal manifestations, food poisoning may tions.23 In developed countries, the annual inci- also be diagnosed in error. Although seeding of dence of invasive infections has remained steady the deep tissues probably occurs through tran- at 3 to 5 cases per 100,000 population,3,24,25 with sient bacteremia from the nasopharynx, reports an average mortality of 29%.24,26 Mortality is rarely document coexisting or antecedent symp- higher among patients in whom streptococcal tomatic pharyngitis (unpublished data). This toxic syndrome or develops might be expected, given the incidence of inva- (38% and 45%, respectively).24,25 sive disease (18 million cases) as compared with Two distinct clinical presentations have been pharyngitis (>600 million cases).22 In children, described: infection with a defined portal of invasive streptococcal infections have been asso- bacterial entry and infection that arises sponta- ciated with varicella zoster33-35 and influenza vi- neously in the deep tissue, without an overt rus infections,36 as well as streptococcal pharyn- wound or lesion (Fig. 1). S. pyogenes gains entry gitis,37 though relatively few cases of necrotizing to the deep tissues through superficial cutane- fasciitis have been reported. ous lesions ( vesicles, insect bites, or The toxicity of group A streptococcal necrotiz- lacerations), after breaches of skin or mucosal ing fasciitis is severe and more fulminant than integrity (due to drug injections, surgical inci- that described by Meleney in 1924.38 Ecchymoses sions, or childbirth), or after penetrating trauma. and bullae develop more rapidly (in 2 to 3 days) The initial lesion may appear to be only mildly and deep-muscle involvement is more common in erythematous, but over a period of 24 to 72 hours, contemporary cases. The mortality is also higher. inflammation becomes extensive, the skin turns Using only “bear claw fasciotomy” and irrigation dusky and then purplish, and bullae appear. with Dakin’s solution (hypochlorous acid) as Bacteremia is frequently present, and metastatic treatment, Meleney reported a mortality of 20%, infections may occur. Very rapidly, the skin be- as compared with a mortality of 30 to 80% in comes frankly gangrenous and undergoes exten- the current era.27 Given the involvement of epider- sive sloughing. The patient is now perilously ill, mis, dermis, , fascia, and mus- with a high temperature and extreme prostration. cle, “necrotizing soft-tissue infection” appears At this stage, mortality is high, even with appro- to be a more accurate term than “necrotizing priate treatment.24,27 fasciitis” to describe the contemporary disease. In approximately 50% of patients with group A streptococcal necrotizing fasciitis or myone- Nonsteroidal Antiinflammatory Drugs crosis, infection initiates deep in the soft tissues, and Group A Streptococcal Infection without a portal of entry, often at sites of non- In the 1980s, an association between the use of penetrating trauma (muscle strain or ).26,28,29 nonsteroidal antiinflammatory drugs (NSAIDs) Initially, only and crescendo pain (rapid and the development of group A streptococcal

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A Defined Portal of Entry

Ecchymoses Bullae Skin or and Bullae mucosal breach swelling Dermal papilla Large bulla Local tissue EPIDERMIS Capillaries damage Exotoxins

Damage to blood supply

Organisms Vascular or spores occlusion

DERMIS Platelet–leukocyte in multiple aggregation tissue layers SUBCUTANEOUS FAT

Blood vessels Damage to MUSCLE Deep fascia deep tissue

BONE

Exotoxins cause local tissue Deeper tissues become infected. Organisms or spores are Erythema and swelling damage. Platelet–leukocyte Larger venules and arterioles are introduced into . become widespread. Bullae aggregates occlude capillaries occluded. Necrosis affects all Exotoxins are released. and ecchymoses develop. and damage vascular endothelium. tissue layers.

B No Defined Portal of Entry Ecchymoses

Bulla

EPIDERMIS

DERMIS Vimentin Gradual upward progression of Myogenic infection Activated progenitor myogenic progenitors Group A Platelet–leukocyte streptococci aggregation

Leukocytes Arterial Deep fascia Venous occlusion occlusion

Streptococci Exotoxins Deep-tissue injury

A nonpenetrating deep-tissue injury Arteries become occluded, causing In susceptible hosts with Exotoxins are released. Venous stimulates a repair response. There necrosis in deep tissue that spreads transient bacteremia, organisms occlusion leads to necrosis in is an influx of leukocytes and activation to upper tissue layers. Bullae and are trafficked to injury site in a deep tissue. of myogenic progenitor cells. vimentin-mediated process. ecchymoses later develop.

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Figure 1 (facing page). Evolution of Necrotizing Fasciitis increased trafficking of circulating group A 49 or Myonecrosis. streptococci to strain-injured muscles in mice. Panel A shows the evolution of infections with a defined portal of entry. A breach in the skin or mucosal integrity Necrotizing Clostridial Infections facilitates the introduction of organisms or spores into Gas gangrene (clostridial myonecrosis) is an soft tissue, resulting in monomicrobial infection (with acute invasion of healthy living tissue that oc- group A streptococcus, Aeromonas hydrophila, or Vibrio vulnificus) or polymicrobial infection (with both aerobes curs spontaneously or as a result of traumatic and anaerobes). Penetrating trauma sufficient to inter­ injury. Recurrent gas gangrene, occurring sev- rupt the blood supply favors the development of gas eral decades after the primary infection, has gangrene (clostridial myonecrosis). proliferate also been described.50 and release exotoxins, which cause local tissue damage Deeply penetrating injuries that compromise and impair inflammatory responses. -induced platelet–leukocyte aggregates occlude capillaries and the blood supply create an anaerobic environ- damage the vascular endothelium, resulting in fluid ment that is ideal for spore germination and leakage, tissue swelling, and erythema. Erythema and bacterial proliferation.51 Such trauma accounts swelling become more widespread, bullae and ecchy­ for approximately 70% of cases of gas gangrene. moses develop, and deeper tissues become infected. Other predisposing conditions are bowel and Exotoxin production leads to occlusion of larger venules and arterioles, with subsequent ischemic necrosis of biliary tract surgery, intramuscular epinephrine all tissue layers, from the dermis to the deep muscula­ injection, retained placenta, prolonged rupture ture. Panel B shows the evolution of group A strepto­ of the membranes, and intrauterine fetal death. coccal infection with no defined portal of entry (cryp­ causes approximately 80% togenic infection). A deep, nonpenetrating tissue injury of such infections; other pathogens include such as muscle strain, sprain, or hematoma stimulates a repair response, including an influx of leukocytes and C. septicum, C. novyi, and C. histolyticum. activation and proliferation of myogenic progenitor cells. Data regarding contamination versus active In a susceptible host with a transient bacteremia (pos­ infection of traumatic wounds come from stud- sibly arising from asymptomatic pharyngeal carriage of ies performed during World Wars I and II. In ), the injury leads to trafficking 1915, Fleming documented that 60.4% of war of the organisms to the injured site. Increased vimen­ 52 tin expression on activated myogenic progenitor cells wounds were contaminated with . Yet 53 and infiltrated macrophages serves as a ligand for MacLennan found that active infection (gas group A streptococcus binding. Bacterial proliferation gangrene or “anaerobic cellulitis”) occurred in with local production of exotoxins (e.g., streptolysin O fewer than 10 patients per 1000 wounded.54 In and streptococcal pyrogenic exotoxin A) ensues. Ab­ 1941, Qvist55 suggested that anaerobic cellulitis sorption of streptolysin O may stimulate intravascular accumulation of platelet–leukocyte aggregates, first in required only débridement of tissue that was postcapillary venules and then in arterioles and larger damaged by trauma itself, whereas in gas gan- vessels, resulting in vascular occlusion. Ischemic de­ grene, was necessary to control struction of the deep soft tissues ensues. Cutaneous rapid invasion of healthy tissue and thus ensure manifestations of necrotizing infection (ecchymoses survival — a premise that guides clinical prac- and bullae) develop later in the course of infection. tice today. Spontaneous (nontraumatic) gas gangrene is necrotizing fasciitis was proposed. Proponents commonly caused by C. septicum, which is more recognized that NSAIDs can suppress critical aerotolerant than other clostridial pathogens.56 neutrophil functions39 and augment the produc- Most infections occur in patients with gastroin- tion of tumor necrosis factor α, a key mediator testinal portals of entry such as adenocarcino- of septic shock.39 Other people argued that ma56 or in those with congenital or cyclic neu- NSAIDs merely mask the tropenia.57 C. sordellii infections can affect women of developing infection, delaying diagnosis and after natural childbirth, as well as after abortion treatment. Numerous clinical and epidemiologic or other gynecologic procedures. Such infections studies have investigated, but not resolved, this can also develop in men, women, and children issue.40-46 Experimental evidence is limited, after traumatic injuries and surgical procedures though two studies clearly showed that non­ or illicit-.58 Common sites include selective NSAIDs (e.g., ketorolac and ibuprofen) the skin, muscle, uterus, and . Systemic accelerated the disease course and worsened signs include an absence of fever, profound hypo- outcomes.47,48 In addition, ketorolac significantly tension, diffuse capillary leak, hemoconcentration

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Table 2. Pitfalls in the Diagnosis of Necrotizing Soft-Tissue Infection.*

Pitfall Explanation Absence of fever Fever is often absent in patients with necrotizing soft-tissue infections because of NSAIDs that are self-administered or prescribed in the emergency department or in postsurgical set­ tings. Fever is also absent in patients with necrotizing infection due to C. sordellii. Absence of cutaneous manifestations Patients with spontaneous or cryptogenic necrotizing infections (i.e., infections without an ­obvious bacterial portal of entry) that begin in the deep soft tissues often do not have ­cutaneous signs of infection until late in the course of the disease. Attributing severe pain to injury Severe pain is a key finding in patients with necrotizing infections. However, when such infec­ or procedure tions develop after surgery or parturition, pain may be erroneously attributed to the proce­ dure itself. Similarly, perineal pain may be attributed to hemorrhoids, epididymitis, or vaginal or rectal trauma. Severe pain associated with spontaneous or cryptogenic infections is often wrongly attributed to muscle strain or venous . If pain is out of proportion to the suspected cause or requires opioids or ketorolac for management, a developing necro­ tizing infection should be considered. Pain may be absent because of the use of narcotics or NSAIDs or because of neuropathy in patients with diabetes. Nonspecific imaging tests In patients with necrotizing infections, radiographs may show only , with no evidence of gas in the deep tissue. Since this finding is consistent with noninfectious causes (e.g., soft- tissue injury and postsurgical and postpartum conditions), it may confound the diagnosis. Attributing systemic manifestations Nausea, vomiting, and diarrhea may be early manifestations of toxemia from group A strepto­ to other causes coccal infection, though they are often wrongly attributed to food poisoning or viral illness.

* NSAIDs denotes nonsteroidal antiinflammatory drugs.

(hematocrit, 50 to 80%), and a marked leuke- coccal infection (i.e., infection with no portal of moid reaction (white-cell count, 50,000 to entry), the process begins deep in the tissues. 150,000 per cubic millimeter). Mortality is 70 to Crescendo pain is the most important clinical 100%, and death occurs within 2 to 4 days after clue for such infection, and its onset typically hospital admission. occurs well before shock or organ dysfunction is manifested. However, crescendo pain may be Diagnosis of Necrotizing absent or attenuated in patients who are receiv- Fasciitis and Other Necrotizing ing analgesic agents, including NSAIDS; in pa- Infections tients who have undergone surgery, childbirth, or trauma, the pain may be incorrectly attributed Diagnostic Pitfalls to normal postoperative soreness, typical post- Early diagnosis of necrotizing infections may be partum discomfort, or the trauma itself, respec- confounded by numerous factors (Table 2), as tively, rather than to acute infection. Pain may discussed below. Physicians must be aware of also be absent in patients with altered mental these potential pitfalls because delays in diagno- status or those with diabetes-related neuropathy. sis and treatment have dire consequences. A basic In these instances, the absence of a strong clini- diagnostic algorithm is shown in Figure 2. cal clue delays the correct diagnosis and appro- priate treatments. Thus, all patients presenting Clinical Findings with a sudden onset of severe pain in an extrem- Classic manifestations of necrotizing fasciitis in- ity, with or without an obvious portal of bacte- clude soft-tissue edema (in 75% of cases), ery- rial entry or the presence of fever, should be thema (72%), severe pain (72%), tenderness evaluated for severe soft-tissue infection on an (68%), fever (60%), and skin bullae or necrosis emergency basis. (38%).8 In a recent case–control study, factors that differentiated necrotizing fasciitis from cel- Imaging Tests lulitis were recent surgery, pain out of propor- Radiographs, computed tomographic (CT) scans, tion to clinical signs, hypotension, skin necro- or magnetic resonance imaging (MRI) studies sis, and hemorrhagic bullae.59 will show soft-tissue swelling in patients with In patients with cryptogenic group A strepto- group A streptococcal infection and will show

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Clinical Symptoms Swelling, erythema, pain

Systemic Signs Tachycardia, >120 beats/min; hypotension; No systemic signs elevated CK level; CRP, >15 mg/dl; LRINEC score, >6

Radiographic Evidence

Gas in the tissue No gas in the tissue

Immediate Surgery Inspection and débridement Inspection and débridement Specimen collection Specimen collection

Gram’s Staining and Culture Gram-positive Mixed aerobes Gram-positive Gram-negative rods and anaerobes cocci rods

Differential Diagnosis Clostridial myonecrosis NF Type I NF Type II NF Type II Cellulitis (aggressive) Nonclostridial crepitant Streptococcus pyogenes Aeromonas Spontaneous — cellulitis Staphylococcus aureus Freshwater Cutaneous Synergistic necrotizing or group A strepto- Vibrio Traumatic — cellulitis coccal myonecrosis Saltwater C. perfringens Progressive bacterial Gynecologic — synergistic gangrene C. sordellii Clostridial anaerobic cellulitis (indolent)

Figure 2. Algorithm for the Diagnosis of Necrotizing Infections. In the algorithm, early clinical signs and symptoms and available results of laboratory tests and imaging studies are used to establish the diagnosis and cause of a diverse array of skin and soft-tissue infections. CK denotes creatine kinase, CRP C-reactive , LRINEC Laboratory Risk Indicator for Necrotizing Fasciitis, and NF necrotizing fasciitis.

gas in the tissues of patients with gas gangrene A study of enhanced CT in patients with docu- or necrotizing fasciitis type I. Imaging evidence mented necrotizing fasciitis as compared with of gas in the tissues, or the presence of crepitus, those who had other musculoskeletal infections should prompt immediate surgical consultation. suggested that the absence of fascial enhance- A finding of swelling alone may not be useful in ment was specific for necrotizing fasciitis.60 patients who have had a traumatic injury or have undergone surgery or childbirth, since swelling Tissue Biopsy, Histologic Tests, and Gram’s cannot be used to distinguish between infection, Staining trauma, and inflammation. MRI may show thick- Gram’s staining of surgically obtained material ening and hyperintensity of intermuscular fascia is crucial for determining the cause of infection

on T2-weighted images, findings that are sensitive and guiding empirical treatment. Percutaneous but not entirely specific for necrotizing fasciitis. biopsy and examination of a frozen section has

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been proposed to aid in the diagnosis of necro- Treatment tizing infection.61,62 However, this technique is subject to sampling error and is not a good Surgical Intervention substitute for open surgical inspection and biop- For patients with aggressive soft-tissue infection sy. Group A streptococcal necrotizing infection or those with mild infection plus evidence of sys- is characterized histologically by the destruction temic toxicity, prompt surgical exploration is ex- of muscle tissue, a paucity of infiltrating phago- tremely important8,32,70 for three reasons: to deter- cytes, and large numbers of gram-positive cocci mine the extent of infection, to assess the need at the site (Fig. 3). The histologic findings are for débridement or amputation, and to obtain similar for gas gangrene, though with more evi- specimens for Gram’s staining and culture. When dence of edema, gas formation, or both. infection is near the vital structures of the neck, surgical intervention may be necessary to pre- Surrogate Markers for Early Diagnosis vent airway obstruction. Reinspection of the sur- of Necrotizing Fasciitis gical site within 24 hours after surgery is recom- A C-reactive protein level of more than 200 mg mended.8,70 Inspection and débridement should per liter,63 a modestly increased white-cell count be continued every 1 to 2 days until necrotic with a marked left shift,64 and an elevated serum tissue is no longer present.8,32,62,70-72 Negative- creatinine level in the absence of hypotension pressure devices have shown promise in facili- are suggestive of severe group A streptococcal tating closure and healing of these complex infection. Marked leukemoid reactions (50 to wounds in small series of patients.73-75 150,000 white cells per cubic millimeter) and There is universal agreement that early surgi- profound hemoconcentration are characteristic cal débridement is crucial in managing these of C. sordellii infection. A white-cell count of complex cases. But how early is early? Pinpoint- more than 15,400 per cubic millimeter plus a ing the critical time for surgical intervention on serum sodium level of less than 135 mmol per the basis of published data is problematic, since liter distinguishes necrotizing fasciitis in gen- the starting point for measuring the time to eral from nonnecrotizing soft-tissue infections, surgery varies among studies, particularly retro- with a negative predictive value of 99% but a spective analyses, with some studies using the positive predictive value of only 26%.64 Elevated time from establishment of a definitive diagno- levels of serum creatine phosphokinase or serum aspartate aminotransferase suggest deep infec- tion involving muscle or fascia (as opposed to cellulitis). The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scoring system uses the total white-cell count and , sodium, glu- cose, creatinine, and C-reactive protein levels to distinguish between mild soft-tissue infections and necrotizing fasciitis.65,66 For adults with LRINEC scores of 5.8 or higher (on a scale of 0 to 13, with higher scores indicating a greater likelihood of necrotizing soft-tissue infection), the positive predictive value for necrotizing fas- ciitis ranged from 57 to 92% in three stud- Figure 3. Histopathological Features of Group A Strepto- ies,4,65,67 with negative predictive values of 86% coccal Necrotizing Fasciitis and Myonecrosis. and 96% in two studies.65,68 The disparities may Routine hematoxylin and eosin staining of a muscle be attributable, in part, to the fact that the specimen from a patient who died from cryptogenic group A streptococcal infection shows the classic fea­ specificity of the LRINEC score is greatest for tures of this infection: widespread tissue destruction, severe disease.9 In a study involving children lack of a tissue inflammatory response, and large num­ with necrotizing fasciitis, the median LRINEC bers of bacteria in the tissues. score was only 3.7.69

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sis, some using the time from initial recognition in group A streptococcus have increased, to 15% of the infection, and others using the time from in the United States82 and to 95.5% in .83 hospital admission. Studies at tertiary care hos- Treatment failures have been reported in cases pitals typically report the shortest times to sur- of resistance.84 In a study of experi- gery, probably because the diagnosis was made mental myonecrosis due to group A streptococcus elsewhere, before admission to the study hos- with resistance to and clindamy- pital. We agree with Bandyopadhyay and col- cin, tedizolid, a second-generation oxazolidinone leagues71 that the definition of the time to sur- , was highly efficacious and superior to gery should be standardized. linezolid.85 Nevertheless, survival is significantly increased among patients taken to surgery within 24 hours Other Necrotizing Fasciitis Type II Infections after admission as compared with those in Current guidelines recommend that A. hydrophila whom surgery is delayed for more than 24 infections be treated with doxycycline plus either hours.8,76 Survival is further increased with ear- ciprofloxacin or ceftriaxone.70 A combination of lier surgical intervention (e.g., within 6 hours),77,78 doxycycline plus either ceftriaxone or cefotaxime supporting the notion that the earlier surgery is is recommended for V. vulnificus infections.70 For performed, the better the outcome. MRSA infections, , linezolid, dapto- mycin, or ceftaroline is likely to be effective, Pharmacologic Treatment though such treatment has not been adequately Polymicrobial Necrotizing Infections studied. For mixed aerobic and anaerobic infections of the head and neck, abdomen, perineum, or gyneco- Traumatic or Spontaneous Gas Gangrene logic organs, definitive treatment should be Treatment with plus clindamycin for based on Gram’s staining, culture, and sensitiv- 10 to 14 days is recommended for traumatic or ity information. Because of antibiotic resistance spontaneous gas gangrene.70 The recommenda- in gram-positive microbes and among the Entero- tion of penicillin is based on in vitro sensitivity bacteriaceae,79 broader antibiotic coverage may data. The recommendation of clindamycin is be necessary, particularly if the patient has re- based on data showing that it is more effective cently been hospitalized or treated with antibiot- than penicillin in animal models of gas gan- ics. Treatment should also be guided by local grene caused by C. perfringens86; clinical trials of antibiograms, since the emergence of resistance clindamycin have not been performed. is geographically determined and specific.80 The Infectious Diseases Society of America (IDSA) Care of Critically Ill Patients publishes guidelines for the treatment of skin Guidelines for the care of critically ill patients and soft-tissue infections.70 The current guide- have recently been published.87 However, prob- lines recommend vancomycin or linezolid plus lems specifically associated with necrotizing one of the following therapies: piperacillin–tazo- infections are of concern, as noted below. bactam, a carbapenem, or ceftriaxone–metroni- dazole. Additional information on specific and Capillary Leak Syndrome alternative treatments is also provided in the Circulating bacterial toxins and host mediators IDSA guidelines. Studies are under way to evalu- cause diffuse endothelial damage. Intravenous ate ceftazidime–avibactam for highly resistant fluid requirements may be extremely high (10 to gram-negative microbes.81 12 liters of normal saline per day). However, profound hypoalbuminemia (0.5 to 1 g per deci- Group A Streptococcal Infections liter) is also common, and replacement with Treatment with clindamycin in combination colloid (albumin) may therefore be necessary to with penicillin for 10 to 14 days is recommended maintain oncostatic pressure. for group A streptococcal infection.70 Clindamy- cin monotherapy should be considered only after Intravascular antibiotic susceptibility has been determined, Bacterial hemolysins cause striking and rapid since both constitutive and inducible resistance reductions in the hematocrit in the absence of

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disseminated intravascular coagulopathy. Thus, ciitis is based on its ability to neutralize extra- the hematocrit may be a better indicator of cellular toxins that mediate pathogenesis. Clini- the need for transfusion than the hemoglobin cal studies suggesting that there are benefits to level. IVIG have had serious limitations, including differences in surgical intervention or clindamy- Cardiomyopathy cin use between the group that received IVIG Global hypokinesia, as indicated by echocar- and the group that did not,95 lack of power due diography and cardiac output, is seen in some to the small sample size,96 low mortality in the patients with streptococcal toxic shock syn- group that did not receive IVIG,97 and differ- drome.88 Among survivors, this cardiomyopathy ences in the incidence of necrotizing fasciitis is reversible, fully resolving in 3 to 24 months between the two study groups.98 Furthermore, after infection. Some patients have survived with both the quantity and quality of neutralizing the use of cardiac-assist devices. Management is vary from batch to batch of difficult, since use of vasopressors increases IVIG. In view of these limitations and the lack afterload, resulting in decreased peripheral per- of data from definitive double-blind, controlled fusion and reduced cardiac output. Symmetric studies, the IDSA does not recommend IVIG for gangrene resulting in loss of one to four ex- necrotizing group A streptococcal infections.70 tremities has been described. Careful monitor- Other investigators are in agreement.72 In a well- ing and maintenance of mean arterial pressure controlled 2017 study involving 4127 patients so that it does not exceed 65 mm Hg in patients with necrotizing fasciitis and streptococcal toxic with this infection seem prudent, though no shock syndrome in 130 hospitals in the United clinical studies have been performed to support States, IVIG had no effect on mortality or length this recommendation. of hospital stay.99 Thus, though IVIG has its ad- vocates, a consensus supporting its use has not Adjunctive Measures been reached. Hyperbaric Oxygen A review of 57 studies performed between 1997 Other Measures and 2003 concluded that hyperbaric oxygen is A phase 2 trial of a new inhibitor of bacterial not useful for the treatment of necrotizing fasci- showed no significant benefit itis,89 a finding that is similar to the results of with respect to survival, number of surgical other studies.8,90,91 In contrast, a significant sur- débridements, or serum cytokine levels.100 vival benefit of hyperbaric oxygen in necrotizing fasciitis was documented in recent studies from Summary the United States and Australia.11,92 Other studies have also suggested a beneficial role of hyper- Necrotizing soft-tissue infections share many baric oxygen in the treatment of gas gan- clinical and pathological features, and all such grene,89,91 though experimental studies showed infections result in extensive tissue destruction. no benefit.93 Recently, a study has been initiated No single clinical laboratory test or group of to evaluate the effect of hyperbaric oxygen on tests can adequately replace surgical inspection inflammatory and vasoactive biomarkers in nec- for diagnosis of these infections. Early diagno- rotizing infections.94 Meanwhile, its benefits re- sis, prompt surgical intervention, and appropri- main controversial. Surgical débridement, which ate antibiotic treatment are essential to reduce is essential for the treatment of necrotizing fas- mortality and improve outcomes. ciitis, should not be delayed in order to pursue hyperbaric oxygen treatment. Dr. Stevens reports receiving grant support from Motif Biosci- ences; and Dr. Bryant, receiving grant support from Merck. No Intravenous Immune Globulin other potential conflict of interest relevant to this article was reported. The rationale for using intravenous immune Disclosure forms provided by the authors are available with globulin (IVIG) in patients with necrotizing fas- the full text of this article at NEJM.org.

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81. Krapp F, Grant JL, Sutton SH, Ozer 87. Rhodes A, Evans LE, Alhazzani W, et al. immune response and effects of hyper- EA, Barr VO. Treating complicated carba­ Surviving Sepsis Campaign: international baric oxygenation — the protocol of the penem-resistant Enterobacteriaceae infec- guidelines for management of sepsis and prospective cohort BIONEC study. BMJ tions with ceftazidime/avibactam: a retro- septic shock: 2016. Intensive Care Med Open 2015;5(5):​ e006995.​ spective study with molecular strain 2017;43:​ 304-77.​ 95. Kaul R, McGeer A, Norrby-Teglund A, characterisation. Int J Antimicrob Agents 88. Stevens DL, Shelly MP, Stiller R, Villa­ et al. Intravenous immunoglobulin ther- 2017;49:​ 770-3.​ senor-S A, Bryant AE. Acute reversible apy for streptococcal toxic shock syndrome 82. DeMuri GP, Sterkel AK, Kubica PA, cardiomyopathy in patients with strepto- — a comparative observational study. Duster MN, Reed KD, Wald ER. coccal toxic shock syndrome. In: ​Proceed- Clin Infect Dis 1999;​28:​800-7. and clindamycin resistance in group A ings of the XVIIth Lancefield Interna- 96. Darenberg J, Ihendyane N, Sjölin J, streptococci isolated from children with tional Symposium on Streptococci and et al. Intravenous immunoglobulin G ther- pharyngitis. Pediatr Infect Dis J 2017;​36:​ Streptococcal Diseases, Athens, June 22– apy in streptococcal toxic shock syndrome: 342-4. 26, 2008. a European randomized, double-blind, 83. Peng XM, Yang P, Liu S, et al. The ge- 89. Wang C, Schwaitzberg S, Berliner E, placebo-controlled trial. Clin Infect Dis netic features of to group Zarin DA, Lau J. Hyperbaric oxygen for 2003;​37:​333-40. A streptococcus and antibiot- treating wounds: a systematic review of 97. Shah SS, Hall M, Srivastava R, Subra- ics among pediatric patients in Beijing the literature. Arch Surg 2003;​138:​272-9. mony A, Levin JE. Intravenous immuno- 2012. Zhonghua Yu Fang Yi Xue Za Zhi 90. Jallali N, Withey S, Butler PE. Hyper- globulin in children with streptococcal 2013;​47:​1040-4. (In Chinese.) baric oxygen as adjuvant therapy in the toxic shock syndrome. Clin Infect Dis 84. Lewis JS II, Lepak AJ, Thompson GR management of necrotizing fasciitis. Am 2009;49:​ 1369-76.​ III, et al. Failure of clindamycin to eradi- J Surg 2005;189:​ 462-6.​ 98. Linnér A, Darenberg J, Sjölin J, Hen- cate infection with beta-hemolytic strep- 91. Willy C, Rieger H, Vogt D. Hyperbaric riques-Normark B, Norrby-Teglund A. Clin- tococci inducibly resistant to clindamycin oxygen therapy for necrotizing soft tissue ical efficacy of polyspecific intravenous in an animal model and in human infec- infections: contra. Chirurg 2012;​83:​960- in patients with tions. Antimicrob Agents Chemother 2014;​ 72. (In German.) streptococcal toxic shock syndrome: a com- 58:​1327-31. 92. Shaw JJ, Psoinos C, Emhoff TA, Shah parative observational study. Clin Infect 85. Bryant AE, Aldape MJ, Bayer CR, McIn- SA, Santry HP. Not just full of hot air: Dis 2014;​59:​851-7. doo E, Stevens DL. Efficacy of tedizolid in hyperbaric oxygen therapy increases sur- 99. Kadri SS, Swihart BJ, Bonne SL, et al. experimental myonecrosis caused by eryth- vival in cases of necrotizing soft tissue Impact of intravenous immunoglobulin romycin/clindamycin-sensitive and -resis- infections. Surg Infect (Larchmt) 2014;​15:​ on survival in necrotizing fasciitis with tant group A streptococcus. In:​ Proceed- 328-35. vasopressor-dependent shock: a propen- ings and Abstracts of 2016 IDWeek, New 93. Stevens DL, Bryant AE, Adams K, sity score-matched analysis from 130 US Orleans, October 26–30, 2016. Mader JT. Evaluation of hyperbaric oxy- hospitals. Clin Infect Dis 2017;​64:​877- 86. Stevens DL, Maier KA, Laine BM, gen therapy for treatment of experimental 85. Mitten JE. Comparison of clindamycin, Clostridium perfringens infection. Clin Infect 100. Bulger EM, Maier RV, Sperry J, et al. rifampin, tetracycline, metronidazole, and Dis 1993;​17:​231-7. A novel drug for treatment of necrotizing penicillin for efficacy in prevention of ex- 94. Hansen MB, Simonsen U, Garred P, soft-tissue infections: a randomized clini- perimental gas gangrene due to Clostridi- Hyldegaard O. Biomarkers of necrotising cal trial. JAMA Surg 2014;​149:​528-36. um perfringens. J Infect Dis 1987;​155:​220-8. soft tissue infections: aspects of the innate Copyright © 2017 Massachusetts Medical Society.

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