Clinical Review & Education

JAMA Surgery | Review

Necrotizing Soft Tissue Infections

A Review
James McDermott, MD; Lillian S. Kao, MD, MS; Jessica A. Keeley, MD; Areg Grigorian, MD; Angela Neville, MD;
Christian de Virgilio, MD

CME at jamacmelookup.com
IMPORTANCE Necrotizing soft tissue infections (NSTIs) are severe life- and limb-threatening
infections with high rates of morbidity and mortality. Unfortunately, there has been minimal
improvement in outcomes over time.

OBSERVATIONS NSTIs are characterized by their heterogeneity in microbiology, risk factors,

and anatomical involvement. They often present with nonspecific symptoms, leading to a
high rate of delayed diagnosis. Laboratory values and imaging help increase suspicion for
NSTI, though ultimately, the diagnosis is clinical. Surgical exploration is warranted when there
is high suspicion for NSTI, even if the diagnosis is uncertain. Thus, it is acceptable to have a
certain rate of negative exploration. Immediate empirical broad-spectrum antibiotics, further
tailored based on tissue culture results, are essential and should be continued at least until
surgical debridement is complete and the patient shows signs of clinical improvement.
Additional research is needed to determine optimal antibiotic duration. Early surgical
debridement is crucial for improved outcomes and should be performed as soon as possible,
ideally within 6 hours of presentation. Subsequent debridements should be performed every Author Affiliations: Department of
12 to 24 hours until the patient is showing signs of clinical improvement and there is no Surgery, Stanford University,
Stanford, California (McDermott);
additional necrotic tissue within the wound. There are insufficient data to support the routine Department of Surgery, McGovern
use of adjunct treatments such as hyperbaric oxygen therapy and intravenous Medical School, The University of
immunoglobulin. However, clinicians should be aware of multiple ongoing efforts to develop Texas Health Science Center at
Houston (Kao); Department of
more robust diagnostic and treatment strategies.
Surgery, Harbor-UCLA Medical
CONCLUSIONS AND RELEVANCE Given the poor outcomes associated with NSTIs, a review of Center, Torrance, California (Keeley,
Neville, de Virgilio); Department of
clinically relevant evidence and guidelines is warranted. This review discusses diagnostic and Surgery, Division of Trauma, Burns,
treatment approaches to NSTI while highlighting future directions and promising and Surgical Critical Care, University
developments in NSTI management. of California, Irvine (Grigorian).
Corresponding Author: Christian de
Virgilio, MD, Department of Surgery,
JAMA Surg. 2024;159(11):1308-1315. doi:10.1001/jamasurg.2024.3365 Harbor-UCLA Medical Center, 1000
Published online September 11, 2024. W Carson St, Torrance, CA 90502
(cdevirgilio@lundquist.org).

N
ecrotizing soft tissue infections (NSTIs) are severe immunocompromise.5 Type 2 NSTIs are commonly caused by group
infections that present a significant risk to life and A Streptococcus or Staphylococcus aureus and usually affect the
limb, characterized by the rapid destruction of soft extremities.6 Twoadditionalsubgroups,type3(Vibrio,Aeromonas,and
tissue, including the skin, subcutaneous fat, fascia, or muscle. Clostridium) and type 4 (fungal infections), have been proposed.7
In-hospital mortality for NSTIs remains high (10%-20%), with The majority of NSTIs originate from bacterial infiltration
minimal improvement over the past 20 to 30 years.1,2 While con- after a breach in skin integrity, often due to burns, insect bites,
sidered rare, with a reported incidence of 3.8 to 10.3 cases per puncture wounds, surgical incisions, or minor cuts. However, in
100 000 persons annually in the United States, NSTI incidence is more than 20% of cases, the cause is unknown.8 NSTIs, particu-
likely underestimated.3 This review discusses current diagnostic larly group A Streptococcus infections, may occur from transient
and management recommendations while highlighting promising bacteremia and hematogenous spread.9
advances on the horizon. The severity of illness is related to both the toxins produced by
the offending pathogens and the host immune response. Toxin-
mediated inflammation results in vascular thrombosis, leading to lo-
cal ischemia and tissue necrosis. This fosters an environment con-
Microbiology and Pathophysiology
ducive to bacterial growth and limits antibiotic delivery to the
NSTIs are categorized as type 1 (polymicrobial) or type 2 (monomicro- necrotic tissue.10,11 Frequently, the inflammatory response trig-
bial). Type 1 is significantly more common, generally seen in gered by toxins and cytokines progresses to septic shock requiring
older patients or immunocompromised patients with comorbidities.4 intensive care unit (ICU) admission, mechanical ventilation, and/or
Type 2 may affect patients of all ages and those without vasopressor support.2

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 Necrotizing Soft Tissue Infections Review Clinical Review & Education

Table 1. Signs and Symptoms of Necrotizing Soft Tissue Infection Table 2. Differential Diagnoses and Distinguishing Features From NSTI
Percentage of patients Differential
Sign at presentation diagnosis Distinguishing features from NSTI
Classic Cellulitis • Often not associated with hemodynamic instability,
shock, or severe pain
Bullae 25.6 • Less associated with violaceous skin changes
Skin necrosis 24.1 Pyoderma • Not associated with sepsis, fever
gangrenosum • Associated with inflammatory bowel disease
Crepitus 20.3 • Progresses slower than NSTI
• Violaceous ulcer edges
Gas on radiographic evaluation 24.8 • Resistant to blunt dissection
Nonspecific • Typically has negative blood and tissue cultures
Pyomyositis • Characterized by abscess formation in muscles
Swelling 80.8 • Imaging shows focal muscle swelling and
Pain or tenderness 79 well-demarcated areas of fluid
Deep vein • Pain is less severe than that of NSTI
Erythema 70.7 thrombosis • Fever may be present, though less common
Warmth 44 than in NSTI
Erysipelas • Raised, sharply demarcated borders
Fever >37.5 °C 40
Hypotension 21.1 Abbreviation: NSTI, necrotizing soft tissue infection.

Laboratory Findings and Scoring Systems: Diagnostic Value

Future Directions Wall et al20 proposed a model to distinguish NSTIs from non-NSTIs
Host genetics, including HLA class II haplotypes, pathogen recog- based on a white blood cell count higher than 15 400/μL or a
nition receptors, and cytokine genes, are believed to contribute serum sodium level lower than 135 mmol/L. A second study added
to clinical presentation and response to treatment. For example, blood urea nitrogen value greater than 15 mg/dL as a further
host variations may largely explain the diversity of group A Strep- criterion.21
tococcus presentations, ranging from cellulitis to NSTI.12 Genetic Wong and colleagues22 subsequently developed the Labora-
heterogeneity may dictate the host-pathogen interactions that tory Risk Indicator for Necrotizing Fasciitis (LRINEC) score that is
contribute to differing modes of entry and immune evasion.13 based on 6 variables (Table 3). In their index study, a cutoff value of
This developing understanding of pathogenesis and genomics 6 points had a positive predictive value of 92% and negative pre-
may inform future diagnostic and treatment strategies. dictive value of 96% in distinguishing necrotizing fasciitis from cel-
lulitis. It should be noted that this study was specific to necrotizing
fasciitis and not all NSTIs.
The LRINEC score has since been evaluated in multiple, largely
Assessment and Diagnosis
retrospective studies with mixed results. Using a cutoff of 6 for di-
Clinical Presentation and Physical Examination agnosing NSTI of the extremities, studies have reported a sensitiv-
NSTIs affect the extremities (57%-73%), perineum (13%-40%), ity of 49% to 75% and specificity of 83% to 85%, while a cutoff of
trunk (13%-26%), and head and neck (2%-10%). 1 4 NSTIs 8 had a sensitivity of 41% and specificity of 95%.23,24
frequently elude early diagnosis, with reported misdiagnosis rates A recent prospective, multicenter trial proposed a new
ranging from 41% to 96%. 1 4 Diagnostic challenge arises clinical risk index score, Necrotizing Soft Tissue Infections
partly because NSTIs often present with common nonspecific (NECROSIS), to identify NSTIs in emergency general surgery
symptoms (Table 1) that make them difficult to differentiate from patients with skin and soft tissue infections. In a comprehensive
other conditions (Table 2).15,16 While there are several “classic analysis including patient demographics, admission vitals, labora-
signs” of NSTI with a higher specificity, they are seen in less than tory results, physical examination, imaging, and operative find-
half of patients.14,17 ings, the authors identified 3 independent predictors for NSTI:
Concern for NSTI should be heightened in patients with systolic blood pressure of 120 mm Hg or less, violaceous skin, and
comorbid risk factors, including diabetes (present in 22%-59% of white blood cell count greater than 15 000/μL.25 The presence of
cases), obesity (17%-39%), cardiovascular disease (9%-45%), all 3 predictors had a 100% specificity and 100% positive predic-
peripheral arterial disease (3%-19%), intravenous drug use (2%- tive value for both the derivation and the validation cohorts.
80%), chronic alcohol use (6%-30%), chronic liver disease (1%- A prospective study showed that surgeons’ suspicion for NSTI
4%), and immunosuppression (4%-30%).18,19 However, up to a increased significantly from 43% to 86% after reviewing labora-
quarter of patients may have no underlying comorbidities.2 tory values, highlighting the utility of laboratory data on clinical
Because the diagnosis can be elusive, if a surgeon does not decision-making.17 However, the decision to proceed with surgical
feel there is enough evidence to warrant exploration, serial physi- management should prioritize clinical assessment.
cal examinations should be performed at least every 4 to 6 hours.
Extension of erythema beyond the initial border, necrotic or viola- Operative Exploration to Rule Out NSTI
ceous skin changes, or clinical worsening should prompt surgical Given the difficulty and urgency in establishing the diagnosis of
exploration. Detailed assessments should be documented and NSTI, some clinicians advocate operative exploration, even when
communicated, particularly if there is a transfer of care to another the diagnosis is uncertain. Findings characteristic of NSTI include
physician. gray, necrotic fascia; obliteration of soft tissue planes; dishwater

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 Clinical Review & Education Review Necrotizing Soft Tissue Infections

Table 3. Laboratory Risk Indicator Table 4. Empirical Antibiotics for Necrotizing Soft Tissue Infections
for Necrotizing Fasciitis (LRINEC) Score in Patients With Normal Kidney Function

Variable Value Score Patient status Antibiotic combination

White blood cell count <15 0 Stable One of the following antibiotics:
(×10 000/μL) • Amoxicillin/clavulanate, 1.2/2.2 g every 8 h
15-25 +1 • Ceftriaxone, 2 g every 24 h + metronidazole,
>25 +2 500 mg every 8 h
• Cefotaxime, 2 g every 8 h + metronidazole,
Hemoglobin, g/dL >13.5 0 500 mg every 8 h
11-13.5 +1 Plus
• Clindamycin, 600-900 mg every 8 h
<11 +2
Unstable One of the following antibiotics:
Sodium, mEq/L ≥135 0 • Piperacillin/tazobactam, 4.5 g every 6 h
<135 +2 • Meropenem, 1 g every 8 h
• Imipenem/cilastatin, 500 mg every 6 h
Glucose, mg/dL ≤180 0
Plus
>180 +1 One of the following antibiotics:
• Linezolid, 600 mg every 12 h
Creatinine, mg/dL ≤1.6 0 • Tedizolid, 200 mg every 24 h
>1.6 +2 Or
One of the following antibiotics:
C-reactive protein <15 mg/dL 0
• Vancomycin, 25-30 mg/kg loading dose,
≥15 mg/dL +4 then 15-20 mg/kg dose every 8 h
• Daptomycin, 6-8 mg/kg every 24 h
SI conversion factors: To convert creatinine to μmol/L, multiply by 88.4; glucose • Telavancin, 10 mg/kg every 24 h
to mmol/L, multiply by 0.0555. Plus
• Clindamycin, 600-900 mg every 8 h

fluid; lack of bleeding; thrombosed vessels; lack of resistance

to finger dissection in normally adherent tissue; or noncontract- potential predictor of prognosis is modeling done by machine
ing muscle. In a retrospective study of 295 patients with sus- learning. A set of 16 predictive parameters available on or before
pected NSTI who went to the operating room, Howell et al 26 the first day of ICU care has been shown to predict 30-day
noted a 20% negative exploration rate. The authors concluded mortality and outperform current scoring systems.39 Continued
that clinicians should accept a certain negative exploration rate to developments in machine learning may yield more extensive clini-
avoid missing or delaying the diagnosis. cal decision support systems to predict multiple outcomes.

Future Directions
Biomarker-based diagnostics are promising diagnostic adjuncts. Imaging
Thrombomodulin has been shown to differentiate true NSTIs Multiple imaging modalities, including plain radiographs, ultra-
from suspected NSTIs. 27 Similarly, Rath et al 28 identified 9 sound, computed tomography (CT), and magnetic resonance
biomarkers that differentiated β-hemolytic streptococcal NSTI imaging have been proposed to help establish the diagnosis of NSTI
from cellulitis: IL-1β, TNF-α, CXCL8, MMP-8, IL-6, pentraxin-3, but consistently fall short in their sensitivity. Given concerns that
IL-22, CCL4, and S100A8. imaging may delay operative intervention, guidelines do not offer
Metabolomic analyses may assist with diagnosis and manage- firm recommendations.6,40-42
ment. In an evaluation of 97 metabolites, the abundance of 33 were Plain radiographs can detect gas in soft tissues, a finding that is
significantly altered in plasma samples of patients with NSTI com- specific (94%) but not sensitive (49%) for NSTIs, as gas is found in
pared with controls without infection.29 Metabolite-specific ef- less than 25% of images.11,14,24 Despite limited sensitivity, plain ra-
fects observed in vitro demonstrated their role in both bacterial diographs are typically used as an initial imaging step because of their
growth and biofilm formation, a complicating feature that may re- accessibility.
quire changes in antibiotic treatment.29 CT is readily available at most hospitals and provides more in-
formation than plain films. It can detect air within soft tissues and
Laboratory Data and Scoring Systems: Prognostic Value other subtle signs such as fascial enhancement or edema, with a re-
Small retrospective studies have identified several factors that may ported diagnostic sensitivity of 89% and specificity of 93%.24 Thus,
suggest a poor prognosis: hyperlactatemia, hyponatremia, leuko- CT may serve to increase suspicion for NSTI but should only be con-
cytosis, and elevated creatinine.21,30-32 NSTI-specific scoring sys- sidered when immediate exploration is not deemed necessary. Given
tems, such as LRINEC, are less accurate than non–disease-specific that lack of availability may delay intervention, magnetic reso-
physiologic scores for prognostication.33-35 nance imaging is not recommended as a diagnostic tool in patients
with high suspicion for NSTI.
Future Directions Ultrasound may be helpful given that it can be performed at the
Multiple studies have attempted to identify markers of disease bedside. In a systematic review, Marks et al43 reported that fluid ac-
severity and mortality risk. Molecules such as ICAM-1, urokinase- cumulation along the fascial plane was the most sensitive (85.4%;
type plasminogen activator receptor (suPAR), pentraxin-3, 95% CI, 72.2%-93.9%), while subcutaneous emphysema was the
and fibrocolin-2 have all demonstrated potential value in NSTI most specific (100%; 95% CI, 92.5%-100%). Given the small num-
prognostication. 36-38 However, perhaps the most promising ber of studies, ultrasound is not yet widely used.

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 Necrotizing Soft Tissue Infections Review Clinical Review & Education

Future Directions hours of presentation.30 Kobayashi et al52 found that delayed

Imaging modalities that differentiate necrotic from viable tissue (>12 hours) surgery is associated with an increased number
have yielded promising results in small studies. Indocyanine green of surgical debridements and higher incidence of septic shock.
perfusion imaging may distinguish NSTIs based on diminished Consistent with these series, Eastern Association for the Surgery
fluorescence in affected tissues.44 Thermal infrared cameras may of Trauma guidelines recommend debridement within 12 hours of
be used to detect temperature differentials in necrotic vs viable suspected diagnosis. In an evaluation of 6 studies comparing
tissue. In a study of perineal NSTIs, preoperative infrared photos patients who underwent early (<12 hours) and late (>12 hours)
correlated with resection margins in 13 of 16 patients (81%).45 operative debridement, early debridement was associated with
Further studies are necessary to determine if such modalities will improved mortality, 14% vs 26% (P = .005).42
affect the extent of debridement and clinical outcomes. More recent joint guidelines from the World Society of
Emergency Surgery, Global Alliance for Infections in Surgery (GAIS),
Surgical Infection Society Europe, World Surgical Infection Society,
and American Association for the Surgery of Trauma advocate for
Treatment
even earlier intervention, within 6 hours of admission, citing a re-
Antimicrobial Therapy cent meta-analysis demonstrating that surgery within this time frame
In all cases of suspected NSTI, empirical broad-spectrum antimicro- offers additional mortality benefit compared with surgery after
bial therapy should be initiated promptly after blood cultures. 6 hours (odds ratio, 0.43; 95% CI, 0.26-0.70; 10 studies included).
This therapy should cover Gram-positive (including methicillin- The authors observed a 19% mortality rate when performed within
resistant S aureus [MRSA]), Gram-negative, and anaerobic organ- 6 hours vs 32% when delayed more than 6 hours.1,6 In summary, if
isms. Typically, this includes an intravenous broad-spectrum there is high suspicion for NSTI, surgery should be performed as soon
β-lactam, with adjustments based on individual patient factors. For as possible, ideally within 6 hours.
suspected MRSA, vancomycin or linezolid should be added, and for
resistant Gram-negative infections, carbapenems are recom- Repeat Surgical Evaluation and Debridement
mended. Empirical therapy recommended by society guidelines can Current society guidelines recommend re-explorations every 12
be found in Table 4.6 to 24 hours after the initial operation or earlier if there are signs of
In unstable patients with systemic symptoms suggestive of toxic disease progression or concerning laboratory results.6 It is not
shock syndrome, clindamycin is recommended to limit exotoxin uncommon for patients to require 3 to 4 operations to obtain
production.6 Empirical antifungal therapy should be considered in source control. 11 In a prospective observational study, Okoye
immunocompromised patients.46 et al53 found that repeat debridement at 24 hours compared with
Antibiotic duration for NSTI varies widely because of a lack of 48 hours after initial source control was associated with lower
high-quality evidence to guide recommendations.47 There is no con- mortality (7% vs 33%) and less acute kidney injury (9% vs 33%).
sensus as to whether a fixed duration is preferred over a variable du-
ration that is based on improvement in clinical and/or laboratory val- Skin-Sparing Debridement
ues. Several recent studies have found no differences in mortality Skin-sparing debridement has been proposed as a less morbid
or amputation rates with short (ⱕ7 days) vs long (>7 days) antibi- alternative to en bloc resection. The approach may be suitable
otic duration.48,49 Prospective and retrospective studies have sug- for cases involving only fascia, when overlying skin and subcuta-
gested that 48 hours of antibiotics after source control is as safe and neous tissue are normal. In this technique, a series of counterinci-
effective as a longer course.50,51 The Infectious Diseases Society of sions permit the removal of subcutaneous necrotic tissue while
America (IDSA) has suggested to continue antibiotics until source preserving viable overlying skin.54 The intent of a skin-sparing
control has been achieved and there is no additional evidence of sys- approach is to limit large open wounds that require skin grafting.
temic infection, including the absence of a fever for 48 to 72 hours.40 Several authors suggest a skin-sparing approach provides equiva-
lent source control and similar mortality rates.54,55 However,
Surgery given limited data, the decision to consider this approach should
Source control with early and aggressive surgical debridement be made with caution, as the risk of inadequate debridement may
is the most important determinant of outcome in NSTIs. 6,40 lead to disease progression.
The goal of debridement is to remove all necrotic tissue so that
only healthy bleeding tissue remains. Given that infection often Role of Amputation
extends beyond observed cutaneous findings, debridement In NSTIs affecting the extremities, amputation is necessary in up
beyond the area of skin changes may be required.11 Culture and to 25% of cases. 1,31 Amputation may be considered when (1)
Gram stain of deep tissue should be obtained during operative source control cannot be achieved with debridement, (2) recon-
debridement, including fungal cultures, to inform subsequent struction is unfeasible, or (3) functional status is expected to be
antibiotic therapy.40 better with amputation than reconstruction. It is important to dis-
cuss the possibility of amputation with the patient or their surro-
Timing of Surgery gate preoperatively.
Urgent surgical debridement is necessary for optimal outcomes,
yet the exact timing continues to be refined. A single-center Surgeon Specialty
series with 124 patients reported a relatively low mortality At some centers, the anatomic location of NSTI may dictate surgi-
rate (17%), with 75% of the patients having surgery within 8.5 cal specialty; for example, Fournier gangrene may be primarily

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 Clinical Review & Education Review Necrotizing Soft Tissue Infections

managed by urology. However, given the time-sensitive nature of Furthermore, HBOT is not readily available at many institutions.
initial debridement, surgeon availability may be more important While HBOT protocols vary by institution, they usually recom-
than surgeon specialty. A small study found similar outcomes mend initiation with 1 to 2 sessions within 24 hours after initial
when patients with Fournier gangrene were managed by general debridement, followed by 1 to 2 sessions per day for several days
surgery or urology services.56 or until no additional necrosis is observed.63

Postoperative Wound Care

Negative pressure wound therapy (NPWT) is an adjunctive treat- Intravenous Immunoglobulin Therapy
ment that applies subatmospheric pressure to the wound surface Intravenous immunoglobulin (IVIG) therapy has been used for
after debridement. The optimal timing for initiating NPWT and its NSTI treatment, primarily to enhance bacterial opsonization and
appropriateness for all patients with NSTIs remain unclear. toxin neutralization.18 Patients with NSTI often have lower levels
Numerous studies suggest that NPWT reduces the size of the of protective antibodies toward key virulence factors including
wound surface, removes exudate and residue, increases tissue streptococcal pyrogenic exotoxin B and superantigens, which
perfusion, and stimulates granulation tissue.57 A recent meta- IVIG could potentially supplement.64
analysis demonstrated that NPWT was associated with lower Current evidence is conflicting regarding the impact of IVIG
mortality but no difference in length of stay, number of debride- on clinical outcomes. First, few patients receive IVIG, limiting the
ments, or complication rates as compared with conventional power of studies to detect a difference.65 Second, observational
dressings.58 studies may be confounded by several factors, including severity
A recent study questioned the use of NPWT in exclusively an- of illness and inconsistent coadministration of clindamycin.
aerobic infections, as oxygen deprivation may be less effective A meta-analysis of 4 observational studies and 1 randomized
against these species. The authors reported that patients with an- clinical trial (RCT) evaluating IVIG in clindamycin-treated patients
aerobic NSTIs treated with NPWT had an increased number of de- with streptococcal toxic shock syndrome observed that mortality
bridements and a higher readmission rate compared with patients decreased from 33.7% to 15.7% with IVIG therapy.66 A multi-
with aerobic or polymicrobial infections.59 center prospective study of patients with streptococcal NSTI
Given the need for frequent wound checks in the early postop- reported improved 90-day mortality with IVIG, though shorter
erative period, it may be best to delay initiation of NPWT until the time to initial and subsequent surgeries may have biased the
patient undergoes repeated debridements and the wound is deemed outcomes.9 When tested in an RCT (INSTINCT trial), IVIG demon-
stable. strated no difference compared with placebo in surrogate out-
comes (cytokines in the first 3 days of treatment) or in clinical
Should Patients With Suspected NSTI Be Transferred? outcomes (mortality, organ failure, use of life support, or 6-month
Given the need for complex multidisciplinary care, patients may quality of life).67,68 Thus, although joint guidelines say IVIG can be
benefit from transfer to specialized, high-volume regional centers considered, IDSA guidelines make no recommendations, recog-
or burn centers, which have been associated with lower mortality nizing the limited evidence available.6,40
rates.2,42 However, the desire to transfer must be tempered by
the urgency of surgical intervention. Patients who are transferred
have higher mortality rates (up to double) compared with those Future Directions
treated immediately at the presenting hospital.21,60 Therefore, As genomic, proteomic, and metabolomic data accumulate, the
initial debridement should ideally occur at the first hospital, or ability to personalize care based on genetic signatures will
systems for rapid transfer should be established, akin to other improve. The Improving Outcome of Necrotizing Fasciitis:
surgical emergencies. One such system, termed a hub-and-spoke Elucidation of Complex Host and Pathogen Signatures That
model, concentrates specialized care at a hub hospital with spoke Dictate Severity of Tissue Infection (INFECT) project is a multi-
hospitals having a mechanism to expeditiously transfer their center prospective observational study that will build under-
patients. This model has been shown to increase the proportion standing of the pathophysiology and prognosis of NSTIs to inform
of patients who undergo debridement within the guideline- diagnosis and individualized treatment.69 Additionally, pathogen
recommended time frame.61 genomics remain an area of interest for vaccine development,
including current preclinical and clinical evaluations of vaccines
Adjuncts against group A Streptococcus.70
Hyperbaric Oxygen Therapy Immune modulators may offer additional future therapies for
Evidence supporting the clinical efficacy of hyperbaric oxygen NSTIs, aimed at attenuating the inflammatory cytokine response and
therapy (HBOT) in NSTIs is limited to observational studies, which decreasing the incidence of persistent organ dysfunction. Relteci-
are prone to selection bias because critically ill patients mod (AB-103), a CD28 T-lymphocyte receptor mimetic, inhibits
may not be stable enough for receipt of HBOT. Two recent meta- T-cell activation by bacterial pathogens. A phase 3 RCT of relteci-
analyses, both including nearly 50 000 patients with NSTIs, indi- mod found significant improvements in the composite end points:
cated significantly lower mortality with HBOT but no effect on alive at day 28, 3 or fewer debridements, no amputation beyond first
amputation rates. 62,63 Guidelines on HBOT use in NSTIs are operation, and day 14 Modified Sequential Organ Failure
mixed: IDSA recommends against HBOT, while other society Assessment score of 1 or less with a point reduction of 3 or more.71
guidelines suggest considering it. HBOT should not delay surgical Additional studies are needed to determine its effectiveness in clini-
debridement nor interfere with aggressive ICU support. 6,40 cal practice.

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 Necrotizing Soft Tissue Infections Review Clinical Review & Education

Box. Top 10 Key Points and Recommendations for NSTIs Prognosis

Rapid diagnosis of NSTI is critical, yet differentiating it from less
serious conditions such as cellulitis remains extremely challenging, NSTIs are associated with high rates of morbidity and mortality,
as less than one-half of patients have “classic” signs on physical which are even higher among those who are socioeconomically dis-
examination. advantaged. Black patients have a higher risk of complications, in-
Laboratory values may raise suspicion for NSTI. However, a low cluding a 40% increased odds of amputation, whereas Hispanic pa-
LRINEC score does not rule out the diagnosis; clinical suspicion tients and patients with Medicaid or Medicare insurance have nearly
should take precedence over LRINEC score in the decision to a 60% increased risk of mortality compared with White or pri-
proceed with surgical management. vately insured patients, respectively.19,72 Contributors to these dis-
Plain radiographs and CT scan may raise suspicion of NSTI but parities require further exploration.
should neither prolong time to definitive surgical care nor deter
Persistent organ dysfunction after 14 days is a strong predic-
surgery if clinical suspicion is high.
tor of increased resource needs, unfavorable discharge outcomes,
Broad-spectrum empirical antibiotics should be initiated in all pa-
and elevated long-term mortality.35 Outside of the acute treat-
tients with suspected NSTI until deep tissue cultures and sensitivi-
ment period, patients require long-term multidisciplinary support
ties enable more targeted therapy. Antibiotics should be contin-
ued at least until surgical debridement is complete and the patient as they recover from critical illness and the consequences of ag-
shows signs of clinical improvement. Additional research is needed gressive surgical debridement or amputation, which are com-
to determine the optimal duration of treatment. monly associated with new challenges in daily activity and pain
Transferring a patient with NSTI to a higher level of care before management.73 Patients recovering from NSTIs report decreased
debridement may be associated with a higher mortality because of health-related quality of life, particularly in the domains of de-
the inherent delays in getting the patient to the operating room. creased physical functioning, greater limitations in daily life, de-
Surgical exploration is acceptable when there is high suspicion for creased feelings of overall health compared with others, and in-
NSTI, even if the diagnosis is not definitively established. It is ac- creased rates of depressive and/or posttraumatic stress
ceptable to have a certain rate of negative explorations given the disorders.74,75 As knowledge about the diagnosis and treatment of
importance of early intervention.
NSTIs evolve, more emphasis should be placed on understanding
Early surgical debridement is crucial. Surgeons should strive to get long-term patient-reported outcomes.
the patient to the operating room within 6 hours of presentation
because early debridement is associated with lower mortality.
Surgical re-exploration should be performed every 12 to 24 hours.
Re-exploration should continue until the patient is showing signs Conclusions
of clinical improvement and it appears that no additional debride-
ment is required. NSTIs are a challenging spectrum of disease with limited high-
The routine use of hyperbaric oxygen therapy is not yet recom-
quality evidence to inform best practice. Diagnosis and timely treat-
mended: more research is needed. If used, it should not interfere ment rely on a high index of suspicion because physical examina-
with surgical management or supportive care. tion findings, laboratory values, and imaging findings are rarely
The routine use of IVIG therapy is not yet supported. IVIG may pathognomonic. The cornerstone of improving outcomes in NSTI
provide benefit in the setting of streptococcal NSTIs and toxic is early and aggressive surgical debridement. Clinicians should be
shock syndrome. aware of the multiple promising diagnostic and treatment modali-
Abbreviations: CT, computed tomography; IVIG, intravenous
ties on the horizon. Key points and recommendations are pre-
immunoglobulin; LRINEC, Laboratory Risk Indicator for Necrotizing Fasciitis; sented in the Box.
NSTI, necrotizing soft tissue infection.

ARTICLE INFORMATION register-based cohort study. BMJ Open. 2020;10 study. Intensive Care Med. 2019;45(9):1241-1251.
Accepted for Publication: June 3, 2024. (10):e041302. doi:10.1136/bmjopen-2020-041302 doi:10.1007/s00134-019-05730-x

Published Online: September 11, 2024. 3. May AK, Talisa VB, Wilfret DA, et al. Estimating 6. Sartelli M, Coccolini F, Kluger Y, et al.
doi:10.1001/jamasurg.2024.3365 the impact of necrotizing soft tissue infections in WSES/GAIS/WSIS/SIS-E/AAST global clinical
the United States: incidence and re-admissions. pathways for patients with skin and soft tissue
Conflict of Interest Disclosures: None reported. Surg Infect (Larchmt). 2021;22(5):509-515. doi:10. infections. World J Emerg Surg. 2022;17(1):3. doi:10.
1089/sur.2020.099 1186/s13017-022-00406-2
REFERENCES
4. Naamany E, Shiber S, Duskin-Bitan H, et al. 7. Morgan MS. Diagnosis and management of
1. Nawijn F, Smeeing DPJ, Houwert RM, Leenen Polymicrobial and monomicrobial necrotizing soft necrotising fasciitis: a multiparametric approach.
LPH, Hietbrink F. Time is of the essence when tissue infections: comparison of clinical, laboratory, J Hosp Infect. 2010;75(4):249-257. doi:10.1016/j.
treating necrotizing soft tissue infections: radiological, and pathological hallmarks and jhin.2010.01.028
a systematic review and meta-analysis. World J prognosis, a retrospective analysis. Trauma Surg
Emerg Surg. 2020;15:4. doi:10.1186/s13017-019- 8. Anaya DA, Patcher Dellinger E. Necrotizing
Acute Care Open. 2021;6(1):e000745. doi:10.1136/ soft-tissue infection: diagnosis and management.
0286-6 tsaco-2021-000745 Clin Infect Dis. 2007;44(5):705-710. doi:10.1086/
2. Hedetoft M, Madsen MB, Madsen LB, 5. Madsen MB, Skrede S, Perner A, et al; INFECT 511638
Hyldegaard O. Incidence, comorbidity and study group. Patient’s characteristics and outcomes
mortality in patients with necrotising soft-tissue 9. Bruun T, Rath E, Madsen MB, et al; INFECT
in necrotising soft-tissue infections: results from a Study Group. Risk factors and predictors of
infections, 2005-2018: a Danish nationwide Scandinavian, multicentre, prospective cohort mortality in streptococcal necrotizing soft-tissue

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 Clinical Review & Education Review Necrotizing Soft Tissue Infections

infections: a multicenter prospective study. Clin extremity necrotizing fasciitis. J Foot Ankle Surg. necrotizing soft-tissue infection. J Investig Med.
Infect Dis. 2021;72(2):293-300. doi:10.1093/cid/ 2022;61(2):384-389. doi:10.1053/j.jfas.2021.09.015 2021;69(7):1330-1338. doi:10.1136/jim-2021-001837
ciaa027 24. Fernando SM, Tran A, Cheng W, et al. 37. Polzik P, Grøndal O, Tavenier J, et al. SuPAR
10. Bonne SL, Kadri SS. Evaluation and Necrotizing soft tissue infection: diagnostic correlates with mortality and clinical severity in
management of necrotizing soft tissue infections. accuracy of physical examination, imaging, and patients with necrotizing soft-tissue infections:
Infect Dis Clin North Am. 2017;31(3):497-511. doi:10. LRINEC score: a systematic review and results from a prospective, observational cohort
1016/j.idc.2017.05.011 meta-analysis. Ann Surg. 2019;269(1):58-65. doi:10. study. Sci Rep. 2019;9(1):5098. doi:10.1038/
11. Hakkarainen TW, Kopari NM, Pham TN, Evans 1097/SLA.0000000000002774 s41598-019-41688-y
HL. Necrotizing soft tissue infections: review and 25. Kim DY, Iavasile A, Kaji AH, et al. Prospective 38. Hansen MB, Rasmussen LS, Garred P, Bidstrup
current concepts in treatment, systems of care, and derivation and validation of a necrotizing soft tissue D, Madsen MB, Hyldegaard O. Pentraxin-3 as a
outcomes. Curr Probl Surg. 2014;51(8):344-362. infections (NECROSIS) score: an EAST multicenter marker of disease severity and risk of death in
doi:10.1067/j.cpsurg.2014.06.001 trial. J Trauma Acute Care Surg. Published online May patients with necrotizing soft tissue infections:
12. Kotb M, Norrby-Teglund A, McGeer A, et al. An 9, 2024. doi:10.1097/TA.0000000000004374 a nationwide, prospective, observational study. Crit
immunogenetic and molecular basis for differences 26. Howell EC, Keeley JA, Kaji AH, et al. Chance to Care. 2016;20:40. doi:10.1186/s13054-016-1210-z
in outcomes of invasive group A streptococcal cut: defining a negative exploration rate in patients 39. Katz S, Suijker J, Hardt C, et al. Decision
infections. Nat Med. 2002;8(12):1398-1404. doi:10. with suspected necrotizing soft tissue infection. support system and outcome prediction in a cohort
1038/nm1202-800 Trauma Surg Acute Care Open. 2019;4(1):e000264. of patients with necrotizing soft-tissue infections.
13. Jahagirdar S, Morris L, Benis N, et al. Analysis of doi:10.1136/tsaco-2018-000264 Int J Med Inform. 2022;167:104878. doi:10.1016/j.
host-pathogen gene association networks reveals 27. Palma Medina LM, Rath E, Jahagirdar S, et al. ijmedinf.2022.104878
patient-specific response to streptococcal and Discriminatory plasma biomarkers predict specific 40. Stevens DL, Bisno AL, Chambers HF, et al.
polymicrobial necrotising soft tissue infections. clinical phenotypes of necrotizing soft-tissue Practice guidelines for the diagnosis and
BMC Med. 2022;20(1):173. doi:10.1186/s12916-022- infections. J Clin Invest. 2021;131(14):e149523. doi: management of skin and soft tissue infections:
02355-8 10.1172/JCI149523 2014 update by the infectious diseases society of
14. Goh T, Goh LG, Ang CH, Wong CH. Early 28. Rath E, Palma Medina LM, Jahagirdar S, et al; America. Clin Infect Dis. 2014;59(2):147-159. doi:10.
diagnosis of necrotizing fasciitis. Br J Surg. 2014;101 INFECT Study group. Systemic immune activation 1093/cid/ciu444
(1):e119-e125. doi:10.1002/bjs.9371 profiles in streptococcal necrotizing soft tissue 41. Duane TM, Huston JM, Collom M, et al. Surgical
15. Howell EC, Keeley JA, Woods AL, et al. Wound infections: A prospective multicenter study. Clin Infection Society 2020 updated guidelines on the
culture utility in negative surgical exploration for Immunol. 2023;249:109276. doi:10.1016/j.clim.2023. management of complicated skin and soft tissue
necrotizing soft tissue infection. Am Surg. 2019;85 109276 infections. Surg Infect (Larchmt). 2021;22(4):383-399.
(10):1175-1178. doi:10.1177/000313481908501022 29. Saccenti E, Svensson M. Systems biology and doi:10.1089/sur.2020.436

16. Zacharias N, Velmahos GC, Salama A, et al. biomarkers in necrotizing soft tissue infections. Adv 42. Gelbard RB, Ferrada P, Yeh DD, et al. Optimal
Diagnosis of necrotizing soft tissue infections by Exp Med Biol. 2020;1294:167-186. doi:10.1007/ timing of initial debridement for necrotizing soft
computed tomography. Arch Surg. 2010;145(5): 978-3-030-57616-5_11 tissue infection: a practice management guideline
452-455. doi:10.1001/archsurg.2010.50 30. Yaghoubian A, de Virgilio C, Dauphine C, Lewis from the Eastern Association for the Surgery of
RJ, Lin M. Use of admission serum lactate and Trauma. J Trauma Acute Care Surg. 2018;85(1):208-
17. Chan T, Yaghoubian A, Rosing D, Kaji A, de 214. doi:10.1097/TA.0000000000001857
Virgilio C. Low sensitivity of physical examination sodium levels to predict mortality in necrotizing
findings in necrotizing soft tissue infection is soft-tissue infections. Arch Surg. 2007;142(9):840- 43. Marks A, Patel D, Sundaram T, Johnson J,
improved with laboratory values: a prospective 846. doi:10.1001/archsurg.142.9.840 Gottlieb M. Ultrasound for the diagnosis of
study. Am J Surg. 2008;196(6):926-930. doi:10. 31. Schwartz S, Kightlinger E, de Virgilio C, et al. necrotizing fasciitis: A systematic review of the
1016/j.amjsurg.2008.07.025 Predictors of mortality and limb loss in necrotizing literature. Am J Emerg Med. 2023;65:31-35. doi:10.
soft tissue infections. Am Surg. 2013;79(10):1102- 1016/j.ajem.2022.12.037
18. Peetermans M, de Prost N, Eckmann C,
Norrby-Teglund A, Skrede S, De Waele JJ. 1105. doi:10.1177/000313481307901030 44. Streeter SS, Ray GS, Bateman LM, et al. Early
Necrotizing skin and soft-tissue infections in the 32. Keeley J, Kaji A, Kim D, et al. Predictors of identification of life-threatening soft-tissue
intensive care unit. Clin Microbiol Infect. 2020;26 mortality in necrotizing soft tissue infection. Am Surg. infection using dynamic fluorescence imaging:
(1):8-17. doi:10.1016/j.cmi.2019.06.031 2014;80(10):989-993. doi:10.1177/ first-in-kind clinical study of first-pass kinetics. Proc
000313481408001017 SPIE Int Soc Opt Eng. 2023;12361:123610B. doi:10.
19. Psoinos CM, Flahive JM, Shaw JJ, et al. 1117/12.2648408
Contemporary trends in necrotizing soft-tissue 33. Breidung D, Malsagova AT, Barth AA, et al.
infections in the United States. Surgery. 2013;153 Diagnostic and prognostic value of the Laboratory 45. Schlaepfer CH, Flynn KJ, Polgreen PM, Erickson
(6):819-827. doi:10.1016/j.surg.2012.11.026 Risk Indicator for Necrotising Fasciitis (LRINEC) BA. Thermal infrared camera imaging to aid
based on an 18 years’ experience. J Plast Reconstr necrotizing soft tissue infections of the genitalia
20. Wall DB, Klein SR, Black S, de Virgilio C. A management. Urology. 2023;175:202-208. doi:10.
simple model to help distinguish necrotizing Aesthet Surg. 2023;77:228-235. doi:10.1016/j.bjps.
2022.11.061 1016/j.urology.2022.12.056
fasciitis from nonnecrotizing soft tissue infection.
J Am Coll Surg. 2000;191(3):227-231. doi:10.1016/ 34. Yilmazlar T, Ozturk E, Alsoy A, Ozguc H. 46. Khoury MK, Heid CA, Cripps MW, et al.
S1072-7515(00)00318-5 Necrotizing soft tissue infections: APACHE II score, Antifungal therapy in fungal necrotizing soft tissue
dissemination, and survival. World J Surg. 2007;31 infections. J Surg Res. 2020;256:187-192. doi:10.
21. Wall DB, de Virgilio C, Black S, Klein SR. 1016/j.jss.2020.06.013
Objective criteria may assist in distinguishing (9):1858-1862. doi:10.1007/s00268-007-9132-1
necrotizing fasciitis from nonnecrotizing soft tissue 35. Brakenridge SC, Wilfret DA, Maislin G, et al. 47. Faraklas I, Yang D, Eggerstedt M, et al.
infection. Am J Surg. 2000;179(1):17-21. doi:10. Resolution of organ dysfunction as a predictor of A multi-center review of care patterns and
1016/S0002-9610(99)00259-7 long-term survival in necrotizing soft tissue outcomes in necrotizing soft tissue infections. Surg
infections: analysis of the AB103 Clinical Composite Infect (Larchmt). 2016;17(6):773-778. doi:10.1089/
22. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. sur.2015.238
The LRINEC (Laboratory Risk Indicator for Endpoint Study in Necrotizing Soft Tissue
Necrotizing Fasciitis) score: a tool for distinguishing Infections trial and a retrospective claims 48. Lyons NB, Cohen BL, O’Neil CF Jr, et al. Short
necrotizing fasciitis from other soft tissue database-linked chart study. J Trauma Acute Care versus long antibiotic duration for necrotizing soft
infections. Crit Care Med. 2004;32(7):1535-1541. Surg. 2021;91(2):384-392. doi:10.1097/TA. tissue infection: a systematic review and
doi:10.1097/01.CCM.0000129486.35458.7D 0000000000003183 meta-analysis. Surg Infect (Larchmt). 2023;24(5):
36. Hedetoft M, Jensen PØ, Moser C, Vinkel J, 425-432. doi:10.1089/sur.2023.037
23. Tarricone A, Mata K, Gee A, et al. A systematic
review and meta-analysis of the effectiveness of Hyldegaard O. Hyperbaric oxygen treatment 49. Horn DL, Chan JD, Li K, et al. Defining the
LRINEC score for predicting upper and lower impacts oxidative stress markers in patients with optimal antibiotic duration in necrotizing skin and
soft tissue infections: clinical experience from a

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 Necrotizing Soft Tissue Infections Review Clinical Review & Education

quaternary referral center. Surg Infect (Larchmt). 59. Afzal H, Dawson E, Fonseca R, et al. Does cytokine response in necrotising soft-tissue
2023;24(8):741-748. doi:10.1089/sur.2022.294 negative pressure wound therapy impact the infection: A post hoc analysis. Acta Anaesthesiol
50. Terzian WTH, Nunn AM, Call EB, et al. Duration outcome for patients with necrotizing soft tissue Scand. 2021;65(9):1293-1299. doi:10.1111/aas.13942
of antibiotic therapy in necrotizing soft tissue infection infected with anaerobic bacteria? Surg 68. Madsen MB, Hjortrup PB, Hansen MB, et al.
infections: shorter is safe. Surg Infect (Larchmt). Infect (Larchmt). 2024;25(3):179-184. doi:10.1089/ Immunoglobulin G for patients with necrotising soft
2022;23(5):430-435. doi:10.1089/sur.2022.011 sur.2023.300 tissue infection (INSTINCT): a randomised, blinded,
51. Kenneally AM, Warriner Z, VanHoose JD, et al. 60. Khoury MK, Pickett ML, Cripps MW, et al. placebo-controlled trial. Intensive Care Med. 2017;
Evaluation of antibiotic duration after surgical Transfer is associated with a higher mortality rate in 43(11):1585-1593. doi:10.1007/s00134-017-4786-0
debridement of necrotizing soft tissue infection. necrotizing soft tissue infections. Surg Infect 69. Madsen MB, Skrede S, Bruun T, et al.
Surg Infect (Larchmt). 2022;23(4):357-363. doi:10. (Larchmt). 2020;21(2):136-142. doi:10.1089/sur.2019. Necrotizing soft tissue infections, a multicentre,
1089/sur.2021.256 091 prospective observational study (INFECT): protocol
52. Kobayashi L, Konstantinidis A, Shackelford S, 61. Ginzberg SP, Roberson JL, Nehemiah A, et al. and statistical analysis plan. Acta Anaesthesiol Scand.
et al. Necrotizing soft tissue infections: delayed Time to transfer as a quality improvement 2018;62(2):272-279. doi:10.1111/aas.13024
surgical treatment is associated with increased imperative: implications of a hub-and-spoke health 70. Vekemans J, Gouvea-Reis F, Kim JH, et al. The
number of surgical debridements and morbidity. system model on the timing of emergency path to group A streptococcus vaccines: World
J Trauma. 2011;71(5):1400-1405. doi:10.1097/TA. procedures. Jt Comm J Qual Patient Saf. 2023;49 Health Organization research and development
0b013e31820db8fd (10):539-546. doi:10.1016/j.jcjq.2023.06.008 technology roadmap and preferred product
53. Okoye O, Talving P, Lam L, et al. Timing of 62. Huang C, Zhong Y, Yue C, He B, Li Y, Li J. The characteristics. Clin Infect Dis. 2019;69(5):877-883.
redébridement after initial source control impacts effect of hyperbaric oxygen therapy on the clinical doi:10.1093/cid/ciy1143
survival in necrotizing soft tissue infection. Am Surg. outcomes of necrotizing soft tissue infections: 71. Bulger EM, May AK, Robinson BRH, et al;
2013;79(10):1081-1085. doi:10.1177/ a systematic review and meta-analysis. World J ACCUTE Study Investigators. A novel immune
000313481307901025 Emerg Surg. 2023;18(1):23. doi:10.1186/s13017-023- modulator for patients with necrotizing soft tissue
00490-y infections (NSTI): results of a multicenter, phase 3
54. Suijker J, Zheng KJ, Pijpe A, Nasroe F, Meij-de
Vries A. The skin-sparing debridement technique in 63. Hedetoft M, Bennett MH, Hyldegaard O. randomized controlled trial of reltecimod (AB 103).
necrotizing soft-tissue infections: a systematic Adjunctive hyperbaric oxygen treatment for Ann Surg. 2020;272(3):469-478. doi:10.1097/SLA.
review. J Surg Res. 2021;264:296-308. doi:10.1016/ necrotising soft-tissue infections: a systematic 0000000000004102
j.jss.2021.03.001 review and meta-analysis. Diving Hyperb Med. 72. Randhawa KS, Ko VH, Turner AL, Merchant AM.
2021;51(1):34-43. doi:10.28920/dhm51.1.34-43 Racial and socioeconomic disparities in necrotizing
55. Tom LK, Maine RG, Wang CS, Parent BA, Bulger
EM, Keys KA. Comparison of traditional and 64. Norrby-Teglund A, Kaul R, Low DE, et al. soft-tissue infection. J Invest Surg. 2022;35(6):
skin-sparing approaches for surgical treatment of Evidence for the presence of streptococcal- 1279-1286. doi:10.1080/08941939.2022.2043960
necrotizing soft-tissue infections. Surg Infect superantigen-neutralizing antibodies in normal 73. Nawijn F, Kerckhoffs MC, Hietbrink F. Quality of
(Larchmt). 2020;21(4):363-369. doi:10.1089/sur. polyspecific immunoglobulin G. Infect Immun. life after intensive care unit admittance for
2019.263 1996;64(12):5395-5398. doi:10.1128/iai.64.12.5395- necrotizing soft tissue infections is deemed
5398.1996 acceptable for patients. Surg Infect (Larchmt).
56. Chawla SN, Gallop C, Mydlo JH. Fournier’s
gangrene: an analysis of repeated surgical 65. Kadri SS, Swihart BJ, Bonne SL, et al. Impact of 2023;24(10):924-929. doi:10.1089/sur.2023.184
debridement. Eur Urol. 2003;43(5):572-575. doi:10. intravenous immunoglobulin on survival in 74. Urbina T, Canoui-Poitrine F, Hua C, et al.
1016/S0302-2838(03)00102-7 necrotizing fasciitis with vasopressor-dependent Long-term quality of life in necrotizing soft-tissue
shock: a propensity score-matched analysis from infection survivors: a monocentric prospective
57. Kim PJ, Attinger CE, Constantine T, et al. 130 US hospitals. Clin Infect Dis. 2017;64(7):877-885.
Negative pressure wound therapy with instillation: cohort study. Ann Intensive Care. 2021;11(1):102.
doi:10.1093/cid/ciw871 doi:10.1186/s13613-021-00891-9
international consensus guidelines update. Int
Wound J. 2020;17(1):174-186. doi:10.1111/iwj.13254 66. Parks T, Wilson C, Curtis N, Norrby-Teglund A, 75. Suijker J, Stoop M, Meij-de Vries A, et al. The
Sriskandan S. Polyspecific intravenous impact of necrotizing soft tissue infections on the
58. Zhang R, Zhang Y, Hou L, Yan C. immunoglobulin in clindamycin-treated patients
Vacuum-assisted closure versus conventional lives of survivors: a qualitative study. Qual Life Res.
with streptococcal toxic shock syndrome: 2023;32(7):2013-2024. doi:10.1007/s11136-023-
dressing in necrotizing fasciitis: a systematic review a systematic review and meta-analysis. Clin Infect Dis.
and meta-analysis. J Orthop Surg Res. 2023;18(1):85. 03371-8
2018;67(9):1434-1436. doi:10.1093/cid/ciy401
doi:10.1186/s13018-023-03561-7
67. Hedetoft M, Madsen MB, Perner A, Garred P,
Hyldegaard O. Effect of immunoglobulin G on

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