□ REVIEW ARTICLE □
1and Yasuharu Tokuda2
Necrotizing fasciitis (NF) is a necrotizing soft tissue infection that can cause rapid local tissue destruction,
necrosis and life-threatening severe sepsis. Predisposing conditions for NF include diabetes, malignancy, alco-
hol abuse, and chronic liver and kidney diseases. NF is classified into two categories (types 1 and 2) based
on causative microorganisms. The initial clinical picture of NF mimics that of cellulitis or erysipelas, includ-
ing fever, pain, tenderness, swelling and erythema. The cardinal manifestations of NF are severe pain at onset
out of proportion to local findings, hemorrhagic bullae and/or vital sign abnormality. In such cases, NF
should be strongly suspected and immediate surgical intervention should be considered, along with broad-
spectrum antimicrobials and general supportive measures, regardless of the findings of imaging tests.
Key words: necrotizing fasciitis, review
(Inter Med 49: 1051-1057, 2010)
Necrotizing fasciitis (NF) is a life-threatening soft tissue
infection that was first described by Hippocrates around the
fifth century. The etiology has been recognized for centuries
and the term “Necrotizing Fasciitis” was first used by
Joseph Jones, a former Confederate Army surgeon, in
1871 (1). From the clinical point of view, NF is defined as a
severe infection of the deep soft tissue, including fascia. It
progresses rapidly, leading to significant morbidity and mor-
tality. NF is classically caused by group A streptococcus
(Type 2 NF) and may develop Streptococcal Toxic Shock
Syndrome (STSS) which is characterized by shock and mul-
tiple organ failure due to toxin by group A streptococcus.
NF sometimes overlaps with STSS [in 40% of patients with
NF, and 6% with other patients (p<0.001)] (2). Distinguish-
ing NF from other soft tissue infections is notoriously diffi-
cult but crucial, since NF is a surgical emergency that
should be treated as a major alarm that requires timely and
aggressive surgical debridement. Hence, this disease chal-
lenges the diagnostic skills and surgical fortitude of physi-
cians. In this review, we provide a broad description of the
clinical characteristics of NF, ranging from epidemiology to
The US Centers for Disease Control and Prevention
(CDC) has estimated that more than 500 to 1,000 cases of
NF are diagnosed each year in the United States (2). How-
ever, the accuracy of this estimate is difficult to ascertain
because of the many synonyms for these entities. The an-
nual rate of NF has been reported to be 0.40 cases per
100,000 population (3), with a recent exponential increase in
this rate (4). NF is caused by infection, and the predisposing
factors are considered to include drugs, hypersensitivity, vas-
cular problems, burn, insect bite, needle stick injury, and
trauma (5-10). NF can lead to severe sepsis, specifically in
patients with immunosuppression, diabetes, malignancy,
drug abuse, and chronic kidney disease (11-15). Several re-
ports also indicate that intravenous drug use is a leading risk
factor for NF (16-19). NF is seen more frequently in winter,
although cases with NF by Vibrio vulnificus are seen more
frequently in summer seasons, is more common in men (4),
and occurs at any age, although the incidence increases with
higher age. About 50% of patients have a history of skin in-
jury, 25% have experienced blunt trauma, and 70% have one
or more chronic illnesses. Half of cases occur in a single
lower limb and one-third in a single upper limb.
１Rollins School of Public Health, Emory University, Georgia, Atlanta, USA and
sive Human Sciences, University of Tsukuba, Ibaraki
Received for publication October 2, 2009; Accepted for publication February 16, 2010
Correspondence to Dr. Taro Shimizu, firstname.lastname@example.org
２Institute of Clinical Medicine, Graduate School of Comprehen-
Inter Med 49: 1051-1057, 2010DOI: 10.2169/internalmedicine.49.2964
F i g u r e 1 . A 5 0 - y e a r - o l d d i a b e t i c w o ma n p r e s e n t e d w i t h f e -
v e r a n d p a i n f u l s w e l l i n g o f t h e l e f t f o o t w i t h e r y t h e ma , l o c a l
h e a t a n d b u l l a e ( a r r o w ) . T h e r e w a s c h r o n i c d i a b e t i c g a n -
g r e n e o f t h e 3 r d p h a l a n x ( a r r o w h e a d ) . S u r g i c a l e x p l o r a t i o n
r e v e a l e d n e c r o t i z i n g s o f t t i s s u e i n f e c t i o n ( n e c r o t i z i n g f a s c i i t i s )
a n d s u b c u t a n e o u s a b s c e s s . B l o o d a n d t i s s u e c u l t u r e g r e w
me t h i c i l l i n - s e n s i t i v e S t a p h y l o c o c c u s a u r e u s . T h i s p h o t o g r a p h
w a s o b t a i n e d w i t h p e r mi s s i o n o f t h e p a t i e n t .
NF is difficult to diagnose in the early stage because of
nonspecific signs such as tenderness, swelling, erythema,
and pain at the affected site that mimic non-severe soft tis-
sue infections (NSTIs) such as cellulitis and erysipe-
las (10, 11, 20). Among them, the cardinal manifestation in
NF is severe pain at onset out of proportion to physical
findings (4, 21, 22). Vibrio and Aeromonas are well known
waterborne organisms that cause NF with high mortality
through infection of patients with chronic illnesses, espe-
cially in the liver. Careful history taking concerning seawa-
ter exposure or fish stings (23) with liver or spleen dysfunc-
tion is the key to narrowing down the candidate organism.
Fever (>38℃) is often absent (44%), but tachycardia
(>100 beats/min) is usually found (59%), while hypotension
(<100 mm Hg) (21%) and tachypnea (>20/min) (26%) are
sometimes present. These three vital sign abnormalities sug-
gest NF rather than NSTI with odds ratios (OR) of 3.4 (1.6-
7.4), 4.5 (1.7-11.8), and 2.6 (1.1-6.0), respectively (24). Al-
though NF can occur anywhere on the body, it is more com-
mon in the extremities (36-55%), trunk (18-64%) and
perineum (up to 36%) (11, 18, 25-27). Infected sites have
erythema (80%), induration (66%), tenderness (54%), fluc-
tuance (35%), skin necrosis (23%), and bullae (11%) (24).
The positive likelihood ratio of the presence of bullae for
NF compared to NSTI is 3.5 (1.0-11.9). In another
study (17), NF patients differed from NSTI with respect to
increased tense edema (23% vs. 3%, p<0.0002), purplish
skin discoloration (10% vs. 1%, p=0.02), and sensory or
motor deficit (13% vs. 3%, p=0.03). Skin necrosis was pre-
sent among 6% of NF patients compared to 2% of those
with NSTI. The initial physical findings of NF are usually
erythematous and ecchymotic skin lesions, but these may
rapidly evolve into hemorrhagic bullae, which indicate the
occlusion of deep blood vessels in the fascia or muscle com-
partments; thus the presence of bullae is an especially im-
portant diagnostic clue (see Fig. 1). There are variants of NF
which involve specific areas of the body, including Lud-
wig’s angina (submandibular space) and Fournier’s gangrene
(scrotum and penis or vulva) and these can show an explo-
sive onset and aggressive clinical course.
Multiple organ dysfunction may reflect liver and kidney
disorders, coagulopathy, and elevated serum creatine kinase
(CK) due to severe sepsis (11, 18, 22, 29, 30). Compared to
patients with NSTI, leukocytosis is commonly present
(84%) (11, 29), especially for patients with WBC >20×109/L
(OR 3.7; 95% CI 1.6-8.5), blood urea nitrogen >18 mg/dL
(OR 6.8; 95% CI 2.9-16.3), and serum creatinine ?1.2 mg/
dL (OR 4.5; 95% CI 1.1-19.5). One study suggested that
WBC >15,400/mm3and serum Na <135 mmol/L with a
careful physical examination may help to separate NF from
NSTI in cases that are strongly suspected to be NF11. An-
other study also suggested that CRP>16 mg/dL or CK >600
IU/L should prompt clinicians to exclude a diagnosis of
group A streptococcus (GAS) NF and to perform a more ex-
pansive diagnostic investigation (31). It is notable that WBC
and CRP may not be useful in patients with liver cirrhosis
because of impairment of protein-productive function of
liver for inflammatory response.
The Laboratory Risk Indicator for NF (LRINEC) score
was developed with the hope of yielding diagnostic clues for
NF, even early in its evolution (29, 32). This score includes
an elevated CRP >150 mg/L (4 points), WBC >25,000/mm3,
blood hemoglobin <11 g/dL, Na <135 mmol/L, serum cre-
atinine >141 μmol/L (2 points each), and blood glucose >10
mmol/L (1 point). The total possible score is 13, and a ret-
rospective study indicated that a score ?6 was highly in-
dicative of NF, with a 92% positive predictive value and a
96% negative predictive value (33, 34). Frozen section bi-
opsy, computed tomography (CT), magnetic resonance im-
aging (MRI), or a bedside finger test should be considered
for patients with equivocal clinical findings but a moderate
or high risk for NF based on the LRINEC score (>5). This
score can be helpful in stratifying patients into risk catego-
ries for NF, in allocating diagnostic resources, and ulti-
mately in aiding the early recognition of NF. However, since
clinical acumen remains of paramount importance, emergent
debridement must be performed regardless of the score in
cases that are strongly suspected to be NF.
Inter Med 49: 1051-1057, 2010DOI: 10.2169/internalmedicine.49.2964
T a b l e 1 . C a u s a t i v e B a c t e r i a o f T y p e 1 a n d T y p e 2 N e c r o t i z i n g F a s c i i t i s
polymicrobial infections including anaerobes.
Streptococcus pyogenes (Group A Streptococcus)
Staphylococcus aureus, including methicillin-sensitive and resistant
Other microbiological etiologies
Enterobacteriaceae (Escherichia coli, Pseudomonas spp., and Klebsiella spp)
The finger test and frozen section have been used as com-
plementary diagnostic modalities in patients with an equivo-
cal diagnosis. The finger test is a bedside procedure in
which, under local anesthesia, a 2-cm incision is made down
to the deep fascia and gentle probing of the index finger is
performed at the level of the deep fascia. Lack of bleeding,
presence of characteristic “dishwater pus”, and lack of tissue
resistance to blunt finger dissection are features of a positive
finger test and indicate NF (35). Another reasonable ap-
proach is a bedside incisional biopsy down to the fascial
level and an immediate frozen section, culture and gram
stain (36). Routine MRI for all patients at the first suspicion
of NF is not cost effective (14). Low tissue oxygen satura-
tion measured by near-infrared spectroscopy throughout the
involved lower extremities is valuable in differentiating NF
from NSTI. Sensitivity is 100% and specificity is 97% at a
cut-off saturation level of <70% (33), and this noninvasive
method may offer a reliable assessment of lower extremities
at risk for NF.
Radiologic studies are only considered as adjunct meas-
ures for doubtful cases and cannot be used to exclude NF,
since many false-negative results can occur with definite NF.
Moreover, the extent of debridement can be determined only
by physical findings in surgery. A plain radiograph is also
usually not helpful, although one study found that 7 of 22
(32%) NF patients had gas on plain X-ray, compared to 6 of
224 (3%) non-NF patients (17). CT (37) or MRI (38) may
localize and clarify the extent of tissue involvement by evi-
dence of soft tissue air (24) in a limited subgroup of NF pa-
tients (39). However, in particular, MRI can be too sensitive
due to its overestimation of deep tissue involvement, and
that does not differentiate NF from cellulitis (40). One thing
we have to note is that the clinical manifestation of patients
with compromised conditions such as diabetes may appear
milder than the degree of actual tissue damage shown in im-
Gram staining of affected tissues can be used for micro-
biological diagnosis in NF. Blood and debrided tissues
should also be sent for culture. Microscopic examination
may reveal coagulation necrosis of superficial fascia, subcu-
taneous fat, and occasionally deep fascia. Inflammatory cel-
lular infiltration, thrombosis of blood vessels, and necrosis
of subcutaneous glands may be present (41), with or without
apparent bacterial infiltration. NF is categorized as types 1
and 2 on the basis of microbiological cultures (22, 28, 42):
type 1 is a polymicrobial infection by aerobic and anaerobic
bacteria in people with immunocompromised or chronic dis-
eases such as diabetes; type 2 involves group A Streptococ-
cus (GAS) with or without a coexisting staphylococcal in-
fection which can occur in any age group even without any
complicated medical illnesses. The pathophysiology of GAS
NF has been associated with Streptococcal M proteins type
1 and 3 (14, 40), exotoxins A and B, or mitogenic factors
that stimulate the immune system to cause cytokine storm,
leading to shock, organ failure, and myocardial and immune
suppression. Proteases and other enzymes generated from
Streptococcus may also contribute to tissue destruction (22).
It is unclear which type is dominant (42-48) and a substan-
tial portion of cultures have been found to be negative for
NF in these studies, which may be due to the prior use of
antibiotics before obtaining the wound culture.
In an analysis of wound and blood cultures (49), blood
cultures with a single organism, multiple organisms and no
organism were found in 27%, 2% and 71% of cases, respec-
tively. For the wound cultures (49), a single organism, mul-
tiple organisms, and no organism were found in 53%, 23%
and 23% of cases, respectively. In terms of monomicrobial
infections, Streptococcul spp. (especially group A), S.
aureus, V. vulnificus, A. hydrophila, Enterobacteriaceae (Es-
cherichia coli, Pseudomonas spp., and Klebsiella spp.),
Clostridium perfringens (gas gangrene) and anaerobic strep-
tococcus are common. Table 1 shows microorganisms caus-
ing NF. Although Aeromonas hydrophila and Vibrio vulnifi-
cus are rare organisms, they produce several virulent factors
that can lead to fatal sepsis more rapidly than in cases with
Streptococcus pyogenes (50-53), resulting in up to a 50%
mortality rate within 48 hours after admission (54). Most
Inter Med 49: 1051-1057, 2010 DOI: 10.2169/internalmedicine.49.2964
T a b l e 2 . T r e a t me n t o f N e c r o t i z i n g F a s c i i t i s , F i r s t - l i n e A n t i mi c r o b i a l
A g e n t , b y I n f e c t i o n T y p e
a If Staphylococcus infection is present or suspected, add an appropriate agent. iv, intravenously.
S. aureus infection
Vancomycin(for resistant strains)
(Alteration from IDSA(Infectious Disease Society of America) guideline: http://www.idsociety.org/Content.aspx?id=9088.)
patients infected with Vibrio vulnificus have a history of un-
derlying chronic illness (cirrhosis, alcoholic liver disease,
gouty arthritis, chronic renal failure, or diabetes mellitus) or
chronic use of steroids (55). Chronic hepatic dysfunction or
adrenal insufficiency may alter neutrophil and macrophage
functions, resulting in immunosuppression. In cirrhotic pa-
tients, these marine organisms can easily establish systemic
bacteremia by gaining access to the gastrointestinal tract and
escaping phagocytosis by the Kuppfer cells of the reticu-
loendothelial system in the liver, due to shunting through
the portal-systemic circulation (56). This can facilitate rapid
spread of infection and result in septic shock.
Patients with suspected NF should be empirically and im-
mediately managed with broad-spectrum antibiotics covering
the commonly suspected organisms. Table 2 shows the first-
line antimicrobial agents of NF. In type 1 infection, the anti-
biotic treatment should be determined based on history,
Gram stain and culture. The advocated initial treatment in-
cludes ampicillin or ampicillin-sulbactam combined with
metronidazole or clindamycin (11, 18, 26, 27). The coverage
of anaerobes is quite essential for type 1 disease. Metronida-
zole or clindamycin, or the use of beta-lactams with beta-
lactamase inhibiter or carbapenems are appropriate choice
for anaerobes. If patients have histories of prior hospitaliza-
tion or antibiotics exposure, broader gram-negative coverage
ampicillin- sulbactam, piperacillin-tazobactum, ticarcillin-
clavulanate, higher generation cephalosporins or carbap-
enems are the candidate agents in this setting. In type 2 dis-
ease, the causative organism is mostly GAS but sometimes
MSSA/MRSA. In place of ampicillin/penicillin, first genera-
tion cephalosporins (such as cefazolin) or vancomycin can
be used for coverage of methicillin-sensitive Staphylococcus
aureus (MRSA), respectively. Several authors suggest that
clindamycin is superior to penicillin in overwhelming strep-
tococcal infections (57), since clindamycin works by inhibit-
ing bacterial protein synthesis and is not subject to the in-
oculum effect of large numbers of slow-growing organisms
teins (22). Furthermore, another study proposed that clini-
cians should consider adding clindamycin to the beta-lactam
antibiotic regimen when NF or myositis is present (58). On
the other hand, it is remarkable that the emerging clindamy-
cin resistance of Streptococcus pyogenes may have serious
implications in the treatment of severe S. pyogenes infec-
tions (59). Antimicrobials should be narrowed down based
on the results of initial blood, wound and tissue cultures, but
should be continued until the infection is under control and
for at least 48 hour after the temperature and WBC have re-
turned to normal or after stabilization of clinical conditions.
Early use of tetracyclines (including doxycycline and mino-
cycline) and third-generation cephalosporins is crucial if Vi-
brio infection is suspected, since this greatly reduces the
mortality rate (60-64). The duration of the antibiotic therapy
for NF is generally recommended from four to six weeks, as
it is deep-seeded infection. Intravenous immunoglobulin
(IVIG) is reasonable and a desirable option to neutralize
streptococcal toxins. Several authors argue that high dose
IVIG may benefit in severe GAS infections (65-69). Al-
though these studies evaluated a small number of patients
and thus there is a need for further studies, it is worth con-
sidering as a possible option in severe cases. Evidence on
adjunctive treatment with hyperbaric therapy has yet to be
established. The guideline for management of NF is avail-
able in the Infectious Diseases Society of America (IDSA)
Surgical debridement is the mainstay of treatment of NF
Inter Med 49: 1051-1057, 2010DOI: 10.2169/internalmedicine.49.2964
and results in significantly improved mortality compared to
cases in which surgery is delayed for even a few hours (25).
When NF is suspected, patients should be brought to an op-
erating room as soon as possible for a “search and destroy”
mission of aggressive and extensive debridement. Involved
tissues should be resected thoroughly until there is no fur-
ther evidence of infection. Initial surgery is the most impor-
tant determinant for survival and the wound must be in-
spected closely after the initial debridement. If further de-
bridement is needed, the patient must be returned to the op-
erating room swiftly. A “second-look” surgery is typically
done 12 to 24 hours after the initial debridement. Patients
with NF may require anywhere from five to 40 sessions of
surgery, and one study found an average of 33 debridements
and grafting procedures (3). Removal of the tissues with
adequate margins is recommended, rather than leaving only
actively infected or necrotic tissue, otherwise it could re-
lapse from the remaining infected tissue. While early ag-
gressivesurgery is crucial
vival (25, 44, 46, 64-73), it is not a predictor of mortality
when the pathogens are Aeromonas or Vibrio (49). In such
cases, more aggressive intervention may be indicated; for
example, an early operation within 12 hours, not merely
within 24 hours (74, 75). The characteristic feature of NF is
easy separation of the fascia from other tissues by blunt dis-
section, due to necrosis of the fascia and liquefaction of
subcutaneous tissue. Muscle is usually spared, but myone-
crosis may develop secondary to the accompanying compart-
ment syndrome. Careful follow-up of the surgical wound is
also important to detect the development of surgical site in-
Surgical consultation is indicated for patients with the fol-
lowing conditions: 1) unusual pain, 2) skin color change
such as ecchymosis, 3) altered mental status, 4) elevated
band formed in the differential WBC count, 5) metabolic
acidosis, and 6) emergence of hemorrhagic bullae, especially
in cirrhotic conditions (56). Prior to surgery, supportive
measures are also of paramount importance, including
hemodynamic support, wound care, and nutritional support.
Hemodynamic instability is often present, and stabilizing
these conditions in an intensive care unit is important to en-
sure that the patient endures the disease and surgery. Once
the infection is controlled, daily dressing is needed at the
bedside under sedation, followed by secondary suturing of
the wounds with or without split skin grafts to cover the ex-
posed underlying tissues. Dressing changes with hydrogel
may assist tissue granulation (19). Although costly, a
vacuum-assisted wound closing (VAC) device has been
found to be effective for non-healing limb wounds, with re-
duced morbidity compared
nique (76). Nutritional support is required from the first day
of admission, for compensation for lost protein and fluid
from the large wounds. Metabolic demands are similar to
those of other major trauma or burns. In general, patients
with severe tissue defects should receive twice their basal
caloric requirements (77). A nasogastric tube for feeding is
sometimes required to maintain adequate enteral nutrition.
The mortality of NF has been reported in recent studies to
be approximately 25%, but it is higher in some re-
ports (10, 11, 18, 19, 25, 43). Patients with toxic shock syn-
drome (TSS) have a higher mortality of 67% (4). An ad-
vanced age (>65 years old); hypotension, leucopenia, and
bacteremia; Aeromonas or Vibrio infection; band-form blood
leukocytes >10%; high APACHE (Acute Physiology, Age,
and Chronic Health Evaluation) II scores (>13); and use of
NSAIDs in GAS NF are also associated with increased mor-
tality (4, 49, 50, 78-80). Regarding the use of specific an-
timicrobials (4), there appears to be a trend toward better
survival with therapy including clindamycin.
There have been few studies on contact prophylaxis, but
this issue has been discussed by the Ontario group (4), who
found a 12% rate of colonization among 152 household
contacts of patients with invasive GAS infections. The sec-
ondary incidence for invasive GAS infection was about 3/
1,000 among household contacts of NF patients, with the
risk estimated to be similar to that in contacts of patients
with sporadic meningococcal infection. Hence, although the
best approach to prophylaxis is unclear, careful hand wash-
ing is recommended among healthcare providers and family
members. All contacts should be counseled about signs and
symptoms of infection and, if these are recognized, advised
to go immediately to an emergency department for a full ex-
amination and prompt treatment.
NF is an uncommon but serious infectious disease for
which accurate diagnosis is often difficult at the initial pres-
entation, which may result in a delay of appropriate surgical
intervention. Predisposing factors and conditions include an
older age, chronic illness (such as alcoholism and diabetes
mellitus) and male gender, as well as possibly underlying
immune deficiency. NF patients commonly present with se-
vere pain at infected sites with erythema and tenderness. NF
should be strongly suspected when the severity of pain
seems to be dissociated from the physical findings (usually
in one limb), along with clinical and laboratory signs of se-
verity and organ dysfunction. Urgent surgical consultation is
required as soon as possible. Treatment includes definitive
surgical debridement in conjunction with antimicrobials and
hemodynamic stabilization. Surgical debridement should be
performed frequently (even daily) until the acute tissue de-
struction has been controlled. Overall mortality remains high
and is increased by factors such as hypotension, bacteremia,
Vibrio or Aeromonas as causative microorganisms, and high
APACHE II scores. Outcomes are also influenced by prompt
Inter Med 49: 1051-1057, 2010 DOI: 10.2169/internalmedicine.49.2964
diagnosis, the timing and extent of surgical treatment, and
management of postoperative complications.
This study was supported by a research grant (No. H19-016)
from the Japanese Ministry of Health, Labor and Welfare.
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