N e c ro t i z i n g So f t - T i s s u e I n f e c t i o n s

a, b
Praveen K. Mullangi, MD *, Nancy Misri Khardori, MD, PhD

KEYWORDS
 Fasciitis  Myonecrosis  Flesh eating bacteria  Soft-tissue infection

KEY POINTS
 Necrotizing soft-tissue infection (NSTI) is a life-threatening, surgical, and medical
emergency.
 A high index of suspicion is important for early recognition and in instituting prompt
therapy without delay.
 Delay in surgical debridement and treatment is associated with increased mortality.
 Early diagnosis, aggressive surgical debridement, aggressive supportive care, and
optimal presumptive antibiotic therapy significantly improve morbidity and mortality asso-
ciated with NSTIs.

Skin and soft-tissue infections account for about 10% of hospitalizations in North
America.1 Most of these are superficial and are treatable with antibiotics and local
care, and patients recover quickly. However, deeper infections can be life threatening,
and require a high index of suspicion and the need for a combined medical and
surgical intervention.
Cellulitis is an acute, spreading, pyogenic inflammation of the dermis and subcuta-
neous tissue. Necrotizing soft-tissue infection (NSTI), on the other hand, is an infec-
tion of the deeper subcutaneous tissues and fascia, characterized by extensive pain,
rapidly spreading necrosis, and gangrene of the skin and underlying structures. NSTIs
by definition include the presence of devitalized or necrotic tissue as part of their
pathophysiology. There is fulminant tissue destruction and gangrenous changes
leading to systemic signs of toxicity, high morbidity, and high mortality. NSTIs are
infrequent, but highly lethal infections. The presence of devitalized or necrotic tissue
provides growth medium for bacteria, and prevents the delivery of host cellular and
humoral defense mechanisms and antimicrobial agents.2 Ambroise Pare, the father
of French surgery, described an infective process similar to present-day necrotizing
fasciitis; however, Joseph Jones, a confederate surgeon, has been credited as the

a
Division of Infectious Diseases, Springfield Clinic, 301 North 8th Street, Springfield, IL 62701,
USA; b Department of Internal Medicine, Division of Infectious Diseases, Eastern Virginia
Medical School, Norfolk, Virginia
* Corresponding author.
E-mail address: [email protected]

Med Clin N Am 96 (2012) 1193–1202

http://dx.doi.org/10.1016/j.mcna.2012.08.003 medical.theclinics.com
0025-7125/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
1194 Mullangi & Khardori

first to describe the clinical manifestations of necrotizing fasciitis.3 The incidence of

NSTI in the United States is estimated to be between 500 and 1500 cases per
year.4 The overall published mortality of NSTI from 67 studies of NSTI with a total
of 3302 patients is 23.5%.2
A variety of terms has been used to describe the NSTIs including phagedena,
hospital gangrene, progressive bacterial synergistic gangrene (Meleney gangrene),
Fournier gangrene, and hemolytic streptococcal gangrene.5 Given the rapidity of
progression and the fulminant nature of these infections, the organisms causing these
infections have been commonly referred to as flesh-eating bacteria. NSTIs include
a wide spectrum of presentations, including necrotizing forms of cellulitis, fasciitis,
and myositis depending on the area and depth of involvement. Blood supply to the
fascia is typically more tenuous than that of the muscle or healthy skin, making the
fascia more vulnerable to infectious process.
Various aerobic and anaerobic pathogens can cause NSTIs either alone or in combi-
nation, and differ from the pathogens that cause nonnecrotizing soft-tissue infections.
Most NSTIs are polymicrobial in nature, and average around 4.4 organisms per infec-
tion in one study.2,6 When only one pathogen was isolated as a cause of NSTI, Strep-
tococcus species was the most common pathogen isolated in about 39% of patients,
followed by Staphylococcus aureus, isolated in about 30% of patients.2
Most commonly, the source of these infections is skin trauma or an underlying lesion
(an ulcer or fissured toe). Exposure history may suggest the specific pathogen; for
example, seawater exposure (Vibrio vulnificus); freshwater exposure (Aeromonas
hydrophila); aquacultured fish (Streptococcus iniae); butcher, clam handler, or veteri-
narian (Erysipelothrix rhusiopathiae).7 In more than 20% of patients with NSTI, the
etiology is unknown and the patients are considered to have idiopathic NSTI.3,8,9
Necrotizing soft-tissue infections are also classified into two distinct entities based
on bacteriology.10 Type I infection involves at least one anaerobic species (Bacter-
oides, Clostridium, or Peptostreptococcus) is isolated in combination with one or
more facultative anaerobic Streptococci (other than Group A) and members of the
Enterobacteriaceae (eg, Escherichia coli, Enterobacter, Klebsiella, and Proteus).
Type II infection is caused by Group A streptococcal infection or other b-hemolytic
streptococcal infection, either alone or in combination with other pathogens, most
commonly S aureus.
Necrotizing fasciitis caused by community-associated methicillin-resistant S aureus
as a monomicrobial infection has also been reported.11

GROUP A STREPTOCOCCAL INFECTIONS

Streptococcus pyogenes is the only species within the group of Group A, b-hemolytic
streptococci. S pyogenes cause a wide variety of infections such as pharyngitis,
erysipelas, scarlet fever, which are milder infections, to the more severe, rapidly inva-
sive, necrotizing skin and soft-tissue infections. The only known reservoir for group A
streptococcal infections (GAS) in nature is the skin and mucous membranes of the
human host. On a global scale, GAS is an important cause of morbidity and mortality
primarily in less developed countries, with more than 500,000 deaths per year. The
importance of GAS infections in the United States was reinforced at the end of the
twentieth century by a resurgence of severe invasive GAS infections (eg, strepto-
coccal toxic shock syndrome and necrotizing fasciitis), with high morbidity and
mortality.
S pyogenes are gram-positive, nonmotile, non–spore-forming, catalase-negative,
aerobic organisms, occurring as pairs or as short to moderate-sized chains in clinical
 Necrotizing Soft-Tissue Infections 1195

specimens, but form long chains when grown in broth media enriched with serum or
blood. On blood agar plates, S pyogenes appears as white to gray colonies
surrounded by zones of complete (b) hemolysis. The organism is enveloped in a hya-
luronic acid capsule that serves as an accessory virulence factor in retarding phago-
cytosis by polymorphonuclear leukocytes and macrophages of the host.12
Hyaluronic acid capsule in GAS is a poor immunogen, as it is chemically similar to
that found in human connective tissue. Antibodies to GAS hyaluronic acid have not
been demonstrated in humans. M protein is the major somatic virulence factor of
group A streptococci. Strains rich in this protein are resistant to phagocytosis by poly-
morphonuclear leukocytes, multiply rapidly in fresh human blood, and are capable of
initiating disease. In the nonimmune host, M protein exerts its antiphagocytic effect by
inhibiting activation of the alternative complement pathway on the cell surface. Strains
that do not express M protein are avirulent. Acquired human immunity to strepto-
coccal infection is based on the development of opsonic antibodies directed against
the antiphagocytic moiety of M protein. Such immunity is type specific and quite
durable, lasting for several years.
Other factors that play a role in pathogenesis of infections are: DNases (DNases A,
B, C, and D), which cause degradation of deoxyribonucleic acid; hyaluronidase, an
enzyme that degrades hyaluronic acid found in the ground substance of connective
tissue; streptokinase, which promotes the dissolution of clots by catalyzing the
conversion of plasminogen to plasmin; and streptococcal pyrogenic exotoxin B
(SpeB), a potent protease and C5a peptidase that cleaves the human chemotaxin
C5a at the PML binding site. These enzymatic agents serve to facilitate the liquefaction
of pus and the spread of streptococci through tissue planes, which is a characteristic
of streptococcal cellulitis and necrotizing fasciitis, and interfere with ingestion and
killing by phagocytosis.
Streptococcal pyrogenic exotoxins (Spe) are a family of bacterial superantigens
associated with streptococcal toxic shock syndrome, necrotizing fasciitis, and other
severe infections. Superantigens are potent immunostimulators that are able to bind
simultaneously to the major histocompatibility complex (MHC) class II molecules
and the T-cell receptor, which results in activation of a large number of T cells express-
ing specific V-b subsets of the T-cell repertoire.12 Superantigen activation of T cells
leads to increased secretion of proinflammatory cytokines.

Clinical Manifestations
Predisposing factors for NSTIs due to S pyogenes are minor cuts, splinters, pene-
trating injuries, varicella lesions, burns, surgical procedures, childbirth, and muscle
strain.13 The initial lesion is mild erythema at the site of injury, which over the next
24 to 72 hours undergoes a rapid evolution with pronounced inflammation. The first
cutaneous clue to streptococcal necrotizing fasciitis is diffuse swelling, followed by
the appearance of bullae filled with clear fluid. There is rapid progression of bulla to
hemorrhagic or violaceous color suggestive of dermal necrosis.1,14,15 There are
marked systemic symptoms, with early onset of shock and organ failure. The patient
with streptococcal gangrene appears perilously ill, with high fever and extreme
prostration.

Treatment
Prompt, aggressive surgical exploration and debridement of suspected deep-seated
streptococcal infection is mandatory. Broad-spectrum antimicrobial therapy to
provide polymicrobial coverage should be instituted initially. Once the streptococcal
cause is confirmed, high-dose penicillin and clindamycin is appropriate. All strains
1196 Mullangi & Khardori

of group A streptococci remain sensitive to penicillin. Clindamycin suppresses

exotoxin and M protein production by group A streptococci, thereby preventing toxin
production.

CLOSTRIDIAL INFECTIONS

Clostridia are anaerobic, gram-positive rods that are capable of forming endospores.
Growth of Clostridium perfringens on blood agar plates is rapid, with colonies often
detected within 12 to 16 hours of inoculation. Colonies are yellowish to gray and
opaque, with irregular borders, and exhibit a characteristic double zone of hemolysis
with an inner zone of b hemolysis surrounded by an outer zone of partial hemolysis.
Clostridia are ubiquitous in nature, being found in soil and sediments and as members
of the intestinal microflora of humans and animals. Clostridial myonecrosis (gas
gangrene) is a life-threatening muscle infection that develops most commonly
following a traumatic injury that is contaminated by clostridial spores. Traumatic
contaminated wounds with vascular compromise lead to an anaerobic environment
that is ideal for proliferation of Clostridia. Traumatic injury accounts for 70% of gas
gangrene cases, and about 80% of these are caused by C perfringens.16 Clostridial
gas gangrene can also occur in the absence of trauma via hematogenous seeding
of skeletal muscle, which is caused by Clostridium septicum and usually occurs in
association with colonic neoplasms.17 Other pathogens include Clostridium novyi,
Clostridium histolyticum, Clostridium bifermentans, Clostridium tertium, and Clos-
tridium fallax.
Many extracellular toxins are produced by clostridial species, of which only a- and
q-toxin have been implicated in the pathogenesis. a-Toxin, a lecithinase, is a hemolytic
toxin that causes damage to cell membranes. In gas gangrene, muscle necrosis is
severe and polymorphonuclear leukocytes (PMNs) are notably absent from infected
tissues, which is in contrast to soft-tissue infections caused by other organisms,
where there is significant influx of PMNs.18 a-Toxin stimulates platelet aggregation
and upregulates adherence molecules on PMNs and endothelial cells. This upregula-
tion leads to a vascular occlusive state, reducing the blood flow to the muscle and
leading to an anaerobic state favorable for clostridial infections.19,20

Clinical Manifestations
Clostridial myonecrosis generally begins within 24 to 72 hours after traumatic injury or
surgery, depending on the size of the inoculum and the extent of the vascular compro-
mise. Initial symptoms may include sudden onset of severe pain in the absence of
obvious physical findings, suggesting a deep tissue infection. Pain is likely related
to toxin-mediated ischemia. Following a penetrating trauma to the skin there is an
initial redness at the site of the wound, followed by a rapidly spreading brown to purple
discoloration of the skin. The progression of gas gangrene is rapid, and within hours of
the initial symptoms gas may be detected within the underlying tissues. Bullae may
develop on the overlying tense skin and may be filled with clear, red, blue, or purple
fluid. Discharge has a characteristic “mousy” odor.21 Gram stain of the discharge
often reveals the typical gram-positive boxcar-shaped rods characteristic of C perfrin-
gens. Given the proischemic properties of the clostridial toxins, wounds from clos-
tridial infections do not bleed easily. Fever is often minimal during the early stages
of disease, but progression to full-blown sepsis with hypotension and multiorgan
failure develops rapidly. Gas in the wound is a relatively late finding and by the time
crepitus is appreciated, the patient may be near death.22 Positive blood cultures
may be noted in about 15% of patients, and even this is a late finding.
 Necrotizing Soft-Tissue Infections 1197

Treatment
Rapid diagnosis of clostridial myonecrosis is critical for proper therapeutic intervention.
Mortality rates associated with gas gangrene approach 60%, and are highest in cases
involving the abdominal wall and lowest in cases involving the extremities.22 The most
important part of therapy for clostridial myonecrosis is prompt surgical debridement of
infected tissues. Penicillin remains the most commonly used antibiotic. Other agents
used for treating clostridial myonecrosis include metronidazole, clindamycin, and
carbapenems, although resistance to clindamycin has been reported.

AEROMONAS INFECTIONS

Aeromonas are gram-negative, nonsporulating, aerobic rods that usually are b-hemo-
lytic on blood agar. Aeromonas species are oxidase positive, and this test distin-
guishes these organisms from the oxidase-negative Enterobacteriaceae. Aeromonas
are ubiquitous inhabitants of fresh and brackish water; they have also been recovered
from chlorinated tap water, including hospital water supplies. Aeromonas are isolated
with increasing frequency in warmer months, and have been associated with diarrheal
disease and are also reported as a cause of traveler’s diarrhea in travelers returning
from Asia, Africa, and Latin America. Aeromonas occasionally cause soft-tissue infec-
tions and sepsis, especially in immunocompromised hosts. Most Aeromonas soft-
tissue infections are caused by Aeromonas hydrophila. A hydrophila wound infections
can manifest as 3 major syndromes: cellulitis, myonecrosis, and ecthyma gangreno-
sum.1 Infections typically occur on the extremities following traumatic aquatic injury
or trauma followed by exposure to fresh water. Aeromonas soft-tissue infections
can develop after exposure to soil-associated injuries. There was a reported outbreak
of A hydrophila wound infections in participants of a mud football competition in
Australia.23 Aeromonas soft-tissue infections have also been reported as a complica-
tion of the use of medicinal leeches in surgery.24,25 Aeromonas species are normal
inhabitants of the foregut of leeches. Leeches lack the requisite proteolytic enzymes
and are dependent on the symbiotic Aeromonas to digest the blood meal. Studies
have shown a 2.5% to 14% incidence of Aeromonas infections following leech
therapy, and it seems that this wide variation is based on the way the leeches are
handled and is also based on the use of prophylactic antibiotics with leech
therapy.25,26

Clinical Manifestations
Aeromonas can cause mild to severe infections. Cellulitis is the most frequently
encountered form of soft-tissue infection. Cellulitis develops within 8 to 48 hours
following trauma, and systemic signs are common.27 Cellulitis is characterized by
intense redness and induration at the site of injury. Suppuration and necrosis around
the wound are frequent, and surgical debridement is often necessary. Myonecrosis
and ecthyma are less commonly seen and typically found in immunocompromised
hosts (eg, chronic liver disease, underlying malignancy).28 Myonecrosis with bullous
lesions is characterized by liquefaction and gangrene of muscles, with gas formation
and crepitus resembling gas gangrene.23 This form of disease requires aggressive
surgical debridement and antimicrobial therapy.

Treatment
The clinically relevant Aeromonas species are resistant to penicillin and ampicillin but
are usually susceptible to third-generation cephalosporins, aztreonam, and carbape-
nems. Most Aeromonas strains produce b-lactamases.
1198 Mullangi & Khardori

Fluoroquinolones are highly active against Aeromonas species, although the exis-
tence of nalidixic acid–resistant strains containing mutations in the gyrA gene raise
concern that fluoroquinolone resistance could easily develop. Aminoglycosides are
usually active, with resistance to tobramycin being more common than resistance
to other aminoglycosides.29

DIAGNOSIS

Although early identification, debridement, and treatment of NSTIs are crucial, it is

difficult to establish the diagnosis of NSTIs. It is worth considering patient factors
that increase the risk of NSTIs, such as injectable drug use, obesity, chronic debili-
tating comorbidities such as diabetes, peripheral vascular disease, immunosuppres-
sion, malignancy, and cirrhosis.30,31 Clinical characteristics that help in identification
of NSTIs include tense edema, pain disproportionate to the appearance, skin discol-
oration, blisters/bullae, necrosis, and crepitus. The sensitivity of these findings is low
and they are present in only 10% to 40% of patients with NSTIs.5 Unexplained tachy-
cardia, marked left shift, and an elevated creatine phosphokinase level are also
important clues to the diagnosis of necrotizing fasciitis, and their presence in the
right setting should prompt surgical inspection of the deep tissues. To complicate
matters further, prior use of antibiotics and nonsteroidal anti-inflammatory drugs
may mask or confound some of these findings, making it difficult to establish the
diagnosis of NSTIs. Given the difficulty in establishing an early diagnosis, a wide
array of diagnostic tools has been tested to diagnose NSTIs accurately and
expeditiously.
Imaging studies such as plain radiography, ultrasonography, computed tomog-
raphy (CT), and magnetic resonance imaging (MRI) have been used. Plain radiography
can only help to identify subcutaneous gas. CT and MRI can identify other causes
such as deep-seated abscesses, fascial thickening, and muscle involvement. These
findings are very specific and helpful when present, but not sensitive in the screening
of patients with NSTIs.
Examination of a frozen-section biopsy specimen from the compromised site has
been studied. When performed early in the course of infection, it has been shown to
avoid the delay in diagnosis and is associated with comparatively decreased
mortality.32
As some of these tests are limited by availability and cost, the LRINEC (Laboratory
Risk Indicator for Necrotizing Fasciitis) score was developed, which is based on
routine, commonly available laboratory investigations. This score can stratify patients
into high, moderate, and low risk categories for NSTIs based on total white blood cell
count, hemoglobin, sodium, creatinine, glucose, and C-reactive protein. An LRINEC
score of 6 or more should raise the suspicion of necrotizing fasciitis, and a score of
8 or more is strongly predictive of NSTI.31 Patients with intermediate and high risk
(score >6) had a positive predictive value of 92% and a negative predictive value of
96% (Table 1).32
The “finger test” is a bedside procedure whereby a 2-cm incision is made down to
the deep fascia under local anesthesia and gentle probing with the index finger is per-
formed. Lack of bleeding, presence of characteristic “dishwater pus,” and lack of
tissue resistance to blunt finger are features of a positive finger test suggestive of
necrotizing fasciitis.33 Measurement of compartment pressure may also be useful,
and if pressures are greater than 40 mm Hg, immediate fasciotomy is indicated.34
Once NSTI is confirmed, the incision is extended and additional debridement is
performed.
 Necrotizing Soft-Tissue Infections 1199

Table 1
LRINEC (laboratory risk indicator for necrotizing fasciitis) score

LRINEC Score
C-reactive protein
<150 0
>150 4
WBC count (cells/mm3)
<15 0
15–25 1
>25 2
Hemoglobin (g/dL)
>13.5 0
11–13.5 1
<11 2
Sodium (mmol/L)
135 0
<135 2
Creatinine (mg/dL)
1.6 0
>1.6 2
Glucose (mg/dL)
180 0
>180 1

LRINEC score: 5, low risk; 6–7, intermediate risk; 8, high risk.
Modified from Wong HC, Khin WL, Heng SK, et al. The LRINEC (Laboratory Risk Indicator for
Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue
infections. Crit Care Med 2004;32:1535–41.

MANAGEMENT

Treatment of NSTI involves the principles of source control, antimicrobial therapy,

supportive care, and monitoring. Whenever NSTI has been confirmed, surgical
debridement is indicated. The impact of early and complete debridement has been
shown to affect the patient outcome in NSTIs. Mortality has been found to be signif-
icantly lower with early and aggressive debridement.6,9,33 Repeat debridements
should be performed at intervals of 24 to 48 hours until no further necrosis or infected
tissue is seen. Clinical presentation of all NSTIs is fairly similar, and time should not be
wasted on identifying the possible causative pathogen. Surgical debridement should
not be delayed, and broad-spectrum antibiotics should be initiated at the earliest
opportunity to cover gram-positive, gram-negative, and anaerobic organisms.
Acceptable regimens include ampicillin-sulbactam or piperacillin-tazobactam plus
clindamycin plus ciprofloxacin and vancomycin. Other options are carbapenems
such as imipenem/cilastatin or meropenem plus metronidazole, or clindamycin plus
vancomycin. Clindamycin is added to reduce toxin production and has also been
shown to decrease cytokine production.35 Antibiotic therapy may be de-escalated
and pathogen directed, based on cultures after surgical debridement and once the
patient is stable.
Intravenous immune globulin (IVIG) has also been used in the treatment of NSTIs,
despite the controversial benefit. IVIG contains neutralizing antibodies against some
streptococcal superantigens and clostridial toxins. One Canadian study showed
IVIG to be beneficial if the NSTI is associated with Group A streptococcal infection
1200 Mullangi & Khardori

in patients who have developed streptococcal toxic shock syndrome.36 IVIG has been
shown to neutralize bacterial mitogenicity and to reduce T-cell production of
interleukin-6 and tumor necrosis factor a.37
The role of hyperbaric oxygen therapy (HBO) in the treatment of NSTIs has been
debated. HBO (100% oxygen at 3 atm) has been recommended for perioperative
use in clostridial myonecrosis, as in vitro studies have shown it to inhibit bacterial
growth and toxin production.23,38 The rationale for the use of HBO in other NSTIs
includes reversal of tissue hypoxia, enhanced neutrophil function, a direct toxic effect
on select bacteria, and enhanced activity of certain antimicrobial agents.38 Evidence
to support the use of HBO is limited because of only small retrospective studies and
the lack of availability of HBO at all centers. However, HBO may hasten wound
closure.6 Therefore the role of HBO therapy remains adjunctive to combined surgical
and medical intervention.

PREDICTORS OF MORTALITY

Advanced age, the presence of 2 or more associated comorbidities (diabetes mellitus,

peripheral vascular disease, chronic liver disease, cancer), and a delay from admission
to operation of more than 24 hours have been shown to affect survival adversely.5 In
one study, the body surface area involved with infection (as expressed in burns) had
a correlation with survival advantage. Truncal and perineal locations of infection
incurred the greatest mortality.6

SUMMARY

NSTI is a life-threatening, surgical, and medical emergency. Clinical presentation, at

least in the initial phase, can be misleading. Various studies have shown that delay
in surgical debridement is associated with increased mortality. A high index of suspi-
cion is important in early recognition and in instituting prompt therapy without delay.
Early diagnosis, aggressive surgical debridement, aggressive supportive care, and
optimal presumptive antibiotic therapy significantly improve morbidity and mortality
associated with NSTIs.

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