Young Et Al. (2005) - Necrotizing Fasciitis - Pathogenesis and Treatment

Review
10.1586/14787210.3.2.279 2005 FutureDrugsLtd ISSN 1478-7210 279 www.future-drugs.com

Necrotizing fasciitis:
pathogenesis and treatment
Michael H Young, David M Aronoff and N Cary Engleberg
Author for correspondence

Universityof Michigan Medical
School and Universityof Michigan
Hospitals, Department of
Microbiologyand Immunology,
3116 Taubman Center, Box 0378
Ann Arbor, MI, USA
KEYWORDS:
antimicrobial therapy, bacterial,
bacterial toxins, clindamycin,
fasciitis, necrotizing, penicillins,
risk factors, septic shock, skin
diseases, streptococcuspyogenes,
superantigens
Necrotizing fasciitis is a rapidly progressive, life-threatening infection and a true infectious
disease emergency. Despite much clinical experience, the management of this disease
remains suboptimal, with mortality rates remaining approximately 30%. Necrotizing fasciitis
rarely presents with obvious signs and symptoms and delays in diagnosis enhance
mortality. Therefore, successful patient care depends on the physicians acumen and
index of suspicion. Prompt surgical debridement, intravenous antibiotics, fluid and
electrolyte management, and analgesia are mainstays of therapy. Adjunctive
clindamycin, hyperbaric oxygen therapy and intravenous immunoglobulin are frequently
employed in the treatment of necrotizing fasciitis, but their efficacy has not been rigorously
established. Improved understanding of the pathogenesis of necrotizing fasciitis has
revealed new targets for rationally designed therapies to improve morbidity and mortality.
Expert Rev. Anti Infect. Ther. 3(2), 279294 (2005)
Necrotizing fasciitis (NF) is a life-threatening
soft-tissue infection characterized by rapidly
progressing inflammation and necrosis of sub-
cutaneous fascial tissues (with or without
involvement of adjacent muscle). Although it
is usually a polymicrobial infection, mono-
microbial infections occur, with group A strep-
tococcus (GAS) being the most important
pathogen of the latter category. NF represents
a subset of all necrotizing soft-tissue infections
(NSTIs), that include clostridial gas gangrene
with myonecrosis, anaerobic cellulitis, and
severe, necrotizing vibrio infections. Fourniers
gangrene represents a subset of NF localized to
the perineum [1]. NF is distinct from more
superficial soft-tissue infections such as erysip-
elas, impetigo and cellulitis, which rarely
progress beyond the superficial portion of sub-
cutaneous fat. This review will focus on the
history, epidemiology, microbiology, patho-
genesis and clinical presentation and manage-
ment of NF, with an emphasis on NF caused
by GAS. Although the initial presentation and
empiric management of patients suffering
from clostridial or waterborne vibrio NSTIs
are similar to more typical NF, these specific
infections are not addressed here.
History of necrotizing fasciitis
NF has existed as a clinically recognized entity
for hundredsof years, albeit under many differ-
ent names. Hippocratesdescribed a fulminant,
fatal complication of erysipelas [2]. Throughout
the 18th and 19th centuries, several European
physicians described cases of rapidly progress-
ing NSTIs by a variety of names, including
phagedena gangrenosa, necrotizing/gangre-
nous erysipelas, nonclostridial gas gangrene,
synergistic necrotizing cellulitis, hemolytic
streptococcal gangrene and bacterial synergis-
tic gangrene [36]. The first description in the
USA was reported in the 1870sby a Confeder-
ate surgeon, who referred to hospital
gangrene [4]. The modern appellation of
necrotizing fasciitis was initially used by Wil-
son in 1952 to encompass the most consistent
feature of this infection fascial necrosis [7].
GASNF asa distinct clinical entity hasbeen
recognized more recently. Meleney described a
syndrome of hemolytic streptococcal gangrene in
1924 that may have been the first modern
description of GAS NF, but this was before
Lancefield had established methodsfor grouping
streptococci [6]. Giulano suggested that mono-
microbial GASfasciitis was a distinct subset of
CONTENTS
History of necrotizing fasciitis
Epidemiology
Microbiology
Risk factors for the
development of & mortality
from necrotizing fasciitis
Pathology
Pathogenesis
Clinical features
Diagnosis
Treatment
Expert opinion
Five-year view
Key issues
References
Affiliations
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Young, Aronoff & Engleberg
280 Expert Rev. Anti Infect. Ther. 3(2), (2005)
NF, which he dubbed Type II (see below) [8]. In 1989, Stevens
and colleagues described a syndrome of streptococcal toxic
shock syndrome (TSS) that was often associated with NF.
These authors were also the first to characterize unique clinical
characteristics associated with GAS NF [9]. Interestingly, GAS
NF became a prominent infectious disease in the lay press dur-
ing the mid-1990s, when several outbreaks were reported, and
the disorder was labeled a flesh-eating disease in the British
tabloid press [10].
Epidemiology
The true incidence of all types of NSTIs is unknown,
although GAS NF is best studied from an epidemiologic
standpoint. It is estimated that 10,000 cases of invasive GAS
disease occur per year in the USA, of which approximately
7% are NF [11]. Since GAS is implicated as the cause of
approximately 10 to 20% of all NF cases, it can be estimated
that 7000 to 14,000 cases of all types of NF may occur in the
USA each year. NF affects all age groups, although adults are
most commonly afflicted, and a slight male predominance is
typical (60%). The overall mortality is approximately 30%,
with higher mortality at the extremes of ages [1214].
Microbiology
Although cultures from NF wounds are often sterile due to
prior antibiotic therapy [13,14], a diverse range of bacteria have
been isolated from active lesions (TABLE1). Giulano was the first
to suggest a classification scheme for NF based on the wound
microbiology [8], dividing NF into two types. Type I, which
represents approximately 80 to 90% of all NF cases, includes
polymicrobial infections with obligate anaerobes, entero-
bacteraciae, and (nongroup A) streptococci [12,15,16]. Wound
cultures from Type I NF yield an average of approximately four
to five different species per lesion [13]. Monomicrobial infec-
tions are found in 15 to 30% of all NF wound cultures, but
GAS is the sole isolate in approximately 10% of cases [13,14].
Type II infections are defined by the presence of GAS, most
commonly as a single agent, but occasionally in a mixed infec-
tion. Multiple GAS M types have been associated with NF;
type M1 is the most prevalent [9,1720]. To this classification,
some authors have suggested a third type, to distinguish fasciitis
caused by marine vibrios [4].
Risk factors for the development of & mortality from
necrotizing fasciitis
In general, risk factors for the development of Type I and II NF
are similar. Type I fasciitis occurs more commonly in immuno-
suppressed patients and rarely develops in young, healthy indi-
viduals. Type II NF appears more capable of developing in
otherwise healthy people (TABLE2). Immunosuppression may be
profound (e.g., patients on high-dose corticosteroids or
infected with HIV) or subtle (e.g., advanced age, diabetes mel-
litus [DM] or alcoholism). Comorbid illnesses appear to
present a risk for the development of NF. In a large retro-
spective analysis of NF, most patients had DM, a third had
hypertension, a third were obese and a quarter had cardiac
disease [13]. Approximately 15 to 18% of patients had malnu-
trition, alcohol abuse, peripheral vascular disease or chronic
pulmonary disease; and 11 to 13% had either a history of
intravenous drug abuse (IVDA) or carcinoma. Antecedent
trauma (including IVDA) is a common theme, ranging from
seemingly innocuous minor abrasions to blunt or penetrating
trauma and may result from surgical incisions or percutane-
ous catheters [4]. However, hematogenous seeding of bacteria
to the fascia may also occur [21,22].
A case-control study by Factor and colleagues identified
specific risk factors for 139 patients with invasive GAS dis-
ease, defined as infection associated with the isolation of GAS
from a normally sterile site [23]. NF represented only a minor-
ity (6%) of these cases (bacteremia and cellulitis were the
most common forms of invasive disease). In adults aged 18 to
44 years, factors associated with invasive disease included
exposure to one or more children with sore throats (relative
risk [RR]: 4.93; p = 0.02), HIV infection (RR: 15.01;
p = 0.04) and history of IVDA (RR: 14.71; p = 0.003). In
adults over 45 years of age, number of people in the home
(RR: 2.68; p = 0.004), DM (RR: 2.27; p = 0.03), cardiac dis-
ease (RR: 3.24; p = 0.006), cancer (RR: 3.54; p = 0.006) and
corticosteroid use (RR: 5.18; p = 0.03) were the most impor-
tant. However, up to 65% have no identifiable risk factor for
invasive GAS disease [22].
Risk factors adversely affecting the prognosis of established
NF include advanced age, female gender, cardiac disease, mal-
nutrition, alcohol abuse, peripheral vascular disease and
chronic pulmonary disease. The combination of age over
60 years, renal failure and DM was associated with a mortality
rate of 64.7% [13]. In another large series by Childers and col-
leagues, higher mortality rates were noted at the extremes of age
(<1 or >60 years), with IVDA, and comorbidities included can-
cer, renal failure and congestive heart failure [12]. Certain clini-
cal features (e.g., positive blood cultures or truncal/perineal
involvement) are associated with a poor outcome.
Concurrent use of nonsteroidal anti-inflammatory drugs
(NSAIDs) has been suggested to pose a potential risk for the
development of GAS NF and/or the worsening of an estab-
lished infection [24,25]. However, a recent review of available
retrospective and prospective studies did not support a
causal relationship [25,26]. These authors noted that the use of
NSAIDs may mask the symptoms of NF and delay diagnosis,
especially when the clinical suspicion for NF is low [26].
Pathology
The histologic findings of NF are the same in both Type I
and II. The essential features of NF are widespread necrosis
of superficial fascia, subcutaneous fat, nerves, arteries and
veins. Deep fascia may be involved as well, but superficial
skin and deeper muscle are typically spared. Early in the dis-
ease process there is obliterative vasculitis with micro-
angiopathic thrombosis at the leading edge of the lesion,
accompanied by acute inflammation in the subcutaneous
Necrotizing fasciitis
www.future-drugs.com 281
tissue [12,15]. Superficial hyaline necrosis may be seen, along
with edema and inflammation of the dermis [3,8] and sub-
cutaneous fat [27]. As the process advances, lesions develop
liquefaction necrosis of all tissue levels. The fascia become
swollen and exhibit a dull grey discoloration. Subepidermal
necrotic bullae, subcutaneous fat and eccrine necrosis, and a
dense neutrophil-predominant inflammatory infiltrate are
noted [27]. Noninflammatory intravascular coagulation and
hemorrhage are also characteristic of later lesions and
myonecrosis may develop as well [27]. Gram-stain of affected tis-
sue may be positive. Strikingly little inflammation is found in
the surrounding tissues [3,8].
To the surgeon, there may be a remarkable lack of resistance
of normally adherent muscular fascia to blunt dissection and
little bleeding of fascia during dissection [28]. A foul-smelling,
dishwater exudate may also be present.
Table1. Microbiology of necrotizing fasciitis.
Organism Common Unusual
Gram -positives Group A streptococcus Erysipelothrix rhusiopathiae
- or -hem olytic streptococci Group B, C and G streptococcus
Staphylococcus aureus Streptococcus pneumoniae
Coagulase-negative staphylococci
Enterococcus spp.
Bacillus spp.
Corynebacterium spp.
Gram -negatives Enterobacteriaceae M arine vibrios
Escherichia coli Aeromonas spp.
Enterobacter spp. Edwardsiella spp.
Klebsiella spp. Hemophilus spp.
Proteus spp. Photobacteriumdamsela
Serratia marcescens Burkholderia pseudomallei
Pseudomonas spp. Pasteurella multocida
Acinetobacter spp. Ochrobactrumanthropi
Citrobacter spp. Eikenella spp.
Anaerobes Peptostreptococcus spp. Flavobacteriumodoratum
Clostridium spp.
Bacteroides spp.
Prevotella spp.
Fusobacterium spp.
Propionibacterium spp.
Veillonella spp.
Lactobacillus spp.
Fungi Candida spp. Aspergillus spp.
M ucorm ycosis
Cryptococcus spp.
Apophysomyces elegans
Absidia corymbifera
Acid-fast bacteria Mycobacteriumtuberculosis
Pathogenesis
Ba c te ria l fa c tors
The underlying pathogenesisof Type I NF ispoorly understood. It
is presumed that diverse bacterial species work together to
enhance the spread of infection, and the growth of invading
microbes is synergistic. Experimentally, this has been demon-
strated in animal models, in which coinoculation of distinct
anaerobic species resulted in larger skin lesions than mono-
microbial inoculation [2931]. However, the validity of this
synergism in human infection remains speculative.
In contrast, the virulence factors of GAS, the cause of Type II
NF, have been well studied [3233]. These include factors that
mediate attachment to host cells, such as protein F, lipotechoic
acid and M protein. The M protein is also intimately involved
in the evasion of the human immune response through inhibi-
tion of opsonization and phagocytosis. M protein directly
binds human fibrinogen to create a molecular camouflage of
sorts, and also binds the complement regulatory Factor H,
which, in turn, inhibits binding of the opsonin C3b. Related
M-like proteins bind immunoglobulins, and C5a peptidase
inhibits chemotaxis of polymorphonuclear leukocytes (PMNs)
by inactivating C5a. Resistance to killing by PMNs is also
mediated by the hyaluronic acid capsule, as GAS strains with
increased capsule are better able to resist phagocytic killing [39].
GAS also produce a number of extracellular exotoxins that
contribute to virulence, including streptokinase, streptolysin O
and S, hyalouronidase, DNAses A, B, C and D and strepto-
coccal pyrogenic exotoxin (Spe) B. Streptolysin O and S are
cytolysins with activity against a range of human cell types.
Streptolysin O is distinguished by its ability in the presence of
oxygen, whereas steptolysin S is oxygen stable. Streptokinase
converts human plasminogen to plasmin, and hyaluronidase
digests the hyaluronic acid of connective tissue ground sub-
stance. The activity of the DNAses is self-explanatory, although
their significance in infection is unknown. Finally, SpeB is a
potent cysteine protease whose precise role is uncertain,
although streptokinase, streptolysin S and SpeB have been
shown to enhance dermal necrosis in animal models [3436].
These virulence factors are differentially utilized by GAS
throughout each stage of infection (initiation, local replication
and dissemination), which requires the highly coordinated reg-
ulation of virulence gene expression. Therefore, it is not sur-
prising that several global regulators of virulence have been
identified. For example, Mga is a DNA-binding protein that
positively regulates expression of the antiphagocytic M protein
gene (emm) and at least eight other putative virulence-related
proteins that enhance colonization or immune evasion. Accord-
ingly, Mga-regulated genes are expressed during the mid-
exponential phase of growth [37]. Alternatively, the two-compo-
nent regulator, CsrRS (CovRS), represses streptococcal capsule
production and several tissue-damaging toxins that are required
for various aspects of necrotizing skin infection in animal mod-
els [3840]. Streptokinase, steptolysin S and SpeB are positively
controlled by other defined regulatory systems [4144]. Invitro,
these regulated toxins are expressed in the stationary phase, sug-
gesting that they may be deployed during infection when the
bacteria have depleted local nutrients and need to spread
through tissue to continue their growth.
GAS also express a host of superantigens (SAg) that appear to
play an important, although as yet unidentified role in infec-
tion. Some are chromosomally encoded, but most are found on
bacteriophages. The best characterized of these include SpeA,
C, F, G, H, I, J, K and L, but also streptococcal superantigen
(SSA) and streptococcal mitogenic exotoxin Z-1 and -2
(SMEZ-1 and -2) [32]. Approximately half of Type II NF cases
are associated with a clinical entity similar to staphylococcal
TSS [17,22,45]. Streptococcal TSS is a form of severe invasive
GAS disease that is characterized by hypotension and multior-
gan dysfunction [22]. As in staphylococcal TSS, streptococcal
TSS appears to be a SAg-mediated process. However, whereas
there is a single SAg responsible for the syndrome in staphylo-
cocci, it has been difficult to assign an essential role to any par-
ticular SAg or combination of SAgs. Multiple M types of GAS
producing myriad SAgs have been isolated from patients with
invasive infections, including NF [9,1719,46]. Most, but not all
isolates from severe invasive GAS cases (including NF) in the
USA and Canada are positive for SpeA, B or C [18,47]. There is
also evidence that GAS SAgs may be directly involved in GAS
NF independent of streptococcal TSS (see below). Analysis of
tissue samples from patients with severe GAS soft-tissue
Table2. Risk factors for necrotizing fasciitis.
Type 1 NF Type II (GAS) NF
Alcoholism Alcoholism
Antecedent traum a Antecedent traum a
Carcinom a Carcinom a
Cardiopulm onary disease Cardiopulm onary disease
Diabetes Diabetes
Iatrogenic procedures Im m unosuppression (e.g., HIV
and corticosteroid use)
Im m unosuppression (e.g., HIV
and corticosteroid use)
Intravenous drug abuse
Intravenous drug abuse M ale gender
M ale gender Peripheral vascular disease
Peripheral vascular disease Recent surgery
Recent surgery Exposure to children w ith sore
throats(?)
Sm oking HLA Class II haplotype(?)
Lack of specific anti-GAS
antibodies
Varicella infection
GAS: Group A streptococcus; HLA: Hum an leukocyte antigen;
NF: Necrotizing fasciitis.
infections revealed that bacterial load and insitu expression of
SpeF correlated with severity of clinical grade [48]. The severity
of soft-tissue infection also correlated with local expression of
interleukin (IL)-1, tumor necrosis factor (TNF)-, interferon
(INF)-, CC chemokine receptor 5, CD 44, and cutaneous
lymphocyte-associated antigen, demonstrating that the
cytokine profile in affected tissues themselves mimics a SAg
response [48].
Host fa c tors
Identical GASstrainscan be isolated from casesof severe invasive
infectionsand from healthy individualsin the complete absence
of disease [4951]. Therefore, in addition to acquired
comorbidities, individual genetic traitsmay influence the course
of the disease in the infected host. Patientswith more severe inva-
sive GASdisease have increased insitu expression of TNF- and
IL-2 and -6 in blood [51], and a recent series of NF patients
showed that nonsurvivorshad elevated levelsof proinflammatory
cytokines compared with survivors [52]. Part of this variability
may be due to host variationsin responses to streptococcal SAgs
[53,54]. Additionally, certain human leukocyte antigen (HLA)
haplotypeshave been associated with increased responsivenessto
streptococcal SAgs invitro and have been clinically associated
with the development of severe invasive GASdisease [51,53,55,56].
Low levels or absence of protective antibodies (e.g., anti-M)
may also facilitate invasive GAS disease [5759]. However, lack of
antibody cannot entirely explain why some patients develop
NF while others develop less severe invasive GAS disease
(e.g., bacteremia or pneumonia) [57].
Clinical features
The stereotypical course of NF involves a normal or slightly
inflamed soft-tissue area that suddenly and dramatically
progressesto overt fasciitis, accompanied by evidence of systemic
toxicity. The natural history of NF was succinctly described by
Meleney as acute inflammatory changes that spread quickly,
accompanied by high fever and eventual prostration [6]. The
overlying skin would become smooth, tense and shiny. Diffuse
erythema without distinct borders, in contrast to erysipelas,
would be present. Within 1 to 2 days, the lesionsmight develop
progressive color changes, from red to purple to blue and then
become frankly gangrenousby the fourth or fifth day, first turn-
ing black, then greenish yellow. From days 7 to 10, provided the
patient had survived, a line of demarcation between viable and
necrotic tissue would become sharply defined. Necrotic skin
would slough to reveal underlying pusand extensive liquefaction
necrosis of subcutaneous tissues, which was significantly more
extensive than would be suspected by the overlying area of
necrotic skin. Pulmonary distressand metastatic abscessesmight
develop aswell.
The signs and symptoms most commonly associated with
Types I and II NF are detailed in TABLE3. The significant
amount of overlap in the presenting signs and symptoms
between the two types make it impossible to reliably distin-
guish the microbial etiology based on clinical presentation
alone. The initial findings may be misleadingly benign (TABLE3),
resembling more innocuous processes, such as cellulitis, arthri-
tis, bursitis or musculoskeletal injury or strain. In a series of 89
patients with NF, only 15% were suspected of having NF on
first presentation [14]. The most common misdiagnoses in these
patients were cellulitis (59%) and abscess (18%) [14]. The rate
of missed diagnoses is also high in GAS NF, with severe local-
ized pain as the presenting symptom in 70 to 90% of
patients[22,60], but an initial misdiagnosis in 35%[61].
Accurate and early diagnosis is important in these cases, since
the outcome of NF depends on rapid institution of treatment
(see below). Although several hard clinical signs: hypotension,
crepitance, skin necrosis, bullae and subcutaneous gas on plain
radiograph [13,62] are specific indicators of NF, many patients
lack these signs on initial presentation to a healthcare provider.
In one series, 61% of NF patients had no hard signs on initial
examination and nonspecific signs and symptoms predomi-
nated [62]. However, exquisite pain, specifically, pain that is dis-
proportionate to what would be expected from the clinical
findings, is seen in nearly 100% of patients with NF [12,14,15,62]
and should strongly suggest the diagnosis. In addition, there are
other clinical findingsthat should be considered red flags, suggest-
ing a possiblenecrotizing process(FIGURE1). For example, a lack of
lymphangitis or lymphadenopathy, which are often seen in less
complicated soft-tissue infections, are rarely seen in NF [6,15].
In most series, the majority of NF cases have an identifiable
source of infection. Reported portals of entry for bacteria are
diverse and range from the obvious (surgical wound) to the
occult (insect bite) (BOX 1). However, a significant number of
cases lack an identifiable focus [1214,16,61,63].
Any anatomic site may be involved in NF, although the
extremities, abdomen and perineum are the most commonly
affected sites [1214,61,62]. Abdominal NF is usually Type I and is
typically related to postsurgical complications [4,63]. Fourniers
gangrene is also typically a polymicrobial infection, and has a
comparatively higher rate of mortality [1].
The overall mortality rate for NF ranges from approximately
20 to 35% and is higher at the extremes of age [1214,28,6264].
Patients with GAS NF are more likely to be seriously ill dur-
ing their course in comparison with Type I NF patients, and
appear to have an increased risk of death compared with
Type I patients [13,21]. This is probably due to the presence
of streptococcal TSS in approximately 50% of patients suf-
fering from GAS NF [22,60,61]. The most important determi-
nant of patient survival is the time between the onset of soft
tissue symptoms (or presentation to a healthcare provider)
and the first operative debridement [3,13,14,67,68]. This under-
scores the need for clinicians to think about the possibility
of an early NF in a patient who presents with acute soft-tissue
pain or inflammation.
Diagnosis
The presence of hard clinical signs requires immediate surgical
evaluation, and certain clinical red flags should motivate
further diagnostic consideration of NF (FIGURE 1). The lack of
fever should not rule out the diagnosis of NF as this is variably
present. If the diagnosis is in doubt, frequent and repeated
examinations of the patient are mandatory.
Routine laboratory evaluation may help distinguish NF
from non-necrotic soft-tissue infections. Based on a compar-
ison of 31 NF cases and 328 non-NF soft-tissue infections,
Wall and colleagues proposed a simple discriminative model
based on the white blood cell count and the serum sodium
concentration [62]. In this model a combination of count
greater than 15.4 x 10
9
/l and serum sodium less than
135 mol/l had a sensitivity of 90%, specificity of 76%,
positive predictive value of 26% and negative predictive
value of 99% [62]. However, this model has not been vali-
dated prospectively. Wong and colleagues have more
recently developed a Laboratory Risk Indicator for necrotiz-
ing fasciitis (LRINEC) in which a score is assigned from a
combination of values for C-reactive protein, white blood
cell count, hemoglobin, serum sodium, creatinine and glu-
cose [28]. A score of less than or equal to five (low risk) was
associated with a lessthan 50% chance of having NF; a score of
six to seven (moderate risk) with a 50 to 75% probability and a
score greater than or equal to eight (high risk) with a greater
than 75% probability of NF. The authors chose a cut-off
score of six, at which the positive predictive value of this
model was 92% and the negative predictive value was 99%.
This model has also not been prospectively analyzed and the
authors themselves advocated surgical intervention when the
index of clinical suspicion is high, regardless of the LRINEC
score [28]. With respect to streptococcal fasciitis, it has been
reported that a C-reactive protein of greater than or equal to
16 mg/dl is strongly associated with GAS NF (sensitivity
89%; specificity 90%; positive predicitve value 44% and
negative predicitve value 99%) [21]. An elevated creatine
kinase of greater than or equal to 600 units/l was also found
to be poorly predictive (sensitivity 58%; specificity 95%;
positive predicitve value 58% and negative predicitve value
95%) [21]. A molecular diagnostic technique for Type II NF,
based on the identification of SAg genes within involved tissue
using polymerase chain reaction remains investigational [69].
Radiographic procedures can be helpful in the evaluation
of suspected cases of NF, but the use of such technologies
should not delay appropriate surgical management of highly
suspicious cases. The ideal radiologic test would successfully
identify patients with early, minimally symptomatic fasciitis,
while excluding patients with less complicated soft-tissue
infections. Plain x-rays are useful in detecting gas in the soft
tissues that may not be detected on physical
examination [70]. However, gas tends to appear late in the
course of NF and the prevalence of soft-tissue gas at the time
of presentation is highly variable (1570% of cases) [13,70].
Computed tomography (CT) scans have the benefit of
improved sensitivity over a plain radiograph, especially
regarding soft-tissue edema, are nearly as rapid and easily
obtained as plain x-rays and better delineate the extent of
infection not obvious to the examiner. Asymmetric fascial
thickening with fat stranding can be found in approximately
80% of cases [71]. CT scans also identify fluid collections
and foreign bodies that may be unapparent on plain films.
However, CT scans may not adequately differentiate severe
cellulitis from NF, and cases of NF with negative CT find-
ings have been reported [71]. There have also been no pro-
spective studies examining the ability of CT to diagnose NF
before clinically obvious signs of disease erupt.
In comparison, magnetic resonance imaging (MRI) has very
high sensitivity (93100%) for diagnosing NF, although pub-
lished reports include patients in whom NF was already clini-
cally suspected at the time of presentation [7275]. Differentiat-
ing NF from severe cellulitis may also prove problematic based
on MRI alone. NF exhibits high signal intensity on T2-
weighted images and contrast-enhanced T1-weighted images
by MRI. However, hyperintense T2 signal can be seen in a
number of conditions with fascial edema but no necrosis,
including abscess, cellulitis, cellulitis with lymphatic obstruc-
tion, cellulitis with venous thrombosis, recent radiation ther-
apy, neoplasm-related soft-tissue swelling, rheumatic disease,
recent surgery, ruptured popliteal cyst and passive edema [73].
Moreover, MRI is often difficult to obtain in a timely manner,
may not detect soft-tissue gas, is comparatively expensive and
may be technically difficult to perform on a critically ill patient.
Wang and Hung recently prospectively examined the utility
of transcutaneous soft-tissue oximetry to diagnose NF of the
lower extremities [76]. They reported significantly decreased
oxygen saturation (SaO
2
) readings within areas of suspected
Box 1. Necrotizing fasciitis: inciting events and
pre-existing conditions.
Soft-tissue injury: superficial abrasions, lacerations,
penetrating traum a, injection drug use, subcutaneous
injections such as insulin injections, surgical w ound, insect
bite, burn, snake bite, chickenpox or zoster
Head and neck: dental abscess, odontogenic infection,
parotitis, peritonsillar abscess or cervical adenitis
Abdom inal: appendicitis, strangulated hernia, colocutaneous
fistula, diverticulitis, perirectal abscess, om phalitis or
perforated viscus
Genitourinary: Bartholins gland cyst, coital injury, septic
abortion, vulvar abscess, postepisiotom y, renal calculus,
pilonidal cyst, cesarean section surgery, tubal ligation
surgery, hysterectom y or traum atic bladder instrum entation
M usculoskeletal: ankle sprain, traum a, foot ulcers, skin
abscess or cellulitis
Iatrogenic: percutaneous endoscopically placed gastrotom y
tube, central lines, percutaneous catheters, chest tube,
peripheral intravenous site, nerve block, cardiac
catheterization or acupuncture
Spontaneous/idiopathic
Hem atogenously seeded
M unchausens syndrom e
NF compared with control patients with cellulitis. Setting a
cut-off SaO
2
value of 70% or less, the sensitivity of this test was
100% and the specificity was 97%. Interestingly, readings
returned to normal after fasciotomy and may be useful to mon-
itor the response to therapy. However, patients with athero-
sclerotic peripheral vascular disease and very obese patients
were not included in this study and only lower extremity
lesions were examined.
The diagnostic gold standard for NF is the finding of fascial
necrosis at the time of surgery. Others have suggested less
invasive, tissue-based diagnostic procedures to help aide the
diagnosis of NF. As early as the 1950s, investigators sug-
gested using the finding of fascial dehiscence as a diagnostic
test. Wilson advocated using a mechanical probe or ones own
finger to probe to the deep fascia through either a spontane-
ous wound opening or creating a small surgical opening [7].
Table 3. Common presenting signs and symptoms of necrotizing fasciitis.
Type I Presented (%) Type II Presented (%)
Symptoms
Intense pain* 7398 Intense pain* 87
Fever 3180 GI (nausea, vom iting and
diarrhea)
47
Num bness 1 Flu-like (fluor aches, chills
and feverishness)
46
W eakness 0.5 Tem perature over 37.7C 45
Altered sensorium 1418
Signs
W arm th 97 Localized edem a 36
Tenderness 98 Localized erythem a 27
Sw elling 7592 Cutaneous lesion 18
Tachycardia 74 Heart rate above 90 73
Erythem a 66100 Hypotension (if streptococcal
TSS present)
18; >95
Foul discharge 47 TSS 4073
Skin discoloration 1849 Acute renal insufficiency
(on presentation)
45
Blistering/bullae 1445 Rash 35
Induration 1245 Crepitus or soft tissue air less than 20
Shock 22
Jaundice 16
Fluctuance 11
Crepitus 036
Sensory or m otor deficits
(e.g.localized anesthesia)
927
Skin sloughing/necrosis 531
Hypotension 418
M ultiorgan dysfunction 4.5
Soft tissue air on x-ray 1757
*Pain out of proportion to exam ination.
Type I [12-15,143]; Type II [13,22,60,61].
GI: Gastrointestinal tract; NF: Necrotizing fasciitis; TSS: Toxic shock syndrom e.
Presently, several authors advocate such a finger test through
a 2 cm incision [12,15,28]. Lack of bleeding and dishwater dis-
charge are both ominoussigns. Blunt dissection isthen performed
using a finger. If the normally adherent subcutaneoustissue easily
dissectsoff deep fascia, then the diagnosisof NF ismade. Unfortu-
nately, while such a test seemslogical and efficient, itsutility has
not been validated by any clinical trials[77]. An alternative bedside
technique employs the use of frozen section cutaneous biopsies
[68,78]. Briefly, thisinvolvestaking a tissue biopsy down to deep fas-
cia of an area of suspected NF and then sending such a biopsy for
prompt frozen section pathology. This modality was found to
reduce the time between presentation and definitive surgical debri-
dement (21h vs. 6 days) and also demonstrated a mortality benefit
(12.5 vs. 72.7%) [68]. Frozen-section tissue biopsy had the
additional benefits of identifying NF cases where the clinical
suspicion waslow and also preventing unnecessary surgery in six
cases[68]. However, biopsy specimensmust be processed and read
by an experienced dermatopathologist immediately, which makes
such a technique impractical at most institutions.
Treatment
Several aspects of NF therapy have confirmed benefit and
have achieved the status of standard of care. The rationale
for these modalities, that is, aggressive surgical debridement,
broad-spectrum empiric antibiotics and hemodynamic sup-
port, are discussed in this section. Elements of care that are
available but do not have firm evidence supporting their use
will be discussed in the expert opinion section that follows.
Yes
Or
Yes
No
No
No
No
Yes
Yes
Yes
'Hard' signs of NF present:
Crepitance
Skin necrosis
Bullae
Focal anaesthesia
Rapid progression of lesion
Gas on x-ray
Hemodynamic instability
Systemic toxicity
Treat as simple soft
tissue infection
(e.g. cellulitis) or
noninfectious process
(e.g. deep venous
thrombosis).
Reevaluate in 24 hours.
Diagnosis
confirmed
Diagnosis
excluded
Negative
evaluation
Positive
evaluation
Blood work negative
but clinical suspicion
for NF high
Signs or symptoms of
soft tissue infection?
Pain out of proportion to
physical examination?
Radiographic imaging:
MRI
CT
Ultrasound
Prompt surgical consultation to
confirm diagnosis of NF:
Diagnosis by surgical
debridement, or
'Finger' probe test, or
Frozen-tissue section
Treat as NF:
Wide surgical debridement
Broad spectrum antibiotics,
including clindamycin
Cardiopulmonary stabilization
Blood cultures and blood work
if not already done
Consider IVIg if GAS suspected
or if criteria for streptococcal TSS
are met
Red flags on physical examination:
Edema extending beyond area
of erythema
Absence of lymphangiitis
or lymphadenopathy
Tachycardia
Myalgias
Constitutional symptoms
Altered mental status
Slow/absent response to antibiotics
Positive blood work?
*
:
LRINEC score 6
WBC 15.9 x 10
9
/l
CRP 16mg/l
CK 600U/l
Acute renal insufficiency
Risk factors for NF:
Diabetes mellitus
Alcoholism
Immunosuppression
Peripheral vascular disease
Intravenous drug abuse
Recent surgery
Abdominal or perineal
localization of disease
Figure1. General approach to the patient with possible necrotizing fasciitis.
*
CBC, m etabolic profile, C-reactive protein, creatinine kinase, blood culture.
M RI, if prom ptly available, is preferred m odality due to high sensitivity. CBC: Com plete blood count; CK: Creatinine kinase; CRP: C-reactive protein;
CT: Com puted tom ography; GAS: Group A streptococcus; IVIg: Intravenous im m unoglobulin; LRINEC: Laboratory risk indicator for necrotizing fasciitis;
M RI: M agnetic resonance im aging; NF: Necrotizing fasciitis; TSS: Toxic shock syndrom e; W BC: W hite blood cell.
Surge ry
Definitive therapy of NF includes immediate and extensive
debridement of all necrotic and devitalized or at-risk-appearing
tissue [3,13,14,63,65,66,79,80]. The goal of the clinician should be
surgical intervention within 24 h of presentation, as the mortal-
ity rate significantly increases beyond this period [14]. Not only
does the timeliness of surgical intervention impact mortality,
but the adequacy of the first debridement is also
important [4,63,7981]. Wide resection, not simple incision and
drainage, should be performed of all tissue that can be easily
elevated off deep fascia with gentle finger dissection [15]. Re-
exploration and further debridements should be aggressively
performed as needed to control the necrotizing process [13].
Multiple trips to the operating suite are the rule, and survival
has been reported in patients with up to 45% of their body sur-
face area debrided [82]. In one series, an average of 2.1 debride-
ments were performed within the first 5 days, with an average
of 3.8 debridements per patient per total hospital stay [13].
Once necrosis has been controlled, surgery should be aimed at
optimizing wound care. Diverting colostomies may be needed
to prevent soilage of abdominal and perineal wounds [13]. NF
patients may require surgical wound closure in order to mini-
mize protein, fluid and electrolyte losses [15]. Temporary clo-
sures may be required until definitive debridement is accom-
plished, at which time split-thickness skin grafting, flaps or free
flaps may be required. In one review, the average time to final
wound closure was 26.4 days after initial surgery [13].
Antibiotic s
Parenteral antimicrobial therapy is an important aspect of NF
management and initial empiric antimicrobials must be
broadly active against a wide range of possible pathogens
including: Gram-negative enteric bacteria, anaerobes and
Gram-positive organisms such as staphylococci and strepto-
cocci. A -lactam/-lactamase combination such as ampicil-
lin/sulbactam, piperacillin/tazobactam or ticarcillin/clavulanate
would be reasonable empiric choices, although increasing resist-
ance to ampicillin/sulbactam by enteric pathogens such as
Escherichia coli may limit its future utility in polymicrobial NF.
Alternative combinations include a third- or fourth-generation
cephalosporin along with metronidazole or clindamycin for
anaerobic coverage. For the penicillin-allergic patient, clin-
damycin plus aztreonam is an acceptable choice. Consideration
should be given to Pseudomonasspp. if NF develops in a previ-
ously hospitalized patient or arises in the proximity of a chroni-
cally infected ulcer (e.g., decubitus ulcer). Similarly, extended
coverage for highly resistant Gram-positive bacteria should be
added in nosocomial or surgical wound-associated infections.
Vancomycin remains the drug of choice in such settings,
although both linezolid and daptomycin are alternatives for
patients unable to receive vancomycin. A recently observed
increase in community-acquired methicillin-resistant Staphy-
lococcus aureus (MRSA) infections raises the question of
whether or not such extended Gram-positive coverage should
be included empirically for all cases of NF. However, most
community-acquired MRSA strains remain susceptible to
numerous antibiotics, including clindamycin, as in a recent
cluster of MRSA-associated NF cases in California [83].
The authors advocate adding clindamycin to the above
empiric regimens until the presence of GAS can be confirmed
or excluded. This recommendation is based upon both animal
studies and human epidemiologic investigations demonstrating
beneficial effects of clindamycin on mortality in GAS NF
(reviewed extensively in [84]). This mollifying effect on GAS NF
may result from the ability of clindamycin to inhibit protein
synthesis, to suppress production of GAS exotoxins and/or vir-
ulence factors [8590] and to enhance the phagocytosis of GAS
by inhibiting M-protein synthesis [84]. Interestingly, clinda-
mycin has been shown to reduce the expression of virulence
proteins in bacterial species against which it has poor antibacte-
rial activity (e.g., Gram-negative bacteria), suggesting it may be
useful in cases of non-GAS NF, although clinical evidence is
lacking [85,87,88,9195]. The host inflammatory response to GAS
infection may be beneficially altered by clindamycin as well.
Unlike -lactam antibiotics, clindamycin doesnot appear to pro-
mote the release of proinflammatory cell wall componentsfrom
dying bacteria [96], and proinflammatory cytokine expression
may be directly downregulated by the drug [90,97,98]. Additionally,
as opposed to -lactams, the potency of clindamycin against GAS
is not reduced by a high microbial burden. This inoculum size
effect (also called the Eagle effect) describes the observed
decreased susceptibility of GASto penicillin when organismsare
present in high density [99]. Thisphenomenon may result from
reduced expression of penicillin-binding proteins in the station-
ary phase of growth [100]. Consequently, in a mouse model of
streptococcal myositis, animals receiving clindamycin survived
better than those treated with penicillin [101]. Although evi-
dence from prospective, randomized trials is lacking, analysis of
available retrospective data suggests a benefit for clindamycin in
invasive GAS disease, including NF [84].
Supportive c a re
Patients with NF are often critically ill and usually require
metabolic and hemodynamic support. Hypotension, respira-
tory distress and shock should be aggressively managed, as
should analgesia. Nutritional support is also
important [12,13,15], especially considering the extensive loss
of fluids, proteins and electrolytes from large surgical
wounds that mimic losses observed in burn victims. Aggres-
sive nutritional support has been shown to improve survival
[12,13,15] and some authors have suggested that patients
receive twice their basal caloric requirement in the acute
phase of management [12,13].
Expert opinion
Our perspectives on the diagnosis and therapy of NF are
summarized in FI GURE 1. The elements of the therapeutic
standard of care are summarized below:
Prompt and aggressive surgical debridement of devitalized
tissue with drainage of any purulent material
Empiric broad-spectrum antibiotics with activity against
community-acquired Gram-positive and -negative patho-
gens as well as obligate anaerobes. Options include:
-lactam/-lactamase combinations, such as ampicillin/sul-
bactam, piperacillin/tazobactam or carbenicillin/clavu-
lanic acid, carbepenems, third- or fourth-generation
cephalosporins plus clindamycin or metronidazole
Focused antimicrobial therapy for Type II NF due to GASwith
high-dose penicillin G or ampicillin and clindamycin, immedi-
ately and until all infected tissueshave been debrided or drained
Hemodynamic and aggressive nutritional support
Additional treatment optionsare available, but they are expen-
sive, and their effectiveness is unclear. These options may be
considered on a case-by-case basis, in extremely ill patients, if
resourcesare available and if there isno contraindication
Hype rba ric oxyge n
While the use of hyperbaric oxygen (HBO) in anaerobic
infections such as clostridial gangrene is supported by experi-
mental data [102], only anecdotal and/or retrospective data are
available in NF. It has been demonstrated that HBO may aug-
ment neutrophil microbicidal activity, impair the virulence of
(or kill) certain bacterial pathogens, promote angiogenesis and
wound healing, increase red blood cell pliability, terminate
lipid peroxidation and reduce local vasoconstriction and
edema [4,103,201]. Retrospective analyses suggest both mortality
and morbidity benefits for HBO in the setting of NF, with
perhaps the most consistent improvement being accelerated
wound healing [4,12,13,15,67,103,104,201]. However, these observa-
tions have not been prospectively validated. Additionally,
HBO is not readily available at most institutions, and there are
the practical difficulties of monitoring and managing a criti-
cally ill patient isolated in a pressurization chamber. Complica-
tions of HBO are common, and include reversible myopia (up
to 20%) that may last for months, otobarotrauma (320%),
pneumothorax, pulmonary oxygen toxicity and CNS oxygen
toxicity with seizures (1:10,000) [201]. Therefore, consider
HBO an adjunctive therapy that should not precede definitive
surgical intervention.
Intra ve nous immunoglobulin & group A stre ptoc oc c us
ne c rotizing fa sc iitis
The role of intravenous immunoglobulins (I VIg) in the
treatment of invasive GAS disease also remains the subject
of debate. Although primarily given as therapy for strepto-
coccal TSS, IVIg has also been used as an adjunctive treat-
ment in GAS NF. Retrospective reviews suggest a mortality
benefit [61,105107]. There are several proposed mechanisms of
action for I VIg. IVIg may directly opsonize GAS and pro-
mote its clearance by the immune system, although a
murine model failed to demonstrate improved bacterial
clearance [108]. It has also been postulated that IVIg may
directly antagonize streptococcal SAgs. The ability of IVIg to
inhibit bacterial SAgs and the immune response to SAgs has
been demonstrated with staphylococcal and streptococcal
SAgs[47,107,109111]. It may also directly modulate immune
cytokine responses through unidentified pathways, includ-
ing interactions with soluble immune components or
cytokines themselves, blockade of Fc receptors, induction of
counter-regulatory cytokines and interruption of the bind-
ing of SAgs to the major histocompatibility complex
(MHC)-II or T-cell receptors [107,112114]. Pooled IVIg has
been shown to contain neutralizing antibodies to several
streptococcal SAgs [47,54,59,109,110,115] and acute plasma taken
from patients treated with IVIg for severe invasive GAS dis-
ease demonstrated significantly increased ability to neutral-
ize streptococcal SAgs [45,47]. One small, retrospective review
by Kaul and colleagues suggested a reduction in overall mor-
tality [17]; however, this study used historic controls, and a
subsequent analysis did not find IVIg to be an independent
predictor of death. Recently, a small randomized, controlled
study of 21 patients given IVIg as treatment for streptococcal
TSS showed decreased mortality at 28 days (10%) compared
with patients not receiving IVIg (36%) [45]. While specifically
investigating streptococcal TSS, over half of patients had
deep-tissue infection, likely including cases of GAS NF.
However, the study size was small and did not reach statisti-
cal significance [45]. Experimentally, an animal model
showed no additional benefit of I VIg compared with anti-
biotics alone [108]. The lack of consensus on the optimal dose
and therapeutic window further complicates the use of IVIg.
IVIg is also expensive, often difficult to obtain, and not
without risks, including anaphylaxis (in individuals with
IgA deficiency) and renal failure. Finally, titers of strepto-
coccal SAg-neutralizing antibodies vary in different prepara-
tions of I VIg [116,117]. This variability confounds studies of
IVIg and has obvious clinical implications.
Ac tiva te d prote in C
Although not specifically targeted against GAS, nor intended
for NF infections, activated Protein C (drotrecogin-; Xigris
)
is a commercially available agent that modifies the course of
sepsis and the response of the contact system [118], a collection
of plasma proteins that have anticoagulant, profibrinolytic,
antiadhesive and proinflammatory functions and serve as
physiologic mediators of vascular biology and inflammatory
reactions [119]. Its potential in NF is theoretic, as microvascular
thrombosis is an important component of such infections, and
sepsis and uncontrolled inflammatory responses often accom-
pany NF. However, there has only been a single case report of
its use in NF with no clear indication of benefit [120].
Five-year view
The basic approach to clinical management outlined above is
unlikely to change over the next 5 years. Promising new diag-
nostic approaches, for example, transcutaneous oximetry, if it
can be validated on a larger scale, might significantly advance
our ability to provide prompt therapy, whereas a more rigorous
evaluation of the efficacy of clindamycin, HBO and IVIg will
allow treatment of NF, in particular GAS NF, to be optimized.
Additionally, a more robust understanding of the pathogenesis
of both GAS and non-GASNF would facilitate the identification
of new targetsfor therapy. In thissection, we will addressseveral
new developments regarding potential therapies for GASNF in
particular. GAS vaccines and novel antimicrobials may provide
potent alternatives to current regimens, and several develop-
ing therapies show promise in controlling the toxin-induced
manifestations of infection.
GAS va c c ine s
Several effortsto produce an effective streptococcal vaccine are in
progress. A multivalent M protein vaccine has been effective in
protecting mice against intranasal challenge with GAS[121], and a
comparable vaccine appearsto be safe and immunogenic in adult
humans [122]. Similarly, a vaccine consisting of a streptococcal
fibronectin-binding protein wasshown to provide protection in a
murine intranasal model [123]. Additionally, a vaccine against the
tissue-destructive toxin, streptolysin S, wasshown to neutralize the
toxin invivo[124], and immunization against both SpeA and C tox-
oidswasfound to be protective for streptococcal TSSin a rabbit
model [125,126]. It is not clear whether such vaccines might offer
protection against NF and further studiesare required.
Nove l a ntibiotic s
GAScontinue to be among the few bacterial speciesthat remain
highly susceptible to penicillin, and consequently penicillins are
likely to remain the drugsof choice in the future. In contrast, mac-
rolide resistance appearsto be an emerging problem in the USA,
and many resistant strains are also resistant to clindamycin [127].
One possibleresponse to thisemerging resistance problem will be
to find alternative antimicrobialsthat offer the same advantagesof
clindamycin in necrotizing infections. Initial studies suggest that
the protein-synthesisinhibitor, linezolid, providesthe same toxin-
inhibiting benefits of clindamycin [85,86]. Alternatively, dapto-
mycin, a pore-forming antibiotic that broadly inhibits metabolic
activity in Gram-positive bacteria, may have a similar benefit in
reducing streptococcal toxin production and limiting tissue
damage, but this remains speculative.
Supe ra ntige n- dire c te d the ra pie s
Other innovative treatments to control the toxic effects of
streptococci involve the inhibition of SAg-mediated
immune dysregulation. These treatments can be divided
into three categories:
Inhibition of SAg production by GAS
SAg neutralization
Suppression of the SAg-induced proinflammatory
cytokine cascade
Inhibition of supe ra ntige n produc tion by GAS
As previously discussed, the ability of clindamycin to inhibit
protein synthesis and reduce expression of streptococcal
SAgs and virulence factors justify its inclusion in antibiotic
regimens for GAS NF. There are newer experimental data
demonstrating that the oxazolidinone antibiotic linezolid
also decreases expression of streptococcal SAgs [85,86]. It has
also been suggested that antisense DNA or small interfering
RNA may be used to downregulate specific virulence
genes[128]. This approach is still highly theoretic, and it
remains to be seen whether this will be clinically applicable.
Also lacking is knowledge regarding the timing of SAg
expression invivo, and therefore the optimum time to
administer such therapy. Interference with quorum sensing
to decrease SAg expression in Gram-positive organisms has
been shown experimentally in staphylococci, offering
another novel strategy, but this modality is also still in its
infancy and not completely understood [128]. Finally, it has
recently been shown that GAS may secrete a pheromone pep-
tide that degrades IL-8, preventing neutrophil influx, which
may represent another potential target for future therapies [129].
Supe ra ntige n ne utra liza tion
Drawing from the observation that I VIg appears to bind and
neutralize streptococcal SAgs, investigators have explored
alternative modalities to inactivate SAgs. As mentioned pre-
viously, specific SAg toxoid vaccines have been shown to
generate protective responses invivo against streptococcal
TSS [125,126]. Another promising approach is treatment with
a peptide SAg antagonist. Arad and colleagues developed a
dodecapeptide based on a -strand-hinge--helix domain
within staphylococcal enterotoxin (SE) B that is conserved
among other Gram-positive SAgs. They demonstrated that
the peptide inhibited SEB-induced expression of Th1
cytokines and protected and rescued mice from SEB-
induced lethal shock [130132]. This peptide was also found to
be protective against lethal shock in mice to SpeA and sta-
phylococcal SAg SEA, both of which have little homology to
SEB [132]. Surviving mice treated with this antagonist also
developed broad immunity to rechallenge to SEB or SpeA
[130132]. It has been speculated that this peptide interferes
with the usual Th1 cytokine response induced by SAgs and
allows a vigorous Th2 response to develop protective anti-
bodies to SAgs [130133]. Interestingly, mice treated with the
peptide and challenged with SEB developed protective cros-
simmunity to staphylococcal TSST-1 and streptococcal
SpeA despite being naive to these SAgs [130132].
Modula tion of supe ra ntige n- induc e d
proinfla mma tory c a sc a de
Some authorshave suggested aphereisor hemadsorption asuseful
adjunctive therapies in the treatment of septic shock, including
GAS-induced shock [134138]. It has been proposed that such
blood purification allows the removal of larger bacterial sub-
stances such as SAgs (>40 kDa) as well as immune complexes,
cytokines and coagulation factors [138]. In small human studies,
survival rates of 50 to 80% in patients suffering from severe
sepsis, septic shock or multiple organ system dysfunction have
been reported using apheresis or plasma exchange [138].
Other novel therapies for invasive GAS infections may arise
from studies focused upon modulating the sepsis response with
designer peptides. Activated protein C (drotrecogin-; Xigris
)
is a commercially available example of such rationally
designed therapies. However, other potential targets exist.
GAS interacts with numerous components of the contact
system and can thus directly promote proinflammatory
responses and alter vascular stability [119,139141]. SpeB has
been shown to cleave high molecular weight kininogen
invivo in a mouse model, and it has been shown that
designer peptides can block this activity [141,142]. Similarly,
M protein has also been shown to induce vascular leak and
treatment with a 2-integrin antagonist prevented this effect
in a murine model [140].
Key issues
Necrotizing fasciitis (NF) is a rapidly progressive, life-threatening infection that affects certain risk groups disproportionately, but
can also occur in healthy individuals of any age.
Early diagnosis is critical, since the ability to intervene and to spare life and lim b depends on prom pt recognition and treatm ent. NF
rarely presents w ith obvious signs and sym ptom s, and delays in recognition and diagnosis contribute to the staggering m orbidity
and m ortality.
A suggested clinical approach to diagnosis and treatm ent in algorithm ic form at is show n in FIGURE 1; how ever, no form alized system
can substitute for an experienced physicians clinical judgm ent in cases such as these.
New diagnostic m odalities, such as transcutaneous oxygen saturation testing, m ay revolutionize our ability in the next few years to
avoid disastrous therapeutic delays.
Surgical debridem ent of devitalized tissues w ithin 24 h w ill rem ain a prim ary goal of therapy.
Clindam ycin added to standard antistreptococcal antim icrobials in order to suppress bacterial toxin production has becom e a
standard of care. New er antistreptococcal drugs, such as linezolid and daptom ycin, m ay replace clindam ycin in this role as
clindam ycin resistance becom es m ore com m on. Intravenous im m unoglobulin, hyperbaric oxygen and activated protein C are still of
uncertain value; their effectiveness in reducing m ortality or m orbidity rem ains to be rigorously established.
Current evidence suggests that a com bination of host im m unogenetic factors and m icrobial toxins converge to produce group A
streptococcus NF. Basic research into the m echanism of superantigen-m ediated disease has already provided prom ising new targets
for rationally designed therapies, and studies of streptococcal virulence factors m ay identify novel targets for vaccine developm ent.
References
Papersof special note have been highlighted as:
of interest
of considerable interest
1 EkeN. Fourniersgangrene: areview of 1726
cases. Br. J. Surg. 87(6), 718728 (2000).
2 DescampsV, Aitken J, LeeMG. Hippocrates
on necrotising fasciitis. Lancet 344(8921),
556 (1994).
3 Dellinger EP. Severenecrotizing soft-tissue
infections. Multiplediseaseentitiesrequiring
acommon approach. J. Am. Med. Assoc.
246(15), 17171721 (1981).
4 Green RJ, DafoeDC, Raffin TA. Necrotizing
fasciitis. Chest 110(1), 219229 (1996).
Excellent general review of the
history and management of necrotizing
fasciitis (NF).
5 Loudon I. Necrotising fasciitis, hospital
gangrene, and phagedena. Lancet 344(8934),
14161419 (1994).
6 Meleney F. Hemolytic streptococcal gangrene.
Arch. Surg. 9, 317614 (1924).
7 Wilson B. Necrotizing fasciitis. Am. Surg.
18(4), 416431 (1952).
8 Giuliano A, LewisF, Hadley K et al.
Bacteriology of necrotizing fasciitis. Am. J.
Surg. 134(1), 5257 (1977).
9 Stevens DL. Streptococcal toxic-shock
syndrome: spectrum of disease,
pathogenesis, and new concepts in
treatment. Emerg. Infect. Dis. 1(3), 6978
(1995).
10 Brown A. Flesh-EatingKiller HasDoctors
Baffled. Press Association Ltd, London,
UK (1994).
11 OBrien KL. Epidemiology of invasive
group a streptococcus disease in the
United States, 19951999. Clin. Infect.
Dis. 35(3), 268276 (2002).
12 Childers BJ, Potyondy LD, Nachreiner R
et al. Necrotizing fasciitis: a fourteen-year
retrospective study of 163 consecutive
patients. Am. Surg. 68(2), 109116
(2002).
Excellent large retrospective review
regarding risk factors, diagnosis and
management of NF.
13 Elliott DC, Kufera JA, Myers RA.
Necrotizing soft tissue infections. Risk
factors for mortality and strategies for
management. Ann. Surg. 224(5),
672683 (1996).
Excellent large retrospective review
regarding risk factors, diagnosis, and
management of NF.
14 Wong CH, Chang HC, Pasupathy S et al.
Necrotizing fasciitis: clinical
presentation, microbiology and
determinants of mortality. J. BoneJoint
Surg. Am. 85A(8), 14541460 (2003).
Large retrospective review with an
excellent KaplanMeier curve of survival
versus time to initial surgical
debridement.
15 Andreasen TJ, Green SD, ChildersBJ.
Massive infectioussoft-tissue injury:
diagnosisand management of necrotizing
fasciitisand Purpura fulminans. Plast.
Reconstr. Surg. 107(4), 10251035 (2001).
16 NicholsRL, Florman S. Clinical
presentationsof soft-tissue infectionsand
surgical site infections. Clin. Infect. Dis.
33(Suppl. 2) S84S93 (2001).
17 Kaul R, McGeer A, Low DE et al.
Population-based surveillance for group A
streptococcal necrotizing fasciitis: clinical
features, prognostic indicators, and
microbiologic analysisof seventy-seven
cases. Ontario Group A Streptococcal
Study. Am. J. Med. 103(1), 1824 (1997).
18 Sharkawy A, Low DE, Saginur R et al.
Severe group a streptococcal soft-tissue
infectionsin Ontario: 19921996. Clin.
Infect. Dis. 34(4), 454460 (2002).
19 StevensDL. Streptococcal toxic shock
syndrome associated with necrotizing
fasciitis. Ann. Rev. Med. 51, 271288
(2000).
An excellent review of group A
streptococcus NF and streptococcal toxic
shock syndrome.
20 StevensDL. Invasive group A streptococcus
infections. Clin. Infect. Dis. 14(1), 211
(1992).
21 Simonart T, Simonart JM, Derdelinckx I
et al. Value of standard laboratory testsfor
the early recognition of Group A
hemolytic streptococcal necrotizing
fasciitis. Clin. Infect. Dis. 32(1), E9E12
(2001).
22 StevensDL, Tanner MH, Winship J et al.
Severe group A streptococcal infections
associated with a toxic shock-like syndrome
and scarlet fever toxin A. N. Engl. J. Med.
321(1), 17 (1989).
23 Factor SH. Invasive group A streptococcal
disease: risk factorsfor adults. Emerg. Infect.
Dis. 9(8), 970977 (2003).
24 Brun-Buisson CJ, Saada M, Trunet P et al.
Haemolytic streptococcal gangrene and
non-steroidal anti-inflammatory drugs. Br.
Med. J. (Clin. Res. Ed.) 290(6484), 1786
(1985).
25 Zerr DM, RubensCE. NSAIDSand
necrotizing fasciitis. Pediatr. Infect. Dis. J.
18(8), 724725 (1999).
26 Aronoff DM, Bloch KC. Assessing the
relationship between theuseof nonsteroidal
anti-inflammatory drugsand necrotizing
fasciitiscaused by group A streptococcus.
Medicine82(4), 225235 (2003).
27 Dahl PR, Perniciaro C, Holmkvist KA et al.
Fulminant group A streptococcal necrotizing
fasciitis: clinical and pathologic findingsin 7
patients. J. Am. Acad. Dermatol. 47(4),
489492 (2002).
28 Wong CH, Khin LW, Heng KSet al. The
LRINEC (Laboratory Risk Indicator for
Necrotizing Fasciitis) score: a tool for
distinguishing necrotizing fasciitisfrom
other soft tissueinfections. Crit. CareMed.
32(7), 15351541 (2004).
29 HiteK LockeM, HesseltineH. Synergism in
experimental infectionswith nonsporulating
anaerobic bacteria. J. Infect. Dis. 84, 1
(1949).
30 RobertsDS. Thepathogenic synergy of
Fusiformisnecrophorusand Corynebacterium
pyogenes. Influenceof theleucocidal exotoxin
of F. necrophorus. Br. J. Exp. Pathol. 48(6),
665673 (1967).
31 RobertsDS. Synergic mechanismsin certain
mixed infections. J. Infect. Dis. 120(6),
720724 (1969).
32 Bisno AL, Brito MO, CollinsCM.
Molecular basisof group A streptococcal
virulence. Lancet Infect. Dis. 3(4), 191200
(2003).
33 Cunningham MW. Pathogenesisof group
A streptococcal infections. Clin. Microbiol.
Rev. 13(3), 470511 (2000).
34 Betschel SD, Borgia SM, Barg NL et al.
Reduced virulence of group A streptococcal
Tn916 mutantsthat do not produce
streptolysin S. Infect. Immun. 66(4),
16711679 (1998).
35 Engleberg NC, Heath A, Vardaman K et al.
Contribution of CsrR-regulated virulence
factorsto the progressand outcome of
murine skin infectionsby Streptococcus
pyogenes. Infect. Immun. 72(2), 623628
(2004).
36 Sun H, Ringdahl U, Homeister JW et al.
Plasminogen isa critical host pathogenicity
factor for group A streptococcal infection.
Science305(5688), 12831286 (2004).
37 McIver KS, Scott JR. Role of Mga in
growth phase regulation of virulence genes
of the group A streptococcus. J. Bacteriol.
179(16), 51785187 (1997).
38 Graham MR, Smoot LM, Migliaccio CA
et al. Virulence control in group A
streptococcusby a two-component gene
regulatory system: global expression
profiling and in vivo infection modeling.
Proc. Natl Acad. Sci. USA 99(21),
1385513860 (2002).
39 Levin JC, WesselsMR. Identification of
csrR/csrS, a genetic locusthat regulates
hyaluronic acid capsule synthesisin group
A streptococcus. Mol. Microbiol. 30(1),
209219 (1998).
40 Miller AA, Engleberg NC, DiRita VJ.
Repression of virulencegenesby
phosphorylation-dependent oligomerization
of CsrR at target promotersin S. pyogenes.
Mol. Microbiol. 40(4), 976990 (2001).
41 ChausseeMS, Sylva GL, Sturdevant DE
et al. Rgg influencestheexpression of
multipleregulatory loci to coregulate
virulencefactor expression in Streptococcus
pyogenes. Infect. Immun. 70(2), 762770
(2002).
42 Granok AB, ParsonageD, RossRP et al. The
RofA binding sitein Streptococcuspyogenesis
utilized in multipletranscriptional pathways.
J. Bacteriol. 182(6), 15291540 (2000).
43 Kreikemeyer B, BoyleMD, Buttaro BA et al.
Group A streptococcal growth phase-
associated virulencefactor regulation by a
novel operon (Fas) with homologiesto two-
component-typeregulatorsrequiresa small
RNA molecule. Mol. Microbiol. 39(2),
392406 (2001).
44 Podbielski A, Woischnik M, Leonard BA
et al. Characterization of nra, a global
negative regulator gene in group A
streptococci. Mol. Microbiol. 31(4),
10511064 (1999).
45 Darenberg J, Ihendyane N, Sjolin J et al.
Intravenousimmunoglobulin G therapy in
streptococcal toxic shock syndrome: a
European randomized, double-blind,
placebo-controlled trial. Clin. Infect. Dis.
37(3), 333340 (2003).
46 Chaussee MS, Liu J, StevensDL et al.
Genetic and phenotypic diversity among
isolatesof Streptococcuspyogenesfrom
invasive infections. J. Infect. Dis. 173(4),
901908 (1996).
47 Norrby-Teglund A, Kaul R, Low DE et al.
Plasma from patientswith severe invasive
group A streptococcal infectionstreated
with normal polyspecific IgG inhibits
streptococcal superantigen-induced T-cell
proliferation and cytokine production.
J. Immunol. 156(8), 30573064 (1996).
48 Norrby-Teglund A, Thulin P, Gan BSet al.
Evidence for superantigen involvement in
severe group a streptococcal tissue
infections. J. Infect. Dis. 184(7), 853860
(2001).
49 Chatellier S, Ihendyane N, Kansal RG
et al. Genetic relatedness and
superantigen expression in group A
streptococcus serotype M1 isolates from
patients with severe and nonsevere
invasive diseases. Infect. Immun. 68(6),
35233534 (2000).
50 Johnson DR, Wotton JT, Shet A et al. A
comparison of group A streptococci from
invasive and uncomplicated infections:
are virulent clones responsible for serious
streptococcal infections?J. Infect. Dis.
185(11), 15861595 (2002).
51 Kotb M, Norrby-Teglund A, McGeer A
et al. Association of human leukocyte
antigen with outcomes of infectious
diseases: the streptococcal experience.
Scand. J. Infect. Dis. 35(9), 665669
(2003).
52 Lungstras-Bufler K, Bufler P, Abdullah R
et al. High cytokine levels at admission
are associated with fatal outcome in
patients with necrotizing fasciitis. Eur.
CytokineNetw. 15(2), 135138 (2004).
53 Kotb M, Norrby-Teglund A, McGeer A
et al. An immunogenetic and molecular
basis for differences in outcomes of
invasive group A streptococcal infections.
NatureMed. 8(12), 13981404 (2002).
Report on the influence of human
major histocompatibility complex
variation on host response to
streptococcal superantigens.
54 Norrby-Teglund A, Chatellier S, Low DE
et al. Host variation in cytokine responses
to superantigensdetermine the severity of
invasive group A streptococcal infection.
Eur. J. Immunol. 30(11), 32473255
(2000).
55 HenriquesNormark B, Normark S.
Hosting for the cruel and the
inconsequential. NatureMed. 8(12),
13491350 (2002).
56 Norrby-Teglund A, Nepom GT, Kotb M.
Differential presentation of group A
streptococcal superantigensby HLA class
II DQ and DR alleles. Eur. J. Immunol.
32(9), 25702577 (2002).
57 Basma H, Norrby-Teglund A, Guedez Y
et al. Risk factorsin the pathogenesisof
invasive group A streptococcal infections:
role of protectivehumoral immunity. Infect.
Immun. 67(4), 18711877 (1999).
58 Mascini E, Hazenberg M. Invasivegroup A
streptococcal disease, association with a lack
of anti-exotoxin antibodies. In: Streptococci
and theHost. Horaud T, Bouvet A, Leclercq
R, DeMontclosH, Sicard M et al (Eds).
Plenum Press, New York, USA (1997).
59 Norrby-Teglund A, PauksensK, Holm SE
et al. Relation between low capacity of
human sera to inhibit streptococcal mitogens
and seriousmanifestation of disease. J. Infect.
Dis. 170(3), 585591 (1994).
60 Bisno AL, Cockerill FR 3rd, Bermudez CT.
The initial out-patient-physician encounter
in group A streptococcal necrotizing
fasciitis. Clin. Infect. Dis. 31(2), 607608
(2000).
Review of the pitfalls of misdiagnosis in
the initial encounter with group A
streptococcus necrotizing fasciitis.
61 Haywood CT, McGeer A, Low DE. Clinical
experiencewith 20 casesof group A
streptococcusnecrotizing fasciitisand
myonecrosis: 1995 to 1997. Plast. Reconstr.
Surg. 103(6), 15671573 (1999).
62 Wall DB, Klein SR, Black Set al. A simple
model to help distinguish necrotizing
fasciitisfrom non-necrotizing soft-tissue
infection. J. Am. Coll. Surg. 191(3),
227231 (2000).
63 McHenry CR, Piotrowski JJ, Petrinic D
et al. Determinantsof mortality for
necrotizing soft-tissue infections. Ann. Surg.
221(5), 558563 (1995).
64 Elliott D, Kufera JA, MyersRA. The
microbiology of necrotizing soft-tissue
infections. Am. J. Surg. 179(5), 361366
(2000).
65 Ward RG, Walsh MS. Necrotizing fasciitis:
10 years experience in a district general
hospital. Br. J. Surg. 78(4), 488489 (1991).
66 Schiodt M. Deep cervical infections an
uncommon but significant problem. Oral
Dis. 8(4), 180182 (2002).
67 Riseman JA, Zamboni WA, CurtisA et al.
Hyperbaric oxygen therapy for necrotizing
fasciitisreducesmortality and the need for
debridements. Surgery108(5), 847850
(1990).
68 Stamenkovic I, Lew PD. Early recognition
of potentially fatal necrotizing fasciitis. The
use of frozen-section biopsy. N. Engl. J.
Med. 310(26), 16891693 (1984).
69 Louie L, Simor AE, Louie M et al.
Diagnosisof group A streptococcal
necrotizing fasciitisby using PCR to
amplify the streptococcal pyrogenic
exotoxin B gene. J. Clin. Microbiol. 36(6),
17691771 (1998).
70 Fisher JR, Conway MJ, Takeshita RT et al.
Necrotizing fasciitis. Importance of
roentgenographic studiesfor soft-tissue gas.
J. Am. Med. Assoc. 241(8), 803806 (1979).
71 Wysoki MG, Santora TA, Shah RM et al.
Necrotizing fasciitis: CT characteristics.
Radiology203(3), 859863 (1997).
72 BrothersTE, Tagge DU, Stutley JE et al.
Magnetic resonance imaging differentiates
between necrotizing and non-necrotizing
fasciitisof the lower extremity. J. Am. Coll.
Surg. 187(4), 416421 (1998).
73 Loh NN, Ch'en IY, Cheung LP et al. Deep
fascial hyperintensity in soft-tissue
abnormalitiesasrevealed by T2-weighted
MR imaging. Am. J. Roentgenol. 168(5),
13011304 (1997).
74 Rahmouni A, Chosidow O, Mathieu D
et al. MR imaging in acute infectious
cellulitis. Radiology192(2), 493496
(1994).
75 Schmid MR, Kossmann T, Duewell S.
Differentiation of necrotizing fasciitisand
cellulitisusing MR imaging. Am. J.
Roentgenol. 170(3), 615620 (1998).
76 Wang TL, Hung CR. Roleof tissueoxygen
saturation monitoring in diagnosing
necrotizing fasciitisof thelower limbs. Ann.
Emerg. Med. 44(3), 222228 (2004).
77 BariePS. Thelaboratory risk indicator for
necrotizing fasciitis(LRINEC) score: useful
tool or paralysisby analysis?Crit. CareMed.
32(7), 16181619 (2004).
78 Majeski J, Majeski E. Necrotizing fasciitis:
improved survival with early recognition by
tissuebiopsy and aggressivesurgical
treatment. South. Med. J. 90(11), 10651068
(1997).
79 Majeski JA, Alexander JW. Early diagnosis,
nutritional support, and immediateextensive
debridement improvesurvival in necrotizing
fasciitis. Am. J. Surg. 145(6), 784787 (1983).
80 VorosD, PissiotisC, GeorgantasD et al.
Role of early and extensive surgery in the
treatment of severe necrotizing soft tissue
infection. Br. J. Surg. 80(9), 11901191
(1993).
81 Ward RG. Necrotising fasciitis. Immediate
surgical opinion isessential. Br. Med. J.
309(6950), 341 (1994).
82 Burge TS, Watson JD. Necrotising fasciitis.
Br. Med. J. 308(6942), 14531454 (1994).
83 Miller LG. Fourteen caseswith necrotizing
fasciitiscaused by community-onset MRSA
in LosAngeles. 42nd Annual Meetingof
IDSA. Boston, MA, USA, 2728 September
2004.
84 Mulla ZD. Treatment optionsin the
management of necrotising fasciitiscaused
by group A Streptococcus. Expert Opin.
Pharmacother. 5(8), 16951700 (2004).
Review of treatment modalities for
GAS NF.
85 CoyleEA. Targeting bacterial virulence: the
roleof protein synthesisinhibitorsin severe
infections. Insightsfrom theSociety of
InfectiousDiseasesPharmacists.
Pharmacotherapy23(5), 638642 (2003).
Review of the role of protein synthesis
inhibitors, for example, clindamycin.
86 CoyleEA, Cha R, Rybak MJ. Influencesof
linezolid, penicillin, and clindamycin, alone
and in combination, on streptococcal
pyrogenic exotoxin a release. Antimicrob.
AgentsChemother. 47(5), 17521755
(2003).
87 Mascini EM, JanszeM, SchoulsLM et al.
Penicillin and clindamycin differentially
inhibit theproduction of pyrogenic
exotoxinsA and B by group A streptococci.
Int. J. Antimicrob. Agents18(4), 395398
(2001).
88 Shibl AM, Al-Sowaygh IA. Differential
inhibition of bacterial growth and hemolysin
production by lincosamideantibiotics.
J. Bacteriol. 137(2), 10221023 (1979).
89 Sriskandan S, McKeeA, Hall L etal.
Comparativeeffectsof clindamycin and
ampicillin on superantigenic activity of
Streptococcuspyogenes. J. Antimicrob.
Chemother. 40(2), 275277 (1997).
90 StevensDL, Bryant AE, Hackett SP.
Antibiotic effectson bacterial viability, toxin
production, and host response. Clin. Infect.
Dis. 20(Suppl. 2), S154S157 (1995).
91 Kishi K, Hirai K, Hiramatsu K et al.
Clindamycin suppressesendotoxin released
by ceftazidime-treated Escherichia coli
O55:B5 and subsequent production of
tumor necrosisfactor alpha and interleukin-
1. Antimicrob. AgentsChemother. 43(3),
616622 (1999).
92 Murakami J, Kishi K, Hirai K et al.
Macrolidesand clindamycin suppressthe
release of Shiga-like toxinsfrom Escherichia
coli O157:H7 in vitro. Int. J. Antimicrob.
Agents15(2), 103109 (2000).
93 Schlievert PM, Kelly JA. Clindamycin-
induced suppression of toxic-shock
syndrome-associated exotoxin
production. J. Infect. Dis. 149(3), 471
(1984).
94 Stevens DL, Maier KA, Laine BM et al.
Comparison of clindamycin, rifampin,
tetracycline, metronidazole and penicillin
for efficacy in prevention of experimental
GAS gangrene due to Clostridium
perfringens. J. Infect. Dis. 155(2),
220228 (1987).
95 Stevens DL, Maier KA, Mitten JE. Effect
of antibiotics on toxin production and
viability of Clostridiumperfringens.
Antimicrob. AgentsChemother. 31(2),
213218 (1987).
96 Van Langevelde P, van Dissd JT,
Ravensbergen E. Antibiotic-induced
release of lipotechoic acid and
peptidoglycan from Staphylococcusaureus:
quantitative measurements and biological
reactivities. Antimicrob. Agents
Chemother. 42, 3078 (1998).
97 Hirata N, Hiramatsu K, Kishi K et al.
Pretreatment of mice with clindamycin
improves survival of endotoxic shock by
modulating the release of inflammatory
cytokines. Antimicrob. AgentsChemother.
45(9), 26382642 (2001).
98 Nakano T, Hiramatsu K, Kishi K et al.
Clindamycin modulates inflammatory-
cytokine induction in lipopolysaccharide-
stimulated mouse peritoneal
macrophages. Antimicrob. Agents
Chemother. 47(1), 363367 (2003).
99 Eagle H. Experimental approach to the
problem of treatment failure with
penicillin. I . Group A streptococcal
infection in mice. Am. J. Med. 13, 3899
(1952).
100 Stevens DL, Yan S, Bryant AE. Penicillin-
binding protein expression at different
growth stages determines penicillin
efficacy invitroand invivo: an
explanation for the inoculum effect. J.
Infect. Dis. 167, 14011405 (1993).
Important study that provides an
experimental basis for the use of
clindamycin in GAS NF.
101 Stevens DL, Gibbons AE, Bergstrom R
et al. The Eagle effect revisited: efficacy
of clindamycin, erythromycin, and
penicillin in the treatment of
streptococcal myositis. J. Infect. Dis. 158,
2328 (1988).
102 Demello FJ, Haglin JJ, Hitchcock CR.
Comparative study of experimental
Clostridiumperfringensinfection in dogs
treated with antibiotics, surgery, and
hyperbaric oxygen. Surgery73, 936
(1973).
103 Kindwall EP. Usesof hyperbaric oxygen
therapy in the 1990s. Cleve. Clin. J. Med.
59(5), 517528 (1992).
104 Nachreiner R, ChildersB, Kizzar R et al.
Adjunctivehyperbaric oxygen therapy for
necrotizing fasciitis: a10-year experience.
Plast. Surg. Forum18, 334335 (1995).
105 Cawley MJ, BriggsM, Haith LR Jr et al.
Intravenousimmunoglobulin asadjunctive
treatment for streptococcal toxic shock
syndromeassociated with necrotizing
fasciitis: casereport and review.
Pharmacotherapy19(9), 10941098 (1999).
106 Kaul R, McGeer A, Norrby-Teglund A et al.
Intravenousimmunoglobulin therapy for
streptococcal toxic shock syndrome a
comparativeobservational study. The
Canadian Streptococcal Study Group. Clin.
Infect. Dis. 28(4), 800807 (1999).
107 Norrby-Teglund A, IhendyaneN,
Darenberg J. Intravenousimmunoglobulin
adjunctivetherapy in sepsis, with special
emphasison severeinvasivegroup A
streptococcal infections. Scand. J. Infect. Dis.
35(9), 683689 (2003).
Excellent review of the potential role
of intravenous immunoglobulin therapy in
the treatment of severe invasive
GAS disease.
108 Patel R, RouseMS, Florez MV et al. Lack of
benefit of intravenousimmuneglobulin in a
murinemodel of group A streptococcal
necrotizing fasciitis. J. Infect. Dis. 181(1),
230234 (2000).
109 Norrby-Teglund A, Kaul R, Low DE et al.
Evidencefor thepresenceof streptococcal-
superantigen-neutralizing antibodiesin
normal polyspecific immunoglobulin G.
Infect. Immun. 64(12), 53955398 (1996).
110 Skansen-Saphir U, Andersson J, Bjork L
et al. Lymphokineproduction induced by
streptococcal pyrogenic exotoxin-A is
selectively downregulated by pooled human
IgG. Eur. J. Immunol. 24(4), 916922
(1994).
111 Takei S, Arora YK, Walker SM. Intravenous
immunoglobulin containsspecific
antibodiesinhibitory to activation of T-cells
by staphylococcal toxin superantigens.
J. Clin. Invest. 91(2), 602607 (1993).
112 Andersson U, Bjork L, Skansen-Saphir U
et al. Pooled human IgG modulatescytokine
production in lymphocytesand monocytes.
Immunol. Rev. 139, 2142 (1994).
113 StevensDL. Rationale for the use of
intravenousgamma globulin in the
treatment of streptococcal toxic shock
syndrome. Clin. Infect. Dis. 26(3), 639641
(1998).
114 Svenson M, Hansen MB, Bendtzen K.
Binding of cytokinesto pharmaceutically
prepared human immunoglobulin. J. Clin.
Invest. 92(5), 25332539 (1993).
115 Norrby-Teglund A, Ihendyane N, Kansal R
et al. Relative neutralizing activity in
polyspecific IgM, IgA, and IgG
preparationsagainst group A streptococcal
superantigens. Clin. Infect. Dis. 31(5),
11751182 (2000).
116 Darenberg J, Soderquist B, Normark BH
et al. Differencesin potency of intravenous
polyspecific immunoglobulin G against
streptococcal and staphylococcal
superantigens: implicationsfor therapy of
toxic shock syndrome. Clin. Infect. Dis.
38(6), 836842 (2004).
117 Norrby-Teglund A, Basma H, Andersson J
et al. Varying titersof neutralizing
antibodiesto streptococcal superantigensin
different preparationsof normal
polyspecific immunoglobulin G:
implicationsfor therapeutic efficacy. Clin.
Infect. Dis. 26(3), 631638 (1998).
118 Bernard GR, Vincent JL, Laterre PF et al.
Efficacy and safety of recombinant human
activated protein C for severe sepsis.
N. Engl. J. Med. 344(10), 699709 (2001).
119 Colman RW, Schmaier AH. Contact
system: a vascular biology modulator with
anticoagulant, profibrinolytic, anti-
adhesive, and pro-inflammatory attributes.
Blood 90(10), 38193843 (1997).
120 Purnell D, Hazlett T, Alexander SL. A new
weapon against severe sepsisrelated to
necrotizing fasciitis. Dimens. Crit. Care
Nurs. 23(1), 1823 (2004).
121 Hall MA, Stroop SD, Hu MC et al.
Intranasal immunization with multivalent
group A streptococcal vaccinesprotects
mice against intranasal challenge
infections. Infect. Immun. 72(5),
25072512 (2004).
122 Kotloff KL, Corretti M, Palmer K et al.
Safety and immunogenicity of a
recombinant multivalent group a
streptococcal vaccine in healthy adults:
Phase 1 trial. J. Am. Med. Assoc. 292(6),
709715 (2004).
123 Guzman CA, Talay SR, Molinari G et al.
Protective immune response against
Streptococcuspyogenesin mice after
intranasal vaccination with the
fibronectin-binding protein SfbI. J. Infect.
Dis. 179(4), 901906 (1999).
124 Dale JB, Chiang EY, Hasty DL et al.
Antibodiesagainst a synthetic peptide of
SAgA neutralize the cytolytic activity of
streptolysin Sfrom group A streptococci.
Infect. Immun. 70(4), 21662170 (2002).
125 McCormick JK, Tripp TJ, Olmsted SB
et al. Development of streptococcal
pyrogenic exotoxin C vaccine toxoids
that are protective in the rabbit model of
toxic shock syndrome. J. Immunol.
165(4), 23062312 (2000).
126 Roggiani M, Stoehr JA, Olmsted SB et al.
Toxoids of streptococcal pyrogenic
exotoxin A are protective in rabbit
models of streptococcal toxic shock
syndrome. Infect. Immun. 68(9),
50115017 (2000).
127 Hasenbein ME, Warner JE, Lambert KG
et al. Detection of multiple macrolide-
and lincosamide-resistant strains of
Streptococcuspyogenesfrom patients in the
Boston area. J. Clin. Microbiol. 42(4),
15591563 (2004).
128 Tarkowski A, Collins LV, Jonsson IM
et al. Microbial superantigens as virulence
factors and ways to counteract their
actions. Scand. J. Infect. Dis. 35(9),
642646 (2003).
129 Hidalgo-Grass C, Dan-Goor M, Maly A
et al. Effect of a bacterial pheromone
peptide on host chemokine degradation
in group A streptococcal necrotising soft-
tissue infections. Lancet 363(9410),
696703 (2004).
130 Arad G, Hillman D, Levy R et al. Broad
spectrum immunity against superantigens
is elicited in mice protected from lethal
shock by a superantigen antagonist
peptide. Immunol. Lett. 91(23),
141145 (2004).
131 Arad G, Hillman D, Levy R et al.
Superantigen antagonist blocksTh1
cytokine gene induction and lethal shock. J.
Leukoc. Biol. 69(6), 921927 (2001).
132 Arad G, Levy R, Hillman D et al.
Superantigen antagonist protectsagainst
lethal shock and definesa new domain for
T-cell activation. NatureMed. 6(4),
414421 (2000).
Describes the basis for novel superantigen
antagonists and their potential
effectiveness.
133 Schlievert PM. Will therapeutic peptidesbe
kryptonite for superantigens?NatureMed.
6(4), 378379 (2000).
134 Cole L, Bellomo R, JournoisD et al. High-
volume haemofiltration in human septic
shock. IntensiveCareMed. 27(6), 978986
(2001).
135 Fenwick P, Ryan C, Sriskandan Set al.
Application of a rat model of streptococcal
shock to evaluate on-line hemoperfusion
and removal of circulating superantigens.
Crit. CareMed. 31(1), 171178 (2003).
136 Ronco C, Inguaggiato P, D'Intini V et al.
The role of extracorporeal therapiesin
sepsis. J. Nephrol. 16(Suppl. 7), S34S41
(2003).
137 Stegmayr BG. Apheresisastherapy for
patientswith severe sepsisand multiorgan
dysfunction syndrome. Ther. Apher. 5(2),
123127 (2001).
138 Stegmayr BG. The presence of
superantigensand complex host responses
in severe sepsismay need a broad
therapeutic approach. Ther. Apher. 5(2),
111114 (2001).
139 Herwald H, Collin M, Muller-Esterl W
et al. Streptococcal cysteine proteinase
releaseskinins: a virulence mechanism.
J. Exp. Med. 184(2), 665673 (1996).
140 Herwald H, Cramer H, Morgelin M et al.
M protein, a classical bacterial virulence
determinant, formscomplexeswith
fibrinogen that induce vascular leakage. Cell
116(3), 367379 (2004).
141 Herwald H, Morgelin M, Bjorck L.
Contact activation by pathogenic bacteria:
a virulence mechanism contributing to the
pathophysiology of sepsis. Scand. J. Infect.
Dis. 35(9), 604607 (2003).
142 Bjorck L, Akesson P, BohusM et al.
Bacterial growth blocked by a synthetic
peptide based on the struction of a human
proteinase inhibitor. Nature337, 385386
(1989).
143 Wall DB, de Virgilio C, Black Set al.
Objective criteria may assist in
distinguishing necrotizing fasciitisfrom
non-necrotizing soft tissue infection. Am. J.
Surg. 179(1), 1721 (2000).
Website
201 OBrien C. Hyperbaric Oxygen Therapy.
UpToDate Online 12.2.
www.uptodate.com
(Accessed March 2005)
Affiliations
Michael H Young, PhD
Ann Arbor VeteransAffairsHospital, Division of
InfectiousDiseases, Department of
Internal Medicine, Ann Arbor, MI, USA
Tel.: +1 734 936 5205
Fax: +1 734 936 2737
tetris@umich.edu
David M Aronoff, MD
Universityof Michigan Hospitals, Division of
InfectiousDiseases, Department of
Internal Medicine, Ann Arbor, MI, USA
Tel.: +1 734 936 5205
Fax: +1 734 936 2737
daronoff@umich.edu
N. CaryEngleberg, MD
Universityof Michigan Medical School and
Universityof Michigan Hospitals, Department of
Microbiologyand Immunology, 3116 Taubman
Center, Box 0378, Ann Arbor, MI, USA
Tel.: +1 734 936 5205
Fax: +1 734 936 2737
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Young Et Al. (2005) - Necrotizing Fasciitis - Pathogenesis and Treatment

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10.1586/14787210.3.2.279 2005 FutureDrugsLtd ISSN 1478-7210 279 www.future-drugs.com

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