Clinical Microbiology and Infection 26 (2020) 8e17

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Clinical Microbiology and Infection

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Narrative review

Necrotizing skin and soft-tissue infections in the intensive care unit

M. Peetermans 1, N. de Prost 2, 3, C. Eckmann 4, A. Norrby-Teglund 5, S. Skrede 6, 7,
J.J. De Waele 8, *
1)
Department of Critical Care, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
2)
Service de R
eanimation M
^pitaux Universitaires Henri Mondor-Albert Chenevier, Assistance Publique-Ho
edicale, Ho ^pitaux de Paris, Cr

eteil, France
3)
Groupe de Recherche Clinique CARMAS, Universit
e Paris-Est Cr

eteil, IMRB, Cr

eteil, France
4)
Department of General, Visceral and Thoracic Surgery, Klinikum Peine, Academic Hospital of Medical University Hannover, Germany
5)
Centre for Infectious Medicine, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden
6)
Department of Medicine, Haukeland University Hospital, Bergen, Norway
7)
Department of Clinical Science, University of Bergen, Bergen, Norway
8)
Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Background: Necrotizing skin and soft-tissue infections (NSTI) are rare but potentially life-threatening
Received 23 March 2019 and disabling infections that often require intensive care unit admission.
Received in revised form Objectives: To review all aspects of care for a critically ill individual with NSTI.
19 June 2019
Sources: Literature search using Medline and Cochrane library, multidisciplinary panel of experts.
Accepted 22 June 2019
Available online 5 July 2019
Content: The initial presentation of a patient with NSTI can be misleading, as features of severe systemic
toxicity can obscure sometimes less impressive skin findings. The infection can spread rapidly, and
Editor: Professor C Pulcini delayed surgery worsens prognosis, hence there is a limited role for additional imaging in the critically ill
patient. Also, the utility of clinical scores is contested. Prompt surgery with aggressive debridement of
Keywords: necrotic tissue is required for source control and allows for microbiological sampling. Also, prompt
Antibiotics administration of broad-spectrum antimicrobial therapy is warranted, with the addition of clindamycin
Sepsis for its effect on toxin production, both in empirical therapy, and in targeted therapy for monomicrobial
Septic shock group A streptococcal and clostridial NSTI. The role of immunoglobulins and hyperbaric oxygen therapy
Skin and soft-tissue infection
remains controversial.
Source control
Implications: Close collaboration between intensive care, surgery, microbiology and infectious diseases,
and centralization of care is fundamental in the approach to the severely ill patient with NSTI. As many
aspects of management of these rare infections are supported by low-quality data only, multicentre trials
are urgently needed. M. Peetermans, Clin Microbiol Infect 2020;26:8
© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction Necrotizing skin and soft-tissue infections are challenging

Necrotizing skin and soft-tissue infections (NSTI) refer to in-
fections of the skin, subcutaneous tissue and superficial fascia, that
are characterized by the development of necrosis in these struc-
tures. The term NSTI covers a range of infections that can occur in
different anatomical locations and develop after the integrity of the
skin (or mucosa) has been breached. NSTI are rare, but destructive
and potentially lethal infections and patients often require admis-
sion to an intensive care unit (ICU).
* Corresponding author. J.J. De Waele, Department of Critical Care Medicine,
Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.
E-mail address: jan.dewaele@ugent.be (J.J. De Waele).
because of a number of characteristics that distinguish them from
other severe infections, including the ones reviewed in this issue of
CMI. Diagnosis in the early phase of the disease is difficult because
skin lesions may appear benign at first and haemodynamic insta-
bility can be absent. A high index of suspicion is required and
diagnosis is often based on clinical clues that may trigger additional
investigations, but their role is limited, notably in the most critically
ill patients. NSTI can progress rapidly; the resulting tissue damage
is often extensive, requiring surgical source control and recon-
structive surgery in most patients and frequently leaving them with
a permanent disability.
The management of these severe cases should prioritize timely
diagnosis and intervention, with a central role for surgery and
appropriate antibiotic therapy. All of this should be executed in a

https://doi.org/10.1016/j.cmi.2019.06.031
1198-743X/© 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17 9

short time frame, so this requires swift decision-making, and Epidemiology

preferably an experienced multidisciplinary team to treat the
patient.
Previous reviews have focused on either specific aspects of
therapy or carede.g. surgery, antibiotic therapy [1,2] or ancillary
treatments such as hyperbaric oxygen [3e5] or immunoglobulins
[6]; a particular anatomical location [7e10]; a specific pathogen
[11e13]; or they took a very broad perspective covering non-
necrotizing infections as well [14e16].
In this narrative review, we want to focus on all aspects of care
for these patients in the ICU, through the eyes of a multidisciplinary
panel reflecting the approach required in severe infections in the
ICU. This overview is based on an extensive literature search
focusing on information published since 2004.
Methods
A literature search was performed on PubMed and the
Cochrane Library on 2 December 2018 (see Fig. 1 for PRISMA flow
diagram). The following MeSH terms were used: ‘intensive care
units’, ‘critical care’, ‘critical illness’, ‘fasciitis, necrotizing’, ‘Four-
nier gangrene’, ‘gas gangrene’, ‘soft tissue infections’ and ‘skin
diseases, infectious’. In addition, the following free text words
were used: ‘intensive care unit’, ‘necrotizing fasciitis’, ‘gas
gangrene’, ‘soft tissue infection’, ‘skin infection’, ‘cellulitis’,
‘myositis’ and ‘necrotizing’. We applied filters for publications
from 1 January 2004 onwards, written in English. Case reports
were excluded, as were articles that did not involve critically ill
patients with NSTI. We also searched the reference lists of relevant
recent review articles [17,18].
Necrotizing skin and soft-tissue infections are rare, with a
population incidence of 4 per 100 000 per year [19e23], and ac-
count for a small proportion of ICU admissions, estimated at 0.2% in
the UK [24] or 1.2% of all critically ill patients admitted with sepsis
in the Netherlands [25]. However, because of the severity of illness,
underlying co-morbidities and intensity of postoperative wound
care, ICU admission is frequently required [22,23,26e31]. One-
quarter to one-half of patients with NSTI develop septic shock
[23,29,30,32] and/or require mechanical ventilation [26,29,33] and
a third exhibit acute kidney injury [30,33,34]. Organ failures tend to
worsen in the first 24 hours of admission [34]. The duration of ICU
stay typically ranges from 5 to 12 days [25,29,31,32,35e38].
The average age of patients with NSTI is 50e60 years old
[23,26,29,31e35,39e41], with a slight male predominance
[22,23,26,27,29e37,39e42]. Necrotizing fasciitis of the extremities is the
most frequent clinical presentation [23,27,29,31e34,36,37,39,41,42],
followed by perineal NSTI, also known as Fournier's gangrene
[26,31e36,41,42] (Table 1). Involvement of the trunk or head and neck
region are less frequent [26,27,31,33,36,39,42]. From 4% to 12 % of pa-
tients with NSTI have a recurrent NSTI [26,27,31,33]. Co-morbidities
associated with NSTI include diabetes mellitus in 22%e59%
[22,23,26,27,29e31,33,35e37,39,42] and obesity in 17%e31%
[26,30,35e37,41,42]. Other risk factors include cardiovascular disease
(9%e45%) or peripheral vascular disease (3%e19%)
[22,23,26,30,31,33,36,39,41,42], intravenous drug use (2%e80%)
[27,33,36,39], immunosuppression (4%e30%) [23,25,30,35,36,42] and
chronic alcohol abuse (6%e27%) [30,33] (Table 1). Of note, up to one-
quarter of patients with NSTI have no obvious predisposing factor
[30,36,37,39]. In 10%e38% of patients with NSTI, a local trauma is noted

Fig. 1. PRISMA flow diagram of literature search. Reasons for exclusion of articles are given. ‘Not NSTI’ indicates articles not involving patients with necrotizing skin and soft-tissue
infections; * ‘other’ reasons for exclusion of screened titles were non-clinical research (n ¼ 7), palliative care setting (n ¼ 1), medicolegal focus (n ¼ 1), conference abstracts (n ¼ 3);
** ‘other’ reasons for exclusion of screened full text articles were non-clinical research (n ¼ 1), therapy coding (n ¼ 1) and mechanistic research about hyperbaric oxygen therapy
(n ¼ 1).
10 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17
Table 1
Clinical pictures of necrotizing skin and soft-tissue infections (based on [17,19,26,27,29e50])
Location of NSTI Relative frequencya
Limb (lower > upper) 70%
Perineal/genital (Fournier's gangrene) 15%
Cervical <5%
Thoraco-abdominal <5%
Orbital <5%
a
The reported figures are estimates and may vary depending on local patient recruitment and case mix.
as the portal of entry; this can range from a minor skin abrasion or insect
bite, to an operative injury or a blunt trauma. NSTI can also develop on
the background of a chronic wound or dermatosis [29e31,33,36,39]. Use
of non-steroidal anti-inflammatory drugs is regularly noted in the weeks
before admission, potentially masking the clinical signs and symptoms
of a developing NSTI; however, a causal relationship is not established
[23,30,42,43].
Patients with NSTI have considerable long-term functional dis-
abilities. In one report, only half of them were able to return directly
home while the others needed further hospitalization or transfer to
an inpatient rehabilitation facility [26]. Importantly, about 10%e
20% of patients with limb NSTI will eventually require amputation
[23,27,30,33,34,36,38,42,45].
About 20%e30% of patients with NSTI die during their hospital
stay [22,24,33,36,39,40], though mortality may be lower depending
on case mix [33,34,46,47]. Risk factors for mortality are disease
severity, reflected by severity of illness scores such as the APACHE II
[33,35,41,45], or hypotension and/or vasopressor need
[23,29,36,39]. Per unit increase in the APACHE II score, studies
found a 16%e18% increased odds of death [33,35]. If a patient is
hypotensive on admission, the mortality doubles [48]; whereas the
odds ratio for mortality is 28.4 (95% CI 1.35e77.8) if vasopressors
are required on admission to ICU [29]. Bacteraemia upon admission
was also reported to be associated with mortality [29]. Other non-
modifiable prognostic factors include age
[22,26,29,32,36,37,40,47,50] and female gender [22,48]. Diabetes is
not consistently associated with mortality risk [21,23,32]. Other co-
morbidities such as cardiac [48], peripheral vascular [36] and
chronic kidney [36] or liver [44] disease worsen prognosis. Poten-
tially modifiable risk factors associated with NSTI mortality include
the delay to surgical intervention [26,46,49], as well as the expe-
rience of the surgeon [33] and the case volume of the hospital [22].
Microbiology
Current knowledge about pathogens involved in NSTI is essen-
tially based on data from retrospective cohort studies that present
data based on culture-dependent detection of microbes from blood
and sterile site tissue cultures [30,47,48,50e52]. Identification of
aetiological agents may assist infection control measures and
antimicrobial therapy decision-making, and may offer prognostic
information. Drug susceptibility tests are useful in fine-tuning of
antimicrobial therapy but, using the current technologies available
in routine in bacteriology laboratories, they are available after at
Portal of entry Main risk factors
Trauma Age >60 years
Chronic leg ulcer Male gender
Burns Immunosuppression
Insect bites Diabetes
Intravenous drug use Obesity
Blunt trauma Chronic lower limb ischaemia
Varicella
Cutaneous Diabetes
Digestive Obesity
Urinary/genital
Tonsillar phlegmon Glucocorticoids
Dental abscess
Gland infection
Postoperative Diabetes
Obesity
Diabetes
Trauma
least 2 or 3 days, which is detrimental based on the severity of NSTI
in critically ill patients [47,51,52].
Necrotizing skin and soft-tissue infections are often categorized
according to causative organisms [17,53]. Type I infections are poly-
microbial with anaerobic, aerobic and facultative anaerobic bacteria
acting synergistically. In contrast, type II infections are mono-
microbial. Streptococcus pyogenes (group A streptococcus; GAS) is the
most frequent pathogen, followed by other b-haemolytic streptococci
such as Streptococcus dysgalactiae, which is emerging [54e57]. In the
case of NSTI caused by GAS, close to 50% of the cases were found to be
associated with streptococcal toxic shock syndrome (STSS) [58,59]. In
fact, because of the frequent association, soft-tissue necrosis,
including necrotizing fasciitis, myositis or gangrene, is included in the
consensus definition of STSS [60]. Staphylococcus aureus, including
methicillin-resistant S. aureus, Clostridium species, Vibrio vulnicifus
and other Gram-negative bacilli are uncommon causes of type II
infection [61e63]. A myriad of bacterial species including multidrug-
resistant (MDR) Gram-negatives may be cultured from NSTI, even
more so in immunocompromised patients [64,65].
Alternatively, NSTI can be categorized according to the
anatomical location of the infection (Table 1), and the microbiology
differs according to the implicated site.
Anogenital and abdominal infections are secondary to gastro-
intestinal or genitourinary infections that eventually spread along
tissue planes. Essentially these are type I infections and pathogens
are similar to those of intra-abdominal and genitourinary infections
[53]. Multidrug-resistant organisms, e.g. extended spectrum b-
lactamase-producing Escherichia coli or Klebsiella spp., are report-
edly emerging in different parts of the world [61,66,67]. In Four-
nier's gangrene the importance of anaerobic bacteria may have
been underestimated [68].
Among deep neck space infections, type I NSTI predominate
[69]. The most important pathogens are viridans streptococci,
staphylococci and Gram-negative anaerobes such as Bacteroides
fragilis, Prevotella, Fusobacterium and Peptostreptococci [69e71].
Clindamycin resistance is frequent among anaerobic bacteria [71],
reaching 20%e40% in the Bacteroides fragilis group in Europe [72].
Upper respiratory tract pathogens such as Streptococcus pyogenes
and Haemophilus influenzae may be encountered, whereas MDR
pathogens are detected in a few cases [71]. There is risk of intra-
thoracic, prevertebral or intracranial spread.
In most cases, in NSTI of the limbs lower extremity infections
predominate (Table 1). Type I infections are possibly more frequent
[17], particularly in the lower limbs, whereas in type II infections,
GAS is the dominant cause [21,30,48,73]. Even if GAS is isolated, in
 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17 11

30% of cases other microorganisms are also found [74]. The risk of
polymicrobial type I infections is increased in diabetes mellitus
[75], including risk for infections with MDR organisms. Risk factors
for methicillin-resistant S. aureus involvement include intravenous
drug abuse, diabetes mellitus and chronic liver disease [75,76]. In
subtropical areas, Vibrio vulnificus is a pathogen causing NSTI after
exposure to seawater or consumption of raw seafood. Major host
risk factors are chronic liver disease and immunosuppression
[63,77].
Diagnosis
Clinical picture
Early recognition of NSTI is a key step of patient management.
Because cutaneous manifestations may be initially absent, the
infection was shown to be misdiagnosed at first presentation in 71%
of cases in a systematic review including 1463 patients [78],
resulting in delayed diagnosis, antibiotic administration and
Table 2
Signs and symptoms of necrotizing skin and soft-tissue infections, according to the
course of the disease
surgery referral. Patients with NSTI typically present with signs of
severe infection, including malaise, myalgia, diarrhoea and
anorexia, which sometimes precede skin lesions [17] (Table 2).
Upon hospital admission, and as compared with patients having
non-necrotizing skin and soft-tissue infections (e.g. cellulitis), pa-
tients with NSTI are more likely to have sepsis or septic shock [79].
The clinical presentation of NSTI varies depending on the location
(Table 1) and the course (Table 2) of the infection. Clinical findings
were reviewed by Goh et al. after a systematic literature search that
identified swelling (present in 81% of NSTI cases), pain/tenderness
(79%), erythema (71%), warmth (44%), bullae (26%), skin necrosis
(24%) (Fig. 2), and crepitus (20%) as the most frequently encoun-
tered signs [78]. Fever was present in 40% of patients and hypo-
tension in 21%, although the frequency of associated organ failures
varies widely between studies, depending on the case mix, rising to
90% when only patients admitted to the ICU were included [25].
Because none of the previously mentioned signs provided a suffi-
cient sensitivity when considered separately, approaches
combining several clinical findings have been proposed and ach-
ieved better diagnostic yields than did each individual finding [80].
In atypical cases, involvement of dermatologists can aid in the
differential diagnosis of NSTI from rare mimics such as pyoderma
gangrenosum [81].

Early Late Very late Laboratory tests

Fever Purple discoloration Frank necrosis
Pain Haemorrhagic bullae Dishwasher pus The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC)
Erythema/warmth Crepitus Hypoaesthesia score has been proposed as a diagnostic tool for distinguishing NSTI
Tenderness Hypotension from other non-necrotizing skin and soft-tissue infections, based
Induration Organ failures
on the following laboratory tests: C-reactive protein, white blood

Fig. 2. Clinical presentation before (left panels) and after (right panels) debridement in patients with lower limb necrotizing skin and soft-tissue infections (NSTI). (a) A 56-year-old
man with right foot Streptococcus pyogenes (group A streptococcus; GAS) NSTI; the picture shows leg and foot swelling with skin necrosis anterior to the external malleolus and
large bullae; an extensive debridement was performed; (b) A 25-year-old woman with bifocal GAS NSTI; the left foot is swollen and has a lilaceous appearance, and there is a
concomitant involvement of the right internal malleolus; (c) Type I NSTI (tissue specimen grew Staphylococcus aureus and Citrobacter koseri) of the right foot in a 54-year-old man;
the picture typically depicts swelling, erythema and skin necrosis.
12 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17
cell count, haemoglobin, and serum sodium, creatinine and glucose
levels. A score 6 was associated with a positive predictive value of
57%e92% and a negative predictive value of 86%e96% [82,83] and
associated with worse hospital outcomes [84]. External validity
seems to be problematic, however; Fernando et al. found that the
score had poor sensitivity and concluded that it should not be used
to rule out NSTI [85]. Because of its limitations, the LRINEC score has
not been widely implemented. Other biomarkers may be elevated
in patients with NSTI, including serum procalcitonin, creatine
phosphokinase and lactate, but none of these have been shown to
provide robust diagnostic yields in NSTI [86e88].
Imaging
For limb NSTI, standard X-rays show gas in the tissues in about
10%e25% of cases and hence contribute little to the diagnosis
[78,89]. Computed tomography scans will most frequently show
soft-tissue swelling, which will not help to discriminate between
necrotizing and non-necrotizing infections. Magnetic resonance
imaging is the most effective method for diagnosing NSTI, showing
thickening of the deep fasciae, with high signal on T2 images and
contrast-enhanced T1 images [90]. Importantly, magnetic reso-
nance imaging should not be performed in patients with septic
shock so as not to delay surgery. Unlike patients with limb NSTI,
those with cervical, thoraco-abdominal and perineal NSTI (Fig. 3)
Fig. 3. Clinical presentation of a patient with Fournier's gangrene in a 74-year-old man
with diabetes and paraplegia. (a) Picture taken upon hospital admission shows a stage
IV sacral pressure ulcer together with scrotal skin necrosis; (b) transversal computed
tomography scan slice depicting gas in the soft tissue and a collection between the
sacral area and the scrotum; (c) postoperative aspect after drainage and right
orchidectomy.
may require a computed tomography scan to explore the portal of
entry of the infection (Table 1) together with its extension [91,92].
When the clinical suspicion of NSTI is high and/or when patients
present with signs of sepsis/septic shock, prompt surgical explo-
ration is warranted to confirm the diagnosis of NSTI, assess the
need for debridement/amputation and obtain tissue specimens for
microbiological analyses. Direct examination and Gram-staining
can aid in diagnosis and antimicrobial decision-making [93].
Postoperatively, patients with septic shock should be admitted to a
critical care area. A proposed algorithm for the management of
patients with suspected NSTI is given in Fig. 4.
Patient transfer
Given the incidence of NSTI, many physicians and surgeons may
only rarely encounter NSTI. Experience in diagnosing and treating
patients (particularly the surgical debridement) may therefore be
limited and a transfer to a specialized centre may be considered. In
a study from France [22], the volume of patients treated was linked
to improved outcomes. The decision to transfer a patient to a
specialized centre should be based on the experience and avail-
ability of a surgeon, the extent and severity of the skin lesions as
well as the delay that would be incurred by the transfer [94]. In
many instances, the first debridement is done in the admitting
hospital, and the patient is transferred to a specialized centre
afterwards.
Surgery
Surgery plays a crucial role in NSTI management, both in diag-
nosis and treatment. Obtaining a frozen section biopsy in unproven
NSTI has been proposed in earlier publications but has been
abandoned meanwhile because of its low accuracy [15,17]. There-
fore, in uncertain cases, early surgical exploration in the operating
theatre is recommended in recent guidelines and reviews to pre-
vent a delay in the diagnosis and treatment of NSTI [17]. A deep
incision provides crucial information about the local tissue condi-
tions: a vivid and unchanged fascia excludes an NSTI. Typical
intraoperative findings in progressive NSTI are colliquative necrosis
of the fascia and the subcutaneous layer with muddy, dishwater-
like fluid [17,26,46,78] (Fig. 5). Moreover, surgical exploration of-
fers the opportunity to obtain samples for culture and Gram-
staining.
Once the diagnosis of NSTI has been established, initial
aggressive debridement of all infected necrotic tissue is indicated
(Figs. 2, 3 and 5); in critically ill patients, a relook within 24 h is
recommended to ensure the adequacy of source control [14]. A
major amputation is rarely necessary in NSTI, except for patients
suffering from clostridial myonecrosis [52].
Several studies have addressed the timing of surgery in NSTI
after admission to the hospital. Many studies are confounded by the
fact that the time of admission does not correlate with the begin-
ning of symptoms [95]. Nevertheless, a strong correlation between
the timing of surgery and mortality was found. Patients who un-
derwent surgery within 6e12 hours after admission had signifi-
cantly lower mortality rates than those who did not [46,96,97]. The
optimal time-frame for intervention has not been established and
different studies use different cut-offs. In patients with septic
shock, Boyer et al. found that time from diagnosis to surgical
treatment of more than 14 h was independently associated with
hospital mortality (adjusted OR 34.5, 95% CI 2.05e572, p 0.007)
[96].
After debridement and once the wound is stable, the subsequent
use of negative pressure therapy allows reduction of wound surface,
extraction of wound exudate and cell detritus, as well as induction of
 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17
Fig. 4. Algorithm for the approach to a patient with suspected necrotizing skin and soft-tissue infection.
granulation [98]. Moreover, it eases wound management and in-
creases patient comfort in the ICU. In Fournier‘s gangrene, a tem-
porary diverting colostomy is helpful to reduce faecal contamination
and control infection of large perianal wounds [99]. Adequate
wound conditioning in NSTI is the prerequisite for secondary-wound
closure with plastic reconstructive techniques [100].
Throughout the treatment, a close cooperation between sur-
geons and intensivists is essential in order to achieve surgical
source control as early as possible in the early stage, and to facilitate
reconstructive surgery later [16,17].
Antibiotics
There are no randomized clinical trials on empirical antimicro-
bial therapy in NSTI available, and data on optimal antibiotic
treatment in NSTI are scarce [18]. Contemporary guidelines and
recommendations offer pragmatic approaches as they are based on
observational studies, experience in treatment of less severe in-
fections, as well as experimental data. Antimicrobial therapy in
NSTI aims to achieve the following goals: (i) adequate activity
against Gram-positive pathogens and Enterobacteriaceae or other
Gram-negative microbes carrying risk for MDR; (ii) reduced toxin
production in infections with Streptococcus pyogenes or Clostridium
perfringens; and (iii) anaerobic coverage necessary in all poly-
microbial infections [15].
Clinical diversity may be huge in NSTI, but sepsis and septic
shock are frequent. It is therefore particularly important to initiate
broad-spectrum, bactericidal antimicrobial therapy without any
delay upon diagnosis [14,15]. Given the severity of illness and the
lack of criteria that allow rapid discrimination between mixed and
GAS infection, a broad-spectrum antibiotic regimen should be
selected, such as piperacillin-tazobactam, a carbapenem or a third-
13
generation cephalosporin combined with metronidazole, always
with the addition of clindamycin to limit potential toxin produc-
tion. Combination therapy using clindamycin is also recommended
in the directed antibiotic therapy for monomicrobial Gram-positive
infection with GAS or Clostridium species [15]. Depending on local
epidemiology, extended coverage for MDR pathogens may be
required.
When aetiology is identified and susceptibility has been tested,
therapy can be adjusted. Type II infection caused by GAS is treated
with penicillin plus clindamycin [15]. GAS is unequivocally sensitive
to benzyl penicillin, but only clindamycin reliably maintains effi-
cacy in infections with large amounts of bacteria in stationary
growth phase [101,102], In addition, clindamycin diminishes
streptococcal toxin production [103], an effect that was also
demonstrated in an in vivo GAS NSTI murine model and was pro-
posed to contribute to the less severe tissue pathology noted in
clindamycin-treated mice [104]. In two prospective observational
studies of invasive GAS infections, including STSS and NSTI cases,
clindamycin was found to be associated with a significantly
improved survival [104e106]. Treatment options in less frequent
aetiologies of monomicrobial NSTI are presented in Table 3.
Duration of therapy is not well defined, but typically it is
continued until operative debridement has been completed and the
patient is recovering, usually lasting around 7e10 days in total.
Intravenous immunoglobulins
Polyspecific intravenous immunoglobulin (IVIG) has been pro-
posed as adjunctive therapy in severe infectious diseases because of
its immunomodulatory functions and ability to opsonize bacteria
and neutralize bacterial toxins. The clinical value of IVIG in sepsis
and NSTI remains to be demonstrated [107e109]. A recent meta-
14 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17

analysis of IVIG treatment of clindamycin-treated GAS toxic shock

syndrome demonstrated a significant survival benefit [110]. The
pooled data included 70 IVIG-treated and 95 non-treated patients
with STSS. IVIG treatment was associated with a significant
reduction in mortality from 33.7% to 15.7%. The INSTINCT ran-
domized trial of IVIG in NSTI of all aetiologies observed no apparent
effect of IVIG on self-reported physical functioning and mortality
[109]. Further studies are needed to evaluate if there is any value of
adjunct IVIG in NSTI subgroups, particularly NSTI caused by GAS.

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HBOT) has been proposed as an

adjunctive therapy for patients with NSTI. HBOT increases tissue
oxygen tension in infected necrotic wounds and might potentiate
antibiotic efficacy [111]. In an international survey on NSTI man-
agement, one-third of responding intensivists considered that
HBOT was a reason for patient referral to another centre [112].
Observational studies have reported conflicting results [73,113];
Devaney et al. recently reported on a cohort of 344 patients with
NSTI, 275 of whom received HBOT, which was a protective factor for
hospital mortality in multivariable logistic regression analysis [73].
However, a Cochrane review that aimed at assessing the evidence
concerning the use of HBOT as an adjunctive treatment for patients
with NSTI failed to identify any trial meeting the inclusion criteria,
so could not support or refute its effectiveness [3]. The latest
guidelines of the Infectious Disease Society of America on NSTI
management did not recommend HBOT because of the lack of ev-
idence and the risk of delaying resuscitation and surgical
debridement [15].

Research perspectives

Many aspects of patient management are supported by clinical

Fig. 5. Clinical findings during surgery in a 65-year-old woman with post-traumatic
necrotizing fasciitis. (a) After primary incisiondnote the typical landscape-like
necrotic areas of the skin and soft tissue; (b) after radical debridementdall necrotic
tissue has been removed, the muscle tissue is vivid and not affected.
data with low to very low quality only. High-quality research is
urgently needed in a number of areas (Table 4). Given the incidence
of NSTI, international collaborative research is the only way to
improve the care of these patients. On this note, a multicentre

Table 3
Directed antibiotic therapy of causes of necrotizing skin and soft-tissue infections

Bacteria isolated Antimicrobial agents Adult recommended dosage

Polymicrobial (streptococci, Staphylococcus aureus, Piperacillin/tazobactam 4.5 g every 6 h

Escherichia coli, Bacteroides spp.) or meropenem 1e2 g every 8 h
or ceftriaxone þ metronidazole 2 g once daily þ 0.5 g every 8 h
or cefotaxime þ metronidazole 1e2 g every 6e8 hþ 0.5 g every 8 h
All with clindamycin 600e900 mg every 6e8 h
Monomicrobial group A streptococcus (Strptococcus pyogenes) Penicillin G 2  106e4  106 units every 4e6 h
or ampicillin 1e2 g every 4e6 h
All with clindamycin 600e900 mg every 8 h
Clostridium spp. Penicillin G 2  106e4  106 units every 4e6 h
or ampicillin 1e2 g every 4e6 h
All with clindamycin 600e900 mg every 8 h
Aeromonas hydrophila Doxycycline 100 mg every 12 h
Plus ciprofloxacin 500 mg every 12 h
or ceftriaxone 1e2 g once daily
Vibrio vulnificus Doxycycline 100 mg every 12 h
Plus cefotaxim 1e2 g every 8 h
or ceftriaxone 1e2 g once daily
Methicillin-resistant S. aureus Linezolid 600 mg every 12 h
or Clindamycin (if susceptible) 600e900 mg every 8 h
or Vancomycin 1 g every 12 h, trough level adjustment
(15e25 mg/mL) or 20e25 mg/kg bolus followed by
25e35 mg/kg/24 h in continuous infusion
ESBL-producing Enterobacterales (E. coli, Klebsiella pneumoniae) Meropenem 1e2 g every 8 h
Tigecyclina 50e100 mg every 12 h

ESBL, extended spectrum b-lactamase.

Adapted from the 2014 Infectious Diseases Society of America guidelines [76]. Antibiotic doses are for intravenous administration.
a
Tigecyclin should not be used as monotherapy.
 M. Peetermans et al. / Clinical Microbiology and Infection 26 (2020) 8e17 15

Table 4
Research agenda on severe necrotizing skin and soft-tissue infections

Domain Research question/aim

Pathophysiology How does the pathophysiology differ depending on causative pathogen and host susceptibility?
Define pathogenic mechanisms and/or host responses that can be used for patient stratification and tailored therapy in NSTI
Diagnosis What biomarkers can help in the diagnosis?
Define endotypes that would allow for studying precision medicine strategies
What is the role of rapid diagnostic techniques?
Treatment Is there a role for intravenous immunoglobulin in Group A streptococcus NSTI?
What is the effect of hyperbaric oxygen therapy?
Is combination therapy with clindamycin superior to monotherapy?
Is aggressive surgery superior to conservative surgery?
What is the appropriate duration of antibiotic therapy?
Is there a benefit of negative pressure therapy?
Organizational Do we need to centralize care for individuals with NSTI?
Outcomes What is the health-related quality of life after NSTI?

NSTI, necrotizing skin and soft-tissue infections.

prospective observational study on NSTI (NCT01790698) [114],
including both documentation of clinical and treatment variables as
well as biobank collection was recently completed, and results are
highly anticipated.
The pathophysiology of NSTI is incompletely understood, for
example, the role of the innate immune response to locally control
these infections or on the other hand, mediate tissue pathology.
Basic research in this field may help to find new targets for di-
agnostics and intervention, as well as provide critical insight to
support patient stratification and personalized medicine in NSTI.
GAS is an important pathogen and deserves particular attention.
Given the low number of patients with NSTI, organizational
aspects of care such as concentrating the care for these patients in a
limited number of experienced hospitals seems logical but has been
incompletely investigated.
Even in the best circumstances, delayed diagnosis is common
and better tools, such as biomarkers, to diagnose and assess the
risk of poor outcomes are a priority. Rapid diagnostic tools are
under development and their role in NSTI could be very impor-
tant. Molecular diagnostics represent important supplements, as
they can detect relevant culture-negative organisms [115,116] and
possibly shorten time to identification. There is a role for diag-
nostic microbiology [117] in the development of novel therapies in
NSTI.
Although the role of early antibiotics and surgery is obvious, the
role of IVIG, HBOT and clindamycin remains unclear. As for the
surgical procedure itself, both the timing and extent of initial
debridement require further study. Optimal duration of therapy is
another area of uncertainty. Non-antibiotic therapiesdfor example,
targeting bacterial virulence factorsdcould offer new treatment
opportunities.
The aftermath of NSTI should not be underestimated and
continued high-level care is important. Better-quality analysis of
the impact of new strategies in reconstructive surgery such as
negative-pressure therapy and optimized aftercare including psy-
chological support and rehabilitation are also mandatory.
Conclusion
Necrotizing skin and soft-tissue infections are life-threatening
and disabling infections that remain a diagnostic and therapeutic
challenge for clinicians. Multidisciplinary management involving
not only intensivists, surgeons, microbiologists and infectious dis-
ease specialists, but also ICU nurses and physiotherapists is war-
ranted. Early recognition of NSTI is a crucial step that should trigger
the initiation of broad-spectrum antibiotics and aggressive surgical
debridement. A major collaborative effort is required to design
pragmatic studies aimed at assessing treatment strategies using
patient-centred outcomes.
Transparency declaration
JDW reports grants paid to his institution from Bayer, Pfizer,
MSD, Grifols and Accelerate, outside the submitted work. The other
authors have nothing to disclose.
Funding
No external funding was received.
Acknowledgments
None.
Contribution
MP collected the data; all authors drafted the text and revised it
critically.
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