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Official reprint from UpToDate®

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Clostridial myonecrosis
AUTHORS: Dennis L Stevens, MD, PhD, Amy Bryant, PhD
SECTION EDITOR: Sandra Nelson, MD
DEPUTY EDITOR: Keri K Hall, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024.

This topic last updated: Aug 24, 2023.

INTRODUCTION

Clostridial myonecrosis (gas gangrene) is a life-threatening muscle infection that develops

either contiguously from an area of trauma or hematogenously from the gastrointestinal tract
with muscle seeding. Early recognition and aggressive treatment are essential.

There are two major presentations of clostridial gas gangrene: traumatic and spontaneous.
Traumatic gas gangrene is most commonly caused by Clostridium perfringens; spontaneous
gangrene is most commonly caused by Clostridium septicum.

Issues related to necrotizing muscle infections due to Clostridium species will be reviewed here.
Issues related to streptococcal necrotizing myositis and infections involving the skin and fascia
are discussed separately. (See "Necrotizing soft tissue infections".)

SPECTRUM OF CLOSTRIDIAL INFECTIONS

Clostridium species are widespread in nature due to their ability to form endospores. They are
commonly found in soil and marine sediments as well as human and animal intestinal tracts.
Categories of clostridial soft tissue infections include wound contamination, anaerobic cellulitis,
myonecrosis (gas gangrene), and necrotizing fasciitis [1].

● Wound contamination with soil containing clostridial spores or vegetative organisms may
occur. In one study, for example, 30 to 80 percent of open traumatic wounds were

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contaminated with clostridial species [2]. However, such contamination in the absence of
devitalized tissue does not necessarily lead to infection.

● Anaerobic cellulitis requires an anaerobic niche such as devitalized tissue to support the
growth of C. perfringens or other clostridial strains. Gas is produced locally and extends
along fascial planes; bacteremia and invasion of healthy tissue (including muscle) does not
occur. Mortality is low with appropriate management, including prompt removal of the
devitalized tissue [1].

● Myonecrosis (clostridial gas gangrene) may be distinguished from the above infections by
the progressive invasion and destruction of healthy muscle and other soft tissues [2].
There are two major presentations of clostridial gas gangrene: traumatic and
spontaneous.

CLOSTRIDIAL MYONECROSIS

Myonecrosis (clostridial gas gangrene) is characterized by rapidly progressive invasion and

destruction of healthy muscle and other soft tissues. Traumatic gas gangrene is most
commonly caused by C. perfringens; spontaneous gangrene is most commonly caused by the
more aerotolerant C. septicum.

Traumatic gas gangrene — Traumatic wounds with vascular compromise (particularly deep
penetrating injuries such as knife wounds, gunshot wounds, and crush injuries) create an
anaerobic environment that is ideal for proliferation of clostridia. Traumatic injury accounts for
about 70 percent of gas gangrene cases, and about 80 percent of these are caused by C.
perfringens [1]. Other pathogens include C. septicum, C. novyi, C. histolyticum, C. bifermentans, C.
tertium, and C. fallax.

Gas gangrene was a common infection in the American Civil War, World War I, and World War II
due to delayed treatment of injuries. In modern times, evacuation to medical facilities, rapid
vascular repair, and antibiotic treatment have dramatically reduced the incidence of this
disease. Gas gangrene caused by C. perfringens continues to occur among victims of natural
disasters where evacuation and treatment are delayed. As an example, following an earthquake
in China, the average time from injury to medical treatment was 3.5 days, and 20 percent of
patients with open wounds developed gas gangrene caused by C. perfringens; mortality was 50
to 80 percent [3].

Conditions associated with traumatic gas gangrene include:

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● Gunshot wounds, knife wounds

● Compound fractures, crush injuries
● Bowel and biliary tract surgery
● Abortion
● Retained placenta
● Prolonged rupture of the membranes
● Intrauterine fetal demise
● Intramuscular injection
● Black tar heroin injection (skin popping) [4]

Traumatic gas gangrene may have other microbes isolated from the site of trauma; however,
clostridia are the major agents causing destruction of healthy tissue.

Recurrent gas gangrene due to C. perfringens has been described in individuals with minor
trauma at sites of previous gas gangrene [5]. Such cases are likely attributable to the
germination of residual C. perfringens spores, which can remain quiescent in tissues not
adequately debrided for decades.

Pathogenesis — Trauma introduces organisms (vegetative or spore forms) directly into deep
tissue. If trauma compromises the blood supply, an anaerobic environment forms with low
oxidation-reduction potential and acidic pH, which is optimal for growth of clostridial organisms
[1,2]. Necrosis of tissue can develop within hours of injury and progresses rapidly (inches per
hour) in the absence of treatment.

In gas gangrene, muscle necrosis is severe, and polymorphonuclear leukocytes (PMNs) are
notably absent from infected tissues. This is in contrast with soft tissue infections caused by
organisms such as Staphylococcus aureus, in which significant influx of PMNs localizes the
infection without adjacent tissue or vascular destruction. In clostridial infection, PMNs arriving
at the site of infection adhere to and accumulate along the endothelium of capillaries, small
arterioles, and postcapillary venules but do not cross the vascular endothelium into infected
tissue [6,7].

Many extracellular toxins are produced by C. perfringens; of these, alpha and theta toxins have
been implicated in pathogenesis:

● Alpha toxin is a hemolytic toxin with both phospholipase C (PLC) and sphingomyelinase
activities. Two independent studies have identified alpha toxin as an essential toxin in
disease. First, genetic interruption of the alpha toxin gene in C. perfringens rendered the
organism avirulent in a mouse myonecrosis model [1]. Complementation of the
chromosomal mutation with a recombinant plasmid carrying a wild-type gene fully
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restored ability to cause disease. Second, vaccination with the C-terminal domain of alpha
toxin (amino acids 247 to 370) protected mice from experimental C. perfringens infection in
part by improving tissue perfusion and restoring the tissue inflammatory response [8,9].

● Theta toxin (also known as perfringolysin O) is a member of the cholesterol-dependent

cytolysin family that includes streptolysin O, pneumolysin, listeriolysin, septicolysin, and
others [10]. These pore-forming toxins contain a conserved amino acid motif. Theta toxin
contributes to pathogenesis by its effects on cells of the vascular and immune systems
[11-13]. However, theta toxin is not essential in causing mortality since isogenic mutant
strains lacking an intact theta toxin structural gene (pfoA) remained lethal in the mouse
myonecrosis model [1].

Molecular and animal studies have shown that alpha toxin is largely responsible for both the
widespread tissue necrosis and the characteristic absence of a tissue inflammatory response.
Alpha toxin potently stimulates platelet aggregation and upregulates adherence molecules on
PMNs and endothelial cells. Experimental intramuscular alpha toxin injection causes a rapid,
irreversible decline in muscle blood flow and concomitant ischemic necrosis of tissue due to the
formation of occlusive intravascular aggregates of activated platelets, leukocytes, and fibrin.
The perfusion deficits expand the anaerobic environment and contribute to the rapidly
advancing margins of tissue destruction characteristic of clostridial gas gangrene.

In addition, large heterotypic aggregates of activated platelets and PMNs reduce the ability of
PMNs to cross the endothelial cell barrier into infected tissues. These processes are largely
dependent on alpha toxin-induced activation of the platelet fibrinogen receptor, glycoprotein
IIb/IIIa [14,15], suggesting that platelet glycoprotein inhibitors (eg, eptifibatide, abciximab) may
be therapeutic for maintaining tissue blood flow. Thus, the major mechanism explaining the
absence of PMNs in tissue is sequestration within the adjacent vasculature. Since alpha and
theta toxin also are cytotoxic to PMNs in high concentrations, the small numbers of PMNs that
do migrate into tissue are likely destroyed by these toxins.

Shock associated with gas gangrene may be attributable to both direct and indirect effects of
alpha and theta toxins. Alpha toxin directly suppresses myocardial contractility and may
contribute to profound hypotension via a sudden reduction in cardiac output [16,17]. In
experimental models, theta toxin causes markedly reduced systemic vascular resistance
combined with a markedly increased cardiac output (ie, "warm shock") [16,17]. This likely occurs
via induction of endogenous mediators such as prostacyclin, platelet activating factor, and
other lipid autocoids that cause vasodilation [18].

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Patients with gram-negative sepsis compensate for hypotension by markedly increasing cardiac
output. However, this adaptive mechanism may not be possible in the setting of shock due to C.
perfringens given the negative inotropic effect of alpha toxin [16]. The roles of other
endogenous mediators such as cytokines (eg, tumor necrosis factor, interleukin-1, interleukin-6)
and vasodilators (such as bradykinin) have not been fully elucidated. (See "Pathophysiology of
sepsis".)

Clinical manifestations — Traumatic gas gangrene usually presents with sudden onset of
severe pain at the site of surgery or trauma [2,19]. The mean incubation period is less than 24
hours (range 6 hours to several days) and depends on the size of the bacterial inoculum and the
extent of vascular compromise. Pain is likely related to toxin-mediated ischemia.

The skin over the infected area initially may appear pale then rapidly develops a bronze
appearance, followed by purple or red discoloration. The skin becomes tense and exquisitely
tender. Overlying bullae may be clear, red, blue, or purple.

Signs of systemic toxicity develop rapidly including tachycardia and fever, followed by shock and
multiorgan failure. In one series, shock was present in 50 percent of patients at the time of
presentation to the hospital [20].

Bacteremia occurs in about 15 percent of cases and may be associated with brisk intravascular
hemolysis ( picture 1). One case report described a patient whose hematocrit dropped from
37 to 0 percent over a 24-hour period; despite transfusion with 10 units of packed red blood
cells over four hours, the hematocrit never exceeded 7 percent [21]. Both alpha and theta toxins
appear to contribute to the marked intravascular hemolysis based upon experimental in vitro
studies performed with recombinant toxins [17,22].

Bacteremia with C. perfringens can occur transiently in patients without gas gangrene, although
the majority of C. perfringens and C. septicum blood isolates are associated with clinically
significant infection [23,24].

Additional complications of clostridial myonecrosis include jaundice, renal failure, hypotension,

and liver necrosis. Renal failure is largely due to the combined effects of hypotension,
hemoglobinuria, and myoglobinuria. Bacterial toxins may also exert a direct effect on renal
tubular cells.

Diagnosis — Pain at a site of traumatic injury together with signs of systemic toxicity and gas
in the soft tissue support the diagnosis of gas gangrene. Physical evidence of crepitus in the
soft tissue is the most sensitive and specific finding on clinical examination [25].

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Radiographic imaging with computerized tomographic (CT) scan or magnetic resonance

imaging (MRI) can reveal gas in deep tissues. Early in the course of infection, CT and MRI are
useful for determining if the infection is localized or spreading along fascial planes.

Blood (both aerobic and anaerobic bottles) and tissue cultures should be obtained; definitive
diagnosis of gas gangrene requires demonstration of large gram-variable rods at the site of
injury ( picture 2 and picture 3). Clostridia can appear both gram positive and gram
negative when stained directly from infected tissues but stain as gram-positive rods when
obtained from culture media [26,27]. Drainage from surgical procedures characteristically lacks
frank pus. Histopathology demonstrates widespread tissue destruction and the presence of
organisms but an absence of neutrophils in the tissue.

Surgical exploration in the setting of traumatic gas gangrene typically demonstrates muscle
that does not bleed or contract when stimulated. Muscle tissue is grossly edematous and may
have reddish-blue to black discoloration. Microscopic evaluation of biopsy material invariably
demonstrates organisms among degenerating muscle bundles and a characteristic absence of
acute inflammatory cells ( picture 4) [2,28]. In the presence of muscle necrosis, necrosis of
skin, fat, subcutaneous tissue, and fascia may also be present.

Needle aspiration or punch biopsy provides an etiologic diagnosis in at least 20 percent of

cases. However, these techniques should not replace thorough surgical exploration and
debridement of the infected site with retrieval of specimens for Gram stain and culture.

Treatment — Treatment of traumatic gas gangrene consists of surgical debridement,

antibiotic therapy, and supportive measures. Patients with trauma who have not received
tetanus immunization for 5 years should receive a booster vaccine against tetanus.

● Surgical debridement − Prompt, aggressive, and thorough surgical inspection and

debridement of devitalized tissue are mandatory to improve survival, preserve limbs, and
prevent complications [29,30]. Initial aggressive debridement of devitalized tissue can
reduce the risk of gas gangrene in contaminated deep wounds. Maintaining vascular
integrity is crucial; prolonged application of tourniquets should be avoided, and traumatic
wounds such as compound fractures should not be surgically closed prematurely [31].
Presence of foreign material in a wound site increases the risk for gangrene. In general,
multiple surgical debridement procedures over the course of several days may be
required. Other surgical interventions may also be warranted depending on individual
circumstances (such as hysterectomy in patients with postpartum clostridial infection) [32].

● Antibiotic therapy − Pending definitive etiologic diagnosis, broad-spectrum empiric

antibiotic treatment is warranted to cover group A Streptococcus, Clostridium species, and
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mixed aerobes and anaerobes. In the setting of polymicrobial infection, Clostridium is

presumed to be a significant pathogen. Piperacillin-tazobactam (4.5 g intravenously every
eight hours) PLUS clindamycin (900 mg intravenously every eight hours) is the preferred
option. Carbapenems are an acceptable alternative to piperacillin-tazobactam.

Definitive antibiotic therapy should consist of the combination of penicillin (3 to 4 million

units intravenously every four hours) plus clindamycin (900 mg intravenously every eight
hours) or tetracycline (500 mg intravenously every six hours) [33]. The combination of
penicillin and clindamycin is the most favorable based on animal models [34]; clinical trials
comparing the efficacy of these agents in humans have not been performed. For patients
with penicillin allergy, clindamycin can be used alone.

The optimal duration of antibiotic treatment has not been defined in clinical trials.
Antibiotics should be continued until no further debridements are needed and the
patient's hemodynamic status has normalized; this duration must be tailored to individual
patient circumstances.

Antibiotic agents with excellent in vitro activity against C. perfringens include penicillin,
clindamycin, tetracycline, chloramphenicol, metronidazole, and a number of
cephalosporins. Studies in mice suggest that clindamycin has significantly greater activity
than penicillin in experimental gas gangrene [29,30,34,35]. Other agents with greater
efficacy than penicillin in experimental myonecrosis models include tetracycline,
erythromycin, rifampin, chloramphenicol, and metronidazole [34,35]. The superior in vivo
efficacy of clindamycin and tetracycline in these studies may be related to the ability of
these agents to inhibit toxin synthesis [36]. The diminished efficacy of penicillin may be
related to ongoing toxin production by organisms that survive in filamentous form, due to
the action of penicillin on cell wall formation [36].

These recommendations are in agreement with the Infectious Diseases Society of America
(IDSA) guidelines for the treatment of skin and soft tissue infections [37].

Although C. perfringens remains largely susceptible to first-line antibiotics, antibiotic

resistance has been reported, highlighting the importance of good anaerobic
microbiology and susceptibility testing to guide optimal clinical management decisions for
clostridial infections. Reports from the United Kingdom, Spain, Canada, and Taiwan found
clindamycin-resistant C. perfringens from various sites [38-42]. A 2019 study from Iran
found that 21.2 percent of C. perfringens isolates were resistant to penicillin [43]. In a two-
year prospective study from Canada, 14.2 percent of clostridium species other than C.
perfringens were penicillin resistant and 21.6 percent clindamycin resistant [42].

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● Adjunctive measures − The use of hyperbaric oxygen (HBO) is controversial, largely due
to the lack of data from randomized controlled trials in humans and to divergent results
from studies in animals. Some nonrandomized studies have reported good results with
HBO therapy when combined with antibiotics and surgical debridement [44]. Patients that
are hemodynamically unstable may not be candidates for HBO therapy. Experimental
studies in animals have failed to demonstrate therapeutic efficacy of HBO alone or the
ability of HBO to enhance antibiotic efficacy [45]. The absolute necessity of surgical
debridement should not be delayed while pursuing HBO treatment. (See "Hyperbaric
oxygen therapy".)

Therapeutic strategies directed against toxin activity in vivo may be valuable adjuncts to
traditional antimicrobial regimens. Antitoxin for passive immunotherapy is not available;
active immunization of experimental animals with the cell-binding domain of alpha toxin is
100 percent protective against a lethal challenge with C. perfringens [8,9]. Future treatment
strategies may include attenuation of toxin-induced vascular leukostasis and resultant
tissue injury by targeting endogenous proadhesive molecules and reducing duration and
severity of shock via anti-cytokine molecules.

Prognosis — The prognosis for gas gangrene of an extremity is more favorable than gas
gangrene of the trunk or visceral organs, since gangrene of an extremity may be debrided more
readily [20,29,30]. Recurrent gas gangrene due to C. perfringens has been described in
individuals with minor trauma at sites of previous gas gangrene [5].

Patients with associated bacteremia and intravascular hemolysis have the greatest likelihood of
progressing to shock and death. Mortality is highest for patients in shock at the time of
diagnosis. In a series of 139 patients treated with antibiotics, surgery, and hyperbaric oxygen,
67 were in shock at admission, and all deaths (27 patients) occurred in this subset; overall
survival was 81 percent [20].

Spontaneous gas gangrene — Spontaneous gas gangrene generally occurs via hematogenous
seeding of muscle with bacteria (usually C. septicum) from a gastrointestinal tract portal of entry.
Gastrointestinal lesions are commonly known or undiagnosed adenocarcinoma of the colon.
(See "Clinical presentation, diagnosis, and staging of colorectal cancer".)

Spontaneous gas gangrene can also occur in patients who have congenital or cyclic
neutropenia and among patients with prior radiation therapy to the abdomen. The diagnosis of
spontaneous gas gangrene is frequently missed or delayed because it is not entertained. (See
'Clinical manifestations' below.)

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C. septicum has been transmitted from contaminated musculoskeletal allografts (tendons,

menisci, femoral condyles) harvested from cadaveric tissues. In a report of 14 such cases, all
came from a single tissue bank in which the rate of infection was 0.07 percent among more
than 20,000 allografts [46].

C. tertium has been associated with spontaneous myonecrosis. It can grow aerobically so may
be mistaken for a contaminant such as a diphtheroid or Bacillus species [29,30]. The organism's
resistance to penicillin, cephalosporins, and clindamycin may facilitate survival in the
gastrointestinal tract, especially in patients receiving broad-spectrum antibiotics [29].

Pathogenesis — C. septicum can grow in normal tissues; it does not require anaerobic
conditions. The presence of a gastrointestinal lesion facilitates entry of the organism into the
bloodstream and then into other tissues [1].

C. septicum produces multiple exotoxins, including [1]:

● Alpha toxin (a lethal, hemolytic, necrotizing toxin)

● Beta toxin (DNase)
● Gamma toxin (hyaluronidase)
● Delta toxin (septicolysin, an oxygen labile hemolysin)
● A protease
● A neuraminidase

The mechanism by which the alpha toxin of C. septicum contributes to pathogenesis is unknown;
unlike the alpha toxin of C. perfringens, the alpha toxin of C. septicum does not possess
phospholipase activity [47].

Clinical manifestations — Spontaneous gas gangrene usually presents with abrupt onset of
severe muscle pain. Occasionally, heaviness or numbness is reported [1,2,48-50]. In some
patients, the first manifestation may be confusion or malaise.

Infection progresses rapidly with development of edema and bullae filled with clear, cloudy,
hemorrhagic, or purplish fluid. The skin around the bullae has a purple hue, perhaps reflecting
vascular compromise resulting from bacterial toxins diffusing into surrounding tissues [48].
Histopathology of muscle and connective tissues demonstrates cell lysis and gas formation;
inflammatory cells are absent [48].

Predisposing factors include [48-50]:

● Colonic malignancy
● Inflammatory bowel disease
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● Diverticulitis
● Gastrointestinal surgery
● Leukemia
● Lymphoproliferative disorders
● Chemotherapy
● Neutropenia
● Radiation therapy
● Advanced AIDS
● Necrotizing enterocolitis, cecitis, or distal ileitis

Diagnosis — Fever and severe pain in an extremity (in the absence of trauma) should raise
suspicion for spontaneous gas gangrene. Distinguishing spontaneous gas gangrene due to
clostridia from streptococcal myositis may be difficult [48]. The presence of tissue crepitus
favors clostridial infection ( image 1) [51,52]. Gas within the soft tissue can also be detected
by radiography, CT scan, or MRI.

Definitive diagnosis of spontaneous gas gangrene requires demonstration of large gram-

variable rods at the site of injury. Gram stain of bullous fluid may be particularly useful. Blood
cultures should also be obtained since bacteremia in C. septicum gangrene usually precedes
cutaneous manifestations by several hours.

Surgical findings are as described for traumatic gas gangrene ( picture 2 and picture 3 and
picture 4). (See 'Diagnosis' above.)

Treatment — Treatment of spontaneous gas gangrene consists of early surgical debridement

and antibiotic therapy. Urgent, thorough surgical debridement is mandatory to improve
survival, preserve limbs, and prevent complications [29,30]. Multiple surgical debridements may
be required.

Pending definitive etiologic diagnosis, broad-spectrum empiric antibiotic treatment is

warranted to cover group A Streptococcus, Clostridium species, and mixed aerobes and
anaerobes. In the setting of polymicrobial infection, Clostridium is presumed to be a significant
pathogen. The preferred regimen is piperacillin-tazobactam (4.5 g intravenously every eight
hours) PLUS clindamycin (900 mg intravenously every eight hours).

Definitive antibiotic therapy for treatment of spontaneous gas gangrene due to C. septicum
should consist of the combination of penicillin (3 to 4 million units intravenously every four
hours) plus clindamycin (900 mg intravenously every eight hours) or tetracycline (500 mg
intravenously every six hours).

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This approach is extrapolated from the treatment of traumatic gas gangrene due to C.
perfringens and is based on animal models; no human trials have compared the efficacy of
antibiotics for treatment of spontaneous gas gangrene. Antibiotic agents with excellent in vitro
activity against both C. septicum and C. perfringens include penicillin, tetracycline, erythromycin,
clindamycin, chloramphenicol, and metronidazole. Agents that inhibit exotoxin production
would likely have greater efficacy in vivo than cell wall–active antibiotics. (See 'Treatment'
above.)

C. tertium is resistant to penicillin, cephalosporins, and clindamycin [29]. Appropriate therapy for
C. tertium infection is vancomycin ( table 1) or metronidazole (500 mg intravenously every 8
hours).

Patients who survive spontaneous gangrene should have colonoscopy to rule out associated
pathology of the gastrointestinal tract.

Prognosis — The mortality of spontaneous gangrene ranges from 67 to 100 percent [53,54].
The majority of deaths occur within 24 hours of onset. Risk factors for a fatal outcome include
underlying malignancy and immunocompromised state.

DIFFERENTIAL DIAGNOSIS

Other clinical entities that must be distinguished from clostridial myonecrosis include:

● Necrotizing infection due to group A Streptococcus – Clostridial myonecrosis and

necrotizing infection due to group A Streptococcus can be difficult to distinguish; both
involve rapid and severe tissue destruction with systemic toxicity ( table 2). The presence
of tissue crepitus on clinical examination or radiographic imaging favors clostridial
infection; the two are distinguished by Gram stain and bacteriologic culture. (See
"Necrotizing soft tissue infections".)

● Wound infection due to Vibrio vulnificus – Both clostridial myonecrosis and infection due to
V. vulnificus can occur following development of a traumatic wound; V. vulnificus generally
occurs following exposure to sea water. The diagnosis of each is established by Gram stain
and culture. (See "Vibrio vulnificus infection".)

● Pyomyositis (muscle abscess, usually caused by S. aureus) – Like clostridial myonecrosis,

pyomyositis can occur following trauma or can develop spontaneously. They differ in that
pyomyositis is not routinely associated with systemic toxicity or the presence of gas in

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tissue on radiographic imaging. The two are distinguished by Gram stain and culture. (See
"Primary pyomyositis".)

● Viral myositis – Viral infection such as acute influenza type A can produce skeletal muscle
injury. It differs from clostridial myonecrosis in that the muscle pain is diffuse rather than
localized, and it is not routinely associated with systemic toxicity or gas in tissues. (See
"Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Myositis
and rhabdomyolysis'.)

● Rhabdomyolysis (muscle necrosis) – Both rhabdomyolysis and clostridial myonecrosis are

associated with muscle pain; rhabdomyolysis has many causes including trauma, drugs,
toxins, and metabolic disorders. Clostridial necrosis is distinguished by the presence of gas
in tissues and Gram stain findings. (See "Rhabdomyolysis: Epidemiology and etiology".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Skin and soft tissue
infections".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
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medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Gangrene (The Basics)")

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SUMMARY AND RECOMMENDATIONS

● Clostridial myonecrosis (gas gangrene) is a life-threatening muscle infection that develops

either contiguously from an area of trauma (usually due to Clostridium perfringens) or
hematogenously from the gastrointestinal tract with muscle seeding (usually due to
Clostridium septicum). (See 'Introduction' above.)

● Traumatic wounds with vascular compromise (particularly deep penetrating injuries such
as knife wounds, gunshot wounds, and crush injuries) create an anaerobic environment
that is ideal for proliferation of clostridia. Most such cases are caused by C. perfringens.
(See 'Traumatic gas gangrene' above.)

● Gas gangrene usually presents with sudden onset of severe muscle pain. Initially, the skin
may appear pale and then rapidly develops a bronze appearance, followed by purple or
red discoloration. The skin becomes tense and exquisitely tender and may have overlying
bullae. Signs of systemic toxicity develop rapidly, including fever and tachycardia, followed
by shock and multiorgan failure. (See 'Clinical manifestations' above.)

● Definitive diagnosis of gas gangrene requires demonstration of large, gram-variable rods

at the site of injury. Histopathology demonstrates characteristic absence of acute
inflammatory cells. Gas in the soft tissue may be observed at the bedside and/or
radiographically. (See 'Diagnosis' above.)

● Treatment of traumatic gas gangrene consists of aggressive and thorough surgical

debridement together with antibiotic therapy. We suggest the following antibiotic
regimen: penicillin (3 to 4 million units intravenously every four hours) together with
clindamycin (900 mg intravenously every eight hours) (Grade 2B). For patients with
penicillin allergy, clindamycin can be used alone.

● The value of hyperbaric oxygen (HBO) is controversial, though some nonrandomized

observational studies have reported good results with HBO in combination with antibiotics
and surgical debridement. However, the absolute necessity of surgical intervention should
not be delayed while pursuing HBO therapy. (See 'Treatment' above.)

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REFERENCES

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Microbiol 1995; 15:191.
2. MACLENNAN JD. The histotoxic clostridial infections of man. Bacteriol Rev 1962; 26:177.
3. Wang Y, Lu B, Hao P, et al. Comprehensive treatment for gas gangrene of the limbs in
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10. Alouf JE, Geoffroy C. The Family of the Antigenically-Related, Cholesterol-Binding ("Sulphydr
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(Eds), Academic Press, New York 1991. p.147.
11. Bryant AE, Bergstrom R, Zimmerman GA, et al. Clostridium perfringens invasiveness is
enhanced by effects of theta toxin upon PMNL structure and function: the roles of
leukocytotoxicity and expression of CD11/CD18 adherence glycoprotein. FEMS Immunol
Med Microbiol 1993; 7:321.
12. Bryant AE, Stevens DL. Phospholipase C and perfringolysin O from Clostridium perfringens
upregulate endothelial cell-leukocyte adherence molecule 1 and intercellular leukocyte
adherence molecule 1 expression and induce interleukin-8 synthesis in cultured human
umbilical vein endothelial cells. Infect Immun 1996; 64:358.

13. Stevens DL, Tweten RK, Awad MM, et al. Clostridial gas gangrene: evidence that alpha and
theta toxins differentially modulate the immune response and induce acute tissue necrosis.

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J Infect Dis 1997; 176:189.

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mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens.
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activation of platelet gpIIbIIIa mediates vascular occlusion and myonecrosis in Clostridium
perfringens gas gangrene. J Infect Dis 2000; 182:808.

16. Stevens DL, Troyer BE, Merrick DT, et al. Lethal effects and cardiovascular effects of purified
alpha- and theta-toxins from Clostridium perfringens. J Infect Dis 1988; 157:272.
17. Asmuth DM, Olson RD, Hackett SP, et al. Effects of Clostridium perfringens recombinant
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18. Whatley RE, Nelson P, Zimmerman GA, et al. The regulation of platelet-activating factor
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d), Churchill Livingstone, Philadelphia 1995. p.13.1.

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for experimental infection with Clostridium perfringens. Clin Infect Dis 1993; 17:231.
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48. Stevens DL, Musher DM, Watson DA, et al. Spontaneous, nontraumatic gangrene due to
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209:385.

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pyogenes: case report and review of the literature. Rev Infect Dis 1987; 9:382.
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myonecrosis. N Engl J Med 2004; 351:e15.
53. Nordkild P, Crone P. Spontaneous clostridial myonecrosis. A collective review and report of
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Topic 7672 Version 31.0

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GRAPHICS

Intravascular hemolysis due to Clostridium perfringens sepsis

This is a peripheral blood smear from a patient with severe intravascular hemolysis due to sepsis with
Clostridium perfringens. Neutrophils show toxic changes, including toxic granulation and vacuoles. There
is an increased number of spherocytes (blue arrows) and polychromatophilic red cells (ie, reticulocytes
[red arrow]). The major finding on this slide is the large number of red blood cell ghosts (black arrows),
due to the intravascular lysis of red cells from the phospholipase and other lytic enzymes elaborated by
the clostridial organisms.

Kindly provided by Dr. German Pihan, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA.

Graphic 53404 Version 5.0

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Clostridium perfringens Gram stain

Gram stain of exudate from a bulla at the site of injection of intravenous drugs (x1000) shows large gram-
positive bacilli and the absence of leukocytes. Clostridium perfringens grew anaerobically from this
specimen on blood agar. Clostridial infection may produce cellulitis or involve deeper tissues, as in gas
gangrene.

Courtesy of Harriet Provine.

Graphic 54494 Version 4.0

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Clostridia in muscle

Tissue Gram stain of muscle biopsy (x400) from a patient with gas gangrene shows numerous gram-
positive bacilli. Clostridium perfringens grew from this specimen.

Courtesy of Stephen Calderwood, MD.

Graphic 80492 Version 4.0

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Necrotic muscle with clostridial gas gangrene

Hematoxylin and eosin-stained biopsy of muscle (x400) from a patient with clostridial gas gangrene
shows extensive necrosis.

Courtesy of Stephen Calderwood, MD.

Graphic 62665 Version 2.0

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Clostridial myonecrosis computed tomography

Necrotizing fasciitis due to Clostridium septicum. Air is demonstrated in the external iliac vein, with air
fluid level (Arrow A). Gas in the soft tissue of the buttock is also seen (Arrow B).

Courtesy of William Mann, MD.

Graphic 69941 Version 4.0

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Approach to vancomycin dosing for adults with normal kidney function*

Loading dose (for patients with known or Load 20 to 35 mg/kg (based on actual body weight,
suspected severe Staphylococcus aureus infection) ¶ rounded to the nearest 250 mg increment; not to
exceed 3000 mg). Within this range, we use a highe
dose for critically ill patients; we use a lower dose
for patients who are obese and/or are receiving
vancomycin via continuous infusion.

Initial maintenance dose and interval Typically 15 to 20 mg/kg every 8 to 12 hours for
most patients (based on actual body weight,
rounded to the nearest 250 mg increment).

In general, the approach to establishing the

vancomycin dose/interval is guided by a
nomogram. Δ

Subsequent dose and interval adjustments Based on AUC-guided (preferred for severe
infection) [1] or trough-guided serum concentration
monitoring. ◊

AUC: area under the 24-hour time-concentration curve.

* Refer to the UpToDate topic on vancomycin dosing for management of patients with abnormal kidney
function.

¶ For patients with known or suspected severe S. aureus infection, we suggest administration of a loading
dose to reduce the likelihood of suboptimal initial vancomycin exposure. Severe S. aureus infections
include (but are not limited to) bacteremia, endocarditis, osteomyelitis, prosthetic joint infection,
pneumonia warranting hospitalization, infection involving the central nervous system, or infection
causing critical illness.

Δ If possible, the nomogram should be developed and validated at the institution where it is used to best
reflect the regional patient population. Refer to the UpToDate topic on vancomycin dosing for sample
nomogram.

◊ Refer to the UpToDate topic on vancomycin dosing for discussion of AUC-guided and trough-guided
vancomycin dosing. For patients with nonsevere infection who receive vancomycin for <3 days (in the
setting of stable kidney function and absence of other risk factors for altered vancomycin kinetics),
vancomycin concentration monitoring is often omitted; the value of such monitoring prior to achieving
steady state (usually around treatment day 2 to 3) is uncertain.

Reference:
1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus
Aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-System Pharmacists, the
Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases
Pharmacists. Am J Health Syst Pharm 2020; 77:835.

Graphic 128911 Version 5.0

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Differential diagnosis of necrotizing myositis and fasciitis

Clinical Gas Myositis

Type I* Type II* Pyomyositis
finding gangrene viral/parasitic

Fever ++ ++++ +++ ++ ++

Diffuse pain + + + + ++++ ¶

Local pain ++ ++++ Δ ++++ ++ ++

Systemic ++ ++++ ++++ + +

toxicity

Gas in tissue ++ – ++++ – –

Obvious portal ++++ ±◊ ++++ § – –

of entry

Diabetes ++++ ± – – –
mellitus

* Type I and type II refer to the forms of necrotizing fasciitis; spontaneous gangrenous myositis is type II.

¶ Pain with influenza consists of diffuse myalgia; pleurodynia may be associated with severe, localized
pain (eg, devil's grip); pain with trichinosis may be severe and localized.

Δ Severe pain is associated with necrotizing fasciitis due to group A streptococcal infection; the pain may
not be severe in type I necrotizing fasciitis because it is commonly associated with diabetes with
neuropathy.

◊ 50% of patients with necrotizing fasciitis due to group A streptococcal infection do not have an obvious
portal of entry.

§ Gas gangrene associated with trauma may be caused by Clostridium perfringens, C. septicum, or C.
histolyticum, which always have an obvious portal of entry; in comparison, spontaneous gas gangrene
caused by C. septicum usually does not have an obvious portal of entry (organisms lodge in tissue as a
result of bacteremia originating from a bowel portal of entry).

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Contributor Disclosures
Dennis L Stevens, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Amy Bryant, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Sandra Nelson, MD No relevant financial relationship(s) with ineligible companies to
disclose. Keri K Hall, MD, MS No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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