Clostridium septicum
Encyclopedia
Clostridium septicum is a gram positive, spore forming
, obligate anaerobic
bacterium.
Clostridium septicum can cause gas gangrene
, but unlike other Clostridium
species like Clostridium perfringens
, no trauma is necessary at the site of the infection. It is thought that the infection is established by hematogenous spread from the gastrointestinal tract. Gas gangrene caused by Clostridium septicum is associated with colorectal cancer
and other defects of the bowel.
Clostridium septicum causes myonecrosis through the release of exotoxins such as the alpha toxin, lethal toxin, and hemolytic toxin
bacterium that is a member of the normal gut flora in humans as well as other animals. C. septicum are spore formers
, with a terminal spore that gives them their drumstick-like shape. They are also motile bacteria, using peritrichous flagellae
to navigate from one environment to the next. C. septicum are fermentative anaerobes
and therefore can live off of a variety of substrates like sugars, amino acids and other organic compounds, generating molecular hydrogen
gas and carbon dioxide
as byproducts of cellular respiration
.
Although non-pathogenic, C. septicum can cause infection quickly if the gut tissue becomes necrotic or inflamed. C. septicum produces four toxins; alpha, beta, gamma and delta, with alpha toxin being necrotic and lethal. Their anaerobic
nature creates susceptibility in areas of decreased blood flow. Although rare, C. septicum infections are often found in individuals with a recent history of trauma, surgery, peripheral vascular disease, diabetes, colon cancer, skin infections or burns and septic abortions
.
. As of 2006, between 1000 and 3000 cases of C. septicum infection were reported in the United States each year, typically accompanied by another pre-existing medical condition. Infection by C. septicum was once thought to be extremely rare, however anaerobic laboratory techniques allowed for the discovery of the true potential of this infectious microbe. Infections are typically seen in settings of trauma, surgery, malignancy, skin infections/burns, and septic abortions
. Sites prone to infection are those with poor vascular
supply, although because of pH
, electrolyte
and omsotic differences, the colon may promote the growth of C. septicum better than most other anatomical regions. One of the more aggressive progenitors of gas gangrene
, C. septicum infection progresses very rapidly, with a mortality rate of approximately 79% in adults, typically occurring within 48 hours of infection. The greatest survival rates are typically seen in patients without pre-existing medical conditions, and with infection localized to the extremities. Gas gangrene proceeds via disruption of blood flow to the infected site, resulting in diminished levels of oxygen
and nutrients ultimately causing premature cell death and tissue necrosis
. Four toxins have been isolated from C. septicum; the lethal alpha toxin, DNase beta-toxin, hyaluronidase
gamma toxin, and the thiol-activated/septicolysin delta toxin. Alpha toxin causes intravascular hemolysis
and tissue necrosis and is well known as the main virulent factor in C. septicum. Symptoms of infection include pain, described as a heaviness or pressure that is disproportionate to physical findings, tachycardia
and hypotension
. Tissue necrosis then causes edema
and ischemia
resulting in metabolic acidosis
, fever
and renal failure
. The carbon dioxide
and hydrogen
produced during cellular respiration
move through tissue planes, causing their separation, producing features characteristic of palpable emphysema
. This also results in a magenta-bronze skin discoloration, and bulla filled with a foul-smelling serosanguinous fluid.
has shown strong correlations with increased levels of malignancy. Generally, patients with C. septicum infections present colonic carcinoma or a tumor that has metastasized to the colon. One particular study by Alpern and Dowell noted 85% comorbidity with malignancy, while another study by Koransky et al. noted 71% comorbidity. This relationship suggests the opportunistic nature of this pathogen raising the possibility that immunosuppression
plays a key role in the ability of C. septicum to cause infection. It seems likely that either the treatment or the malignancy itself impairs the immune function of the gastrointestinal mucosa allowing C. septicum to gain access to the circulatory system.
, otherwise known as myonecrosis; a disease characterized by extensive tissue destruction, edema
, thrombosis
and fluid-filled bullae. Alpha toxin is a pore-forming toxin exotoxin
that is secreted as a protoxin that requires proteolytic cleavage of a 5kDa peptide from its carboxy-terminal in order to become active. Cleavage is typically initiated by the cell surface protease furin
. Once activated, the toxin can oligomerize and form ion-permeable pores through the cell membrane. Pores formed by alpha toxin are approximately 1.5nm in diameter, allowing the release of potassium ions from erythrocytes, thus disrupting the ionic equilibrium within the cell. Alpha toxin binds GPI-anchored cell surface receptors including the human folate receptor (hFR), as well as the neuronal molecules contactin, and Thy-1 (CD90).
of C. perfringens
, another bacterium implicated in the pathogenesis of gas gangrene
. C. septicum alpha toxin does, however, exhibit similarities to aerolysin
, another beta-pore forming toxin. Alpha toxin and aerolysin share approximately 72% sequence similarity and have numerous functional similarities as well. Both proteins require cleavage by furin
or a furin-like protease
, and then oligomerize to form transmembrane pores. Similarities between the two toxins have also been discovered through analysis of the crystal structure of aerolysin. Aerolysin is a bi-lobal protein
consisting of four domains (D1-D4). The smallest lobe of aerolysin is missing in the alpha toxin of C. septicum, implying that the alpha toxin is mono-lobal with three domains, similar to domains D2-D4 in aerolysin. Further research has led to the conclusions that the D1 domain is involved in receptor-binding and the D3 domain functions to prevent premature oligomerization of alpha toxin.
, discolored or edematous
skin, and a gram-stain of bullous drainage showing gram-positive bacilli without spores and few leukocytes. Physical manifestations of infection include pain caused by infiltration of the infected muscle with edema
and gas, tachycardia
, muscle and skin discoloration and the presence of a brown, watery discharge with a foul smell within the wounds. Treatment for C. septicum infection includes antibiotic administration, surgical intervention and hyperbaric oxygen therapy
(HBOT). Oftentimes in severe cases amputation
becomes the only viable option remaining to clear the infection.
Endospore
An endospore is a dormant, tough, and temporarily non-reproductive structure produced by certain bacteria from the Firmicute phylum. The name "endospore" is suggestive of a spore or seed-like form , but it is not a true spore . It is a stripped-down, dormant form to which the bacterium can reduce...
, obligate anaerobic
Obligate anaerobe
Obligate anaerobes are microorganisms that live and grow in the absence of molecular oxygen; some of these are killed by oxygen. -Metabolism:...
bacterium.
Clostridium septicum can cause gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
, but unlike other Clostridium
Clostridium
Clostridium is a genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle...
species like Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
, no trauma is necessary at the site of the infection. It is thought that the infection is established by hematogenous spread from the gastrointestinal tract. Gas gangrene caused by Clostridium septicum is associated with colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and other defects of the bowel.
Clostridium septicum causes myonecrosis through the release of exotoxins such as the alpha toxin, lethal toxin, and hemolytic toxin
General and Morphological Information
C. septicum is a large, gram-positive, rod-shapedBacillus (shape)
The word bacillus may be used to describe any rod-shaped bacterium, and such bacilli are found in many different taxonomic groups of bacteria. However, the name Bacillus, capitalized and italicized, refers to a specific genus of bacteria...
bacterium that is a member of the normal gut flora in humans as well as other animals. C. septicum are spore formers
Endospore
An endospore is a dormant, tough, and temporarily non-reproductive structure produced by certain bacteria from the Firmicute phylum. The name "endospore" is suggestive of a spore or seed-like form , but it is not a true spore . It is a stripped-down, dormant form to which the bacterium can reduce...
, with a terminal spore that gives them their drumstick-like shape. They are also motile bacteria, using peritrichous flagellae
Flagellum
A flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...
to navigate from one environment to the next. C. septicum are fermentative anaerobes
Anaerobic organism
An anaerobic organism or anaerobe is any organism that does not require oxygen for growth. It could possibly react negatively and may even die if oxygen is present...
and therefore can live off of a variety of substrates like sugars, amino acids and other organic compounds, generating molecular hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
gas and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
as byproducts of cellular respiration
Cellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
.
Although non-pathogenic, C. septicum can cause infection quickly if the gut tissue becomes necrotic or inflamed. C. septicum produces four toxins; alpha, beta, gamma and delta, with alpha toxin being necrotic and lethal. Their anaerobic
Anaerobic
Anaerobic is a word which literally means without oxygen, as opposed to aerobic.In wastewater treatment the absence of oxygen is indicated as anoxic; and anaerobic is used to indicate the absence of a common electron acceptor such as nitrate, sulfate or oxygen.Anaerobic may refer to:*Anaerobic...
nature creates susceptibility in areas of decreased blood flow. Although rare, C. septicum infections are often found in individuals with a recent history of trauma, surgery, peripheral vascular disease, diabetes, colon cancer, skin infections or burns and septic abortions
Septic abortion
A septic abortion or septic miscarriage is a form of miscarriage that is associated with a serious uterine infection. The infection carries risk of spreading infection to other parts of the body and cause septicaemia, a grave risk to the life of the woman.-Causes:A septic abortion can occur when...
.
Ecology and Habitat
C. septicum is a resident bacterium of the human microflora, however it can be found in almost any anoxic habitat in which exists organic compounds. Under unfavorable conditions, C. septicum forms endospores allowing it to survive under harsh conditions such as extreme temperature, dry land, and nutrient-deficient habitats.Pathogenesis
C. septicum is one of several bacteria responsible for myonecrosis, otherwise known as gas gangreneGas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
. As of 2006, between 1000 and 3000 cases of C. septicum infection were reported in the United States each year, typically accompanied by another pre-existing medical condition. Infection by C. septicum was once thought to be extremely rare, however anaerobic laboratory techniques allowed for the discovery of the true potential of this infectious microbe. Infections are typically seen in settings of trauma, surgery, malignancy, skin infections/burns, and septic abortions
Septic abortion
A septic abortion or septic miscarriage is a form of miscarriage that is associated with a serious uterine infection. The infection carries risk of spreading infection to other parts of the body and cause septicaemia, a grave risk to the life of the woman.-Causes:A septic abortion can occur when...
. Sites prone to infection are those with poor vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
supply, although because of pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
and omsotic differences, the colon may promote the growth of C. septicum better than most other anatomical regions. One of the more aggressive progenitors of gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
, C. septicum infection progresses very rapidly, with a mortality rate of approximately 79% in adults, typically occurring within 48 hours of infection. The greatest survival rates are typically seen in patients without pre-existing medical conditions, and with infection localized to the extremities. Gas gangrene proceeds via disruption of blood flow to the infected site, resulting in diminished levels of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
and nutrients ultimately causing premature cell death and tissue necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
. Four toxins have been isolated from C. septicum; the lethal alpha toxin, DNase beta-toxin, hyaluronidase
Hyaluronidase
The hyaluronidases are a family of enzymes that degrade hyaluronic acid.In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1.-Use as a drug:...
gamma toxin, and the thiol-activated/septicolysin delta toxin. Alpha toxin causes intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
and tissue necrosis and is well known as the main virulent factor in C. septicum. Symptoms of infection include pain, described as a heaviness or pressure that is disproportionate to physical findings, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
. Tissue necrosis then causes edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
resulting in metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. The carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
and hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
produced during cellular respiration
Cellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
move through tissue planes, causing their separation, producing features characteristic of palpable emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
. This also results in a magenta-bronze skin discoloration, and bulla filled with a foul-smelling serosanguinous fluid.
Association with Malignancy
C. Septicum derived gas gangreneGas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
has shown strong correlations with increased levels of malignancy. Generally, patients with C. septicum infections present colonic carcinoma or a tumor that has metastasized to the colon. One particular study by Alpern and Dowell noted 85% comorbidity with malignancy, while another study by Koransky et al. noted 71% comorbidity. This relationship suggests the opportunistic nature of this pathogen raising the possibility that immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
plays a key role in the ability of C. septicum to cause infection. It seems likely that either the treatment or the malignancy itself impairs the immune function of the gastrointestinal mucosa allowing C. septicum to gain access to the circulatory system.
Alpha Toxin
The alpha toxin produced by C. septicum is the underlying cause of gas gangreneGas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
, otherwise known as myonecrosis; a disease characterized by extensive tissue destruction, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
and fluid-filled bullae. Alpha toxin is a pore-forming toxin exotoxin
Exotoxin
An exotoxin is a toxin excreted by a microorganism, like bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host...
that is secreted as a protoxin that requires proteolytic cleavage of a 5kDa peptide from its carboxy-terminal in order to become active. Cleavage is typically initiated by the cell surface protease furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...
. Once activated, the toxin can oligomerize and form ion-permeable pores through the cell membrane. Pores formed by alpha toxin are approximately 1.5nm in diameter, allowing the release of potassium ions from erythrocytes, thus disrupting the ionic equilibrium within the cell. Alpha toxin binds GPI-anchored cell surface receptors including the human folate receptor (hFR), as well as the neuronal molecules contactin, and Thy-1 (CD90).
Alpha-toxin and Aerolysin
Quite surprisingly, the alpha toxin of C. septicum is not related to the alpha toxinClostridium perfringens alpha toxin
Clostridium perfringens alpha toxin is a toxin produced by the bacterium Clostridium perfringens and is responsible for gas gangrene and myonecrosis in infected tissues. The toxin also possesses hemolytic activity....
of C. perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
, another bacterium implicated in the pathogenesis of gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
. C. septicum alpha toxin does, however, exhibit similarities to aerolysin
Aerolysin
In molecular biology, aerolysin is a cytolytic toxin exported by Aeromonas hydrophila, a Gram-negative bacterium associated with diarrhoeal diseases and deep wound infections. The mature toxin binds to eukaryotic cells and aggregates to form holes leading to the destruction of the membrane...
, another beta-pore forming toxin. Alpha toxin and aerolysin share approximately 72% sequence similarity and have numerous functional similarities as well. Both proteins require cleavage by furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...
or a furin-like protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
, and then oligomerize to form transmembrane pores. Similarities between the two toxins have also been discovered through analysis of the crystal structure of aerolysin. Aerolysin is a bi-lobal protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
consisting of four domains (D1-D4). The smallest lobe of aerolysin is missing in the alpha toxin of C. septicum, implying that the alpha toxin is mono-lobal with three domains, similar to domains D2-D4 in aerolysin. Further research has led to the conclusions that the D1 domain is involved in receptor-binding and the D3 domain functions to prevent premature oligomerization of alpha toxin.
Diagnosis and Treatment
If left untreated, the mortality rate for C. septicum infection nears 100%. A study by Cline and Turnbull offers that diagnosis be based on findings of pain disproportionate to clinical findings or injury, marked tachycardiaTachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, discolored or edematous
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
skin, and a gram-stain of bullous drainage showing gram-positive bacilli without spores and few leukocytes. Physical manifestations of infection include pain caused by infiltration of the infected muscle with edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and gas, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, muscle and skin discoloration and the presence of a brown, watery discharge with a foul smell within the wounds. Treatment for C. septicum infection includes antibiotic administration, surgical intervention and hyperbaric oxygen therapy
Hyperbaric oxygen therapy
Hyperbaric medicine, also known as hyperbaric oxygen therapy , is the medical use of oxygen at a level higher than atmospheric pressure. The equipment required consists of a pressure chamber, which may be of rigid or flexible construction, and a means of delivering 100% oxygen...
(HBOT). Oftentimes in severe cases amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
becomes the only viable option remaining to clear the infection.