Clostridia (other pathogenic strains C. perfringens, C. septicum)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has clostridial infection? What should you expect to find?

C. perfringens is most likely associated with three clinical syndromes: necrotizing or gangrenous soft tissue infections, endometritis following childbirth or abortion, and foodborne gastroenteritis.
Necrotizing soft tissue infections caused by C. perfringens are also referred to as “gas gangrene” or clostridial myonecrosis when muscle is involved. The key symptoms of C. perfringens soft tissue infection include severe pain (that might be out of proportion to your physical exam) at a site of recent trauma or surgery. Symptoms generally start within 1-3 days of such an insult. The triad of severe pain at a site of recent trauma, signs of systemic toxicity, and evidence of gas in the involved soft tissues should be a major red flag, although these may not all be present. Because signs and symptoms can progress rapidly to threaten both life and limb, acute clostridial soft tissue infections are a medical emergency.
It is important to note that many different clostridia can cause a clinically indistinguishable soft tissue infection; these include C. perfringens, C. septicum, C. sordellii, C. histolyticum, and C. novyi. Because antimicrobial susceptibilities are relatively similar among these clostridia, this should not influence empiric antibiotic choices. An exception is the rarely isolated C. tertium, which can be resistant to penicillins, cephalosporins, and clindamycin.

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In cases of endometritis, patients may present with refractory and fulminant shock and little else. Some women present with weakness, nausea, vomiting, and abdominal or pelvic pain. A recent history of childbirth, medical abortion, surgical abortion, spontaneous abortion, or amniocentesis is a significant clue. This syndrome can be caused by either C. perfringens or C. sordellii.
Sometimes, necrotizing soft tissue infections with shock can present spontaneously without any antecedent trauma. The clostridia implicated in these (presumably) hematogenous infections include C. septicum, C. tertium, C. perfringens, and C. novyi. Such infections are associated with occult malignancy, including hematological neoplasms and colorectal tumors and neutropenia.
C. perfringens gastroenteritis is primarily accompanied by profuse, watery diarrhea (more than 80% of patients), and vomiting (minority have this, about 10%). Abdominal cramps are very common. Fever may be present. Symptoms are self-limited and resolve within 24-48 hrs.
Key physical exam findings of C. perfringens gangrene or necrosis include tachycardia, hypotension, and minimal or no fever. Dermatological exam may reveal evidence of a surgical wound or trauma with ischemic skin changes, including palor or blue discoloration. Bullae may be present and may be hemorrhagic. The fluids within the necrotic tissues (often first seen in the operating room) have been described as “dish water” in appearance and may have a “mousy,” sweet odor not similar to feculent stool anaerobes. Crepitus (the feeling of gas within palpable soft tissues) should be a major alarm but may be absent or develop only late in the course of infection. The shock is often vasopressor and volume-replacement refractory.
In C. perfringens endometritis, a toxic shock syndrome may be present and is characterized by tachycardia, hypotension, and a curious absence of fever. Diffuse edema may occur, and there may be non-purulent vaginal discharge.

How did the patient develop this disease? What was the primary source from which the infection spread?

Clostridia are spore-forming anaerobes that are very environmentally hardy. For the most part, clostridia are soil organisms, but they also colonize or contaminate the enteric tracts of animals and humans. Thus, for clostridial necrotizing soft tissue infections, including myositis or gangrene, there is usually a history of blunt or penetrating trauma, which may include iatrogenic (surgical) trauma.
C. perfringens or C. sordellii endometritis usually follows within 1 week or so of childbirth or abortion, although simple obstetric or gynecological procedures, such as amniocentesis or cervical excisions, may precede infection. This is generally a disease of previously well, reproductive-age women.
All patients who survive an episode of spontaneous clostridial gangrene (that which occurs in the absence of trauma) should be investigated for occult gastrointestinal sources, particularly colonic tumors, diverticulae, or ulcers.
Gastroenteritis is acquired by ingesting vegetative C. perfringens organisms, which may contaminate improperly handled foods. Meats are commonly implicated. This can occur as part of a common-source outbreak. Generally, improperly cooked or stored meat products will be implicated. For example, cooked food that sits out at room temperature for long periods of time can allow heat-resistant spores of C. perfringens to germinate and reproduce to large numbers. Soon after ingestion, these large numbers of bacteria make enterotoxin, which causes symptoms. Symptoms are not quite as rapid as occur in staphylococcal food poisoning (within 2-8 hours), but they do occur soon after ingestion. Symptoms usually begin within 6-15 hours of ingesting contaminated food. Thus, a dietary history, especially of the preceding 24 hours, is important. Ask about the ingestion of red meat or poultry and whether other people are sick.
Injection of black tar heroin into the skin or soft tissues can introduce clostridial spores that germinate in the relatively hypoxic environment to cause severe infection. Both C. sordellii and C. novyi are notorious for this, although C. perfringens can also cause this.

Which individuals are of greater risk of developing clostridial infection?

A history of trauma or surgery may precede clostridial soft tissue infections. Other causes of ischemic tissue can serve as a nidus for infection and include frostbite, electrical burns, or pressure sores.
Occasionally, injection drug users who inject contaminated heroin into their skin or soft tissues can develop sepsis, bacteremia, and necrotizing infections caused by clostridia, including C. perfringens, C. sordellii, and C. novyi. Be sure to ask about injection drug use and look for evidence of skin popping (waxy, atrophic, cigar-burn size scars on the extremities).
Clostridial toxic shock syndrome associated with endometritis can occur in otherwise healthy women, but a clue is a recent childbirth, abortion, or gynecological procedure.
Gastroenteritis may follow within 6-15 hours after eating meat that was improperly stored.

Beware: there are other diseases that can mimic clostridial infections:

Necrotizing soft tissue infections, including fasciitis and myositis, can be caused by many different bacteria and do not require the presence of clostridia. In addition, several clostridial species other than C. perfringens can cause clostridial myonecrosis and gangrene. These include C. novyi, C. septicum, C. histolyticum, C. bifermentans, and C. sordellii. Clinically, it is very difficult to distinguish clostridial gangrene from other microbial etiologies until cultures return. The key initial empiric management issues of surgical source control, hemodynamic support, and antibiotic therapy are similar, no matter what the causative agents are.
The presence of refractory shock (toxic shock) in women of reproductive age suggests the possibility of a shock-inducing infection of the female reproductive tract. In addition to C. perfringens, these include C. sordellii, Group A Streptococcus (S. pyogenes), and Staphylococcus aureus. It is impossible without culture or molecular data to differentiate C. sordellii toxic shock syndrome from C. perfringens, and the management approach is similar. Although clostridial pathogens are more commonly associated with therapeutic, spontaneous, or illegal abortions, Group A Streptococcus tends to complicate childbirth and S. aureus tends to be tampon-associated. However, these are all difficult to tell apart, and empiric therapy for a young woman with toxic shock syndrome should include coverage for all these organisms.
Staphylococcal food poisoning can be rapid, but generally occurs within 2-8 hours after ingestion, and the primary symptom is vomiting, not diarrhea. Diarrhea is typical of C. perfringens.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Peripheral white blood cell (WBC) with differential is consistent. Some patients exhibit hemolytic anemia, which can be dramatic, due to the production of hemolysins by C. perfringens. Women with C. perfringens or C. sordellii endometritis and toxic shock can have a dramatic leukocytosis, or leukemoid reaction, with WBC counts above 50,000/uL.
As opposed to the hemolysis of C. perfringens, patients with C. sordellii septic shock may have hemoconcentration due to extravasation of extracellular fluid from leaky capillaries. Toxic shock with a leukemoid reaction and hemoconcentration should trigger the thought of C. sordellii infection.
Blood cultures should be performed for patients with soft tissue infection or suspected endometritis; about 15% of patients have bacteremia.
Liver tests should be checked. Hyperbilirubinemia can occur. Transaminitis is characteristic of streptococcal and staphylococcal toxic shock syndromes.
Basic metabolic profile should be done to look for acute kidney injury (AKI), which can accompany the shock of C. perfringens soft tissue infections. AKI can also result from massive hemoglobinuria or myoglobinuria if hemolysis or rhabdomyolysis are present.
Creatine kinase to look for evidence of myonecrosis is consistent. This is particularly important after trauma or in the presence of a suspected necrotizing soft tissue infection.

Results that confirm the diagnosis

A positive culture for clostridia from a deep tissue culture obtained from a patient who has a clinically compatible illness should always be considered a true positive and not a contaminant. However, clostridial spores can contaminate the skin or feces, so isolating clostridia from superficial sites without necrotic or gangrenous soft tissues should be considered suspicious for contamination.
Blood cultures are not commonly positive in gangrene or C. sordellii toxic shock syndrome, but, when positive, they are diagnostic.
Isolating C. septicum from the bloodstream should suggest a colorectal source.
Polymerase chain reaction (PCR) can be performed from tissue samples for invasive clostridia, but such tests are not commercially available, and communication with the Centers for Disease Control and Prevention (CDC) or a specialty lab may be necessary.

What imaging studies will be helpful in making or excluding the diagnosis?

Plain radiographs (X-rays) may reveal gas in the deep soft tissues or the presence of foreign bodies.
Computed tomography scans and magnetic resonance imaging studies are best for detailed anatomic information regarding gas, inflammatory changes, edema, and necrosis in the deep tissues. However, do not send unstable patients to get scans.
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What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has costridial infection, what therapies should you initiate immediately?

General and/or Gynecological Surgery
Infectious Diseases

For soft tissue infections and gynecological infections, it is imperative to involve surgical consultants as soon as possible. Surgical source control is the primary concern. Hemodynamic stabilization and goal-directed therapy for shock and sepsis are critical. Empiric antimicrobials should be broad and cover clostridia, Group A Streptococcus, methicillin-resistant Staphylococcus aureus, and gastrointestinal microbes, such as anaerobic and aerobic Gram negative rods.

Most of the non-difficile clostridia are sensitive to penicillin G, although some resistance has been noted in C. perfringens and susceptibility should not be assumed.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

For patients with severe and complicated soft tissue infections, including female reproductive tract infections, initial coverage should be broad (Table I). Consider:

Table I.

Organism	Antibiotic	Dose	Comments
C. histolyticumC. novyiC. perfringensC. sordelliiC. septicum	Penicillin G	3-4 million units iv every 3-4 h (18-20 million units each day)	Dose adjustment needed in renal failure
C. histolyticumC. novyiC. perfringensC. sordelliiC. septicum	Piperacillin-tazobactam	4.5 gm iv every 8 h or 3.375 gm iv every 6 h	Dose adjustment needed in renal failure
C. histolyticumC. novyiC. perfringensC. sordelliiC. septicum	Clindamycin	600-900 mg iv every 8 h	Should be combined with other empiric medications to (hopefully) reduce toxin production.
Same + C. tertium	Vancomycin	15 mg/kg iv every 12 h	Dose adjustment needed in renal failure
Same + C. tertium	Imipenem	1 gram iv every 8 h	Other carbapenems are active as well.Dose adjustment needed in renal failure
Same + C. tertium	Metronidazole	500 mg iv every 8 h	Some resistance reported in C. tertium.
Same + C. tertium	Chloramphenicol	50-100 mg/kg po/IV divided q6h (maximum of 4 gm/day)	With so many options, this probably will never need to be used but is active.
Same + C. tertium	Daptomycin	6 mg/kg iv daily	Monitor CK for myotoxicity. Active in vitro (including C. terium) but few clinical data.
Same + C. tertium	Linezolid	600 mg po or iv q12 h	Like clindamycin, this can probably reduce toxin production.
Same + C. tertium	Tigecycline	100 mg iv load followed by 50 mg iv q12 h	Significant nausea may occur. Low blood levels achieved due to large volume of distribution.

A beta lactam antibiotic + beta lactamase inhibitor combination, such as ticarcillin + clavulanic acid OR piperacillin + tazobactam: The combination of ampicillin + sulbactam can be used, but, when gastrointestinal tract bacteria are possibly involved, it is best to avoid this drug combination because of increasing levels of resistance in aerobic and anaerobic Gram negative bacteria. As an alternative to these medications, carbapenems, including doripenem, ertapenem, imipenem, and meropenem, can be used. Ertapenem should be avoided if Pseudomonas is suspected, but this is rare in gangrenous infections.
Clindamycin OR linezolid can be added to the above if there is a possibility of toxic shock syndrome; these medications potentially reduce toxin production by shock-inducing streptococci, S. aureus, and perhaps clostridia. Linezolid and clindamycin both have activity against methicillin-resistant S. aureus, although this is less predictable with clindamycin. Thus, if linezolid is not used, then vancomycin or another MRSA-active compound should be prescribed in addition to clindamycin.
For the penicillin or beta lactam allergic patient, consider aztreonam PLUS an aminoglycoside (OR fluoroquinolone if there are contraindications to the aminoglycoside) for aerobic Gram negative bacteria. ADD metronidazole OR clindamycin to cover anaerobes, and ADD an MRSA-active agent (linezolid is preferred if clindamycin is not being used too).

2. Other key therapeutic modalities.

For patients with toxic shock syndrome of any variety (streptococcal (most common), staphylococcal (next most common), or clostridial (least common)), consideration should be given to using empiric intravenous immune globulin (IVIg). Although of unproven benefit, clinical use (and small studies) suggests a benefit in streptococcal toxic shock. Theoretical reason for use in any toxic shock syndrome includes the potential for antibody binding of free toxin. Consideration for IVIg should be made if it is readily available and the patient is already receiving appropriate antimicrobial medications.

Another controversial topic is the use of hyperbaric oxygen (HBO). HBO may help open soft tissue defects heal, but patients with sepsis and hemodynamic instability should not be sent to the HBO chamber.

What complications could arise as a consequence of this disease?

What should you tell the family about the patient's prognosis?

The mortality of clostridial gangrene without toxic shock syndrome is probably about 10-30%, although data are not definitive. In patients with a complicated soft tissue infection and toxic shock syndrome (refractory hypotension and acute organ dysfunction) caused by clostridia, mortality is high (above 40% with C. perfringens, and higher with many other clostridia). Women with reproductive tract toxic shock syndrome caused by C. sordellii or C. perfringens have mortalities approaching 100%.

C. perfringens food poisoning is a self-limited illness.

How do you contract this disease and how frequent is this disease?

C. perfringens food poisoning is common. It is acquired by the oral ingestion of large numbers of vegetative bacteria, replicated in red meat or poultry that sat at room temperature for too long. This bacterium has a very short doubling time in meat, so large numbers of bacteria can be present when meat is improperly refrigerated after cooking. When enteritis occurs, it may be part of an outbreak and is usually not an isolated event.

Clostridial gangrene is uncommon; exact incidence rates are unknown. Contaminated wounds are an important risk factor, and clostridia needs to be considered in anyone who presents with toxic shock, particularly in the presence of a necrotizing soft tissue infection or an obstetrical/gynecological infection.

Clostridial sepsis, shock, and gangrene need to be considered in patients who are active injection drug users.

Patients with gastrointestinal malignancies, recent gastrointestinal surgery, profound immunosuppression, and diverticulitis are at increased risk for spontaneous (non-traumatic) gas gangrene caused by C. septicum.

The incidence of clostridial gas gangrene is not well defined, but probably fewer than 3,000 cases occur in the United States each year.

Clostridial toxic shock in women of reproductive age, caused by C. perfringens or C. sordellii, is rare, and exact incidence data are unknown. A recent study in California suggested that perhaps 1 in 200 deaths in women of reproductive age was due to these infections.

C. perfringens has been implicated in causing nearly a million cases of foodborne illness each year in the United States.

There is very little, if any, person-to-person spread of non-C. difficile clostridial infections.

Clostridia can colonize the gastrointestinal (GI) tract of food chain livestock, such as sheep, cattle, pigs, and chicken. Meat can be contaminated with spores, and this can contribute to C. perfringens foodborne illness.

How do Clostridium species cause disease?

Clostridial infections primarily cause signs and symptoms through the actions of their toxins. This point is underscored by the facts that nontoxigenic clostridia are usually innocuous and vaccines against clostridial infections generally target the toxins. For many clostridia, the term “alpha toxin” is used to describe their most potent or lethal toxin. This can be a cause for confusion, because many clostridia express alpha toxins that are structurally and mechanistically distinct.

C. perfringens and related clostridia cause gangrene, necrotizing soft tissue infections, shock, and gastroenteritis through the production of an array of toxins. These include a lecithinase (also called phospholipase C and, in C. perfringens, alpha toxin). The alpha toxin of C. perfringens is very important in causing myonecrosis and hemolysis. It can induce platelet activation, microvascular thrombosis, and local ischemia, and, therefore, can create tissue necrosis and an anaerobic milieu for the bacterium. C. perfringens also express a theta toxin (also called perfringolysin O), which is a cholesterol-dependent cytolysin that may contribute to infection.

Other C. perfringens toxins of importance include additional hemolysins, proteases, collagenase, hyaluronidase, DNAse, and neuraminidase. It is notable that the enterotoxin of C. perfringens (called CPE) is carried on a plasmid and is much less commonly found in non-enteritis clinical isolates.

C. sordellii strains come in three major varieties with respect to toxin production. The major virulence factors for C. sordellii are its two large clostridial cytotoxins, called lethal toxin (TcsL) and hemorrhagic toxin (TcsH). These toxins cause cytoskeletal disruption in endothelial cells, leading to vascular collapse and toxic shock. Strains found in nature and in human infections carry genes encoding both toxins, only lethal toxin, or neither toxin. So far, no strains that just carry the gene for hemorrhagic toxin have been identified. Lethal toxin alone is sufficient to cause toxic shock syndrome, and antibodies against TcsL protect animals from death, suggesting that intravenous immunoglobulin might be of some use in patients with C. sordellii toxic shock.

It is not known whether antibodies against either TcsL or TcsH exist in pooled human immunoglobulin, but these toxins cross react with C. difficile toxins B and A, respectively; and antibodies against those toxins can be found in normal serum. Nontoxigenic C. sordellii (negative for TcsL and TcsH) probably cannot cause typical toxic shock syndrome, but these strains have been associated with bacteremia, sepsis, and endometrial infections. It appears that most strains of C. sordellii possess DNAse, collagenase, and phospholipase C (lecithinase) activities.

C. septicum produces four major toxins believed important to its pathogenesis. These include an alpha toxin (lethal, hemolytic, necrotizing activity), beta toxin (DNAse), gamma toxin (hyaluronidase), and a delta toxin (an oxygen-labile hemolysin). It also makes a protease and neuraminidase.

C. novyi makes a phospholipase and a large cytotoxin, called alpha toxin (TcnA), that are probably important for causing gangrenous soft tissue infections.

What other clinical manifestations may help me to diagnose and manage clostridial infections?

Think about clostridial gangrene when rapidly progressive soft tissue infections are present, particularly if there is pain out of proportion to exam or crepitus. If an X-ray shows gas in the soft tissues, think clostridia.

Refractory shock in a previously healthy woman should raise the notion of clostridial toxic shock syndrome. Both Group A Streptococcus and S. aureus can also cause toxic shock in healthy women.

Leukemoid reaction, hemoconcentration, and the absence of fever suggest C. sordellii toxic shock.

Ask about injection drug use in patients with clostridial soft tissue infections or bacteremia.

Ask about consumption of meat-based foods that might have been left out at room temperature for too long. If close contacts had profuse watery diarrhea at the same time as your patient, ask if they ate similar food.

Ask about recent childbirth, abortion, amniocentesis, or gynecological procedures to suggest clostridial endometritis and toxic shock.

How can clostridial infection be prevented?

Preventing foodborne C. perfringens infection is best done by keeping meat at the proper temperature. Cooked meats should be served hot (>140ºF) as soon as possible after cooking. The dish should be rapidly cooled on ice or by refrigeration if it will not be consumed immediately. Reheating cold meats should achieve an internal temperature of 165ºF or higher to kill bacteria that may have grown during cooling.

There are no human-use vaccines or preventive medications available for clostridial soft tissue infections, although this is an active area of research.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Aldape, MJ, Bryant, AE, Stevens, DL. “infection: epidemiology, clinical findings, and current perspectives on diagnosis and treatment”. Clin Infect Dis. 2006 Dec. vol. 43. 1. pp. 1436-46. (This is an excellent review of C. sordellii infections.)

(This is a helpful resource provided by the CDC.)

Stevens, DL, Aldape, MJ, Bryant, AE. “Life-threatening clostridial infections”. Anaerobe. vol. 18. 2012. pp. 254-9. (This is a wonderful review of pathogenesis, clinical presentation, diagnosis, and management of severe clostridial infections. The bibliography is also very good. These authors are experts in severe clostridial infections.)

Zane, S, Guarner, J. “Gynecologic clostridial toxic shock in women of reproductive age”. Curr Infect Dis Rep. vol. 13. 2011. pp. 561-70. (This is a very complete review of postpartum and postabortion clostridial toxic shock syndrome. These authors have been studying this phenomenon for a number of years.)

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