Clostridial Gas Gangrene


Background

Clostridial gas gangrene is a highly lethal necrotizing soft tissue infection of skeletal muscle caused by toxin- and gas-producing Clostridium species. The synonym clostridial myonecrosis better describes both the causative agent and the target tissue. Prior to the advent of antibiotics and mobile army surgical hospitals, as many as 5% of battlefield injuries were complicated by this condition. However, the incidence rate dropped to less than 0.01% during the Vietnam War. Presently, 90% of contaminated wounds demonstrate clostridial organisms, but fewer than 2% develop clostridial myonecrosis. This underscores the importance of host and local wound factors in the development of this process, rather than the mere presence of the organisms in the wound.

Clostridial myonecrosis may also occur following surgery, most often of the gastrointestinal or biliary tract, and following septic abortions. [1Clostridium perfringens, Clostridium septicum, and Clostridium histolyticum are the principal causes of trauma-associated gas gangrene, and their incidence increases dramatically in times of war, hurricanes, earthquakes, and other mass-casualty conditions. There has also been an increased incidence of spontaneous gas gangrene caused by C septicum in association with gastrointestinal abnormalities and neutropenia. [2]

Similarly, over the last 15 years, a toxic shock–like syndrome associated with Clostridium sordellii infection has been increasingly recognized in individuals skin-popping black tar heroin and in women undergoing childbirth or other gynecologic procedures, including medically induced abortion. [2]

Pathophysiology

Clostridia are gram-positive, anaerobic, spore-forming bacilli commonly found throughout nature (with the exception of the North African desert). Cultivated rich soil has the highest density of organisms. In addition, clostridia have been isolated from normal human colonic flora, skin, and the vagina. More than 150 Clostridium species have been identified, but only 6 have been demonstrated to be capable of producing the fulminant condition known as clostridial gas gangrene. Usually, more than 1 species is isolated from clinical specimens. A study by Mendez et al suggests that sugar may inhibit the production of alpha and theta toxins that trigger the gas. [3]

Clostridium perfringens, previously known as Clostridium welchii, is the most common cause of clostridial gas gangrene (80-90% of cases). Other clostridia species responsible for the condition include Clostridium novyi (40%), Clostridium septicum (20%), Clostridium histolyticum (10%), Clostridium bifermentans (10%), and Clostridium fallax (5%).

Infections are characterized by a very low level of host inflammation in response to organism-associated exotoxins. In fact, it is more of a response to the exotoxins than a classic immune response to invading organisms. Purulence is often absent. The process of myonecrosis can spread as fast as 2 cm/h. This results in systemic toxicity and shock that can be fatal within 12 hours. Overwhelming shock with accompanying renal failure usually leads to death.

Infection requires 2 conditions to coexist. First, organisms must be inoculated into the tissues. Second, oxygen tension must be low enough for the organisms to proliferate. These organisms are not strict anaerobes; 30% oxygen tension in the tissues allows for free growth of these bacteria, but 70% oxygen tension restricts their growth. Inoculation of organisms into low oxygen tension tissues is followed by an incubation period that usually ranges from 12-24 hours. However, this period can be as brief as 1 hour or as long as several weeks. The organisms then multiply and produce exotoxins that result in myonecrosis.

Although not very well understood, exotoxins appear to be tissue-destructive soluble antigens produced by clostridia. They include lecithinase, collagenase, hyaluronidase, fibrinolysin, hemagglutinin, and hemolysin toxins. C perfringens produces at least 17 identifiable exotoxins that are used for species typing (eg, type A, type B, type C).

Theta toxin causes direct vascular injury, cytolysis, hemolysis, leukocyte degeneration, and polymorphonuclear cell destruction. These effects on leukocytes may explain the relatively minor host inflammatory response that is observed in tissues of patients with clostridial myonecrosis.

Kappa toxin, also produced by C perfringens, is a collagenase that facilitates the rapid spread of necrosis through tissue planes by destroying connective tissue.

Alpha toxin is produced by most clostridia and has phospholipase C activity. This potent lecithinase causes lysis of red blood cells, myocytes, fibroblasts, platelets, and leukocytes. It also may decrease cardiac inotropy and trigger histamine release, platelet aggregation, and thrombus formation. [4]

Epidemiology

Frequency

United States

Approximately 1000 cases of clostridial gas gangrene are reported per year.

International

Although no published data exist, prevalence is most likely higher in countries other than the United States because of lack of access to health care in other parts of the world.

Mortality/Morbidity

If properly treated, the overall mortality rate is 20%-30%. If untreated, the process is 100% fatal.

Spontaneous cases carry a mortality rate of 67-100%.

With trunk involvement, the mortality rate is higher (60%) than the mortality rate associated with involvement of the extremities, which carries a better prognosis.

A longer incubation period, presence of significant comorbidities, and development of shock increase the risk of mortality.

Race

No race predilection exists.

Sex

No sex predilection exists.

Age

Age does not seem to be an independent risk factor. However, because elderly individuals more often have significant comorbidities, they are at higher risk for mortality than younger patients.

Prognosis

Most patients do fairly well if they survive the initial critical period.

Shock in patients presenting with clostridial myonecrosis portends a worse prognosis.

CLINICAL PRESENTATION


Medical Care

Successful therapy requires rapid diagnosis and aggressive early treatment. [6The physician must maintain a high index of suspicion for this uncommon but potentially fatal process. Any patient in whom clostridial gas gangrene is suspected should be considered critically ill.

Obtain early consultation with a surgeon for debridement.

Administer supplemental oxygen.

Restore intravenous fluid volume and monitor urine output with an indwelling bladder catheter.

Transfer to an intensive care unit that has telemetry and pulse oximetry.

Ensure that tetanus immunity is adequate.

Antibiotic therapy

Broad-spectrum empiric antibiotic treatment is warranted to cover group A StreptococcusClostridium species, and mixed aerobes and anaerobes.

Definitive antibiotic therapy should consist of the combination of penicillin plus clindamycin or tetracycline. Optimal duration of therapy has not been defined, and it should be continued until no further debridement is planned and hemodynamic stability has been achieved.

Antibiotics against C septicum in animal models demonstrated higher susceptibility to penicillin, clindamycin, and tetracycline, but considerably lower susceptibility to vancomycin. [13]

Hyperbaric oxygen therapy

The role of hyperbaric oxygen (HBO) treatment as adjunctive therapy remains controversial. Some nonrandomized studies have reported good results with HBO therapy when combined with antibiotics and surgical debridement. [14]

Clostridia lack superoxide dismutase, making them incapable of surviving in the oxygen-rich environment created within a hyperbaric chamber. This inhibits clostridial growth, exotoxin production, and exotoxin binding to host tissues.

Hyperbaric oxygen therapy may also promote host polymorphonuclear cell function.

Animal studies have clearly demonstrated a survival advantage when this therapy is combined with antibiotics and debridement. However, no randomized controlled studies of humans exist to support this finding.

Hyperbaric oxygen should be used at the discretion of the treating physician but should never cause a delay in surgical debridement. Transporting a patient from one facility to another merely to administer hyperbaric oxygen probably is not warranted and may be detrimental.

Administer therapy 3 times a day for 2 days, then twice a day for several more days, until the disease process is well under control.

The dose is usually 2.5 atmospheres absolute (ATA) oxygen for 120 minutes or 3 ATA oxygen for 90 minutes. The pressure at sea level equals 1 ATA.

Complications include fire, seizures, decompression sickness, middle ear barotrauma, and claustrophobia.

Future management

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.

Treatment guidelines

The reader is also referred to the 2014 guidelines published by the Infectious Diseases Society of America (IDSA) for the treatment of clostridial gas gangrene (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America). [15]

Surgical Care

Clostridial gas gangrene represents a true surgical emergency.

It requires prompt aggressive debridement of all involved tissues.

Extensive extremity involvement may require amputation.

Because the disease process may continue to involve additional tissue, daily exploration and further debridement may be necessary.

Wound exploration reveals gas, watery discharge, and necrotic muscle. Muscle tissue may be pale, edematous, and may not bleed when cut or contract when stimulated with electricity.

If the patient survives, the wound may be closed at a later date or allowed to heal secondarily (by wound contraction and spontaneous re-epithelialization).

Consultations

Consultations are as follows:

  • Infectious disease specialists

  • General, trauma, or burn surgeon

  • Plastic surgeon

Diet

Ensure that the patient receives adequate nutritional support during this period of increased energy requirements.

During the period of critical illness, administration of enteral or parenteral nutrition may be required.

Consultation with a nutritionist ensures optimal nutritional replacement.

Frequently monitor nutritional status through serum markers and nitrogen balance determination.

Activity

Once patients have survived the critical period of illness, they may benefit from occupational or physical therapy to restore preinjury function.

Further Inpatient Care

If patients survive, they typically are hospitalized for several weeks.

Transfer

Transfer is required infrequently and may be detrimental to the patient.

As long as the treating facility has the capability and experience to provide adequate surgical and intensive care, no transfer is necessary.

Transfer merely to obtain access to hyperbaric oxygen therapy is not indicated.

MEDICATION


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antibiotics

Class Summary

Penicillin is the preferred drug for clostridial infections. Patients allergic to penicillin may be treated with clindamycin or chloramphenicol.

Penicillin G (Pfizerpen)

Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Piperacillin/tazobactam (Zosyn)

Beta-lactamase inhibitor indicated in gynecologic infections, intra-abdominal infections, and skin and skin structure infections, including diabetic foot infections.

Metronidazole (Flagyl, Metro)

Exact mechanism of action not fully elucidated. Disrupts DNA and inhibits nucleic acid synthesis.

FDA approved for the treatment of anaerobic infections: intra-abdominal infections, skin and skin-structure infections, and bone and joint infections.

Tetracycline

Inhibits bacterial protein synthesis. May also cause alterations in the cytoplasmic membrane. Bacteriostatic antibiotic.

Alternative in PCN-allergic patients. 

Chloramphenicol

Inhibits protein synthesis by binding to 50S ribosomal subunits, preventing amino acids from being transferred to the growing peptide chains, which in turn inhibits protein synthesis.

Use in serious infections for which less potentially dangerous drugs are ineffective or contraindicated.

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