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.[1] Clostridium 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]
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]
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.
Obtaining a thorough medical history is important. It helps the physician identify risk factors that may affect the progression of the disease and the prognosis.
Perform a thorough physical examination before focusing on the involved body part, as follows:
Vital signs - May indicate systemic toxicity and include no or low-grade fever, tachycardia (relative tachycardia), tachypnea, hypotension, or hypoxia
Edema bullae
Erythema with purplish black discoloration
Extreme tenderness
Brownish skin discoloration (bronzing, brawny) with bullae
Profuse, "dish-watery," serous drainage from ruptured bullae
Discharge - May have a peculiar, "mousy," sweet odor
Minimal crepitant bullae
Crepitant tissue - May extend well beyond any skin discoloration, edema, or bleb formation
Mental status - Paradoxically, may be depressed early during the disease course; sensorium then may clear as the disease progresses and the patient is near death
The disease process must include tissue inoculation and a low oxygen tension environment. More than 50% of cases are preceded by trauma.[5, 6] Other cases occur spontaneously or in patients after operative procedures.
Trauma
Compound fractures
Foreign bodies
Frostbite
Thermal or electrical burns
Subcutaneous or intravenous injection of medications or illicit drugs
Pressure sores
Motor vehicle crashes
Postoperative
Gastrointestinal tract surgery
Genitourinary tract surgery
Abortion
Amputation
Tourniquets, casts, bandages, or dressings applied too tightly
Spontaneous
This also is known as nontraumatic, idiopathic, or metastatic gas gangrene.
It most often is mixed infection caused by C septicum, C perfringens, and C novyi. Several series report a mortality rate that approaches 100%.
The gastrointestinal tract is the source of organisms. The organisms escape the bowel by translocation, enter the bloodstream, and seed distant sites where they can cause gas gangrene. This process may also result in a more localized infection that involves the viscera or intra-abdominal compartment.
Approximately 80% of patients without trauma have an overt or occult malignancy. Of these, approximately 40% are hematologic malignancies and an additional 34% are colorectal.[7] Survival from this process should initiate a search for an occult malignancy if none has been documented previously in patients without trauma.
The white blood cell count may be normal or elevated. Immature forms are usually increased.
Elevated liver function test results may indicate progressive hepatic dysfunction.
Elevated blood urea nitrogen and creatinine may indicate azotemia, renal insufficiency, or renal failure.
Myonecrosis may elevate serum aldolase, potassium, lactate dehydrogenase, and creatine phosphokinase levels.
Profound anemia may result from severe intravascular hemolysis.
Arterial blood gas determinations and chemistry panel analysis may reveal metabolic acidosis.
Disseminated intravascular coagulation may result from exotoxin release.
A Gram stain of the wound discharge reveals gram-positive rods and an absence of polymorphonuclear cells. Other organisms are also present in up to 75% of cases. This test is essential for rapid diagnosis.
An assay for sialidases (neuraminidase) produced by clostridia also may be performed on serum and wound discharge. These tests provide rapid (< 2 h) confirmation of Gram stain results.
Most clinical microbiology laboratories use a combination of fermentation reactions and detection of short-chain fatty acid end-products for definitive identification of Clostridium species.
Radiographs reveal fine gas bubbles within the soft tissues, dissecting into the intramuscular fascial planes and muscles. Other necrotizing soft tissue infections produce abundant gas, in contrast to the paucity of gas of clostridial gas gangrene.
Intra-abdominal clostridial gas gangrene is evaluated most readily with CT scanning, which demonstrates extraluminal gas.
Blood and bullous fluid cultures reveal clostridia but take at least 48 hours to perform. They are not useful because the delay almost certainly results in death.
Although not widely used at present by clinical microbiology laboratories, rapid polymerase chain reaction methods for identification of C perfringens are available.[8]
In the future, methods such as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry will likely be used for rapid identification of organisms, including Clostridium species.[9, 10, 11, 12]
Successful therapy requires rapid diagnosis and aggressive early treatment.[6] The 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 Streptococcus, Clostridium 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]
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).
Clinical Context:
Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Clinical Context:
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.
Clinical Context:
Beta-lactamase inhibitor indicated in gynecologic infections, intra-abdominal infections, and skin and skin structure infections, including diabetic foot infections.
Clinical Context:
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.
Shahab Qureshi, MD, FACP, Attending Physician in General Internal Medicine, St Catharine's General Hospital; Associate Clinical Professor (Adjunct), McMaster University School of Medicine, Canada
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Disclosure: Received royalty from Baxter International for other.
Chief Editor
John Geibel, MD, MSc, DSc, AGAF, Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, Professor, Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital; American Gastroenterological Association Fellow; Fellow of the Royal Society of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Don R Revis, Jr, MD, Consulting Staff, Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Florida College of Medicine
Disclosure: Nothing to disclose.
Fred A Lopez, MD, Associate Professor and Vice Chair, Department of Medicine, Assistant Dean for Student Affairs, Louisiana State University School of Medicine
Disclosure: Nothing to disclose.
References
Mandell, Douglas, and Bennett. Gas Gangrene and Other Clostridium-Associated Diseases. Principles and Practice of Infectious Diseases. Eighth.
