Figure 18-1
.Pathogenesis of gas gangrene caused by C perfringens. A = macroscopic, B = microscopic
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Clostridial wound infections may be divided into three categories: gas gangrene or clostridial myonecrosis, anaerobic cellulitis, and superficial contamination. Gas gangrene can have a rapidly fatal outcome and requires prompt, often severe, treatment. The more common clostridial wound infections are much less acute and require much less radical treatment; however, they may share some characteristics with gas gangrene and must be included in the differential diagnosis.
Gas gangrene is an acute disease with a poor prognosis and often fatal outcome (Fig. 18-1
). Initial trauma to host tissue damages muscle and impairs blood supply. This lack of oxygenation causes the oxidation-reduction potential to decrease and allows the growth of anaerobic clostridia. Initial symptoms are generalized fever and pain in the infected tissue. As the clostridia multiply, various exotoxins (including hemolysins, collagenases, proteases, and lipases) are liberated into the surrounding tissue, causing more local tissue necrosis and systemic toxemia. Infected muscle is discolored (purple mottling) and edematous and produces a foul-smelling exudate; gas bubbles form from the products of anaerobic fermentation. As capillary permeability increases, the accumulation of fluid increases, and venous return eventually is curtailed. As more tissue becomes involved, the clostridia multiply within the increasing area of dead tissue, releasing more toxins into the local tissue and the systemic circulation. Because ischemia plays a significant role in the pathogenesis of gas gangrene, the muscle groups most frequently involved are those in the extremities served by one or two major blood vessels.
Clostridial septicemia, although rare, may occur in the late stages of the disease. Severe shock with massive hemolysis and renal failure is usually the ultimate cause of death. The incubation period, from the time of wounding until the establishing of gas gangrene, varies with the infecting clostridial species from 1 to 6 days, but it may be as long as 6 weeks. Average incubation times for the three most prevalent infecting organisms are as follows: C perfringens, 10–48 hours; C septicum, 2–3 days; and C novyi, 5–6 days. Because the organisms need time to establish a nidus of infection, the time lag between wounding and the appropriate medical treatment is a significant factor in the initiation of gas gangrene.
Like gas gangrene, clostridial cellulitis is an infection of muscle tissue, but here the infecting organisms invade only tissue that is already dead; the infection does not spread to healthy, undamaged tissue. Clostridial cellulitis has a more gradual onset than gas gangrene and does not include the systemic toxemia associated with gas gangrene. Pain is minimal, and although only dead tissue is infected, the disease can spread along the planes between muscle groups, causing the surrounding tissue to appear more affected than it actually is. Anaerobic cellulitis may cause formation of many gas bubbles, producing infected tissue that looks similar to the gaseous tissue of gas gangrene. Some tissue necrosis does occur, but it is caused by decreased blood supply and not invasion by the infecting organism. With adequate treatment, anaerobic cellulitis has a good prognosis.
Superficial contamination, the least serious of the clostridial wound infections, involves infection of only necrotic tissue. Usually, the patient experiences little pain, and the process of wound healing proceeds normally; however, occasionally an exudate may form and the infection may interfere with wound healing. Superficial wound contamination caused by clostridia usually involves C perfringens, with staphylococci or streptococci, or both, as frequent co-isolates.
The clostridia that cause gas gangrene are anaerobic, spore-forming bacilli, but some species may not readily sporulate, e.g., C perfringens.
Clostridial wound infections usually are polymicrobic because the source of wound contamination (feces, soil) is polymicrobic. In gas gangrene and anaerobic cellulitis, the primary pathogen can be any one of various clostridial species including C perfringens (80%), C novyi (40%), C septicum (20%), and, occasionally, C bifermentans, C histolyticum, or C fallax. Other bacterial isolates may be any of a wide number and variety of organisms (for example, Proteus, Bacillus, Escherichia, Bacteroides, Staphylococcus). The distinctive or unique properties of the causative agents of gas gangrene are difficult to list; morphologic characteristics and biochemical reactions vary among these species, and a reliable laboratory manual should be consulted for their proper identification. Isolation of 107 or more clostridia per milliliter of wound exudate is strong evidence for a clostridial wound infection.
The most frequently isolated pathogen, C perfringens, has five types, designated A, B, C, D, and E. Each of these types produces a semi-unique spectrum of protein toxins. Alpha-toxin (a lecithinase, also called phospholipase-C) and theta-toxin (oxygen-labile cytolysin) are both considered important in the disease pathology. Alpha-toxin is lethal and necrotizing; it lyses cell membrane lecithins, disrupting cell membranes and causing cell death. Theta-toxin also contributes to rapid tissue destruction by several mechanisms. At the site of infection, theta-toxin acts as a cytolysin, promoting direct vascular injury; lower toxin concentrations activate polymorphonuclear leukocytes and endothelial cells, promoting distal vascular injury by stimulating leukocyte adherence to the endothelium. The result is leukostasis, thrombosis, decreased perfusion, and tissue hypoxia. Theta-toxin also mediates the production of shock through induction of inflammatory mediators such as platelet activating factor, tumor necrosis factor, interleukin 1 and interleukin 6.
).Host defenses against gas gangrene and other clostridial wound infections are mostly ineffective. Even repeated episodes of clostridial wound infection do not seem to produce effective immunity.
Clostridial spores are ubiquitous in the soil, on human skin, and in the gastrointestinal tracts of humans and animals. Thus, the causative agents of clostridial wound infections are not environmentally restricted. Even operating theaters can be habitats for infecting clostridial organisms and spores. The incidence of clostridial wound infections has declined with the advance of prompt, adequate medical treatment. Historically, war casualties have had the greatest incidence of gas gangrene; however, the prompt evacuation and medical attention given United States casualties in the Vietnam war greatly decreased the incidence of gas gangrene in these soldiers, emphasizing the importance of prompt medical treatment.
Diagnosis of clostridial wound infections is based on clinical symptoms coupled with Gram stains and bacterial culture of clinical specimens. Gas gangrene, once initiated, may spread and cause death within hours. By the time the typical lesions of gas gangrene are evident, the disease usually is firmly established and the physician must treat the patient on a clinical basis without waiting for laboratory confirmation. Characteristic lesions and the presence of large numbers of Gram-positive bacilli (with or without spores) in a wound exudate provide strong presumptive evidence. In contrast to tissue infections caused by Staphylococcus aureus, there is typically an absence of polymorphonuclear leukocytes at the site of infection, likely due to the presence of clostridial toxins. Spores are rare in cultures of C perfringens, the most common etiologic agent of these diseases. A commonly used laboratory test for presumptive identification of C perfringens is the Nagler reaction which detects the presence of alpha-toxin (phospholipase-C), one of the most prominent toxins produced by C perfringens. However, several other species of clostridia also have a positive Nagler reaction, and thus this test is not entirely specific for C perfringens.
Discussion of the differential diagnosis of clostridial wound infections appropriately includes streptococcal myositis, as this disease can be characterized by an edematous, necrotizing, often gaseous lesion. Like anaerobic cellulitis and superficial contamination with clostridia, streptococcal myositis is a relatively localized disease, but its later stages may include some systemic toxicity that mimics the toxemia of gas gangrene.
Correction of the anaerobic conditions combined with antibiotic treatment form the basis for therapy. Penicillin is the drug of choice for all clostridial wound infections; chloramphenicol is a second-choice antibiotic. Successful treatment of the less severe forms of clostridial wound infections includes local debridement and antibiotic therapy; after these measures are taken, patient recovery usually proceeds along a steady, positive course. Treatment of gas gangrene includes radical surgical debridement coupled with high doses of antibiotics. Blood transfusions and supportive therapy for shock and renal failure also may be indicated.
The usefulness of gas gangrene antitoxin is currently a disputed matter. Some physicians maintain that the efficacy of this polyvalent antitoxin has been proved in the past, but better medical care now may have eliminated the need for its use. Others believe that because of insufficient data, antitoxin should be administered systemically as early as possible after diagnosis, and that the antitoxin should be injected locally into tissue that cannot be excised.
Obviously, prevention of wound contamination is the single most important factor in controlling clostridial wound infections. In the past, immunization has been considered a possible preventive measure for gas gangrene; however, several factors have discouraged the use of active immunization, including difficulty in preparing a suitable antigenic toxoid, availability of prompt wound treatment, and accessibility of effective therapeutic agents.
