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Botulism, gas gangrene, and clostridial gastrointestinal infections 

Botulism, gas gangrene, and clostridial gastrointestinal infections
Chapter:
Botulism, gas gangrene, and clostridial gastrointestinal infections
Author(s):

Dennis L. Stevens

, Michael J. Aldape

, and Amy E. Bryant

DOI:
10.1093/med/9780199204854.003.070624_update_001

Update:

Botulism—information on five clinical forms.

Updated on 31 May 2012. The previous version of this content can be found here.
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Essentials

Botulism

Human botulism is caused by seven serological types of C. botulinum, which is ubiquitously distributed in the soil. Poisoning usually results from ingestion of preformed toxin in food, although this is rapidly inactivated at ordinary cooking temperatures, but it can also result from contaminated wounds. C. botulinum toxin binds irreversibly to the neuromuscular junction and is the most lethal known microbial toxin.

Clinical features, diagnosis, and treatment—there are five forms of clinical botulism: (1) foodborne botulism—ingestion of food contaminated by preformed toxin; (2) wound botulism—infection of a wound with Cl. botulinum and in vivo toxin production (3) infant botulism—ingestion of clostridial spores that colonize the gastrointestinal tract and release toxin; (4) adult enteric infectious botulism—similar to infant botulism; (5) inhalational botulism—considered a potential agent of bioterrorism. Clinical presentation is with symptoms suggesting gastrointestinal tract illness, followed by neurological symptoms including diplopia, blurred vision, dizziness, and difficulty with speech or swallowing, leading on to generalized flaccid paralysis. The diagnosis can be confirmed by testing for botulinum toxin in the patient’s serum, urine, or stomach contents, or in the suspect food. Treatment requires (1) supportive care—this, including mechanical ventilation, may be needed for many months until new synapses have developed; (2) antitoxin—this reduces case fatality and shortens the illness.

Gas gangrene

Gas gangrene is caused by C. perfringens (most commonly), C. histolyticum, C. novyii, C. sordellii, and C. septicum, which occur naturally in soil and in the gastrointestinal tracts of humans and animals. Common causes of the condition are severe trauma that interrupts the blood supply to the soft tissues (gunshot wounds, penetrating or crushing injuries) with contamination by dirt, vegetation, or clothing containing vegetative forms of clostridia or spores. Skin popping of black tar heroin is another recently recognized cause. The clostridia responsible elaborate a wide range of toxins with varying effects: the principle toxin of C. perfringens is α‎-toxin, a phospholipase C that cleaves phosphatidylcholine in eukaryotic cell membranes and activates neutrophils, platelets, and endothelial cells, causing obstruction of local blood flow.

Clinical features—severe and sudden pain is the most characteristic symptom. Infection progresses rapidly with local ecchymosis, blistering, massive swelling, and crepitus indicating gas in the tissue as progressive necrotizing soft-tissue infection destroys muscle, fascia, fat, and skin. Without rapid and appropriate treatment, bacteraemia, hypotension, and multiple organ failure ensue.

Diagnosis and treatment—diagnosis must be made on clinical grounds, although Gram stain of the wound discharge or tissue sample may be helpful. Treatment requires (1) early recognition and aggressive surgical debridement of devitalized tissue; (2) antimicrobials—most commonly penicillin and clindamycin (which suppresses α‎-toxin production); (3) anti-α‎-toxin serum. The benefit of hyperbaric oxygen (HBO) has not been proven in controlled trials. In an experimental model of gas gangrene, HBO did not improve the efficacy of clindamycin or penicillin.

Prevention—prophylactic antibiotic treatment reduces the risk, but this depends upon factors including the time interval between the injury and surgical debridement.

Particular forms of gas gangrene—(1) C. septicum can grow at ambient oxygen tensions, causing ‘spontaneous gas gangrene’ in normal tissues, most commonly when bacteria spread from a colonic adenocarcinoma to uninjured muscle. (2) C. sordellii causes haemoconcentration, leukaemoid reaction without fever, and gradually progressive shock that is fatal in 75 to 80% of patients. Women infected during parturition, after medical abortion, or following gynaecological surgery almost always die.

C. perfringens gastrointestinal infections

Food poisoning—if foods such as meat and heavy gravy infected with type A strains of C. perfringens are allowed to sit at room temperature, bacilli can multiply greatly. If the food is then inadequately heated before consumption, preformed heat labile enterotoxin, combined with toxin produced in the gut, causes self-limiting abdominal pain and diarrhoea, usually without fever or vomiting.

Necrotizing enterocolitis—C. perfringens type C β‎-toxin causes fulminating enterocolitis that destroys intestinal mucosa. Epidemic outbreaks occured in postwar Germany (Darmbrand) and New Guinea (enteritis necroticans, ‘pig bel’) following ingestion of contaminated food, or dramatic change from vegetarian to meat diets. Treatment consists of supportive care and antibiotics (usually benzylpenicillin). Complications, e.g. intestinal perforation, may require surgery, in which case mortality is high. A toxoid vaccine is protective and should be considered in areas of Papua New Guinea where the disease still occurs.

Acknowledgement: The authors acknowledge inclusion of material from the chapter in the previous edition by Dr H E Larson.

Botulism

Definition

Botulism is an acute symmetrical descending paralysis caused by a neurotoxin produced by Clostridium botulinum. Food contaminated by C. botulinum spores and elaborated toxin produces illness when ingested. Wound infections with C. botulinum or intestinal tract colonization in infants and adults occasionally cause botulism. Although the illness is most commonly described in humans, botulism can occur in wild ducks feeding off the bottoms of alkaline lakes in the western United States of America. The illness is called ‘limber neck’.

Occurrence

C. botulinum is ubiquitously distributed in the soil. The surfaces of potatoes, vegetables, and other foods are easily contaminated with spores, which survive brief heating at 100°C. Autoclaving or use of pressure cookers that are appropriately adjusted are very effective at killing spores. In the 1920s in the United States of America, pressure cookers calibrated at sea level which were then used at several thousand feet above sea level in the western states were the cause of outbreaks of botulism among families that home-canned food. The anaerobic conditions created by canning, smoking, or fermentation facilitate clostridial growth and toxin release. Canned food with neutral pH, such as canned corn, is particularly prone to promoting the growth of clostridia. Spores germinate in sausage or cheese kept for extended periods at room temperature. An 18th-century report associated paralytic illness with eating sausages, hence botulus, a Latin word for ‘sausage’. Cases have been associated with fermented milk in Africa, cheese sauce on baked potatoes in North America, fermented stew in Japan, and imported fish in the United Kingdom.

Although past outbreaks typically involved small groups of people, home-canned peppers served in a restaurant caused two large outbreaks in the United States of America. Outbreaks caused by commercially processed foods are infrequent, but contamination of hazelnut purée added to commercially produced yoghurt caused 27 cases of botulism in Wales and north-west England in 1989, the largest recorded outbreak in the United Kingdom. Most of the contaminated cartons could not be accounted for, suggesting that the attack rate varied or that mild symptoms were not diagnosed as botulism. Commercially prepared chopped garlic in soybean oil caused 36 cases dispersed over 8 provinces and states in North America.

Some outbreaks involved only single contaminated items, such as in the Loch Maree episode in 1922 where eight people died after eating duck paste, the 1978 outbreak in Birmingham involving four people who ate tinned Alaskan salmon, and one case in 1989 following a meal on a commercial airliner. Uneviscerated fresh fish have been associated with botulism, usually where there have been deficiencies in refrigeration.

Purified botulinum toxin has recently come into therapeutic use. Toxin injections produce temporary muscle weakness and are effective in the treatment of strabismus, blepharospasm, and torticollis, and are also used for cosmetic purposes. Treatment doses are considered too small to elicit systemic symptoms. Under experimental conditions, aerosolized botulinum toxin causes illness in monkeys, and the toxin has been utilized as an agent for biological warfare or terrorist activity. For example, botulinum toxin was loaded into Scud missile warheads by Iraq during the first Gulf War and stockpiled by the Aum Shinrikyo cult in Japan.

The toxin

There are seven serological types of botulinum toxin (A–G). Types A, B, and E account for nearly all human cases. Serotypes implicated in outbreaks of botulism parallel the geographical distribution of soil spores. Type E is nearly always associated with fish, but outbreaks caused by fish products can also involve types A and B.

C. botulinum toxin is heat labile and rapidly inactivated at ordinary cooking temperatures. It is a protein neurotoxin, and a dose as small as 0.1 µg is sufficient to cause death in humans. The 150-kDa molecule is composed of two peptide chains connected by disulphide bonds. One chain binds to and penetrates the neuron, and the other cleaves a protein essential for neurotransmitter release, reducing acetylcholine availability for impulse transmission. Toxin types A, C, and E hydrolyse a protein in the presynaptic membrane while types B, D, F, and G hydrolyse a protein in the synaptic vesicle.

Pathogenesis

Botulinum toxin is absorbed directly across mucous membranes. Locally acting toxin may produce some symptoms but cranial nerve paralysis results from blood stream distribution. Cranial nerves are preferentially affected because botulinum toxin binds more rapidly to sites where the cycles of depolarization and repolarization are frequent. Binding is irreversible and the toxin cannot thereafter be neutralized by antitoxin. Recovery occurs when nerve terminals sprout from the axon to form new motor endplates.

Botulinum toxin blocks impulse transmission mediated by acetylcholine at neuromuscular junctions, at autonomic ganglia, and at parasympathetic nerve terminals. Nerve stimulus transmission is blocked because the toxin prevents release of acetylcholine from the presynaptic membrane. Impulse conduction within peripheral nerves and muscle contraction are not affected. The synthesis of acetylcholine and impulse transmission within terminal nerve fibrils remain intact. On the other hand, the miniature endplate potentials spontaneously generated by release of acetylcholine in a resting nerve decrease and eventually disappear in the presence of toxin. If a poisoned nerve is stimulated repetitively, temporary summation of acetylcholine release occurs producing an augmented response.

History

The symptoms of botulism vary from mild fatigue to severe weakness and collapse leading to death within a day. Initially, nausea, vomiting, abdominal bloating, and dryness in the mouth and throat may suggest gastrointestinal tract illness. Diplopia, blurred vision, dizziness, unsteadiness on standing, and difficulty with speech or swallowing are common early neurological symptoms. Subsequently, there is progression to weakness or paralysis in the limbs, and generalized weakness and lassitude. The dryness of the mouth and throat may become so severe as to cause pain. Eventually there may be difficulty holding up the head, constipation, urinary hesitancy, and problems in breathing. The incubation period is between 12 and 72 h. Patients with short incubation periods are likely to have ingested large amounts of toxin. However, individuals are known to have ingested large amounts of contaminated food without developing symptoms.

Physical examination

Negative findings in botulism are pertinent. Higher mental functions are preserved, although sometimes patients are drowsy. Sensation is intact. Fever is unusual. The mouth is dry and the tongue is furrowed. Lateral rectus weakness in the eyes produces internal strabismus. Failure of accommodation is common and the pupils may be fixed in mid position or dilated and unresponsive to light. Ptosis, weakness of other extraocular muscles, and inability to protrude the tongue or to raise the shoulders are other early findings. Weakness in the limbs is of the flaccid, lower motor neuron type and deep tendon reflexes are initially preserved. Facial muscles may be spared; gag and corneal reflexes are not lost.

Weakness of the respiratory muscles develops early in relation to other findings and deterioration can be rapid. Paralysis descends symmetrically from cranial nerves to upper extremities to respiratory muscles to the lower extremities in a proximal to distal pattern. Hypotension without compensatory tachycardia, intestinal ileus, and urinary retention are evidence of the widespread autonomic paralysis. Symptoms and signs can be confined to the autonomic nervous system.

Diagnosis

The diagnosis in the first case of an outbreak can be missed because cranial nerve symptoms and signs are ignored in what is apparently a gastrointestinal disturbance. The differential diagnosis usually lies between botulism and the descending form of acute inflammatory polyneuropathy or Guillain–Barré syndrome. There can be similarities in the clinical presentation and progression of symptoms in the two diseases. Patients with botulism have normal cerebrospinal fluid findings and respiratory weakness and failure develop early, before the presence of severe limb weakness. Patients with the Guillain–Barré syndrome have marked limb weakness before the development of respiratory failure. Sensation and mental status are preserved in botulism.

Other diagnoses that may be considered include diphtheria, intoxication with atropine or organophosphorus compounds, myasthenia gravis, cerebrovascular disease involving the brainstem and producing bulbar palsy, paralytic rabies, tick paralysis, and neurotoxic snake bite. Botulism is distinguished from polymyositis and periodic paralysis by its rapid progression and cranial nerve abnormalities. Sometimes patients with other types of poisoning are thought to have botulism, most often with an outbreak of staphylococcal food poisoning. Individuals with carbon monoxide poisoning have been mistakenly been thought to be poisoned by food, but they invariably have headaches and altered consciousness. Poisoning from chemicals or fish produces rapid onset of symptoms. Mushroom poisoning is characterized by severe abdominal pain.

Appropriate samples for microbiological investigation should also be collected: suspected food sample; faeces, rectal washout, vomitus, and gastric contents in suspected foodborne or infant botulism; pus or tissue in wound botulism. These should be inoculated into a cooked meat broth or other anaerobic medium.

The diagnosis of botulism can be confirmed by testing for botulinum toxin in the patient’s serum, urine, stomach contents, or in the suspect food. 10 ml of serum should be taken before antotoxin treatment. Mice are inoculated intraperitoneally with 0.5 ml of sample, with and without mixing with polyvalent botulinum antitoxin, and observed for signs of botulism. Electromyography can be helpful in confirming a diagnosis of botulism. Single or low-frequency stimuli evoke muscle action potentials that are reduced in amplitude; tetanic or rapid stimuli produce an enhanced response. Nerve conduction velocities are normal. This result readily differentiates botulism from the Guillain–Barré syndrome. Patients with myasthenia gravis usually have muscle action potentials of normal or minimally decreased amplitude.

Treatment

The priorities in management are assessment of respiratory function followed by administration of antitoxin. Respiration should be monitored closely with a view to elective intubation since deterioration can occur rapidly. Prolonged respiratory support may be required. Profound hypotension can be secondary to hypoxaemia, acidosis, and accumulated fluid deficits or can be a feature of the autonomic paralysis. Treat autonomic paralysis by expanding the intravascular volume using whole blood, protein, and/or saline while monitoring central venous pressure or by infusing a low dose of dopamine.

Trivalent (types A, B, and E) antitoxin reduces case fatality and shortens the course of the illness. To be useful it must be given early, before free circulating toxin has bound to its peripheral targets and before the diagnosis can be confirmed by animal tests. Heptavalent equine antitoxin is available from the Health Protection Agency in the United Kingdom and through the State Departments of Health in the United States; one-half of the dose is given intramuscularly and one-half intravenously. An intradermal 0.1-ml test dose is given, but most serum reactions are not predicted by this test. As the antitoxin is derived from horse serum, serum sickness and anaphylaxis may occur. A pentavalent ovine antitoxin is available for military use only. One study of 132 patients with type A foodborne botulism reported reduced mortality in those treated with antitoxin compared with those who were not. Earlier administration appears to reduce the duration of symptoms and duration of mechanical ventilation.

Human-derived botulinum immunoglobulin (called BIG-IV or BabyBIG) is available for use in infants less than 1 year of age who are diagnosed with infant botulism. BG-IV should be administered as early as possible in the illness.

Many years ago it was shown that patients dying of botulism carried bacilli in their intestine. The discovery that clinical disease can result from toxin formed within the gastrointestinal tract of infants and adults makes antimicrobial treatment theoretically appealing. Gastric lavage, repeated high enemas, and cathartics have been utilized in an attempt to remove unabsorbed toxin. Drugs capable of reversing neuromuscular blockade have been used to treat patients with botulism, but without any noticeable effect on respiratory muscle weakness or tidal volume.

The mortality from botulism in the early part of the 20th century was 60 to 70%, but this improved to 23% for cases reported between 1960 and 1970 since the use of respiratory support. In a single large outbreak in 1977 there were no deaths among 59 cases. Recovery from botulism depends on the formation of new neuromuscular junctions; clinical improvement thus takes weeks to months. One severe case required respiratory support for 173 days with eventual recovery. Very prolonged fatigue and dyspnoea on exertion can be due to factors other than the neuromuscular blockade.

Wound botulism

Symptoms and signs of botulism can develop in people with injuries. Recognition may be complicated by the presence of fever from wound infection or gas gangrene, or by the absence of gastrointestinal symptoms. The diagnosis is confirmed by electromyography; botulinum toxin is detected in serum in only about one-half of the reported cases. The incubation period averages 7 days with a range of 4 to 17 days. Clinical findings and management are the same as for patients with food-borne botulism. Since 1991, wound botulism has increasingly become a complication of injection drug abuse; small abscesses at injection sites yield C. botulinum. An epidemic of wound botulism in the United States of America has been associated with the injection of black tar heroin. C. botulinum can be recovered from wounds in the absence of clinical botulism.

Infant botulism

Sporadically, cases of botulism are recognized in infants less than 6 months of age. Previously healthy babies develop constipation, which progresses over 3 to 10 days to poor feeding, irritability, a hoarse cry, and weakness in head control. Examination shows a generally weak, hypotonic, afebrile infant. Abnormalities in eye movements and pupillary reactions are sometimes present and deep tendon reflexes are reduced or absent. There is considerable range in severity; respiratory failure can develop but most recover completely.

The diagnosis can be confirmed by finding C. botulinum and toxin in the faeces, and by electromyography. Botulinum toxin is not present in the serum. The disease is thought to follow ingestion of C. botulinum spores, which multiply in the infant’s gastrointestinal tract and produce toxin. Excretion of C. botulinum and toxin may continue for as long as 3 months. Honey has been a source of spores in some cases. Other than supportive measures, no consistent pattern in treatment using antitoxin, antibiotics, cathartics, or enemas has been established.

Gas gangrene

Definition

Gas gangrene is a rapidly developing and spreading infection of muscle caused by toxin-producing clostridial species. Gas gangrene is accompanied by bacteraemia, hypotension, and multiorgan failure and is invariably fatal if untreated.

Aetiology

Clostridia are mainly saprophytes, occurring naturally in soil and in the gastrointestinal tracts of humans and animals. Most cases of gas gangrene are caused by Clostridium perfringens type A, but some are due to C. novyi and a few to C. septicum, C. histolyticum, C. sordellii, and C. fallax; not uncommonly more that one species is isolated. Oxygen inhibits growth of most, although C. septicum is quite aerotolerant.

Gas gangrene has been a major cause of wound infection on the battlefield, although recently civilian and iatrogenic traumas have become more common. Disease development requires an anaerobic environment and contamination of the wound with spores or vegetative organisms usually through soil contact. However, proximity to faecal sources of bacteria is also a risk factor for cases occurring after hip surgery, adrenaline injections into the buttock, or amputation of the leg for ischaemic vascular disease. Wound contamination with dirt, shrapnel, or bits of clothing reduces local oxygen concentrations. Traumatic gas gangrene develops in deep wounds involving large muscle masses in the shoulder, hip, thigh, and calf and particularly in those situations where damage to major arteries has occurred. Thus, gunshot wounds, crush injuries, and open fractures account for most of the cases. High-velocity bullets of large calibre are commonly used in contemporary times in civilian and military firearms and these produce extensive tissue damage. Necrotic tissue, foreign bodies, and ischaemia in a wound reduce the locally available oxygen and favour outgrowth of vegetative cells and spores.

The incidence of gas gangrene after trauma reflects the speed at which injured people can be evacuated and receive appropriate treatment. During the Vietnam and Falklands conflicts there were very few cases of gas gangrene among American and British wounded cared for by highly organized surgical teams. This reduction was likely due to more timely cleansing of wounds, maintaining blood flow by vascular surgery, and the use of antibiotics. In comparison, when a jet airliner crashed in the Florida everglades, eight of the 77 injured survivors developed the disease.

Nontraumatic or ‘spontaneous gas gangrene’ occurs without a preceding injury. Classically, it presents as a primary infection of the perineum or scrotum or in a limb secondary to seeding from clostridial colonization of a colonic neoplasm. These cases are most commonly caused by the more aerotolerant C. septicum where production of superoxide dismutase permits the organisms to survive in the presence of small amounts of oxygen.

Recently, C. novyi, C. sordellii, and C. perfringens have been associated with necrotizing soft tissue infections at injection sites in drug addicts. Outbreaks of these infections were reported in Scotland, Ireland, England, and the United States of America in 2000 and were characterized by extensive soft tissue necrosis, hypotension, severe constitutional toxicity, and a high case fatality rate.

C. sordellii infections have been described in women following natural childbirth or therapeutic abortion, and in men, women, and children following a variety of traumatic and surgical procedures. The infections are perhaps the most aggressive of all clostridial infections, in part because of a unique syndrome of absence of fever, profound hypotension, diffuse capillary leak, haemoconcentration, and leukaemoid reaction resulting in 70% mortality within 2 to 4 days of hospital admission. The toxins responsible for this remarkable infection have not been fully elucidated.

Toxins

The clinical and histological manifestations of gas gangrene are attributable to the production of potent bacterial exotoxins. The clostridia responsible for gas gangrene elaborate a wide range of toxins. More than 12 have been described for C. septicum, C. novyi, and C. perfringens. The principal toxin of C. perfringens is α‎-toxin, a phospholipase C. This toxin cleaves phosphatidylcholine found in cell membrane of eukaryotic cells, releasing diacylglycerol and phosphorylcholine. In small doses, this toxin can hyperactivate a variety of cells including neutrophils, platelets, endothelial cells, and macrophages; in high doses it is cytotoxic. Interestingly, this toxin can cause the rapid and irreversible cessation of blood flow to normal tissue. This perfusion deficit is the consequence of toxin-induced platelet/neutrophil aggregates that irreversibly occlude small to medium-sized vessels. Experimentally, active or passive immunization against α‎-toxin is protective against active infection. A second toxin, θ‎-toxin, is a cholesterol-dependent thiol-activated cytolysin that lyses red blood cells and other cells by its ability to form pores in cell membranes. Electron microscopy of θ‎-toxin-treated cells shows arc and ring structures of 7.5 to 18 nm appearing in the plasma membrane as early as 1 h postexposure. These plasma membrane defects increase with time and can be visualized adjacent to toxin molecules that have been labelled with ferritin. α‎-Toxin and θ‎-toxin are not readily detected in the tissues or serum of patients with gas gangrene, possibly because the toxin binds rapidly and irreversibly to lipid moieties in the cytoplasmic membranes.

History

The incubation period of gas gangrene is usually less than 4 days, often less than 24 h, and occasionally as short as 1 to 6 h. Pain is the most characteristic symptom. Patients describe this as severe or excruciating and sudden in onset. Evolution of symptoms and signs can be very rapid. Toxicity may prevent the patient from giving an adequate history.

Physical examination

Early on, it may be difficult to account for the patient’s pain by objective physical findings. Swelling, bluish discoloration, or darkening of the skin occurs at the affected site. The traumatic or surgical wounds become oedematous and a thin, serous discharge emerges from the site. Pain steadily increases in severity; the overlying skin becomes stretched and develops a brown or ‘bronzed’ discoloration. Haemorrhagic vesicles and finally areas of frank necrosis appear. A sweet odour from the wound has been described. Gas is not invariably present early in the course, but radiographs may detect gas earlier than can physical examination. Later, crepitus and exquisite tenderness are present in the wound.

Profound constitutional changes occur. Patients become sweaty and febrile, and though alert and oriented, are very distressed. The pulse is elevated out of proportion to the fever. Death may occur within 48 h. At operation, infected muscle appears dark red with purple discoloration; frank gangrene and liquefaction may be seen. Involved muscle does not bleed when cut or contract when directly stimulated.

Rapidly progressing necrotizing infections of the soft tissue may be monomicrobic, caused by clostridia, Streptococcus pyogenes, Staphylococcus aureus, Vibrio vulnificus, or Aeromonas hydrophila. Alternatively, necrotizing infections may be polymicrobic and caused by mixed aerobic and anaerobic microbes. Clostridia and polymicrobial infections are usually associated with gas in the tissue, whereas the others are not. Polymicrobial necrotizing infections occur most commonly following gastrointestinal surgery, penetrating injury to the abdomen, surgical incisions in the vaginal mucosa (episiotomy), or in diabetic patients with peripheral vascular disease. All of these necrotizing infections may destroy fascia, but frequently also destroy muscle, subcutaneous tissue, and skin.

Diagnosis

The diagnosis of gas gangrene must be made on clinical grounds and prompt recognition and treatment improve the prognosis. Sudden deterioration in a postoperative patient or following trauma requires examination of the wound and surrounding tissue. Cases of primary gas gangrene and cases following elective surgery may have a higher fatality because recognition is delayed. Gram’s staining of the wound discharge, of an aspirate, or of a needle biopsy may aid diagnosis. In gas gangrene there are many large plump Gram-positive bacilli, usually without spores. Few, if any, polymorphonuclear leucocytes are present in the tissues or exudates, likely due to toxin-induced inhibition of cellular extravasation.

CT scanning can detect gas deep in muscle, but the absence of gas does not exclude the diagnosis. Culture of clostridia does not confirm a diagnosis of gas gangrene as simple colonization without clinical disease occurs in up to 30% of traumatic wounds.

Treatment

Surgical removal of all affected muscle is essential to eliminate the conditions that allow the organism to grow. High-velocity missiles distribute energy radially from their path, producing more extensive tissue damage than missiles at low speeds or with a small mass. Thus, wounds should be excised widely by resection back to healthy, viable muscle and skin. Closure should be delayed for 5 to 6 days until it is certain that the wound is free of infection.

Administration of appropriate antimicrobial agents is also required. Penicillin has been the drug of choice based on in vitro susceptibility testing, but experimental evidence has demonstrated that clindamycin or tetracycline is superior to penicillin. This improved efficacy is most likely because these two protein synthesis inhibitors prevent the production of toxins. This has led to the use of penicillin and clindamycin as combination therapy. Ceftriaxone or erythromycin are alternative choices for severely penicillin-allergic patients.

Hyperbaric oxygen therapy (typically 100% oxygen at 303 kPa for 60–120 min, 2–3 times daily) has been used to treat gas gangrene; however, an effect on mortality has never been shown by controlled trials and comparable survival rates have been achieved without using it. Experimental studies have demonstrated that hyperbaric oxygen alone was neither effective in an animal model of C. perfringens gas gangrene nor did it improve the efficacy of clindamycin or penicillin.

Therapeutic administration of gas gangrene antitoxin made from horse serum is controversial. Use during the Second World War reduced mortality, but serum sickness and other allergic reactions occurred. It is no longer produced in the United States of America. In recent studies, active immunization of animals with a truncated, nontoxic form (C-domain) of the α‎-toxin was 100% protective against active muscle infection with C. perfringens.

Prevention

Prophylactic antibiotic treatment reduces the risk of gas gangrene but this depends on the time interval between the injury and surgical debridement, the associated vascular deficit, the presence of foreign body, the presence of a compound or open fracture, and the duration of antibiotic administration. Patients have clearly developed gas gangrene after prophylactic administration of β‎-lactam antibiotics. Gas gangrene can develop from wounds contaminated with either vegetative organisms or spores. Antibiotics may be more effective in the former case since spores, until they germinate, are not affected by antibiotics. Metronidazole or clindamycin may be useful in patients who are hypersensitive to β‎-lactam antibiotics. Experimentally, active immunization against the α‎-toxin provides impressive protection against C. perfringens gas gangrene, but no active or passive vaccine is currently available.

Clostridial infections of the gastrointestinal tract

Necrotizing enterocolitis

Definition

Necrotizing enterocolitis is a fulminating clinical illness characterized by extensive necrosis of the intestinal mucosa and wall. Terms such as darmbrand (Germany), enteritis necroticans, pig bel (Papua New Guinea), or gas gangrene of the bowel describe geographic variants. Cases occur sporadically in adults or as epidemics in all ages. Necrotizing enterocolitis occurs in infants, and some of these cases have demonstrated clostridia in the wall of the intestine.

Aetiology

Gram’s staining of the necrotic mucosa and the bowel wall shows many Gram-positive bacilli that are typically identified as C. perfringens (C. welchii). Sporadic cases usually yield C. perfringens type A. However, in the German and especially in the Papua New Guinea outbreaks, there is substantial evidence implicating C. perfringens type C. Type C produces large amounts of β‎-toxin, which has lethal and necrotizing effects. Papua New Guinea highlanders have a high prevalence of antibodies to β‎-toxin; antibodies are rare in people who live where the disease is uncommon. Patients with pig bel have rising levels of antibodies to β‎-toxin, and specific passive or active immunization prevents disease. It is not clear whether exogenous human infection with these organisms occurs or whether the lesions are produced by the overgrowth of endogenous clostridia. Sweet potato, a local dietary staple, contains an inhibitor of trypsin. Combined with a low-protein diet this may impair the ability of the intestine to inactivate endogenously produced β‎-toxin. However, the methods used for roasting the pigs offer many opportunities for clostridial contamination.

History and physical examination

Sporadic cases in patients over 50 years of age or among those recovering from gastric surgery are regularly reported from Scandinavia, Europe, the United States of America, Australia, and the Middle East. Alternatively, epidemic outbreaks as described in post-war Germany and among the highlanders of Papua New Guinea follow ingestion of contaminated food or a dramatic change in eating habits. Severe intermittent abdominal pain is the first symptom and pain rapidly becomes continuous. Bloody diarrhoea and vomiting are common. Patients quickly develop tachycardia, followed by hypotension and evidence of multiorgan failure. On examination there is fever with abdominal distension, localized or diffuse tenderness, and reduced bowel sounds. A tender mass may be palpated. Following resolution of infection, malabsorption and partial small bowel obstruction may develop because of intestinal scarring.

Treatment and prevention

Patients with suspected pig bel should be treated with nasogastric suction and intravenous fluids. Pyrantel is given by mouth and the bowel rested by fasting. Benzylpenicillin, 1 MU, is given intravenously every 4 h and the patient observed for complications requiring surgery. Mild cases recover without surgical intervention, but if surgical indications are present the mortality ranges from 35 to 100%, in part due to perforation of the intestine. As pig bel continues to be a common disease in Papua New Guinea, consideration should be given to the use of a C. perfringens type C toxoid vaccine in local areas. Two doses spaced 3 to 4 months apart are preventive.

Clostridium perfringens food poisoning

Occurrence and clinical findings

In the United Kingdom and the United States of America, food poisoning caused by C. perfringens is the third most common type of food-borne illness. Meat and poultry are responsible for at least 90% of the outbreaks, which occur where food is prepared in large quantities. Two-thirds of the reported outbreaks are in schools, hospitals, factories, restaurants, or catering establishments, and in a typical outbreak 35 to 40 people are affected. An estimated 12 000 cases were associated with a single outbreak in 1969.

The circumstances surrounding an outbreak repeat themselves with monotonous regularity. A meat dish is prepared by stewing, braising, boiling, or steaming and this is allowed to stand at ambient temperatures for a period of 4 to 24 h. The food is served cold or after rewarming. Six to 12 h after eating the meal, people complain of cramping abdominal pain and then diarrhoea. Vomiting is unusual and fever inconsequential. Twelve to 24 h later the diarrhoea and pain have subsided. Fatal cases occur rarely; at autopsy they show severe enterocolitis.

Undoubtedly many cases of C. perfringens food poisoning occur at home but are not reported. Antibodies to the toxin mediating the symptoms are very common and it is likely that nearly everyone has experienced this disease once or more in their lifetime.

Aetiology

C. perfringens is an ubiquitous sporulating anaerobe with an unparalleled virtuosity for production of biologically significant toxins. The clinical effects of infection with any particular strain may depend largely on its toxin-producing capacity. Strains associated with food poisoning have several special characteristics. They are type A, although their production of α‎-toxin is variable; the organisms are often heat resistant to 100°C. Eighty-six per cent of food-poisoning strains produce a specific heat-labile enterotoxin. Toxin production in vitro is closely associated with sporulation rather than with the multiplication of vegetative cells. In vivo, toxin probably acts by damaging enterocyte membranes. Free enterotoxin has been detected in diarrhoeal stool after C. perfringens food poisoning. Antibody to enterotoxin increases after such episodes, and ingestion of 8 to 12 mg enterotoxin by volunteers produces abdominal pain and diarrhoea.

C. perfringens is a normal human faecal organism, is regularly found in the intestinal tract of domestic animals, often contaminates raw meat, and can be carried by flies. The distribution of enterotoxin-producing strains may be more restricted. However, surface contamination of meat with C. perfringens is common and subsequent rolling or grinding distributes these organisms throughout. Spores germinate and multiply to 106 to 107 cells/g in the anaerobic environment created when meat or meat gravy cools slowly or stands at ambient temperature. Reheating may not kill these cells and, when ingested, they multiply still further, sporulate, and release their toxin.

Enterotoxin-producing strains of C. perfringens may sometimes cause diarrhoea by means of overgrowth in the gut. Patients, usually elderly, can experience diarrhoea without known contact with contaminated food. The diarrhoea may be short lived or persist intermittently for several months. Colony counts of 108 to 1010/g of faeces are associated with the presence of high titres of free toxin. Previous antimicrobial treatment may encourage the overgrowth and the same strain has been found to cross-infect patients.

Further reading

Botulism

Arnon SS, et al. (2006). Human botulism immune globulin for the treatment of infant botulism. N Engl J Med, 354, 462–71.Find this resource:

Cherington M (2004). Botulism: update and review. Semin Neurol, 24, 155–63.Find this resource:

Chertow DS, et al. (2006). Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. JAMA, 296, 2476–79.Find this resource:

Fox CK, Keet CA, Strober JB (2005). Recent advances in infant botulism. Pediatr Neurol, 32, 149–54.Find this resource:

Lalli G, et al. (2003). The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol, 11, 431–7.Find this resource:

Sobel J (2009). Diagnosis and treatment of botulism: a century later, clinical suspicion remains the cornerstone. Clin Infect Dis, 48, 1674–5.Find this resource:

Gas gangrene

Aldape MJ, Bryant AE, Stevens DL (2006). Clostridium sordellii infection: epidemiology, clinical findings and current perspectives on diagnosis and treatment. Clin Infect Dis, 43, 1436–46.Find this resource:

Bryant AE, Stevens DL (1996). Phospholipase C and perfringolysin O from Clostridium perfringens upregulate ELAM-1 and ICAM-1 expression, and induce IL-8 synthesis in cultured human umbilical vein endothelial cells. Infect Immun, 64, 358–62.Find this resource:

Bryant AE, et al. (1993). Clostridium perfringens invasiveness is enhanced by effects of theta toxin upon PMNL structure and function. FEMS Immunol Med Microbiol, 7, 321–36.Find this resource:

Bryant AE, et al. (2000). Clostridial gas gangrene I: cellular and molecular mechanisms of microvascular dysfunction. J Infect Dis, 182, 799–807.Find this resource:

Bryant AE, et al. (2000). Clostridial gas gangrene II: phospholipase C-induced activation of platelet gpIIbIIIa mediates vascular occlusion and myonecrosis in C. perfringens gas gangrene. J Infect Dis, 182, 808–15.Find this resource:

Bryant AE, et al. (2006). Clostridium perfringens phospholipase C-induced platelet/leukocyte interactions impede neutrophils diapedesis. J Med Microbiol, 55, 495–504.Find this resource:

Centers for Disease Control (2000). Update: Clostridium novyi and unexplained illness among injecting-drug users. MMWR Morb Mortal Wkly Rep, 49, 543–5.Find this resource:

    Cohen AL, et al. (2007). Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstet. Gynecol, 110, 1027–33.Find this resource:

    Darke SG, King AM, Slack WK (1977). Gas gangrene and related infection: classification, clinical features and aetiology, management and mortality. A report of 88 cases. Br J Surg, 64, 104–12.Find this resource:

    Maclennan JD (1962). The histotoxic clostridial infections of man. Bacteriol Rev, 26, 177–276.Find this resource:

    Shouler PJ (1983). The management of missile injuries. J R Nav Med Serv, 69, 80–4.Find this resource:

    Stevens DL, Bryant AE (2005). Clostridial gas gangrene: clinical correlations, microbial virulence factors, and molecular mechanisms of pathogenesis. In: Proft T (ed) Microbial toxins: molecular and cellular biology, pp. 313–35. Horizon Bioscience, Norfolk, UK.Find this resource:

      Stevens DL, et al. (1993). Evaluation of therapy with hyperbaric oxygen for experimental infection with Clostridium perfringens. Clin Infect Dis, 17, 231–7.Find this resource:

      Stevens DL, et al. (2004). Immunization with the C-domain of alpha-toxin prevents lethal infection, localizes tissue injury, and promotes host response to challenge with Clostridium perfringens. J Infect Dis, 190, 767–73.Find this resource:

      Gastrointestinal infections

      Abrahao C, et al. (2001). Similar frequency of detection of Clostridium perfringens enterotoxin and Clostridium difficile toxins in patients with antibiotic-associated diarrhea. Eur J Clin Microbiol Infect Dis, 20, 676–7.Find this resource:

      Alfa MJ, et al. (2002). An outbreak of necrotizing enterocolitis associated with a novel clostridium species in a neonatal intensive care unit. Clin Infect Dis, 35, S101–S105.Find this resource:

      Bos J, et al. (2005). Fatal necrotizing colitis following a foodborne outbreak of enterotoxigenic Clostridium perfringens type A infection. Clin Infect Dis, 40, e78–e83.Find this resource:

      Fisher DJ, et al. (2005). Association of beta2 toxin production with Clostridium perfringens type A human gastrointestinal disease isolates carrying a plasmid enterotoxin gene. Mol Microbiol, 56, 747–62.Find this resource:

      Lawrence GW, et al. (1990). Impact of active immunisation against enteritis necroticans in Papua New Guinea. Lancet, 336, 1165–7.Find this resource:

      Li DY, et al. (2004). Enteritis necroticans with recurrent enterocutaneous fistulae caused by Clostridium perfringens in a child with cyclic neutropenia. J Pediatr Gastroenterol Nutr, 38, 213–15.Find this resource:

      Obladen M (2009). Necrotizing Enterocolitis – 150 Years of Fruitless Search for the Cause. Neonatology, 96, 203–10.Find this resource:

      Sobel J, et al. (2005). Necrotizing enterocolitis associated with Clostridium perfringens type A in previously healthy north American adults. J Am Coll Surg, 201, 48–56.Find this resource: