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Harrison’s Manual of Medicine



Other Clostridial Infections
Mixed Anaerobic Infections

EPIDEMIOLOGY   Tetanus, while preventable by immunization, has a worldwide distribution. In the U.S., most disease occurs in elderly unimmunized or incompletely immunized pts and follows an acute injury such as a puncture wound, abrasion, or laceration with exposure to soil.
PATHOGENESIS   Under conditions of low oxidation-reduction potential, germination and toxin production follow contamination of a wound with spores of Clostridium tetani. The toxin tetanospasmin is transported to the nerve cell body and migrates across the synapse to presynaptic terminals, blocking the release of inhibitory neurotransmitters. Rigidity results from increases in the resting firing rate of the alpha motor neuron with diminished inhibition.
CLINICAL MANIFESTATIONS   The median incubation period after injury is 7 d. The first symptoms are increased tone in the masseter muscles (trismus or lockjaw) followed by dysphagia, stiffness, or pain in the neck, shoulder, and back muscles. Contraction of facial muscles produces risus sardonicus, and contraction of back muscles causes an arched back (opisthotonos). Muscle spasms may be violent, may be provoked by even the slightest stimulation, and may threaten ventilation. Fever may or may not develop; mentation is unimpaired. Autonomic dysfunction commonly complicates severe cases. Complications can include pneumonia, fractures, muscle rupture, deep vein thrombophlebitis, pulmonary emboli, decubitus ulcer, and rhabdomyolysis. Neonatal tetanus develops in children born to unimmunized mothers after unsterile treatment of the umbilical cord stump.
DIAGNOSIS   The diagnosis of tetanus is made clinically. The organism frequently cannot be recovered from wounds of pts with tetanus and may be recovered from wounds of pts without tetanus.

Goals of treatment are to eliminate the source of toxin, neutralize unbound toxin, prevent muscle spasms, and provide support (especially respiratory) until after recovery. Pts should be admitted to a quiet room in intensive care. Antibiotic therapy is given to eradicate vegetative cells, the source of toxin. Although of unproven value, the use of penicillin G (10–12 million U qd IV for 10 d) has been recommended; metronidazole (500 mg q6h or 1 g q12h IV) is preferred by some experts on the basis of the latter drug’s excellent antimicrobial activity and a survival rate higher than that obtained with penicillin in one nonrandomized trial. Additional specific antimicrobial therapy should be given for active infection with other organisms. Human tetanus immune globulin (TIG) at a dose of 3000–6000 units IM should be given promptly to neutralize circulating and unbound toxin. Pooled IV immunoglobulin may be an alternative to TIG. Diazepam is used to treat muscle spasms; large doses (³250 mg/d) may be required. Mechanical ventilation and therapeutic paralysis with a nondepolarizing neuromuscular blocking agent may be required for severe spasms or laryngospasm. However, because prolonged paralysis after discontinuation of therapy with such agents has been described, both the need for continued therapeutic paralysis and the occurrence of complications should be assessed daily. Optimal therapy for sympathetic overactivity is not clear; labetalol, esmolol, clonidine, morphine sulfate, parenteral magnesium sulfate, and continuous spinal or epidural anesthesia have been used.
Pts must be actively immunized against tetanus, since natural disease does not induce immunity. The preventive regimen for adults is three doses of tetanus and diphtheria toxoids (Td), with the first and second doses administered IM 4–8 weeks apart and the third dose 6–12 months after the second. A booster dose is required every 10 years. For any wound, Td should be given if (1) the pt’s immunization status is unknown, (2) fewer than three doses have been given in the past, (3) more than 10 years have elapsed since the administration of three doses, or (4) the pt has received three doses of fluid (nonadsorbed) vaccine. For contaminated or severe wounds, a booster is given if more than 5 years have elapsed since immunization. In addition, TIG (250 mg IM) should be administered for all but clean, minor wounds if the pt’s immunization status is incomplete or unknown. Vaccine and TIG should be administered with separate syringes at separate sites.

EPIDEMIOLOGY   Botulism is caused by neurotoxins elaborated by Clostridium botulinum, an anaerobic gram-positive organism with subterminal spores. Human botulism occurs worldwide. Food-borne botulism is acquired from ingestion of food contaminated with preformed toxin—most commonly, home-canned food. Wound botulism develops when wounds, including those contaminated by soil, those of chronic IV drug users, and those related to cesarean delivery, are contaminated with C. botulinum. Infant botulism occurs when an infant ingests spores and toxin is elaborated in the intestine. Botulism of undetermined classification is produced in older children and adults by a mechanism similar to that described for infant botulism.
CLINICAL MANIFESTATIONS   Food-Borne Botulism   The incubation period for botulism is usually 18–36 h after ingestion of food containing toxin. Cranial nerve involvement marks the onset of symptoms, which usually consist of diplopia, dysarthria, and/or dysphagia. Paralysis is symmetric and descending and can lead to respiratory failure and death. Nausea, vomiting, and abdominal pain may precede or follow the onset of paralysis. Dizziness, blurred vision, dry mouth, and dry or sore throat are common. Fever usually is not documented. Ptosis is common; fixed or dilated pupils are noted in 50% of cases. The gag reflex can be suppressed, and deep tendon reflexes can be either normal or decreased. Paralytic ileus, severe constipation, and urinary retention are common.
Wound Botulism   The presentation of wound botulism is similar to that of food-borne disease except that the incubation period is longer (~10 d) and no GI symptoms develop.
DIAGNOSIS   The diagnosis of botulism must be suspected on clinical grounds in the context of an appropriate history. Conditions often confused with botulism include myasthenia gravis and Guillain-Barré syndrome. Definitive diagnosis is made by the demonstration of toxin in serum; however, the test may be negative despite infection and cannot be conducted in all laboratories. Other fluids that may yield toxin are vomitus, gastric fluid, and stool. Isolation of the organism from food is not diagnostic.

Pts should be monitored carefully, particularly for signs of respiratory failure. In food-borne illness, trivalent equine antitoxin (types A, B, and E) should be administered as soon as possible after laboratory specimens are collected. A repeat dose is probably not necessary but may be given after 2–4 h. Cathartics may be used unless there is ileus. Antibiotics are of unproven value. Wound botulism is treated with exploration and debridement of the wound and the administration of penicillin (to eradicate the organism) and equine antitoxin. Supportive treatment is undertaken for infant botulism. Antitoxin and management advice are available at any time from state health departments or the CDC (404-639-2206; emergency number, 404-639-2888).

PATHOGENESIS   Despite the isolation of clostridial species from many severe traumatic wounds, the incidence of serious infections due to these organisms is low. Tissue necrosis and a low oxidation-reduction potential appear to be essential to the development of serious disease. Clostridial disease is mediated by toxins.
CLINICAL MANIFESTATIONS   Food Poisoning   C. perfringens is the second or third most common cause of food poisoning in the U.S. Primary sources are recooked meats, meat products, and poultry. Symptoms develop 8–24 h after ingestion and include epigastric pain, nausea, and watery diarrhea lasting for 12–24 h. Fever and vomiting are uncommon.
Antibiotic-Associated Colitis   Strains of C. difficile that produce toxins detectable in the stool have been identified as the major cause of colitis in pts with antibiotic-associated diarrhea. Any antibiotic (including metronidazole and vancomycin, which are used to treat the infection) can cause this syndrome, which is defined as diarrhea that has no other cause and that develops during antibiotic treatment or within 4 weeks of its discontinuation. Diarrhea is usually watery, voluminous, and without gross blood or mucus. Most pts have abdominal cramps and tenderness, fever, and leukocytosis with a marked left shift. Four categories of diarrhea have been based on the appearance of the colon: (1) normal colonic mucosa; (2) mild erythema with some edema; (3) granular, friable, or hemorrhagic mucosa; and (4) pseudomembrane formation.
Suppurative Deep-Tissue Infection   Clostridia are recovered, with or without other organisms, in a variety of conditions with severe local inflammation but usually without systemic signs attributable to toxins. These conditions include intraabdominal sepsis, empyema, pelvic abscess, SC abscess, frostbite with gas gangrene, infection of stumps in amputees, brain abscess, prostatic abscess, perianal abscess, conjunctivitis, infection of renal cell carcinomas, and infection of aortic grafts. At least 50% of cases of emphysematous cholecystitis are caused by clostridial species.
Skin and Soft Tissue Infections
1.   Localized infections: Localized clostridial infections of skin and soft tissues tend to be indolent and devoid of systemic signs of toxicity, pain, and edema. Typical examples include cellulitis, perirectal abscesses, and diabetic foot ulcers. Gas may be present in the wound and the immediate surrounding tissues but is not present intramuscularly. A form of suppurative myositis is found in heroin addicts.
2.   Spreading cellulitis and fasciitis with systemic toxicity: This syndrome is abrupt in onset, with rapid spread of suppuration and gas through fascial planes. Myonecrosis is absent, but overwhelming toxemia develops and can be rapidly fatal. On examination, crepitance is prominent, but there is little localized pain. This syndrome is most common among pts with carcinoma, especially of the sigmoid or cecum. Massive hemolysis may be present.
3.   Clostridial myonecrosis (gas gangrene): Clostridial myonecrosis occurs in deep necrotic wounds, often following trauma or surgery. The incubation period is short—always ❤ d, often <24 h. In contrast to spreading cellulitis, gas gangrene begins with sudden pain in the region of the wound. Local swelling and edema follow, accompanied by a thin hemorrhagic exudate. Toxemia, hypotension, renal failure, and crepitance ensue; the pt often has a heightened awareness of surroundings before death.
4.   Clostridial bacteremia and sepsis: Clostridial bacteremia may occur transiently without clinical sepsis. The most common predisposing foci are the intestinal and biliary tracts and the uterus, although half of pts have an unrelated illness. Often, fever has resolved and the pt’s clinical condition has improved by the time blood cultures become positive; thus the pt must be assessed clinically rather than simply treated on the basis of the culture result. Clostridial sepsis is uncommon but is almost always fatal and follows clostridial infections of the uterus (esp. after septic abortion), colon, or biliary tract. Pts develop sepsis 1–3 d after abortion, with fever, chills, malaise, headache, severe myalgias, abdominal pain, nausea, vomiting, and (occasionally) diarrhea. Oliguria, hypotension, jaundice, and hemoglobinuria secondary to hemolysis develop rapidly. Like those with gas gangrene, pts with clostridial septicemia exhibit increased alertness and apprehension. In cases with bowel or biliary-tree sources, localized infection may not develop. Pts have chills and fever, and 50% have intravascular hemolysis. In pts with malignancy, C. septicum causes rapidly fatal septicemia with fever, tachycardia, hypotension, abdominal pain, nausea, and vomiting. Only 20–30% of these pts develop hemolysis; death may occur within 12 h.
DIAGNOSIS   The diagnosis of clostridial infection must be based primarily on clinical findings because the mere presence of clostridia in a wound does not necessarily indicate severe disease. The detection of gas by radiography provides a clue, but gas is sometimes documented in mixed anaerobic-aerobic infections as well. Clostridial myonecrosis can be diagnosed by examination of a frozen section of muscle. Pts may have hemolytic anemia, hemoglobinuria, and disseminated intravascular hemolysis. C. difficile–associated colitis is most often diagnosed by ELISA for toxin A. Tissue culture, with appropriate neutralization by antitoxin, is the “gold standard” but requires a tissue culture facility.

Until recently, penicillin G was the antibiotic of choice for clostridial infections of tissues. Studies in experimental models of infection demonstrated that protein synthesis inhibitors may be preferable to cell wall–active drugs. In these studies clindamycin treatment enhanced survival more than penicillin therapy, and the combination of clindamycin and penicillin was superior to penicillin alone. For severe clostridial sepsis, clindamycin may be used at a dose of 600 mg IV q6h in combination with high-dose penicillin (3–4 million U IV q4h). A number of other antibiotics can be considered in the case of penicillin allergy, but the sensitivity of the infecting strain to these alternative drugs should be evaluated. Drainage of infected sites or surgery is a mainstay of therapy for clostridial myonecrosis. Amputation may be required for rapidly spreading infection in a limb; repeated debridement is necessary for abdominal wall myonecrosis; and hysterectomy must be performed for uterine myonecrosis. C. difficile enterocolitis is treated by discontinuation of the offending antibiotic. Treatment with metronidazole (500 mg tid PO) or vancomycin (125 mg qid PO) for 10–14 d shortens the duration of symptoms. The dose of vancomycin may be increased to 500 mg qid PO in severe cases. If pts fail to respond to PO metronidazole after 48 h, it is reasonable to switch to vancomycin. Relapses are much more common than treatment failures. Multiple relapses have been treated with tapering doses of vancomycin or cholestyramine or by repopulating the colon with normal flora via Saccharomyces boulardii administration.

CLINICAL MANIFESTATIONS   Head and Neck   Infections of the head and neck that involve anaerobes include gingivitis (trench mouth, Vincent’s stomatitis), pharyngeal infections (including Ludwig’s angina), fascial infections in which oropharyngeal organisms from mucous membranes or sites of dental manipulation spread to potential spaces in the head and neck, sinusitis, and otitis. Complications of these infections include osteomyelitis of the skull or mandible, intracranial infection (such as brain abscess), mediastinitis, pleuropulmonary infection, and suppurative thrombophlebitis of the internal jugular vein (Lemierre’s syndrome), often due to Fusobacterium spp.
Central Nervous System   When sought by optimal bacteriologic methods, anaerobes are found in 85% of brain abscesses. Anaerobic gram-positive cocci predominate; fusobacteria and Bacteroides spp. are next most common.
Pleuropulmonary Sites   Four clinical syndromes are associated with anaerobic pleuropulmonary infection produced by aspiration: aspiration pneumonia, necrotizing pneumonia, lung abscess, and empyema. Aspiration pneumonia generally develops slowly, with low-grade fever, malaise, and sputum production, in pts with a predisposition for aspirating. Necrotizing pneumonia can be indolent or fulminating and is characterized by numerous small abscesses. Pts with lung abscess typically present with a syndrome of fever, chills, malaise, weight loss, and foul-smelling sputum developing over a period of weeks. Empyema is a manifestation of long-standing anaerobic pulmonary infection and has a clinical presentation similar to that of lung abscess. Pts may also have pleuritic chest pain and chest wall tenderness. Empyema can result from subdiaphragmatic extension.
Intraabdominal Sites   See Chap. 81.
Pelvic Sites   Anaerobes are encountered frequently in tubo-ovarian abscess, septic abortion, pelvic abscess, endometritis, and postoperative wound infection, especially after hysterectomy.
Skin and Soft Tissue   Anaerobes are sometimes isolated in cases of crepitant cellulitis, synergistic cellulitis, gangrene, necrotizing fasciitis, cutaneous abscess, rectal abscess, and axillary sweat gland infection (hidradenitis suppurativa). Synergistic (Meleney’s) gangrene is a progressive, exquisitely painful skin process, with erythema, swelling, induration, and a central zone of necrosis. Anaerobic cocci and Staphylococcus aureus are common pathogens. While necrotizing fasciitis is usually attributed to group A streptococci, it can be caused by anaerobes, including Peptostreptococcus and Bacteroides spp. Fournier’s gangrene involves cellulitis of the genital and perineal areas.
Bones and Joints   Anaerobic osteomyelitis usually develops by extension of a soft tissue infection. Septic arthritis often is not polymicrobial and can arise from hematogenous seeding; the most common isolates are Fusobacterium spp.
Bacteremia   Bacteroides fragilis is the most common anaerobic isolate from the blood. The clinical presentation of anaerobic bacteremia may be quite similar to that of sepsis due to aerobic gram-negative bacilli. Septic thrombophlebitis and septic shock are uncommon. Mortality increases with the age of the pt.
DIAGNOSIS   When infections develop in proximity to mucosal surfaces normally harboring an anaerobic flora, anaerobes should be considered as potential etiologic agents. The presence of gas in tissues is highly suggestive but not diagnostic. Cultures of suspected sites should be processed for anaerobes, usually in a transport medium, and should be conveyed rapidly to the laboratory. Since laboratory isolation of the pathogen(s) can be time-consuming, diagnosis must sometimes be presumptive.

Successful therapy for anaerobic infection involves a combination of appropriate antibiotics, surgical resection, and drainage. If anaerobic infection is suspected, effective empirical treatment can nearly always be administered, since patterns of antimicrobial susceptibility are usually predictable. Antibiotics active against Bacteroides, Prevotella, Porphyromonas, and Fusobacterium spp. are listed according to their predicted activity in Table 95-1. Although most mild oral anaerobic infections respond to penicillin, serious infections should be treated as if penicillin-resistant organisms are involved. Clindamycin is superior in the treatment of lung abscess. For infections below the diaphragm, agents active against Bacteroides spp. (frequently penicillin- resistant) are listed under group 1 in Table 95-1. Recommended doses for commonly used group 1 drugs are listed in Table 95-2. Anaerobic infections that have failed to respond to treatment should be reassessed, with a consideration of antibiotic resistance, of the need for additional drainage, and of superinfection with aerobic organisms. Since most infections involving anaerobes are bacteriologically mixed and involve aerobic bacteria, therapy must also be directed at those organisms.

Table 95-1 Antimicrobial Therapy for Infections Involving Commonly Encountered Anaerobic Gram-Negative Rods

Table 95-2 Doses and Schedules for Treatment of Serious Infections due to Commonly Encountered Anaerobic Gram-Negative Rods


For a more detailed discussion, see Abrutyn E: Tetanus, Chap. 143, p. 918; Abrutyn E: Botulism, Chap. 144, p. 920; Kasper DL, Zaleznik DF: Gas Gangrene, Antibiotic-Associated Colitis, and Other Clostridial Infections, Chap. 145, p. 922; and Kasper DL: Infections due to Mixed Anaerobic Organisms, Chap. 167, p. 1011, in HPIM-15.



  1. Management of non-clostridial gas gangrene of the neck is a challenge not just for the thoracic surgeon, but additionally for the infectious disease physician. For the surgeon, proximity of the great vessels and other sensitive structures makes for a high-risk surgery. For the physician, prompt but accurate institution of empirical therapy while waiting for the bacterial culture reports is no less than a decent challenge. Notably, many clinicians (including us) are unconvinced about the worth of hyperbaric oxygen therapy (while the possibility of clostridial infection still remains) due to inconclusive research findings.

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