BACTERIAL INFECTIONS CAUSED BY CLOSTRIDIA

The pathogenic species, in the vegetative form, produce various tissue-destructive and neural exotoxins that have been biochemically and serologically delineated. Clostridium sp are found in normal flora, particularly in the colon. Clostridia may become pathogenic when the tissues show a lowered oxidation-reduction potential, a high lactate concentration, and a low pH. Such an abnormal anaerobic environment may develop with primary arterial insufficiency or after severe penetrating or crushing injuries. The deeper and more severe the wound, the more prone the patient is to anaerobic infection, especially if even minimal contamination by foreign particles has occurred.

Clostridial infection is increasingly a nosocomial problem, particularly in postoperative and immunocompromised patients. Severe clostridial sepsis may complicate intestinal perforation and obstruction. 

Tetanus (Lockjaw)

An acute infectious disease caused by Clostridium tetani, characterized by intermittent tonic spasms of voluntary muscles; spasm of the masseters accounts for the name "lockjaw."

Epidemiology and Pathogenesis

Worldwide, tetanus causes 50,000 deaths annually. In the USA, elderly patients are especially prone to developing tetanus, as are patients with burns, surgical wounds, or a history of injecting drug abuse. Infection may also develop postpartum in the uterus (maternal tetanus) and in a newborn's umbilicus (tetanus neonatorum). Clinical disease does not confer immunity. Tetanus is a preventable disease of great significance, particularly the neonatal form in developing countries.

The manifestations of tetanus are caused by an exotoxin (tetanospasmin) elaborated by C. tetani, a slender, motile, gram-positive, anaerobic, spore-forming bacillus. Spores remain viable for years and can be found in soil and animal feces. Tetanus may follow trivial or even inapparent wounds if the oxygen content in the injured tissues is low.

The toxin may enter the CNS along the peripheral motor nerves or may be bloodborne to the nervous tissue. The tetanospasmin binds to the ganglioside membranes of nerve synapses, blocking release of the inhibitory transmitter from the nerve terminals and thereby causing a generalized tonic spasticity, usually superimposed with intermittent tonic convulsions. Once fixed, the toxin cannot be neutralized.

Symptoms and Signs

The incubation period ranges from 2 to 50 days (average, 5 to 10 days). The most frequent symptom is jaw stiffness. Other symptoms include difficulty in swallowing; restlessness; irritability; stiff neck, arms, or legs; headache; fever; sore throat; chills; and tonic spasms. Later, the patient has difficulty opening his jaws (trismus); facial muscle spasm produces a characteristic expression with a fixed smile and elevated eyebrows (risus sardonicus). Rigidity or spasm of abdominal, neck, and back muscles--even opisthotonos--may occur. Sphincteral spasm causes urinary retention or constipation. Dysphagia may interfere with nutrition. Characteristic painful, generalized tonic spasms with profuse sweating are precipitated by minor disturbances such as a draft or noise or by jarring the bed. The patient's mental status is usually clear, but coma may follow repeated spasms. During generalized spasms, the patient is unable to speak or cry out because of chest wall rigidity or glottal spasm. This also interferes with respiration, causing cyanosis or fatal asphyxia. The immediate cause of death may not be apparent.

The patient's temperature is moderately elevated except when a complicating infection, such as pneumonia, is present. Respiratory and pulse rates are increased. Reflexes are often exaggerated. Moderate leukocytosis is usual.

Localized tetanus can occur, with spasticity of a group of muscles near the wound but without trismus. The spasticity may persist for weeks. Cephalic tetanus, more common in children, is associated with chronic otitis media; the incidence is greatest in Africa and India. All cranial nerves can be involved, especially the 7th. Cephalic tetanus may become generalized. Bilateral perceptual deafness has occurred after tetanus in a newborn.

Diagnosis

A history of a wound in a patient with muscle stiffness or spasm is a clue. Tetanus can be confused with meningoencephalitis of bacterial or viral origin, but the combination of an intact sensorium, normal CSF, and muscle spasms suggests tetanus. Trismus must be distinguished from peritonsillar or retropharyngeal abscess or another local cause. The phenothiazines can induce a tetanus-like rigidity.

C. tetani sometimes can be cultured from the wound, but its absence does not negate the diagnosis.

Prognosis

Tetanus has a worldwide mortality rate of 50%; mortality is highest in young and old patients and in drug abusers. The prognosis is poorer if the incubation period is short and symptoms progress rapidly or if treatment is delayed. The course tends to be milder when there is no demonstrable focus of infection.

Prophylaxis

Primary immunization against tetanus with either the fluid or adsorbed toxoid is superior to giving antitoxin at the time of injury. Routine diptheria, tetanus, pertussis (DTP) immunization and booster recommendations are discussed under Childhood Immunizations. Immunization in a pregnant woman produces both active and passive immunity in the fetus and should be given at a gestational age of 5 to 6 mo with a booster at 8 mo. Passive immunity develops with maternal toxoid given before a gestational age of 6 mo.

At the time of injur, patients who have received tetanus toxoid within 5 yr need no additional dose. Those whose last immunization was > 5 yr ago should receive a booster of 0.5 mL tetanus toxoid. Those who have never received primary immunization should get 250 to 500 U of tetanus immune globulin. (A larger dose is needed for more serious wounds.) At the same time, the first of three 0.5-mL doses of adsorbed tetanus toxoid should be given sc or IM at another injection site. The 2nd and 3rd doses of toxoid are given at monthly intervals. Tetanus antitoxin 3000 to 5000 U IM should be used only if tetanus immune globulin is not available. (Caution: Tetanus antitoxin is made from horse or bovine serum so take into account the Hypersensitivity to Drugs  for necessary precautions.)

Treatment

Therapy involves maintaining an adequate airway; ensuring early and adequate use of human immune serum globulin; neutralizing nonfixed toxin; preventing further toxin production; providing sedation; controlling muscle spasm, hypertonicity, fluid balance, and intercurrent infection; and providing continuous nursing care.

General principles: The patient should be kept in a quiet room. In moderate or severe cases, the patient should be intubated. Tracheotomy should be performed when intubation is expected to be prolonged--ie, more than 7 days. Mechanical ventilation may be necessary; it is essential when neuromuscular blockade is required to control muscle spasms that impair respirations. IV hyperalimentation avoids the hazard of aspiration secondary to feeding by gastric tube. Since constipation is usual, stools should be kept soft; a rectal tube may help to control distention. Bladder catheterization is required if urinary retention occurs. Chest physiotherapy, frequent turning, and forced coughing are essential to prevent pneumonia. Analgesia with narcotics is often needed. Patients with protracted tetanus may manifest a very labile and overactive sympathetic nervous system, including periods of hypertension, tachycardia, and myocardial irritability. Ongoing monitoring is indicated, and alfa- or beta-blockers (eg, propranolol, labetalol) or bethanidine may be needed. The patient should receive a full immunizing course of toxoid after recovery.

Antitoxin: The benefit of antiserum depends on how much tetanospasmin is already bound to the synaptic membranes. For adults, a single IM injection of 3000 U of tetanus immune globulin is generally recommended, with a range of 1,500 to 10,000 U, depending on wound severity. Because the patient's serum antitoxin level is not well maintained and a considerable risk of serum sickness exists, antitoxin of animal origin is far less preferable. If horse serum must be used, however, the usual dose is 50,000 U IM or IV (Caution: Hypersensitivity to Drugs). If necessary, immune globulin or antitoxin can be injected directly into the wound, but this is not as important as proper wound care.

Wound care: Because dirt and dead tissue promote multiplication of C. tetani, prompt, thorough debridement--especially of deep puncture wounds--is essential. Penicillin and the tetracyclines are effective against C. tetani but are not substitutes for adequate debridement and immunization.

Management of muscle spasms: The benzodiazepines, chlorpromazine, and short-acting barbiturates help reduce excessive neuroexcitability and may help muscle spasm. Diazepam can help control seizures, counter muscle rigidity, and induce sedation. The dosage range is variable and requires meticulous titration and close observation. The most severe cases may require 10 to 20 mg IV q 3 h. Less severe cases can be controlled with 5 to 10 mg po q 2 to 4 h. Dosage in infants > 30 days is 1 to 2 mg IM or IV, slowly repeated q 3 to 4 h as necessary. In children > 5 yr, 5 to 10 mg IM or IV is repeated q 2 to 4 h. Diazepam may not preclude reflex spasms, and effective respiration may require neuromuscular blockade with a curariform agent such as pancuronium bromide or vecuronium bromide. (d-Tubocurarine, in contrast to pancuronium bromide, may manifest histamine release with unwanted hypotension.) Use of pyridoxine in reducing spasms and even mortality in neonatal tetanus has been very limited but encouraging.

Antibiotics: Although the role of antibiotic therapy is minor in contrast to wound debridement and general support, either penicillin G 2 million U IV q 6 h or tetracycline 500 mg IV q 6 h should be given for 10 days. Children should be given penicillin G 100,000 U/kg/day in 4 to 6 doses or tetracycline 30 to 40 mg/kg/day in 4 divided doses (in children > 7 yr; tetracycline should be avoided in children < 7 yr). Metronidazole 30 mg/kg/day in 4 divided doses is also effective. A larger amount of ischemic tissue warrants a higher dosage in all patients. Neither antibiotic is likely to prevent secondary infections (eg, pneumonia); if they develop, specimens for culture should be taken, sensitivity tests performed, and an appropriate antibiotic given if necessary.

Clostridial Uterine Infection

Clostridial infections can cause suppurative tubo-ovarian and uterine abscess without evident toxicity. Serious uterine infection may be a complication of septic abortion; rarely, it follows relatively uncomplicated pelvic surgery or childbirth. The patient is typically febrile and in a toxic state, the lochia is foul-smelling, and the uterus is tender. Gas sometimes escapes through the cervix. Hemolytic anemia may develop as a result of clostridial septicemia and the effect of exotoxin lecithinase on the RBC membrane. With severe hemolysis and coexisting toxicity, acute renal failure can occur. The mortality rate is then about 50%.

Early diagnosis requires a high index of suspicion. Early and repeated Gram stains and cultures of the lochia and blood are indicated, although C. perfringens occasionally can be isolated from the healthy vagina and lochia. X-rays may show local gas production.

Treatment is debridement by curettage and use of penicillin G 20 million U/day for at least 1 wk. Hysterectomy may be necessary and can be lifesaving if debridement is insufficient. If acute tubular necrosis develops, renal dialysis is needed. The usefulness of hyperbaric 02 has not been established (see below).

Clostridial Wound Infections 

Clostridial wound infections may occur as a contained local cellulitis, local or spreading myositis, or, most seriously, progressive myonecrosis (gas gangrene). Infection develops hours or days after injury, usually in an extremity after severe crushing or penetrating trauma devitalizes tissue. Similar spreading myositis or myonecrosis may occur in operative wounds, particularly in patients with underlying occlusive vascular disease. 

Anaerobic wound infections, particularly those due to Clostridium sp, can progress from initial injury through the stages of cellulitis to myositis to myonecrosis with shock, toxic delirium, and finally death within one to several days. 

Clostridial cellulitis (anaerobic cellulitis) occurs as a localized infection in a superficial wound, usually >= 3 days after initial injury. Infection may spread extensively along fascial planes, often with evident crepitation and abundant bubbling of gas, but toxicity is much less severe than with extensive myonecrosis. Bullae frequently are evident with foul-smelling, serous, brown exudate. Discoloration and gross edema of the extremity are rare. 

Clostridial infections associated with primary vascular occlusion of an extremity rarely extend beyond the line of demarcation or progress to severe toxic myonecrosis. 

An initially localized deep clostridial myositis spreads rapidly. Toxins produce an anaerobic environment, with edema, pain, gas, and subsequent myonecrosis, often with dramatic progression over a period of hours. In myonecrosis (gas gangrene), the exudate is serous and brown but not necessarily foul-smelling. In about 80% of cases, gas crepitation can be felt late in the course of disease. The wound site may be pale initially, but it becomes red or bronze and finally turns blackish green. The patient's condition becomes progressively toxic; shock and renal failure occur, although the patient often remains alert until the terminal stage. Unlike in clostridial uterine infection, septicemia and overt hemolysis are rare in gas gangrene of the extremities, even in terminally ill patients. 

Whenever massive hemolysis occurs, mortality of 70 to 100% can be expected in the presence of acute renal failure and septicemia. Early suspicion and intervention are essential. Anaerobic cellulitis uniformly responds to treatment; however, established and progressive myositis with an associated systemic toxemia has a mortality rate of >= 20%. 

Diagnosis 

Although localized cellulitis, myositis, and spreading myonecrosis may be distinct enough to permit clinical differentiation and appropriate treatment, diagnosis often requires thorough surgical wound exploration and visual evaluation of tissues. For example, in myonecrosis, muscle tissue is observed to be necrotic. The affected muscle is a lusterless pink, then deep red, and finally gray-green or mottled purple. X-rays may show local gas production, and CT and MRI can help delineate the extent of gas and necrosis. 

Wound exudate should be cultured for anaerobic and aerobic organisms; clostridia may be isolated in pure culture or associated with other anaerobes, aerobes, or both. Smears show gram-positive clostridia. Typically, few polymorphonuclear leukocytes are found in the exudate and free fat globules may be demonstrated with Sudan stain. Many wounds, particularly if open, are contaminated with both pathogenic and nonpathogenic clostridia without evident invasive disease. The significance of such a finding must be determined clinically. 

Differential Diagnosis 

Other anaerobic and aerobic bacteria, including members of the family Enterobacteriaceae and of Bacteroides, Streptococcus, and Staphylococcus sp, alone or mixed, frequently cause clostridia-like severe cellulitis, extensive fasciitis, or gas gangrene in traumatic and postoperative wounds. If polymorphonuclear leukocytes are abundant and the smear shows many chains of cocci, an anaerobic streptococcal or staphylococcal infection should be suspected. Abundant gram-negative bacilli may indicate infection with one of the Enterobacteriaceae or a Bacteroides sp (see also Mixed Anaerobic Infections, below). Detection of specific antigenic toxins in the wound or blood is useful only in the rare case of botulism acquired through a wound. Clostridia may also be present but inconsequential. 

Treatment 

Treatment is determined by severity and locale. An incidental finding of clostridia on culture without clinical evidence of anaerobic infection does not require treatment. However, when clinical infection is present, rapidly initiated empiric antibiotic intervention is mandatory. 

Thorough drainage and debridement are often more important than antibiotics. Penicillin G remains the drug of choice against clostridia; 10 to 20 million U/day IV should be given immediately for severe cellulitis and myonecrosis. Although resistance is rare, relative resistance has occurred with some strains of C. ramosum. Metronidazole is equivalently effective in treating clostridial infection. While chloramphenicol and metronidazole are active against most anaerobic bacteria, including clostridia, some strains of the latter are resistant to erythromycin, tetracycline, and clindamycin. Early use of broad-spectrum antibiotics (eg, ticarcillin combined with clavulanate potassium or ampicillin combined with sulbactam) is appropriate when other anaerobes and aerobes are present. A 3rd-generation cephalosporin or clindamycin in combination with an aminoglycoside is appropriate for some mixed clostridial infections, but these antibiotics are relatively less active, and resistance to aminoglycosides occurs with clostridia. 

For wound botulism, early administration of specific or polyvalent antitoxin (see Botulism) is valuable. Hyperbaric O2 therapy may be helpful in extensive myonecrosis, particularly in extremities, as a supplement to antibiotics and surgery. 

Hyperbaric O2 therapy seems to have potential to salvage tissue and lessen mortality and morbidity if started early. 

Necrotizing Enteritis 

Inflammation of the small and large bowels caused by C. perfringens. 

In addition to C. perfringens food poisoning, clostridia occasionally cause acute inflammatory, sometimes necrotizing, disease in the small and large bowels. Such clostridial enterotoxemias can occur as isolated cases or as outbreaks, and some appear due, at least in part, to contaminated meat. A similar process may occur in patients being treated for leukemia. Pigbel, which occurs in New Guinea, presumably results from eating pork contaminated by C. perfringens type C; it varies from mild diarrhea to fulminant toxemia with dehydration, causing shock and sometimes death. Newborns and young children seem to be at greater risk than adults. An association with anorexia nervosa in older children has been made. An experimental toxoid vaccine has been developed but is not available commercially. Necrotizing enteritis occurs in populations with protein deprivation, poor food hygiene, episodic meat feasting, and staple diets containing trypsin inhibitors, such as in New Guinea, parts of Africa, Central and South America, and Asia. 

Neonatal necrotizing enterocolitis (NEC), which occurs in neonatal intensive care units, may be caused by C. perfringens, C. butyricum, and C. difficile, although the role of these organisms needs further study (see Necrotizing Enterocolitis). 

C. difficile-Induced Diarrhea 

C. difficile, the proximate cause of antibiotic-associated colitis (see also Ch. 29), is an increasingly recognized cause of nosocomial diarrhea. C. difficile-induced diarrhea occurs both alone and in limited outbreaks and is transmitted from person to person. It occurs in up to 8% of hospitalized patients and is responsible for 20 to 30% of nosocomial diarrheas. Extremes of age, severe underlying disease, prolonged hospital stay, and living in a nursing home are risk factors. 

Infection produces a cytotoxin and an enterotoxin. Antibiotic-induced changes in the GI flora are the dominant predisposing host factor. The natural history varies from an asymptomatic carrier state, particularly in infants and the elderly, to a severe necrotizing colitis. Limited tissue dissemination occurs rarely, as does sepsis and acute abdomen. Semiformed (not liquid) stool, fecal leukocytes, and prior cephalosporin use are typical. Asymptomatic patients colonized with C. difficile in their stools outnumber symptomatic patients 3:1. Reactive arthritis has been reported after C. difficile-induced diarrhea. 

Diagnosis is generally made by assaying for C. difficile toxin in stool. A single sample is usually adequate, but repeat samples should be submitted when suspicion is high and the first sample is negative. Infection control measures are vital to reduce the spread of C. difficile from health care workers to patients and between patients. Molecular epidemiologic types of DNA patterns can assist in determination of clonal spread. Reduction of clindamycin usage hospital-wide has reduced the incidence. Relapses can occur in 15 to 20% of patients. 

Oral metronidazole 250 to 500 mg q 6 h is the therapy of choice. If the patient does not respond or relapses, oral metronidazole as above can be repeated for 21 days, or oral vancomycin 125 to 500 mg q 6 h for 10 days may be given. Some patients require bacitracin 500 mg po q 6 h for 10 days, cholestyramine resin, or Saccharomyces boullardii yeast. For patients failing all treatments, anecdotal reports support fecal enema (an enema with feces from an uninfected donor to replace normal colonic flora) for eradicating C. difficile colitis. A few patients have required total colectomy for cure. 

ACTINOMYCOSIS

A chronic infectious disease caused by Actinomyces israelii, characterized by multiple draining sinuses.

Etiology 

The causative anaerobic, gram-positive microorganisms, species of Actinomyces or Propionobacterium (most commonly A. israelii), are often present comensally on the gums, tonsils, and teeth. However, many, if not most infections are polymicrobial, with other bacteria (oral anaerobes, staphylococci, streptococci, or Enterobacteriaceae) frequently cultured from lesions. Actinomycosis most often occurs in adult males. In the cervicofacial (lumpy jaw) form, the most common portal of entry is decayed teeth; in the thoracic form, pulmonary disease results from aspiration of oral secretions; in the abdominal form, disease presumably results from a break in the mucosa of a diverticulum, the appendix, or during trauma; in a localized pelvic form, actinomycosis is a complication of certain types of intrauterine device (IUD) contraceptives. Spread from primary sites occurs rarely, presumably by hematogenous spread from primary sites of infection. 

Symptoms and Signs 

The characteristic lesion is an indurated area of multiple, small, communicating abscesses surrounded by granulation tissue. Tissue lesions tend to form sinus tracts that communicate to the skin and drain a purulent discharge containing yellow sulfur granules. Infections spread to contiguous tissue, but only rarely hematogenously. Other anaerobic bacteria are usually also present. 

The cervicofacial form (lumpy jaw) usually begins as a small, flat, hard swelling, with or without pain, under the oral mucosa or the skin on the neck, or as a subperiosteal swelling of the jaw. Subsequently, areas of softening appear and develop into sinuses and fistulas with a discharge that contains the characteristic sulfur granules (rounded or spherical, usually yellowish, granules up to 1 mm in diameter). The cheek, tongue, pharynx, salivary glands, cranial bones, meninges, or brain may be affected, usually by direct extension. 

In the abdominal form, the intestines (usually the cecum and appendix) and the peritoneum are infected. Pain, fever, vomiting, diarrhea or constipation, and emaciation are characteristically present. One or more abdominal masses with signs of partial intestinal obstruction appears. Draining sinuses and intestinal fistulas may develop and extend to the external abdominal wall. 

In the thoracic form, lung involvement resembles TB. Extensive invasion may occur before chest pain, fever, and productive cough appear. Perforation of the chest wall, with chronic draining sinuses, may result. 

In the generalized form, infection spreads hematogenously to the skin, vertebral bodies, brain, liver, kidney, ureter, and (in women) pelvic organs. A long list of diverse symptoms of infection, such as back pain, headache, abdominal discomfort, and lower abdominal pain, may occur related to any of these sites. 

A local pelvic form may occur, particularly in women. Symptoms include vaginal discharge along with pelvic or lower abdominal pain. 

Diagnosis 

Diagnosis is based on symptoms, x-ray findings, and identification of A. israelii in sputum, pus, or biopsy specimen. In pus or tissue, the microorganism appears as tangled masses of branched and unbranched wavy filaments or as the distinctive sulfur granules. These consist of a central mass of tangled bacterial filaments, pus cells, and debris, with a midzone of interlacing filaments surrounded by an outer zone of radiating, club-shaped, hyaline and refractive filaments that take the eosin stain in tissue but are positive on Gram stain. 

Nodules in any location may simulate malignant growths. Lung lesions must be distinguished from those of TB and neoplasms. Most abdominal lesions occur in the ileocecal region and are difficult to diagnose, except during laparotomy or when draining sinuses appear in the abdominal wall. Aspiration liver biopsy should be avoided because it can produce a persistent sinus. A tender, palpable mass suggests appendiceal abscess or regional enteritis. 

Prognosis and Treatment 

The disease is slowly progressive. Prognosis relates directly to early diagnosis; it is most favorable in the cervicofacial form and progressively worse in the thoracic, abdominal, and generalized forms, especially if the CNS is involved. The course depends on the extent of pelvic infection and the duration before diagnosis. 

Most patients respond to prolonged courses of antibacterial therapy, but usually slowly because of extensive tissue induration and relatively avascular fibrosis. Therefore, treatment must be continued for at least 8 wk and occasionally for >= 1 yr until after signs and symptoms have resolved. Extensive and repeated surgical procedures may be required. Sometimes, small abscesses need to be aspirated, large ones drained, or fistulas excised surgically. High doses of penicillin G, usually 12 to 18 million U/day IV, are usually given first and are generally curative. Oral penicillin V (1 g qid) may be substituted after about 2 to 6 wk. Tetracycline 500 mg po q 6 h may be given instead of penicillin. Minocycline, clindamycin, or erythromycin also have been successful in some cases. Treatment must be continued for several weeks after apparent cure. Treatment regimens may be broadened to cover other pathogens cultured from lesions. Anecdotal reports have suggested that hyperbaric oxygen therapy might have been useful in selected cases.

MIXED ANAEROBIC INFECTIONS 

Hundreds of species of nonsporulating anaerobes are part of the normal flora of the skin, mouth, intestinal tract, and vagina. If this commensal relationship is disrupted (eg, by surgical or other trauma, poor blood supply, tissue necrosis), a few of these species can cause infections associated with high morbidity and mortality. After entry by this route, organisms can spread hematogenously to distant sites. Because aerobic and anaerobic bacteria frequently are found in the same infected site, infections may be mixed and the anaerobes may be overlooked unless appropriate procedures for isolation and culture are used. Anaerobes can be the major cause of infection in the pleural spaces and the lungs; in intra-abdominal, gynecologic, CNS, upper respiratory tract, and cutaneous diseases; and in bacteremia. 

Etiology and Pathogenesis 

A useful classification is based on Gram stain characteristics. The principal anaerobic gram-positive cocci that produce disease are the peptococci and the peptostreptococci, which are part of the normal flora of the mouth, upper respiratory tract, and large intestine. The principal anaerobic gram-negative bacilli include Bacteroides fragilis, Prevotella melaninogenica, and the genus Fusobacterium. The B. fragilis group is part of the normal bowel flora and includes the anaerobic pathogens most frequently isolated from intra-abdominal infections. The species that make up this group (B. fragilis, B. thetaiotaomicron, B. distasonis, B. vulgatus, B. ovatus, B. caccae, and B. merdae) are classified together because they were formerly designated subspecies of B. fragilis. The organisms in the Prevotella group and Fusobacterium sp are part of the indigenous oral flora. 

Anaerobic infections can usually be characterized by these features: (1) they tend to occur as localized collections of pus or abscesses, (2) the reduced PO2 tension and low oxidation-reduction potential that prevail in avascular and necrotic tissues are critical for the survival of anaerobes, and (3) when bacteremia occurs, it is only rarely associated with disseminated intravascular coagulation (DIC) and purpura. 

Some anaerobic bacteria possess distinct virulence factors; those of B. fragilis probably account for its frequent isolation from clinical specimens despite its relative rarity in normal flora. This organism has a polysaccharide capsule that apparently stimulates abscess formation. An experimental model of intra-abdominal sepsis has shown that B. fragilis alone can cause abscesses, whereas other Bacteroides sp require the synergistic effect of a facultative organism. Another virulence factor, the potent endotoxin of Fusobacterium, is implicated in septic shock associated with severe pharyngitis caused by this organism. 

Symptoms and Signs 

Infections caused by mixed anaerobic organisms are not discussed here. Anaerobes are rare in UTI, septic arthritis, and infective endocarditis. 

The following provide clinical clues to the presence of anaerobic organisms: infection adjacent to mucosal surfaces bearing anaerobic flora; ischemia, neoplasm, penetrating trauma, foreign body, or perforated viscus; spreading gangrene involving skin, subcutaneous tissue, fascia, and muscle; feculent odor in pus or infected tissues; abscess formation; gas in tissues; septic thrombophlebitis; and failure to respond to antibiotics that do not have significant antianaerobic activity. 

Bacteremia complicating mixed anaerobic infections may result in fever, rigors, and a critical illness. Shock may develop, and although extremely rare in pure Bacteroides sepsis, DIC may occur in Fusobacterium sepsis. 

Diagnosis 

Special techniques of specimen collection, transport, and culture are necessary to isolate and identify pathogenic anaerobes. Because contaminants may easily be mistaken for pathogens, specimens must be free of contamination by normal flora. Blood, pleural fluid, transtracheal aspirates, pus obtained by direct aspiration, culdocentesis and suprapubic aspirates, and biopsies of normally sterile sites are free of contamination and may be cultured. When liquid specimens are obtained by needle and syringe, air should be expelled from the syringe and the needle should be inserted into a sterile rubber stopper. 

Brief exposure to air may kill some fastidious anaerobes, such as those found in pulmonary infections, but the most virulent of the anaerobic species are somewhat tolerant to O2. B. fragilis will not grow aerobically but will survive for a few hours in the presence of O2. Transport to the laboratory should be expeditious; delays can lead to overgrowth of aerobic bacteria and result in failure to identify anaerobes. 

Gram stains and aerobic cultures should be obtained for all specimens. Anaerobic cultures should be placed on special media plates and incubated for 48 to 72 h before examination. Susceptibility data may not be available for >= 1 wk after initial culture, and sensitivity testing of anaerobes is exacting and should conform to National Committee for Clinical Laboratory Standards guidelines. However, if the species of bacteria is known, susceptibility patterns usually can be predicted; therefore, many laboratories do not routinely perform anaerobic susceptibility tests. 

Anaerobic infection should be considered when a Gram stain of pus from an infected site shows mixed pleomorphic bacterial flora. Since Bacteroides sp are poorly visible on Gram stain, careful inspection is required to observe the characteristic variable and filamentous rods. When the culture from an obviously necrotic, infected site showing mixed flora by Gram stain demonstrates only beta-hemolytic streptococci, a single aerobic species such as Escherichia coli, or no growth, the implication is that anaerobic microorganisms failed to grow because of inadequate transportation or bacteriologic techniques. 

Prognosis and Prevention 

Morbidity and mortality are as great from anaerobic and mixed bacterial sepsis as from sepsis caused by a single aerobic organism. Anaerobic infections are often complicated by deep-seated tissue necrosis. The overall mortality rate for severe intra-abdominal sepsis and mixed anaerobic pneumonias tends to be high; B. fragilis bacteremia is associated with significant mortality, especially in the elderly and in patients with malignancy. 

Preventive measures include early treatment of localized infection to prevent bacteremia and metastatic disease: debridement of necrotic tissue, removal of foreign bodies, reestablishment of circulation, and early antimicrobial treatment of traumatic wounds. Early surgical exploration, drainage, closure of bowel perforation, and antimicrobial treatment of penetrating abdominal wounds are essential. Bowel preparation (eg, with neomycin and erythromycin) should be performed on patients undergoing elective colonic surgery. Parenteral antibiotics can also be used prophylactically in the immediate postoperative period. Cefoxitin or a combination of either metronidazole or clindamycin with gentamicin or tobramycin may be used. In clean-contaminated surgery, prophylactic antibiotics given as a single dose before surgery and continued for 24 h after can reduce the postoperative infection rate of 20 to 30% to 4 to 8%. 

Treatment 

For deep-seated anaerobic infection, pus should be drained and devitalized tissue surgically removed. Antibiotics given in conjunction with surgery help to control bacteremia, reduce secondary or metastatic suppurative complications, and prevent local spread of infection around the surgical site. 

Because anaerobic culture results may not be available for 3 to 5 days, an antibiotic usually must be started before definitive laboratory results are known. Antibiotics sometimes work even when some of the bacterial species in a mixed infection are resistant to the antibiotic, especially if adequate drainage is performed. Treating anaerobes in mixed infections reduces the number of organisms in wounds and the number of abscesses formed. Abscesses and inciting sites of infection, such as organ perforations, must be closed or drained. Devitalized tissue, foreign bodies, and necrotic tissue must be removed. Any closed-space infections, such as empyemas, must be drained, and, whenever possible, the blood supply should be reestablished. Septic thrombophlebitis may require vein ligation as well as antimicrobial therapy. 

Oropharyngeal anaerobic infections should be treated with penicillin G. Infrequently, oral anaerobic infections fail to respond and should be treated with a drug effective against penicillin-resistant anaerobes (see below). 

Lung abscesses should be treated with clindamycin or a beta-lactam/beta-lactamase combination. In patients allergic to penicillin, clindamycin or metronidazole (with an agent active against aerobes) is useful. 

GI or female pelvic anaerobic infections, which likely contain B. fragilis, may be penicillin-resistant. Resistance has also been described for 2nd-generation cephalosporins and clindamycin. No single regimen has been shown to be superior. The following drugs have excellent in vitro activity and are effective: metronidazole, imipenem/cilastatin, piperacillin/tazobactam, ampicillin/sulbactam, meropenem and ticarcillin/clavulanic acid. Drugs that are somewhat less active in vitro but are usually efficacious include clindamycin, cefoxitin, and cefotetan. Metronidazole 500 to 750 mg IV q 8 h (for children, 30 mg/kg/day in three doses) given with an aminoglycoside (eg, gentamicin 5 mg/kg/day in three divided doses) can be used for intra-abdominal infection or any infection arising from a colonic source to cover enteric gram-negative flora. Serum levels of gentamicin should be monitored because of potential nephrotoxicity and ototoxicity. Clindamycin 900 mg IV q 8 h (for children, 30 mg/kg/day in three divided doses) is an alternative to metronidazole in this regimen. Metronidazole is active against clindamycin-resistant B. fragilis, has unique anaerobic bactericidal activity, and usually avoids the pseudomembranous colitis sometimes associated with clindamycin. Concerns about its potential mutagenicity have not been of clinical consequence. Cefoxitin and cefotetan have good anaerobic coverage. The best in vitro activity is shown by metronidazole, imipenem, meropenem, and the beta-lactam/beta-lactamase combinations. All but metronidazole can be used as monotherapy since these drugs also have good activity against aerobes.

(source: Merck)