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Toxin-Mediated Infections

TETANUS

Tetanus is a disease of global incidence produced by the toxin of Clostridium tetani. The risk of acquiring it increases in people > 60 years of age and in neonates, especially in Third World countries where poor sanitary conditions predispose to umbilical stump contamination. Immunization campaigns have played a crucial role in bringing about the observed decreasing incidence in the United States.

The pathogenesis of tetanus involves the absorption of preformed toxin, or, less commonly, invasion of toxin-producing organisms from contaminated wounds; it may complicate surgical wounds colonized with C tetani. Incubation periods vary depending on the portal of entry. The toxin tetanospasmin blocks the transmission of inhibitory neurons, which results in flexor and extensor muscle spasms that are triggered by sensory stimuli.

Most cases progress over 2 weeks. With adequate supportive therapy (Box 2), complete recovery may be seen in 1 month. Autonomic dysfunction and respiratory compromise are potential complications. Mortality rates are 1:100,000 in North America and 28:100,000 in Third World countries.

Clinical Findings

Signs and Symptoms

Muscle spasms are accompanied by pain and manifest as decorticate posturing with intact sensorium. "Risus sardonicus" is the term used to describe the facial expression produced by increased tone of the orbicularis oris. Trismus (or "lockjaw") is often present as a heralding manifestation of generalized disease.

Toxin-Mediated Infections

Diagnosis

Diagnosis of tetanus is made clinically; conditions that might have similar features are strychnine poisoning and dystonic reactions.

Treatment

Treatment should be supportive. Sedation is important: benzodiazepines, propofol, and in severe cases, paralyzing agents can be used; the role of antibiotics is controversial (see Box 2). When autonomic dysfunction is present, alpha and beta adrenergic blocking agents are recommended.

BOTULISM

This clinical syndrome is caused by the neurotoxin of C botulinum. There are seven types (A-G) of neurotoxin, all of which inhibit the release of acetylcholine at the level of peripheral neuromuscular junctions. In the majority of cases, the disease is acquired by ingestion of preformed toxin in home-canned vegetables, fruits, and fish. In Japan, the former Soviet Union, Scandinavia, and the Great Lakes region of the United States, type E toxin causes disease in people who consume raw or lightly smoked fish. There are four categories of botulism:

  • Food borne (most common)
  • Wound botulism caused by the absorption of toxin from a wound contaminated by C botulinum (the rarest form)
  • Infant botulism resulting from in vivo elaboration of toxin by colonizing organisms in the bowel
  • Undetermined, which refers to cases that occur in individuals > 1 year old in whom no food or wound source is identified

Clinical Findings

Signs and Symptoms

Symptoms and signs arise 12-36 h after food ingestion and consist of acute onset and progressive flaccid paralysis involving the facial musculature and the cranial nerves bilaterally, then descending symmetrically to the pharynx, thoracic region, and the upper and lower extremities. This evolves into respiratory failure without impairment of consciousness. Fever is classically absent.

In cases of infant botulism, which is found in children 6 days to 11 months old, constipation is the initial symptom, followed by lethargy, feeding difficulties, altered cry, floppiness, ophthalmoplegia, and respiratory failure.

Laboratory Findings

Besides clinical findings and careful history, stool and serum toxin assays help establish the diagnosis.

Differential Diagnosis

Differential diagnosis of botulism includes myasthenia gravis, Lambert-Eaton paraneoplastic syndrome, and Guillain-Barre syndrome.

Treatment

Treatment is mainly supportive; antitoxin made from equine serum can be used. In the United States, it is obtained through state health departments or the Centers for Disease Control. The standard dose is one vial intravenously and one vial intermittently. It may be repeated every 4 h in severe progressive cases. Clinical trials evaluating its efficacy are lacking. Full recovery takes from 3 months to 1 year. Risk of death ranges from 4 to 25%, depending on the promptness with which the diagnosis is made.

ANTIBIOTIC-ASSOCIATED COLITIS

Clostridium difficile is the principal causative agent of antibiotic-associated colitis. Two types of toxin are produced by C difficile: (1) an enterotoxin (the most important in its pathogenesis) and (2) an enterotoxin that is cytophatic. This organism is present in the bowel flora of = 50% of neonates. This rate declines to 4% by age 2 years. However, antibiotic treatment and hospitalization have been proven to increase the carriage rate = 46%. Chemotherapeutic agents (for malignancies) and antibiotics (most commonly ampicillin, clindamycin, and the cephalosporins) are associated with C difficile pseudomembranous colitis. Bowel stasis and surgery predispose to this disease as well, although, in some cases, no identifiable risk factor is found.

Clinical Findings

Signs and Symptoms

Clinical presentation ranges from mild diarrhea to toxic megacolon. Fever is present frequently, and pseudomembrane formation is characteristic.

Laboratory Findings

The diagnosis is confirmed by toxin assays and cell culture cytotoxicity assays that neutralize with antisera to toxin B. Colonoscopy may provide helpful information by enabling direct observation of the classical pseudomembranes in the colonic mucosal surface. Stool cultures are not diagnostic because of the considerable rates of asymptomatic carrier states.

Treatment

In treating patients who have C difficile-associated pseudomembranous colitis, if possible, an attempt to stop or narrow broad-spectrum antibiotic therapy (if the patient is receiving it for other reasons) should be made. Oral metronidazole is the first choice for treatment (Box 2). Oral vancomycin should be avoided to prevent further selection of vancomycin-resistant enterococci but can be used in cases of relapse or as a second choice in patients unable to tolerate metronidazole.

Diagnosis of Anaerobic Bacterial Infections

The likelihood of anaerobes being part of the infecting flora should be carefully considered when obtaining cultures. In general, anaerobic cultures are needed in complicated infections, in debilitated hosts (those with underlying chronic illnesses or malignancies as well as elderly individuals), in cases where prolonged therapy is anticipated, and in infections where empiric therapy is failing.

Toxin-Mediated Infections

Specimens from the oral cavity, upper respiratory tract, or vagina are rich in indigenous anaerobic flora and therefore not useful for diagnostic purposes. Fluid obtained from normally sterile sites, as well as pus or tissue samples are preferred. Fluid or pus from these sites should be inoculated into special anaerobic vials for transport to the microbiology laboratory, and in the case of tissues, an airtight bag might be used.

Cultures are grown in both selective (directed at specific pathogens) and nonselective media; this approach increases the diagnostic yield. An anaerobic environment must be maintained.

Newer diagnostic techniques include detecting the metabolic end products of carbohydrate fermentation by gas-liquid chromatography. Toxin assays are available for the diagnosis of botulism and C difficile-associated colitis.

Treatment of Anaerobic Bacterial Infections

The first principle of treatment for anaerobic bacterial infections is to keep in mind that in most cases, other pathogens coexist as part of a polymicrobial flora; therefore, adequate antibiotic coverage for those should be provided as well (Box 2). Drainage of abscesses and surgical debridement of wounds to remove devitalized tissue are of great importance to achieve therapeutic success.

Historically, penicillin has been one of the most useful antibiotics against anaerobic bacteria, but the increasing frequency of ß-lactamase-producing strains of B fragilis, Prevotella melaninogenica, and Porphyromonas spp. has limited its value. Penicillin G is still the drug of choice for clostridia, but C perfringens, C ramosum, C clostridiforme, and C butyricum exhibit some degree of resistance.

Cephalosporins in general should not be considered drugs of choice for gram-negative anaerobic coverage, but cefoxitin and ceftizoxime exhibit some activity against these bacteria. Cefoxitin has been used as monotherapy in uncomplicated intra-abdominal infections. First-generation cephalosporins (eg, cefazolin) are active against gram-positive anaerobic cocci.

Tetracycline and its derivatives, frequently administered in the past, are now mostly inactive. Quinolones such as ciprofloxacin and ofloxacin have very poor coverage, but newer compounds with increased anaerobic activity are being developed.

Chloramphenicol has good anaerobic coverage, although occasional resistance may be seen with B fragilis and certain clostridia. Penetration to the central nervous system is adequate. The main limiting factor preventing widespread use of chloramphenicol is toxicity (risk of bone marrow suppression, mainly with oral formulations).

Clindamycin is one of the drugs of choice when anaerobes are suspected, however, its spectrum against aerobic gram-negative bacilli is limited; in the setting of polymicrobial infections, the addition of an aminoglycoside, second- or third-generation cephalosporin, or aztreonam is recommended. The central nervous system penetration of clindamycin is very poor. About 30% of Bacteroides gracilis and some organisms in the B fragilis group can be resistant to clindamycin.

Metronidazole is another potent antianaerobic drug with even less activity against aerobes than clindamycin. It should not be used as monotherapy if aerobes are suspected. Central nervous system penetration is good.

The combination of ß-lactams with ß-lactamase inhibitors is active against most anaerobes as well as against many aerobes. These agents include amoxicillin-clavulanic acid (oral) the intravenous ampicillin-sulbactam, ticarcillin-clavulanic acid, and piperacillin-tazobactam.

The carbapenems (imipenem and meropenem) have excellent anaerobic activity as well as broad gram-positive and gram-negative aerobic coverage. Both the ß-lactam and ß-lactamase inhibitor combinations and the carbapenems are typically more expensive than combination regimens using older agents.

Prevention

Preventive measures are aimed at minimizing contamination of sterile sites with fluids that contain high amounts of normal microbial flora (as is the case with intra-abdominal postsurgical infections) (Box 59-3). Preventing aspiration of oropharyngeal contents into the lower airways is important to control anaerobic pneumonitis and empyemas. For obstetrical infections, reducing the duration of labor (if possible) can help. Good cleansing and debridement of wounds decreases the risk of soft tissue infections. Ensuring adequate vascular supply is also important in these situations.

In C tetani infections, active, and in some cases passive, immunization are important (Table 2). Avoiding the unnecessary use of broad-spectrum antibiotics for prolonged periods of time is one of the cornerstones for preventing C difficile-associated colitis.

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