Harrisons Manual of Medicine, 18th Ed.

CHAPTER 101. Anaerobic Infections

DEFINITIONS

• Anaerobic bacteria: require reduced oxygen tension for growth; do not grow on the surface of solid media in 10% Co2 in air

• Microaerophilic bacteria: grow in an atmosphere of 10% Co2 in air or under anaerobic or aerobic conditions, but grow best if only a small amount of atmospheric oxygen is present

• Facultative bacteria: grow in the presence or absence of oxygen

TETANUS

Microbiology, Epidemiology, and Pathogenesis

Tetanus is characterized by increased muscle tone and spasms caused by tetanospasmin (“tetanus toxin”), a toxin produced by Clostridium tetani.

• C. tetani is a spore-forming, anaerobic gram-positive rod that is ubiquitous in soil and whose spores are highly resilient.

• Worldwide, tetanus is a common disease because of low rates of vaccination. In 2006, ~290,000 people—most of them in Southeast Asia and Africa—died of tetanus; maternal and neonatal infections accounted for ~60% of these deaths. In contrast, only 28 cases were reported in the United States in 2007.

• After spores contaminate wounds (typically puncture wounds or, in the case of neonates, the umbilical stump) and reach a suitable anaerobic environment (e.g., devitalized tissue), organisms proliferate and release toxin.

– The toxin blocks release of inhibitory neurotransmitters (glycine and γ-aminobutyric acid) in presynaptic terminals, and rigidity results from an increased resting firing rate of the α-motor neurons.

– A toxin dose as low as 2.5 mg/kg can be fatal.

Clinical Manifestations

C. tetani can cause a usually mild local disease confined to the muscles near the wound or a more severe generalized disease (e.g., neonatal disease).

• If the cranial nerves are involved in localized cephalic tetanus, the pt may aspirate or develop airway obstruction due to pharyngeal or laryngeal muscle spasm. This situation is associated with a poor prognosis.

• The early symptoms of generalized tetanus often include trismus (lockjaw), muscle pain and stiffness, back pain, and difficulty swallowing. As the disease progresses, painful muscle spasms develop and can sometimes be strong enough to cause crush fractures.

– Without ventilatory support, respiratory failure is the commonest cause of death in tetanus.

– Autonomic disturbance (e.g., labile blood pressure; GI stasis; increased tracheal secretions; acute, high-output renal failure) is maximal during the second week of severe tetanus, and death due to cardiovascular events becomes the major risk.

Diagnosis

The diagnosis is made on clinical grounds. Culture of C. tetani from a wound provides supportive evidence.

TREATMENT Tetanus

• The mainstays of early treatment are the elimination of ongoing toxin production and the neutralization of circulating toxin.

– The entry wound should be identified, cleaned, and debrided of necrotic material in order to remove anaerobic foci of infection and prevent further toxin production.

– Metronidazole (400 mg rectally or 500 mg IV q6h for 7 days) is the preferred antibiotic. Penicillin (100,000–200,000 IU/kg qd) is an alternative but theoretically may increase spasms.

– Antitoxin should be given as early as possible.

– Standard treatment consists of a single IM dose of tetanus immune globulin (TIG; 3000–6000 IU) or equine antitoxin (10,000–20,000 IU). However, there is evidence that intrathecal TIG (50–1500 IU) inhibits disease progression and leads to a better outcome than IM-administered TIG.

• TIG is preferred as it is less likely to cause an anaphylactoid reaction.

• Monitoring and supportive care in a calm, quiet environment are important because light and noise can trigger spasms.

– Spasms are controlled by heavy sedation with benzodiazepines, chlorpromazine, and/or phenobarbital; magnesium sulfate can also be used as a muscle relaxant. The doses required to control spasms also cause respiratory depression; thus it is difficult to control spasms adequately in settings without mechanical ventilation.

– Cardiovascular instability in severe tetanus is notoriously difficult to treat; increased sedation (e.g., with magnesium sulfate or morphine) or administration of short-acting agents that work specifically on the cardiovascular system (e.g., esmolol, calcium antagonists, inotropes) may be required.

• Recovery from tetanus may take 4–6 weeks. Because natural disease does not induce immunity, recovering pts should be immunized.

Prevention

Vaccination effectively prevents disease.

• “Catch-up” vaccination schedules recommend a three-dose primary course followed by two further doses for unimmunized adolescents. For persons who have received a complete primary course in childhood but no further boosters, two doses at least 4 weeks apart are recommended.

• Individuals sustaining tetanus-prone wounds should be immunized if their vaccination status is incomplete or unknown or if their last booster was given >10 years earlier. Pts sustaining wounds not classified as clean or minor should also undergo passive immunization with TIG.

Prognosis

A shorter incubation period (time from wound to first symptom) or onset period (time from first symptom to first generalized spasm) is associated with worse outcome.

BOTULISM

Microbiology, Epidemiology, and Pathogenesis

Botulism is a paralytic disease caused by neurotoxins elaborated by Clostridium botulinum, an anaerobic spore-forming gram-positive bacterium, as well as a few other toxigenic Clostridium species.

• Botulism is caused by the toxin’s inhibition of acetylcholine release at the neuromuscular junction through an enzymatic mechanism.

– C. botulinum toxin types A, B, E, and (rarely) F cause human disease, with toxin type A causing the most severe syndrome.

– Toxin type E is associated with foods of aquatic origin.

• Transmission is usually due to consumption of foods contaminated with botulinum toxin, but contamination of wounds with spores also can result in disease.

– Most U.S. food-borne cases are associated with home-canned food.

– Infant botulism is the most common form of the disease in the United States, with ~80–100 cases reported annually.

• Toxin is heat-labile (inactivated when heated for 10 min at 100°C), and spores are heat-resistant (inactivated at 116°–121°C or with steam sterilizers or pressure cookers); these properties underscore the importance of properly heating foods.

• Botulinum toxin is the most toxic substance known and thus is of concern as a potential weapon of bioterrorism (Chap. 33).

Clinical Manifestations

Botulism occurs naturally as four syndromes: (1) food-borne illness; (2) wound infection; (3) infant botulism; and (4) adult intestinal toxemia, which is similar to infant botulism. The disease presents as symmetric cranial nerve palsies (diplopia, dysarthria, dysphonia, ptosis, and/or dysphagia) followed by symmetric descending flaccid paralysis that may progress to respiratory arrest and death.

• Food-borne botulism occurs 18–36 h after ingestion of food contaminated with toxin and ranges in severity from mild to fatal (within 24 h). Nausea, vomiting, and abdominal pain may precede or follow the onset of paralysis; constipation due to paralytic ileus is nearly universal. Fever is usually absent.

• Wound botulism occurs when spores contaminate wounds (e.g., in black-tar heroin users) and germinate. The clinical syndrome is indistinguishable from food-borne botulism except that GI symptoms are generally absent.

• In infant botulism and adult intestinal toxemia, spores germinate in the intestine and produce toxin, which is absorbed and causes illness. This form in infants has been associated with contaminated honey; thus honey should not be fed to children <12 months of age. Adult pts typically have some anatomic or functional bowel abnormality or have a bowel flora disrupted by recent antibiotic use.

Diagnosis

The clinical symptoms suggest the diagnosis. The definitive test is the demonstration of the toxin in clinical specimens (serum, stool, gastric aspirates, wound material) with a mouse bioassay (i.e., paralysis in a mouse after injection with the clinical sample).

• The results may not be available for up to 48 h, so clinical decisions (e.g., to administer botulinum antitoxin) need to be made in their absence.

• This test may yield a negative result even if the pt has botulism; additional tests may be necessary to rule out other conditions.

TREATMENT Botulism

• The mainstays of treatment are meticulous supportive care and immediate administration of botulinum antitoxin—the only specific treatment.

– Adults are given an equine antitoxin available through the CDC (770-488-7100); infant botulism is treated with a human-origin antitoxin (licensed as BabyBIG®) available through the California Department of Public Health (510-231-7600).

– In wound botulism, suspect wounds and abscesses should be cleaned, debrided, and drained promptly, and antimicrobial therapy (e.g., penicillins) should be guided by clinical judgment, as its clinical efficacy has not been established.

Prognosis

Toxin binding is irreversible, but nerve terminals do regenerate. In the United States, 95% of pts recover fully, but this process may take many months.

OTHER CLOSTRIDIAL INFECTIONS

Microbiology and Pathogenesis

Clostridia are pleomorphic, gram-positive, spore-forming organisms. Most species are obligate anaerobes; some (e.g., C. septicum, C. tertium) can grow—but not sporulate—in air.

• In humans, clostridia reside in the GI and female genital tracts and on the oral mucosa.

• Clostridial species produce more protein toxins than any other bacterial genus; the C. perfringens epsilon toxin is among the most lethal and is considered a potential agent of bioterrorism (Chap. 33).

Epidemiology and Clinical Manifestations

Life-threatening clostridial infections range from intoxications (e.g., food poisoning, tetanus) to necrotizing enteritis/colitis, bacteremia, myonecrosis, and toxic shock syndrome (TSS).

• Clostridial wound contamination: Of open traumatic wounds, 30–80% are contaminated with clostridial species. Diagnosis and treatment of clostridial infection should be based on clinical signs and symptoms, given that clostridia are isolated with equal frequency from both suppurative and well-healing wounds.

• Polymicrobial infections involving clostridia: Clostridial species can be involved in infection throughout the body; 66% of intraabdominal infections related to compromised mucosal integrity involve clostridia (most commonly C. ramosum, C. perfringens, and C. bifermentans).

• Enteric clostridial infections: Disease ranges from food-borne illnesses and antibiotic-associated colitis (Chap. 91) to extensive necrosis of the intestine (e.g., enteritis necroticans and necrotizing enterocolitis, which are due to toxigenic C. perfringens type C and type A, respectively).

• Clostridial bacteremiaC. perfringens causes 79% of clostridial bacteremias; when associated with myonecrosis, clostridial bacteremia has a grave prognosis.

– C. septicum is also commonly associated with bacteremia (<5% of cases). More than 50% of pts with C. septicum bacteremia have a GI anomaly or an underlying malignancy. Neutropenia (of any origin) is also associated with clostridial bloodstream infection.

• Pts with clostridial bacteremia—particularly that due to C. septicum—require immediate treatment, as infection can metastasize and cause spontaneous myonecrosis.

• Clostridial skin and soft-tissue infections: Necrotizing clostridial soft-tissue infections are rapidly progressive and are characterized by marked tissue destruction, gas in the tissues, and shock. Most pts develop severe pain, crepitus, brawny induration with rapid progression to skin sloughing, violaceous bullae, and marked tachycardia.

– C. perfringens myonecrosis (gas gangrene) is accompanied by bacteremia, hypotension, and multiorgan failure and is invariably fatal if untreated.

• If due to trauma, gas gangrene has an incubation period of 6 h to <4 days. Disease initially presents as excruciating pain at the affected site and the development of a foul-smelling wound containing a thin serosanguineous discharge and gas bubbles.

• Spontaneous gas gangrene results from hematogenous seeding of normal muscle with toxigenic clostridia from a GI source. Confusion, extreme pain in the absence of trauma, and fever should heighten suspicion.

– TSS: Endometrial clostridial infection (particularly with C. sordellii) is usually related to pregnancy and proceeds rapidly to TSS and death.

• Systemic manifestations, including edema, effusions, profound leukocytosis (50,000–200,000/μL), and hemoconcentration (Hct of 75–80%), are followed by the rapid onset of hypotension and multiple-organ failure.

• Fever is usually absent.

– Other clostridial skin and soft-tissue infections include crepitant cellulitis (involving subcutaneous or retroperitoneal tissues in diabetic pts), cellulitis and abscess formation due to C. histolyticum, and endophthalmitis due to C. sordellii or C. perfringens.

Diagnosis

Isolation of clostridia from clinical sites does not in itself indicate severe disease. Clinical findings and presentation must also be taken into account.

TREATMENT Other Clostridial Infections

Table 101-1 lists treatment regimens for clostridial infections.

TABLE 101-1 TREATMENT OF CLOSTRIDIAL INFECTIONS

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MIXED ANAEROBIC INFECTIONS

Microbiology, Epidemiology, and Pathogenesis

Nonsporulating anaerobic bacteria are important components of the normal flora of mucosal surfaces of the mouth, lower GI tract, skin, and female genital tract and contribute to physiologic, metabolic, and immunologic functions of the host.

• Most clinically relevant anaerobes are relatively aerotolerant and can survive for as long as 72 h in the presence of low levels of oxygen.

– Clinically relevant anaerobes include gram-positive cocci (e.g., Peptostreptococcus species), gram-positive rods (e.g., spore-forming clostridia and Propionibacterium acnes), and gram-negative bacilli (e.g., the B. fragilis group in the normal bowel flora, Fusobacterium species in the oral cavity and GI tract, Prevotella species in the oral cavity and female genital tract, and Porphyromonas species in the oral flora).

• Infections caused by anaerobes are typically polymicrobial (including at least one anaerobic organism and sometimes involving microaerophilic and facultative bacteria) and occur when organisms penetrate a previously sterile site that has a reduced oxidation-reduction potential—e.g., from tissue ischemia, trauma, surgery, perforated viscus, shock, or aspiration. Bacterial synergy, bacterial virulence factors, and mechanisms of abscess formation are factors involved in the pathogenesis of anaerobic infections.

• Anaerobes account for 0.5–12% of all cases of bacteremia, with B. fragilis isolated in 35–80% of these cases.

Clinical Manifestations

The clinical presentation of anaerobic infections depends, in part, on the anatomic location affected.

• Mouth, head, and neck infections: Odontogenic infections (e.g., dental caries, periodontal disease, gingivitis) are common, can spread locally, and may be life-threatening.

– Acute necrotizing ulcerative gingivitis (trench mouth, Vincent’s stomatitis) is associated with bleeding tender gums, foul breath, and ulceration with gray exudates, often affecting malnourished children, pts with leukemia, or pts with a debilitating illness. Widespread destruction of bone and soft tissue can develop. Lesions heal but leave disfiguring defects.

– Acute necrotizing infection of the pharynx is associated with ulcerative gingivitis. Pts have a sore throat, foul breath, fever, a choking sensation, and tonsillar pillars that are swollen, red, ulcerated, and covered with a gray membrane. Aspiration of infected material can lead to a lung abscess.

– Peripharyngeal infections include peritonsillar abscess (quinsy; caused by a mixed flora including anaerobes and group A streptococci) and submandibular space infection (Ludwig’s angina), which arises from the second and third molars in 80% of cases and is associated with swelling (which can lead to respiratory obstruction), pain, trismus, and displacement of the tongue.

– Chronic sinusitis and otitis (Chap. 64) are commonly due to anaerobes.

– Complications of anaerobic mouth, head, and neck infections include Lemierre’s syndrome, osteomyelitis, CNS infections (e.g., brain abscess, epidural abscess, subdural empyema), mediastinitis, pleuro-pulmonary infections, and hematogenous dissemination.

• Lemierre’s syndrome, which is typically due to Fusobacterium necrophorum, is an acute oropharyngeal infection with secondary septic thrombophlebitis of the internal jugular vein and frequent metastasis, most commonly to the lung.

• Pleuropulmonary infections include aspiration pneumonia (which is difficult to distinguish from chemical pneumonitis due to aspiration of gastric juices), necrotizing pneumonitis, lung abscesses, and empyema. Bacterial aspiration pneumonia is associated with a depressed gag reflex, impaired swallowing, or altered mental status; anaerobic lung abscess usually arises from a dental source.

• Intraabdominal infections: See Chap. 90.

• Pelvic infections: See Chap. 92 for more details. Anaerobes, typically in combination with coliforms, are isolated from most women with genital tract infections (e.g., Bartholin gland abscess, salpingitis, tuboovarian abscess, endometritis) that are not caused by a sexually transmitted pathogen. The major anaerobic pathogens are Bacteroides fragilis, Prevotella species (bivia, disiens, melaninogenica), anaerobic cocci, and Clostridium species.

• Skin and soft tissue infections: See Chap. 93 for more details. These infections most frequently occur at sites prone to contamination with feces or with upper airway secretions.

• Bone and joint infections: Anaerobic bone and joint infections usually occur adjacent to soft tissue infections. Actinomycosis is the leading cause of anaerobic bone infections worldwide; Fusobacteriumspecies are the most common anaerobic cause of septic arthritis.

Diagnosis

The three critical steps in successfully culturing anaerobic bacteria from clinical samples are (1) proper specimen collection, with avoidance of contamination by normal flora; (2) rapid specimen transport to the microbiology laboratory in anaerobic transport media; and (3) proper specimen handling. A foul odor is often indicative (and nearly pathognomonic) of an anaerobic infection.

TREATMENT Mixed Anaerobic Infections

• Appropriate treatment requires antibiotic administration (Table 101-2), surgical resection or debridement of devitalized tissues, and drainage.

TABLE 101-2 TREATMENT OF SERIOUS INFECTIONS DUE TO COMMONLY ENCOUNTERED ANAEROBIC GRAM-NEGATIVE RODS

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– Given that most infections involving anaerobes also include aerobic organisms, therapeutic regimens should include agents active against both classes of organisms.

– Infections above the diaphragm usually reflect the orodental flora, which includes many organisms that produce β-lactamase. Accordingly, the recommended regimens include clindamycin, a β-lactam/β-lactamase inhibitor combination, or metronidazole in combination with a drug active against microaerophilic and aerobic streptococci.

– Infections below the diaphragm must be treated with agents active against Bacteroides species, such as metronidazole, β-lactam/β-lactamase inhibitor combinations, or carbapenems. Treatment should also cover the aerobic gram-negative flora, including enterococci (e.g., ampicillin or vancomycin) when indicated.

• Pts with anaerobic infections that fail to respond to treatment or that relapse should be reassessed, with consideration of additional surgical drainage or debridement. Superinfection with resistant gram-negative facultative or aerobic bacteria should also be considered.

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For a more detailed discussion, see Thwaites CL, Yen LM: Tetanus, Chap. 140, p. 1197; Sobel J, Maslanka S: Botulism, Chap. 141, p. 1200; Bryant AE, Stevens DL: Gas Gangrene and Other Clostridial Infections, Chap. 142, p. 1204; and Kasper DL, Cohen-Poradosu R: Infections Due to Mixed Anaerobic Organisms, Chap. 164, p. 1331, in HPIM-18.