Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

59. Important Anaerobes

Jorge Villacian MD

James Steckelberg MD

Essentials of Diagnosis

  • Foul odor of draining purulence.
  • Presence of gas in tissues.
  • No organism growth on aerobic culture media.
  • Infection localized in the proximity of mucosal surface.
  • Presence of septic thrombophlebitis.
  • Tissue necrosis and abscess formation.
  • Association with malignancies (especially intestinal).
  • Mixed organism morphologies on Gram stain.

General Considerations

  1. Epidemiology and Ecology.Anaerobic bacteria are the predominant component of the normal microbial flora of the human body. The following sites harbor the vast majority of them:
  • Skin: Mostly gram-positive bacilli such as Propionibacterium acnes
  • Gastrointestinal tract: In the oral cavity Prevotellaspp., Porphyromonas spp., Peptostreptococcus spp., microaerophillic streptococci, and Fusobacterium spp. are the most important anaerobes found; they significantly outnumber aerobic bacteria (1000:1 ratio). On the colonic lumen, Bacteroides fragilis, other Bacteroides spp., clostridia, and the previously mentioned oral flora are by far the predominant colonizing organisms (1000:1 ratio to aerobes) and play a crucial role in maintaining the delicate balance of local microflora as well as in metabolizing bile acids and cholesterol and absorbing vitamin K.
  • Respiratory tract: Fusobacterium nucleatum, B fragilis, Prevotella melaninogenica, and Peptostreptococcusspp. are the most common anaerobic organisms in this site.
  • Female genital tract: Lactobacillusspp., the predominant species in this location, protect against bacterial vaginosis.
  • Exogenous infectious sources: In nature, species of the Clostridiumgenus are found in decaying vegetation, soil, ocean sediment, and in human and animal gastrointestinal tracts. Tetanus and botulism (caused by the toxins of C tetani and C botulinum) are examples of exogenously acquired anaerobic infections. The facultative gram-negative anaerobic bacillus Capnocytophaga canimorsus is part of the normal oral flora of canine species, but in susceptible hosts such as immunocompromised individuals, it may cause septic shock and disseminated intravascular coagulation, an example of an animal-to-human transmission of infection.
  1. Microbiology.Anaerobes are defined as bacteria that cannot grow on the surface of solid media in an atmosphere containing ≥ 18%–20% of oxygen even when this atmosphere is enriched with ≤ 10% of CO2. The degree of oxygen tolerance differs among these microorganisms; a facultative anaerobe is a bacterium that can grow in either the presence or absence of oxygen, and a strict anaerobe is one that requires < 0.5% oxygen to grow on an agar surface. Microaerophilic is a term used for bacteria that grow poorly aerobically but distinctly better under 10% CO2.

Anaerobic bacterial species are numerous; taxonomic data are sometimes confusing and have undergone recent changes. For the purpose of this chapter, we have focused on the most representative pathogens (Table 59-1).

  1. Pathogenesis.The pathogenic role of anaerobic bacteria was well established at the beginning of the 1900s. Most infections that involve anaerobes arise from the host's normal indigenous flora, as these bacteria are widely distributed among humans and other animal species. Organisms that are most important are those present in significant numbers at the sites of infection as well as those with high virulence or greater antimicrobial resistance.

The characteristic pathologic features of anaerobic infections are suppuration, abscess formation, and tissue destruction. Several factors contribute to the survival and spread of these organisms:

Microbial Factors:

  • Anaerobic environment causes defective neutrophil killing and microbial growth is slower; therefore antibiotic susceptibility decreases.
  • Bacterial enzymes such as collagenase and hyaluronidase promote tissue destruction.
  • Organisms such as B fragilishave a polysaccharide capsule that impairs phagocytosis.
  • Toxin-mediated effects are important in the pathogenicity of most of the genus Clostridium. This occurs in the form of absorption of preformed toxin such as in cases of botulism or as a result of bacterial overgrowth and toxin production, which is the mechanism of antibiotic-associated C difficile colitis.

Table 59-1. Important anaerobic bacteria.

Gram-Positive Bacilli

Gram-Positive Cocci

Gram-Negative Bacilli

Gram-Negative Cocci

Spore forming:

o   Clostridium botulinum

o   C tetani

o   C difficile

o   C septicum

o   C ramosum

o   Nonspore forming:

o   Propionibacterium spp.

o   Lactobacillus spp.

o   Bifidobacterium spp.

o   Actinomyces spp.

o   Microaerophilic streptococci

o   Peptococcus niger

o   Prevotella melaninogenica

o   Peptostreptococcus spp

o   B fragilis

o   Porphyromona spp

o   Prevotella melaninogenica

o   Fusobacterium nucleatum

o   F necrophorum

o   Veillonella spp.

  • Synergism plays a crucial role in anaerobic pathogenesis, especially in the context of mixed infections because the presence of other aerobic bacteria helps create the optimal environmental conditions for the proliferation and virulence of anaerobes.

Host Factors:

Normal anaerobic flora become pathogenic under circumstances in which natural barriers that prevent it from gaining access to sterile sites are disrupted. This might happen by a variety of different mechanisms and depends on the site in which the florae occur.

  • In pleuropulmonary infections, the usual precipitating factor is an alteration of the level of alertness that may impair the gag and cough reflexes. General anesthesia, cerebrovascular accidents, a variety of drug overdoses, and alcohol intoxication are examples of situations in which normal oropharyngeal flora gains access to the “sterile” lower respiratory tract; dysphagia, and esophageal or gastric outlet obstruction may also lead to aspiration of large amounts of anaerobes.
  • Trauma and tissue ischemia are two important mechanisms that predispose to anaerobic infection: seriously contaminated wounds are an example in which poor blood flow and tissue necrosis provide an ideal environment for C perfringensto grow and produce significant amounts of toxin eventually leading to gas gangrene.
  • Systemic diseases, such as diabetes mellitus in which the immune response is impaired and vascular compromise might be present, predispose to soft tissue infections of the lower extremities in which anaerobic organisms are commonly found. The presence of foreign devices in different sites may be associated with certain anaerobic infections.Classically, women with intrauterine devices may develop actinomycosis. Central nervous system shunts can become infected with skin colonizing Propionibacteriumspp.

Iatrogenic Factors:

  • In postsurgical abdominal infections, manipulation of bowel causes translocation of bacteria intothe peritoneal cavity: anaerobes are universally present as copathogens in a polymicrobial flora.
  • Administration of broad-spectrum antimicrobial agents alters the normal colonic flora and allowsC difficileto proliferate uninhibited; toxin production by this organism leads to the development of antibiotic-associated pseudomembranous colitis.

CLINICAL SYNDROMES

Box 59-1 summarizes different clinical syndromes associated with anaerobic bacteria. The sections that follow describe the various syndromes, including clinical findings. For some syndromes, specific diagnosis and treatment information is included as well. For other syndromes, see summary diagnosis and treatment sections at the end of the chapter.

HEAD & NECK

  1. EAR & PARANASAL SINUSES

The flora in as many as two-thirds of chronic sinusitis and otitis cases includes B fragilis, Prevotella spp., Peptostreptococcus spp., and Porphyromonas spp. It is not surprising that ~50% of patients with chronic otitis media are infected with anaerobic bacteria, B fragilis being the most common. Mastoiditis may arise as a complication in some of these cases.


Clinical findings related to these infections are found in Chapter 9.

BOX 59-1 Infections Frequently Associated with Anaerobic Bacteria

Site

Clinical Syndrome

Anaerobe Involved

Head & Neck

· Chronic sinusitis

· Chronic otitis media/mastoiditis

· Odontogenic infections

· Periodontal infections

· Peritonsillar abscess

· Neck space infections

· Bacteroides fragilis group

· Porphyromonas spp.

· Prevotella spp.

· Peptostreptococcus spp.

· Fusobacterium spp.

· Necrophorum spp.

Central Nervous System

· Brain abscess

· Subdural empyema

· Epidural abscess

· B fragilis group

· Peptostreptococcus spp.

· Fusobacterium spp.

· Prevotella spp.

· Actinomyces spp.

· Microaerophilic streptococcus

Respiratory Tract

· Aspiration pneumonitis

· Empyema

· B fragilis group

· Prevotella melaninogenica

· Bacteroides spp.

· Peptostreptococcus spp.

· Fusobacterium spp.

· Clostridia

· Veillonella spp.

Intra-abdominal

· Peritonitis

· Intra-abdominal abscess

· Appendicitis

· Pyogenic liver abscess

· Postsurgical wound infections

· Enteritis necroticans

· Neutropenic enterocolitis

· Bacteroides spp.

· Peptostreptococcus spp.

· Fusobacterium spp.

· Lactobacillus spp.

· Eubacterium spp.

· Clostridia

Female Genital Tract

· Endometritis

· Amnionitis

· Septic abortion

· Postsurgical wound infections

· Pelvic inflammatory disease

· IUD-related bacterial vaginosis

· Peptostreptococcus spp.

· Prevotella spp.

· Porphyromonas spp.

· Clostridia

· Actinomyces spp.

· Eubacterum nodatum

Skin, Soft Tissue, and Bone Infections

· Bite wound infections

· Diabetic foot infections

· Infected decubitus ulcers

· Burn wound infections

· Paronychia

· Breast abscess

· Infected sebaceous and pilonidal cysts

· Anaerobic cellulitis

· Necrotizing fasciitis

· Myonecrosis (gas gangrene)

· Chronic osteomyelitis

· B fragilis group

· Fusobacterium spp.

· Prevotella spp.

· Porphyromonas spp.

· Clostridia

· Peptostreptococcus spp.

Toxin-Mediated Clostridial Diseases

· Botulism

· Tetanus

· Antibiotic-associated pseudomembranous colitis

· Clostridium botulinium

· C tetani

· C difficile

  1. ORAL CAVITY

This site is heavily colonized with anaerobes. Consequently, many infections involving oral cavity structures as well as the pharyngeal spaces involve anaerobic bacteria.

Clinical Findings

Odontogenic infections including endodontal processes and periapical and dental abscesses may become more serious by spreading to the perimandibular space; here they present with pain and swelling and require surgical intervention. Gingivitis, pyorrhea, and periodontitis involve anaerobes as well; an extreme of this type of process is necrotizing ulcerative gingivitis (Vincent's angina or trench mouth), which manifests as severe tissue destruction, pain, and malodorous discharge. AIDS and Down's syndrome are conditions that predispose to periodontal disease and subsequently to odontogenic infections.

  1. PHARYNGEAL SPACES

Clinical Findings

Ludwig's angina is a bilateral infection of the sublingual and submandibular spaces that commonly involves anaerobic bacteria and causes swelling of the oral tissues, especially at the base of the tongue, where it may lead to respiratory compromise. It manifests as indurated cellulitis and begins on the mouth. A dental source of infection can be found in 50–90% of cases. Lemiere's syndrome is a life-threatening complication of Fusobacterium necrophorum infection in the posterior compartment of the lateral pharyngeal space, which consists of suppurative thrombophlebitis of the internal jugular vein often accompanied by bacteremia and metastatic abscesses to the lungs and liver. Surgical intervention is almost always necessary in conjunction with intravenous antibiotics.

  1. Signs and Symptoms.Clinical features ofinfection of the pharyngeal spaces are dysphagia, hoarseness, nuchal rigidity, fever, and trismus. InLudwig's angina, a brawny, boardlike swelling ofthe submandibular spaces, which does not pit onpressure, is present when the mouth is held openand the tongue is pushed up to the roof of the mouth.
  2. Imaging.Once the diagnosis is made (see below), imaging studies help delineate the extent of the process. Soft tissue x-ray of the neck may show widening of the different pharyngeal spaces involved. Ultrasonography, radionuclide scanning, and computerized tomography (CT) are useful for localizing infections of the head and neck.

CENTRAL NERVOUS SYSTEM

Oral anaerobes are commonly involved in brain abscesses, occasionally in epidural and subdural empyemas, and very rarely in meningitis. These infections usually arise in the setting of chronic otitis media, sinusitis, or odontogenic processes. Less frequently, brain abscesses can be secondary to hematogenous spread from distant sites in which case they tend to be multiple. Anaerobic infections can also be found as a complication of neurosurgical procedures.

Clinical Findings

  1. Signs and Symptoms.Clinical features are those of a space-occupying lesion, including headache, vomiting, altered mental status, focal neurologic symptoms, and seizures. Fever is present in only half of cases; depending on the location of the lesion, corresponding neurologic deficits can be seen. Funduscopic examination may reveal papilledema.
  2. Laboratory Findings.Microbiology findings may include B fragilis, Peptostreptococcus, Fusobacterium, Prevotellaspp., Actinomyces, Propionibacterium, or microaerophilic streptococci in conjunction with aerobic organisms such as staphylococci, streptococci, and gram-negative bacilli.

Invasive procedures such as lumbar puncture should only be performed after careful physical exam to evaluate for increased intracranial pressure or impending herniation. Cerebrospinal fluid examination may show a moderate pleocytosis, high protein concentration, and normal glucose level suggestive of parameningeal inflammatory foci.

  1. Imaging.The diagnosis is confirmed by contrast-enhanced CT or magnetic resonance imaging.

RESPIRATORY TRACT

Aspiration of oral and dental flora results in anaerobic pleuropulmonary infections. Predisposing conditions are alterations in mental status, gingivitis, and periodontal disease.

Clinical Findings

  1. Signs and Symptoms.Pulmonary abscesses of anaerobic origin usually have an indolent subacute or chronic presentation with symptoms such as malaise, weight loss, pleuritic chest pain, and cough that may be accompanied by foul smelling sputum and can be mistaken for malignancy; a febrile response depends on the patient's age and immune status.

Pathologically, early in the course, pneumonitis is present and then may evolve to form an abscess causing significant tissue destruction. The pleural cavity is frequently involved, and this results in empyema. Commonly affected anatomical sites are dependent regions such as the posterior segments of the upper lobes and the superior segments of the lower lobes (see Imaging section below).

  1. Laboratory Findings.Organisms of the B fragilisgroup, other Bacteroides spp., Prevotella melaninogenica, Fusobacterium spp., peptostreptococci, Peptococcus spp., gram-negative bacilli such as Clostridium spp., or occasionally gram-positive cocci of the Veillonella spp. are found. In most cases, aerobic organisms are also present, and successful treatment needs to cover such pathogens as well.

For microbiologic diagnosis, expectorated sputum is not useful as a result of the presence of abundant normal anaerobic flora of the upper airways and oropharyngeal cavities; therefore, invasive procedures including bronchoscopy with bronchoalveolar lavage is important in identifying the causative organisms. Empyema fluid should always be inoculated into appropriate anaerobic vials and sent for anaerobic culture.

  1. Imaging.Initial findings on chest x-ray are those of a pneumonic infiltrate. This may evolve to form abscesses in which air-fluid levels can be detected. For optimal delineation of extent of involvement, CT of the chest should be performed.

INTRA-ABDOMINAL

The gastrointestinal tract harbors a rich microbial flora, and any process that involves perforation or manipulation of a hollow viscus could potentially result in the translocation of bacteria into normally sterile sites. In the oral cavity, there are 107–108 anaerobes/mL of oral contents; the proportion is 10–1000/mL in the stomach, 104–106 anaerobes/mL in the terminal ileum, and 1011/g of stool in the colon.

  1. BOWEL

Upper-gastrointestinal-tract processes such as perforated peptic ulcer tend to involve gram-positive anaerobic and aerobic bacteria, whereas lower-tract diseases like appendicitis and colonic perforations are associated with coliforms and anaerobic gram-negative species including B fragilis, Bacteroides spp., and Fusobacterium spp. Therefore, peritonitis (secondary to perforated viscus) and intra-abdominal abscesses always involve anaerobes as a component of a mixed flora. Postsurgical infections may have an anaerobic component as well. See Chapter 12 for clinical findings related to these infections.

Colonic malignancies are commonly associated with members of the Clostridium species—septicum, tertium, and perfringens, all of which may cause bacteremia and gas gangrene of the bowel. Enteritis necroticans (caused by C perfringens) and neutropenic enterocolitis or typhlitis (caused by C septicum) are two representative severe clostridial bowel infections.

  1. LIVER & BILIARY TREE

Biliary tract infections in nonobstructed biliary systems seldom involve anaerobes, but in patients with obstruction caused by tumors, B fragilis or C perfringens can be present. Bacterial liver abscesses are usually polymicrobial, and anaerobes constitute part of the flora.

The diagnosis of hepatic or intra-abdominal anaerobic abscesses is made with imaging studies such as CT. If large abscesses are present, drainage is a component of successful therapy and can be achieved either surgically or in some cases by percutaneous CT or ultrasound-guided techniques. See Chapter 12 for clinical findings related to these infections.

FEMALE GENITAL TRACT

Alteration of the normal microbial flora of the female genital tract causes bacterial vaginosis, which predisposes to different infections in which anaerobes are frequently encountered. These are usually mixed and include endometritis, pelvic inflammatory disease, and tubo-ovarian abscesses, as well as obstetric infections such as amnionitis, septic abortions, septic pelvic thrombophlebitis, and postsurgical wound infections.

Pelvic inflammatory disease is associated in 30–40% of cases with anaerobes; these infections and their sequelae result in high rates of infertility, ectopic pregnancy, and premature delivery.

Anaerobic pathogens encountered are Peptostreptococcus spp., Prevotella spp., Porphyromonas spp., and members of the clostridia family. B fragilis is not usually involved in gyneco-obstetric infections but, when present, carries a poor prognosis. Actinomyces spp. and Eubacterium nodatum are associated with infections in women with intra-uterine contraceptive devices. In addition to targeting anaerobes, antimicrobial treatment should cover aerobic bacteria as well as atypical organisms such as chlamydia.

Clinical Findings

  1. Signs and Symptoms.Clues to anaerobic pelvic infection are foul smelling discharge, presence of gas in tissues, and septic thrombophlebitis.
  2. Laboratory Findings.The diagnosis of bacterial vaginosis is suggested by secretions with a pH of > 4.5, a “fishy” odor when treated with 10% hydrogen peroxide, and visualization of “clue” cells.

SKIN, SOFT TISSUE, & BONE INFECTIONS

A wide variety of infections at these sites involve anaerobic bacteria. Specific pathogens depend on the mechanism of injury disrupting normal skin barrier defenses as well as on the state of the host's immune system. Infections can be localized or widespread and life threatening and may invade deep structures such as bone.

Bite wounds and clenched fist injuries often involve anaerobes, but antibiotic coverage must also include oral aerobic organisms, in particular, Eikinella corrodens in human bites and Pasteurella multocida in animal bites. Infected decubitus ulcers, pilonidal and sebaceous cysts, diabetic foot and burn wound infections, breast abscesses, and paronychia (mainly in children who suck their thumbs) have a polymicrobial flora in which anaerobes are present.

Involvement of the fascia leads to serious infections including necrotizing fasciitis and soft tissue gas gangrene (associated with C perfringens). When the perineal and scrotal regions are affected, this syndrome is known as Fournier's gangrene.

Clinical Findings

  1. Signs and Symptoms.Signs and symptoms in general range from pain, erythema, swelling, and suppuration at the site of infection to bacteremia, sepsis syndrome, and tissue crepitance in the most serious cases. The absence of fever may reflect overwhelming infection.
  2. Laboratory Findings.Microbiologic diagnosis is difficult and superficial swabs are usually not helpful. Deep tissue specimens obtained surgically are preferred in severe cases or when prolonged therapy is anticipated. The organisms that are most frequently encountered in diabetic foot and decubitus ulcer infections include B fragilis, Fusobacteriumspp., Prevotella melaninogenica, Porphyromonas, Peptostreptococcus, and members of the Clostridium genus. Gas gangrene is associated with C perfringens and C septicum. Necrotizing fasciitis involves Bacteroides spp. as well as clostridia.

BACTEREMIA

Anaerobes cause from 5 to 10% of all bacteremias. B fragilis and related species account for 60–80% of all cases, followed by clostridia and peptostreptococci. Organisms such as Propionibacterium usually represent contamination of blood cultures by skin organisms. For true bacteremias, the common portals of entry are the gastrointestinal tract, female genital tract, lower respiratory tract, head and neck, and skin. Fewer than 5% of neutropenic bacteremias are secondary to anaerobes.

Clinical Findings

  1. Signs and Symptoms.Clinical presentation will depend on the site of primary infection and can include fever, chills, and malaise. As previously mentioned, clostridial bacteremias should prompt the search for colonic malignancies.

OSTEOMYELITIS

It is not uncommon to find anaerobes in cases in which the predisposing factor is vascular insufficiency as in diabetic foot ulcers. Other examples are skull or facial bone infections arising from chronic otitis media, sinusitis, or mastoiditis. Clinically, these infections tend to run indolent courses and may occasionally present with foul smelling drainage through sinus tracts. Gram-negative bacilli and peptostreptococci are frequently involved.

TOXIN-MEDIATED INFECTIONS

  1. 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 59-2), 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

  1. 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.

BOX 59-2 Treatment of Infections Caused by Anaerobes1

Group

First Choice

Alternatives

Comments

Anaerobic Gram-Negative Bacilli

Metronidazole, 500 mg IV every 6 h

Clindamycin, 900 mg IV every 8 h

Fusobacterium spp. sensitive to penicillin G; carbapenems2 or β-lactam–β-lactamase inhibitor combinations3 also effective

Anaerobic Gram-Negative Cocci (Veillonella spp.)

Penicillin G, 10–24 million U IV, continuous infusion or every 4–6 h interval dosing

Clindamycin, 900 mg IV every 8 h

Metronidazole activity unpredictable; not recommended for treatment

Anaerobic Gram-Positive Nonspore-Forming Bacilli

Penicillin G, 10–24 million U IV, continuous infusion or every 4–6 h interval dosing

Clindamycin, 900 mg IV every 8 h

Widespread resistance to metronidazole

Anaerobic Gram-Positive Spore-Forming Bacilli (Clostridium spp.)

Penicillin G, 10–24 million U IV, continuous infusion or every 4–6 h interval dosing

Metronidazole, 500 mg IV every 6 h

In resistant organisms, carbapenems2 or β-lactam–β-lactamase inhibitors3effective

Anaerobic Gram-Positive Cocci

Penicillin G, 10–24 million U IV, continuous infusion or every 4–6 h interval dosing

Clindamycin, 900 mg IV every 8 h

 

Antibiotic-Associated Colitis

Metronidazole, 250 mg orally three times a day (7–14 days)

Vancomycin, 125 mg orally four times a day (7–10 days)

Stop other antibiotics if possible

1Combination therapy directed against concomitant aerobic pathogens is of paramount importance in successful treatment of anaerobic infections; other agents used will depend on specific infection sites and resistance patterns of other organisms. All dosing information is for adult patients with normal renal and hepatic functions. Pediatric dosing: penicillin G, 25, 000 U/kg/d; metronidazole, 30 mg/kg/d; clindamycin, 25 mg/kg/d (in patients with normal renal and hepatic functions).
2Imipenem, 500 mg IV every 6 h, or meropenem, 1 g IV every 8 h if resistance to other first-line agents is encountered.
3Ticarcillin-clavulanic acid, 3.1 g IV every 6 h; piperacillin-tazobactam, 3.375 g IV every 6 h; ampicillin-sulbactam, 1.5–3.0 g IV every 6 h; amoxicillin-clavulanic acid, 500 mg orallyevery 8 h.

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 59-2). When autonomic dysfunction is present, alpha and beta adrenergic blocking agents are recommended.

  1. 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

  1. 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.

  1. Laboratory Findings.Besides clinical findings and careful history, stool and serum toxin assays help establish the diagnosis.
  2. Differential Diagnosis.Differential diagnosis of botulism includes myasthenia gravis, Lambert-Eaton paraneoplastic syndrome, and Guillain-Barré 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.

  1. 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

  1. Signs and Symptoms.Clinical presentation ranges from mild diarrhea to toxic megacolon. Fever is present frequently, and pseudomembrane formation is characteristic.
  2. 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 59-2). 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.

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 59-2). Drainage of abscesses and surgical débridement 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 theincreasing frequency of β-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.

BOX 59-3 Prevention and Control of Anaerobic Infections

· Thorough cleansing and débridement of wounds

· Avoid contamination of sterile sites with “normal” flora from adjacent structures

· Ensuring good vascular supply to tissues

· Minimize use of broad-spectrum antibiotics

· Prevent aspiration of oropharyngeal contents into lower airways

· Attempt to reduce duration of labor (in the case of obstetrical infections)

· Immunization (see Table 59-1) and, when appropriate, toxin neutralization

The combination of β-lactams with β-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 β-lactam and β-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 débridement of wounds decreases the risk of soft tissue infections. Ensuring adequate vascular supply is also important in these situations.

Table 59-2. Tetanus immunization.

Active Immunization

· DTP (diphtheria, pertussis, tetanus): Recommended doses (IM) should be given at 2, 4, 6, and 15–18 mo, and at 4–6 years of age.

· DT (diphtheria, tetanus): Recommended for patients above 7 years old; 2 doses (IM) 4–8 weeks apart and a third dose 6–12 mo later confer immunity for at least 5 years; boosters should be given to all patients every 10 years and more frequently if high-risk activities have occurred
Passive Immunization
Human tetanus immunoglobulin (500 IU IM) may shorten the duration and lessen the severity of tetanus cases; should be administered prophylactically to patients not immunized during the previous 5 years who have a tetanus-prone wound or if immunodeficiency is suspected; active immunization should also be initiated at the time the immunoglobulin is given

In C tetani infections, active, and in some cases passive, immunization are important (Table 59-2). 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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