Jorge Villacian MD
James Steckelberg MD
Essentials of Diagnosis
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).
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:
Table 59-1. Important anaerobic bacteria.
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.
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
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
This site is heavily colonized with anaerobes. Consequently, many infections involving oral cavity structures as well as the pharyngeal spaces involve anaerobic bacteria.
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.
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.
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.
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.
Aspiration of oral and dental flora results in anaerobic pleuropulmonary infections. Predisposing conditions are alterations in mental status, gingivitis, and periodontal disease.
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).
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.
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.
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.
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.
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.
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.
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.
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.
BOX 59-2 Treatment of Infections Caused by Anaerobes1
Diagnosis of tetanus is made clinically; conditions that might have similar features are strychnine poisoning and dystonic reactions.
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.
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:
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.
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.
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.
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
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.
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.
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.
Aldridge KE: The occurrence, virulence and antimicrobial resistance of anaerobes in polymicrobial infections. Am J Surg 1995;169(Suppl 5A):2S.
Bokkenheuser V: The friendly anaerobes. CID 1993;16 (Suppl 4):S427.
Bonten M: Diagnosis and treatment of nosocomial pneumonia. Br Jr Hosp Med 1995;57(7):335.
Connor DH et al (editors): Pathology of Infectious Diseases, Appleton & Lange, 1997.
Eschenbach DA: Bacterial vaginosis and anaerobes in obstetric-gynecologic infection. Curr Inf Dis 1993;16 (Suppl 4):S282.
Finegold SM: Overview of clinically important anaerobes. Curr Inf Dis 1995;20(Suppl 2):S205.
Finegold SM et al: Current perspectives on anaerobic infections: Diagnostic approaches. Inf Dis Clin North Am 1993;7(2):257.
Goldstein EJC: Selected nonsurgical anaerobic infections: Therapeutic choices and the effective armamentarium. Curr Inf Dis 1994;18(Suppl 4):S273.
Gorbach SL: Antibiotic treatment of anaerobic infections. Curr Inf Dis 1994;18(Suppl 4):S305.
Gorbach SL et al (editors): Infectious Diseases. WB Saunders, 1992.
Mandell G et al (editors): Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.
Murray PR et al: Manual of Clinical Microbiology, 6th ed. ASM Press, 1995.
Rosenblatt JE: Clinical relevance of susceptibility testing of anaerobic bacteria. Curr Inf Dis 1993;16(Suppl 4):S446.
Sanders CV, Aldridge KE: Current antimicrobial therapy of anaerobic infections. Eur J Clin Microbiol Infect Dis 1992;11(11):999.