Anaerobic bacteria are organisms that require reduced oxygen tension for growth, failing to grow on the surface of solid media in 10% CO2 in air. (In contrast, microaerophilic bacteria can grow in an atmosphere of 10% CO2 in air or under anaerobic or aerobic conditions, although they grow best in the presence of only a small amount of atmospheric oxygen, and facultative bacteria can grow in the presence or absence of air.) This chapter describes infections caused by nonsporulating anaerobic bacteria. Most clinically relevant anaerobes, such as Bacteroides fragilis, Prevotella melaninogenica, and Fusobacterium nucleatum, are relatively aerotolerant. Although they can survive for sustained periods in the presence of up to 2–8% oxygen, generally they do not multiply in this environment. A far smaller number of pathogenic anaerobic bacteria (which are also part of the normal flora) die after brief contact with oxygen, even in low concentrations.
Most human mucocutaneous surfaces harbor a rich indigenous flora composed of aerobic and anaerobic bacteria. These surfaces are dominated by anaerobic bacteria, which often account for 99.0–99.9% of the culturable flora and range in concentration from 109/mL in saliva to 1012/mL in gingival scrapings and the colon. Most of the normal anaerobic flora cannot be grown or characterized by current laboratory methods. The major reservoirs of these bacteria are the mouth, lower gastrointestinal tract, skin, and female genital tract (Table 164-1). In the oral cavity, the ratio of anaerobic to aerobic bacteria ranges from 1:1 on the surface of a tooth to 1000:1 in the gingival crevices. Anaerobic bacteria are not found in appreciable numbers in the normal upper intestine until the distal ileum. In the colon, the proportion of anaerobes increases significantly, as does the overall bacterial count; for example, there are 1011–1012 organisms per gram of stool, and >99% of these organisms are anaerobic, with an anaerobe-to-aerobe ratio of ∼1000:1. In the female genital tract, there are ∼109 organisms per milliliter of secretions, with an anaerobe-to-aerobe ratio of ∼10:1.
Table 164-1 Anaerobic Human Flora: An Overview |Favorite Table|Download (.pdf)
Table 164-1 Anaerobic Human Flora: An Overview
|Anatomic Site||Total Bacteriaa||Anaerobic/Aerobic Ratio||Potential Pathogens|
|Fusobacterium nucleatum, Prevotella melaninogenica, Prevotella oralis group, Bacteroides ureolyticus group, Peptostreptococcus spp.|
Terminal ileum and colon
|Bacteroides spp. (principally members of the B. fragilis group), Prevotella spp., Clostridium spp., Peptostreptococcus spp.|
|Female genital tract||107–109||10:1||Peptostreptococcus spp., Bacteroides spp., Prevotella bivia|
Commensal anaerobes have been implicated as crucial mediators of physiologic, metabolic, and immunologic functions of the mammalian host. One of the most important roles that anaerobes serve as components of the normal colonic flora is colonization resistance, in which their presence effectively interferes with colonization by potentially pathogenic bacterial species through the depletion of oxygen and nutrients, the production of enzymes and toxic end products, and the modulation of the host's intestinal innate immune response. Bacteroides and other intestinal bacteria ferment carbohydrates and produce volatile fatty acids that are reabsorbed and used by the host as an energy source. The anaerobic intestinal microflora is also responsible for the production of secreted products that promote human health (e.g., vitamin K and bile acids).
The anaerobic intestinal flora influences the development of an intact mucosa and of mucosa-associated lymphoid tissue. Colonization of germ-free mice with a single species, Bacteroides thetaiotaomicron, affects the expression of various host genes and corrects deficiencies of nutrient uptake, metabolism, angiogenesis, mucosal barrier function, and enteric nervous system development. The symbiosis factor polysaccharide A of B. fragilis influences the normal development and function of the mammalian immune system and protects mice against colitis in a model of inflammatory bowel disease.
Hundreds of species of anaerobic bacteria have been identified as part of the normal flora of humans. Despite the complex array of bacteria in the normal flora, relatively few species are isolated commonly from human infection. Anaerobic infections occur when the harmonious relationship between the host and the bacteria is disrupted. Any site in the body is susceptible to infection with these indigenous organisms when a mucosal barrier or the skin is compromised by surgery, trauma, tumor, ischemia, or necrosis, all of which can reduce local tissue redox potentials. Because the sites that are colonized by anaerobes contain many species of bacteria, disruption of anatomic barriers allows the penetration of many organisms, resulting in mixed infections involving multiple species of anaerobes combined with facultative or microaerophilic organisms. Such mixed infections are seen in the head and neck (chronic sinusitis, chronic otitis media, Ludwig's angina, and periodontal abscesses). Brain abscesses and subdural empyema are the most common anaerobic infections of the central nervous system (CNS). Anaerobes are responsible for pleuropulmonary diseases such as aspiration pneumonia, necrotizing pneumonia, lung abscess, and empyema. These organisms also play an important role in various intraabdominal infections, such as peritonitis and intraabdominal and hepatic abscesses (Chap. 127). They are isolated frequently in female genital tract infections, such as salpingitis, pelvic peritonitis, tuboovarian abscess, vulvovaginal abscess, septic abortion, and endometritis (Chap. 130). Anaerobic bacteria are also found often in bacteremia and in infections of the skin, soft tissues, and bones.
The taxonomic classification of anaerobes is rapidly evolving, with frequent changes in nomenclature based on newly discovered relationships among bacterial species. Infections caused by anaerobic bacteria most frequently are due to more than one organism. These polymicrobial infections may be caused by one or several anaerobic species or by a combination of anaerobic organisms and microaerophilic or facultative bacteria acting synergistically. The major anaerobic gram-positive cocci that produce disease are Peptostreptococcus species; the major species of this genus that are involved in infections are P. micros, P. magnus, P. asaccharolyticus, P. anaerobius, and P. prevotii. Clostridia (Chap. 142) are spore-forming gram-positive rods that are isolated from wounds, abscesses, sites of abdominal infection, and blood. Gram-positive anaerobic non-spore-forming bacilli are uncommon as etiologic agents of human infection. Propionibacterium acnes, a component of the skin flora and a rare cause of foreign-body infections, is one of the few nonclostridial gram-positive rods associated with infections. The principal anaerobic gram-negative bacilli found in human infections are the B. fragilis group as well as Fusobacterium, Prevotella, and Porphyromonas species.
The most important potential anaerobic pathogens found in the upper airways and isolated from clinical specimens of oral and pleuropulmonary infections are the Fusobacterium species F. necrophorum, F. nucleatum, and F. varium; P. melaninogenica; the Prevotella oralis group; Porphyromonas gingivalis; Porphyromonas asaccharolytica; Peptostreptococcus species; and the Bacteroides ureolyticus group.
The B. fragilis group contains the anaerobic pathogens most frequently isolated from clinical infections. Members of this group are part of the normal bowel flora; they include several distinct species, such as B. fragilis, B. thetaiotaomicron, B. vulgatus, B. uniformis, B. ovatus, and Parabacteroides distasonis. B. fragilis is the most important clinical isolate, although it is isolated in lower numbers than some other Bacteroides species from cultures of commensal fecal flora.
In female genital tract infections, organisms normally colonizing the vagina (e.g., Prevotella bivia and Prevotella disiens) are the most common isolates. However, B. fragilis is not uncommon.
Anaerobic bacterial infections usually occur when an anatomic barrier is disrupted and constituents of the local flora enter a site that was previously sterile. Because of the specific growth requirements of anaerobic organisms and their presence as commensals on mucosal surfaces, conditions must arise that allow these organisms to penetrate mucosal barriers and enter tissue with a lowered oxidation-reduction potential. Therefore, tissue ischemia, trauma, surgery, perforated viscus, shock, and aspiration provide environments conducive to the proliferation of anaerobes. The introduction of many bacterial species into otherwise-sterile sites leads to a polymicrobial infection in which certain organisms predominate. Three major factors are involved in the pathogenesis of anaerobic infections: bacterial synergy, bacterial virulence factors, and mechanisms of abscess formation. The ability of different anaerobic bacteria to act synergistically during polymicrobial infection contributes to the pathogenesis of anaerobic infections. It has been postulated that facultative organisms function in part to lower the oxidation-reduction potential in the microenvironment, allowing the propagation of obligate anaerobes. Anaerobes can produce compounds such as succinic acid and short-chain fatty acids that inhibit the ability of phagocytes to clear facultative organisms. In experimental models, facultative and obligate anaerobes synergistically potentiate abscess formation. Virulence factors associated with anaerobes typically confer the ability to evade host defenses, adhere to cell surfaces, produce toxins and/or enzymes, or display surface structures such as capsular polysaccharides and lipopolysaccharide (LPS) that contribute to pathogenic potential. The ability of an organism to adhere to host tissues is important to the establishment of infection. Some oral species adhere to the epithelium in the oral cavity. P. melaninogenica actually attaches to other microorganisms. P. gingivalis, a common isolate in periodontal disease, has fimbriae that facilitate attachment. Some Bacteroides strains appear to be piliated, a characteristic that may account for their ability to adhere.
The most extensively studied virulence factor of the nonsporulating anaerobes is the capsular polysaccharide complex of B. fragilis. This organism is unique among anaerobes in its potential for virulence during growth at normally sterile sites. Although it constitutes only 0.5–1% of the normal colonic flora, B. fragilis is the anaerobe most commonly isolated from intraabdominal infections and bacteremia. One polysaccharide of B. fragilis, polysaccharide A, has a unique zwitterionic motif of charged sugars that confers distinct biologic properties, such as the ability to promote abscess formation. Intraabdominal abscess induction is related to the capacity of this polysaccharide to stimulate the release of cytokines and chemokines—in particular, interleukin (IL) 8, IL-17, and tumor necrosis factor α (TNF-α)—from resident peritoneal cells. The release of cytokines and chemokines results in the chemotaxis of polymorphonuclear neutrophils (PMNs) into the peritoneum, where they adhere to mesothelial cells induced by TNF-α to upregulate their expression of intercellular adhesion molecule 1 (ICAM-1). PMNs adherent to ICAM-1-expressing cells probably represent the nidus for an abscess. Polysaccharide A also activates T cells to produce certain cytokines, including IL-17 and interferon γ, that are necessary for abscess formation. Furthermore, when the same polysaccharide is administered to experimental animals prophylactically or therapeutically, it confers protection against abscess induction after challenge with microorganisms capable of inducing abscesses. This protection is mediated by IL-10-producing T cells.
Anaerobic bacteria produce a number of exoproteins that can enhance the organisms' virulence. The collagenase produced by P. gingivalis may enhance tissue destruction. An enterotoxin has been identified in B. fragilis strains associated with diarrheal disease in animals and young children. Exotoxins produced by clostridial species, including botulinum toxins, tetanus toxin, C. difficile toxins A and B, and five toxins produced by C. perfringens, are among the most virulent bacterial toxins in mouse lethality assays. Anaerobic gram-negative bacteria such as B. fragilis possess LPSs (endotoxins) that are 100–1000 times less biologically potent than endotoxins associated with aerobic gram-negative bacteria. This relative biologic inactivity may account for the lower frequency of disseminated intravascular coagulation and purpura in Bacteroides bacteremia than in facultative and aerobic gram-negative bacillary bacteremia. An exception is the LPS from Fusobacterium, which may account for the severity of Lemierre's syndrome.
Approach to the Patient: Infections Due to Mixed Anaerobic Organisms
The physician must consider several points when approaching the patient with presumptive infection due to anaerobic bacteria.
Most of the organisms colonizing mucosal sites are harmless commensals; very few cause disease. When these organisms do cause disease, it often occurs in proximity to the mucosal site they colonize.
For anaerobes to cause tissue infection, they must spread beyond the normal mucosal barriers.
Conditions favoring the propagation of these bacteria, particularly a lowered oxidation-reduction potential, are necessary. These conditions exist at sites of trauma, tissue destruction, compromised vascular supply, and complications of preexisting infection, which produce necrosis.
There is a complex array of infecting flora. For example, as many as 12 types of organisms can be isolated from a suppurative site.
Anaerobic organisms tend to be found in abscess cavities or in necrotic tissue. The failure of an abscess to yield organisms on routine culture is a clue that the abscess is likely to contain anaerobic bacteria. Often smears of this “sterile pus” are found to be teeming with bacteria when Gram's stain is applied. Although some facultative organisms (e.g., Staphylococcus aureus) are also capable of causing abscesses, abscesses in organs or deeper body tissues should call to mind anaerobic infection.
Gas is found in many anaerobic infections of deep tissues but is not diagnostic because it can be produced by aerobic bacteria as well.
Although a putrid-smelling infection site or discharge is considered diagnostic for anaerobic infection, this manifestation usually develops late in the course and is present in only 30–50% of cases.
Some species (the best example being the B. fragilis group) require specific therapy. However, many synergistic infections can be cured with antibiotics directed at some but not all of the organisms involved. Antibiotic therapy, combined with debridement and drainage, disrupts the interdependent relationship among the bacteria, and some species that are resistant to the antibiotic do not survive without the co-infecting organisms.
Manifestations of severe sepsis and disseminated intravascular coagulation are unusual in patients with purely anaerobic infection.
Difficulties in the performance of appropriate cultures, contamination of cultures by components of the normal flora, and the lack of readily available, reliable culture techniques have made it impossible to obtain accurate data on incidence or prevalence. However, anaerobic infections are encountered frequently in hospitals with active surgical, trauma, and obstetric and gynecologic services. Depending on the institution, anaerobic bacteria account for 0.5–12% of all cases of bacteremia.
Anaerobic Infections of the Mouth, Head, and Neck
(See also Chap. 31) Anaerobic bacteria are commonly involved in infections of the mouth, head, and neck. The predominant isolates are components of the normal flora of the upper airways—mainly the Bacteroides oralis group, pigmented Prevotella species, P. asaccharolytica, Fusobacterium species, peptostreptococci, and microaerophilic streptococci.
Soft tissue infections of the oral-facial area may or may not be odontogenic. Odontogenic infections—primarily dental caries and periodontal disease (gingivitis and periodontitis)—are common and have both local consequences (especially tooth loss) and the potential for life-threatening spread to the deep fascial spaces of the head and neck. Infections of the mouth can arise from either a supragingival or a subgingival dental plaque composed of bacteria colonizing the tooth surface. Supragingival plaque formation begins with the adherence of gram-positive bacteria to the tooth surface. This form of plaque is influenced by salivary and dietary components, oral hygiene, and local host factors. Supragingival plaque can lead to dental caries and, with further invasion, to pulpitis (endodontic infection) that can further perforate the alveolar bone, causing periapical abscess. Subgingival plaque is associated with periodontal infections (e.g., gingivitis, periodontitis, and periodontal abscess) that can further disseminate to adjacent structures such as the mandible, causing osteomyelitis of the maxillary sinuses. Periodontitis may also result in spreading infection that can involve adjacent bone or soft tissues. In the healthy periodontium, the sparse microflora consists mainly of gram-positive organisms such as Streptococcus sanguinis and Actinomyces species. In the presence of gingivitis, there is a shift to a greater proportion of anaerobic gram-negative bacilli in the subgingival flora, with predominance of Prevotella intermedia. In well-established periodontitis, the complexity of the flora increases further. The predominant isolates are P. gingivalis, P. intermedia, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Treponema denticola, and Tannerella forsythensis.
Necrotizing Ulcerative Gingivitis
Gingivitis may become a necrotizing infection (trench mouth, Vincent's stomatitis). The onset of disease is usually sudden and is associated with tender bleeding gums, foul breath, and a bad taste. The gingival mucosa, especially the papillae between the teeth, becomes ulcerated and may be covered by a gray exudate, which is removable with gentle pressure. Patients may become systemically ill, developing fever, cervical lymphadenopathy, and leukocytosis. Occasionally, ulcerative gingivitis can spread to the buccal mucosa, the teeth, and the mandible or maxilla, resulting in widespread destruction of bone and soft tissue. This infection is termed acute necrotizing ulcerative mucositis (cancrum oris, noma). It destroys tissue rapidly, causing the teeth to fall out and large areas of bone—or even the whole mandible—to be sloughed. A strong putrid odor is frequently detected, although the lesions are not painful. The gangrenous lesions eventually heal, leaving large disfiguring defects. This infection most commonly follows a debilitating illness or affects severely malnourished children. It has been known to complicate leukemia or to develop in individuals with a genetic deficiency of catalase.
Acute Necrotizing Infections of the Pharynx
These infections usually occur in association with ulcerative gingivitis. Symptoms include an extremely sore throat, foul breath, and a bad taste accompanied by fever and a sensation of choking. Examination of the pharynx demonstrates that the tonsillar pillars are swollen, red, ulcerated, and covered with a grayish membrane that peels easily. Lymphadenopathy and leukocytosis are common. The disease may last for only a few days or, if not treated, may persist for weeks. Lesions begin unilaterally but may spread to the other side of the pharynx or the larynx. Aspiration of the infected material by the patient can result in lung abscesses.
Peripharyngeal Space Infections
These infections arise from the spread of organisms from the upper airways to potential spaces formed by the fascial planes of the head and neck. The etiology is typically polymicrobial and represents the normal flora of the mucosa of the originating site.
Peritonsillar abscess (quinsy) is a complication of acute tonsillitis caused mainly by a mixed flora containing anaerobes and group A Streptococcus. In submandibular space infection (Ludwig's angina), 80% of cases are caused by infection of the tissues surrounding the second and third molar teeth. This infection results in marked local swelling of tissues, with pain, trismus, and superior and posterior displacement of the tongue. Submandibular swelling of the neck can impair swallowing and cause respiratory obstruction. In some cases, tracheotomy may be life-saving. Cervicofacial actinomycosis (Chap. 163) is caused by a branching, gram-positive, non-spore-forming, strict/facultative anaerobe that is a part of the normal oral flora. This chronic disease is characterized by abscesses, draining sinus tracts, fistula, bone destruction, and fibrosis. It can easily be mistaken for malignancy or granulomatous disease. Actinomycosis less frequently involves the thorax, abdomen, pelvis, and CNS.
Anaerobic bacteria have been implicated in chronic sinusitis but play little role in acute sinusitis. In several studies on chronic sinusitis, anaerobic bacteria were found in 12–93% of cases, depending on the method used to collect specimens. Predominant isolates were pigmented Prevotella, Fusobacterium, and Peptostreptococcus species. Aerobic gram-negative bacilli and S. aureus have also been implicated in chronic sinusitis. Polymicrobial infection is common and may be synergistic.
Anaerobic bacteria are much more easily implicated in chronic suppurative otitis media than in acute otitis media. Purulent exudate from chronically draining ears has been found to contain anaerobes, particularly Bacteroides species, in up to 50% of cases. B. fragilis has been isolated from up to 28% of patients with chronic otitis media.
Complications of Anaerobic Head and Neck Infections
Contiguous cranial spread of these infections may result in osteomyelitis of the skull or mandible or in intracranial infections such as brain abscess and subdural empyema. Caudal spread can produce mediastinitis or pleuropulmonary infection. Hematogenous complications may also result from anaerobic infections of the head and neck. Bacteremia, which occasionally is polymicrobial, can lead to endocarditis or other distant infections. Lemierre's syndrome, which has been uncommon in the antimicrobial era, is an acute oropharyngeal infection with secondary septic thrombophlebitis of the internal jugular vein and frequent metastasis, most commonly to the lung. F. necrophorum is the usual cause. This infection typically begins with pharyngitis, which is followed by local invasion in the lateral pharyngeal space with resultant internal jugular vein thrombophlebitis. A typical clinical triad seen in recent series is pharyngitis, a tender/swollen neck, and noncavitating pulmonary infiltrates.
CNS infections associated with anaerobic bacteria are brain abscess (Chap. 381), epidural abscess, and subdural empyema. Anaerobic meningitis is rare and is usually related to parameningeal collection or shunt infection. If optimal bacteriologic techniques are employed, as many as 85% of brain abscesses yield anaerobic bacteria, which usually originate from otorhinolaryngeal infection. However, intraabdominal or pelvic infections can occasionally lead to bacteremia with an anaerobic organism that seeds the cerebral cortex. Commonly isolated are Peptostreptococcus, Fusobacterium, Bacteroides, Prevotella, Propionibacterium, Eubacterium, Veillonella, and Actinomyces species. Facultative or microaerophilic streptococci and coliforms are often part of a mixed infecting flora in brain abscesses.
Anaerobic pleuropulmonary infections result from the aspiration of oropharyngeal contents, often in the context of an altered state of consciousness or an absent gag reflex. Four clinical syndromes are associated with anaerobic pleuropulmonary infection produced by aspiration: simple aspiration pneumonia, necrotizing pneumonia, lung abscess, and empyema. Many of these infections have an indolent course that may serve as a clinical clue differentiating them, for example, from pneumococcal pneumonia, which often presents with abrupt onset, shaking chills, and rapid progression.
Bacterial aspiration pneumonitis must be distinguished from two other clinical syndromes associated with aspiration that are not of bacterial etiology. One syndrome results from aspiration of solids, usually food. Obstruction of major airways typically results in atelectasis and moderate nonspecific inflammation. Therapy consists of removal of the foreign body.
The second aspiration syndrome is more easily confused with bacterial aspiration. Mendelson's syndrome, a chemical pneumonitis, results from regurgitation of stomach contents and aspiration of chemical material, usually acidic gastric juices. Pulmonary inflammation—including the destruction of the alveolar lining, with transudation of fluid into the alveolar space—occurs with remarkable rapidity. Typically this syndrome develops within hours, often following anesthesia when the gag reflex is depressed. The patient becomes tachypneic, hypoxic, and febrile. The leukocyte count may rise, and the chest x-ray may evolve suddenly from normal to a complete bilateral “whiteout” within 8–24 h. Sputum production is minimal. The pulmonary signs and symptoms can resolve quickly with symptom-based therapy or can culminate in respiratory failure, with the subsequent development of bacterial superinfection over a period of days. Antibiotic therapy is not indicated unless bacterial infection supervenes.
In contrast to these syndromes, bacterial aspiration pneumonia develops over a period of several days or weeks rather than hours. It is seen in patients who are hospitalized and have a depressed gag reflex, impaired swallowing, or a tracheal or nasogastric tube; elderly patients; and patients with transiently impaired consciousness in the wake of seizures, cerebrovascular accidents, or alcoholic blackouts. Patients who enter the hospital with this syndrome typically have been ill for several days and generally report low-grade fever, malaise, and sputum production. In some patients, weight loss and anemia reflect a more chronic process. Usually the history reveals factors predisposing to aspiration, such as alcohol overdose or residence in a nursing home. Examination sometimes yields evidence of periodontal disease. Sputum characteristically is not malodorous unless the process has been under way for at least a week. A mixed bacterial flora with many PMNs is evident on Gram's staining of sputum. Expectorated sputum is unreliable for anaerobic cultures because of inevitable contamination by normal oral flora. Reliable specimens for culture can be obtained by transtracheal or transthoracic aspiration—techniques that are rarely used at present. Culture of protected-brush specimens or bronchoalveolar lavage fluid obtained by bronchoscopy is controversial.
Chest x-rays show consolidation in dependent pulmonary segments: in the basilar segments of the lower lobes if the patient has aspirated while upright and in either the posterior segment of the upper lobe (usually on the right side) or the superior segment of the lower lobe if the patient has aspirated while supine. The organisms isolated from the lungs reflect the pharyngeal flora; pigmented and nonpigmented Prevotella species, Peptostreptococcus species, Bacteroides species, Fusobacterium species, and anaerobic cocci are the most common isolates. While most patients with aspiration pneumonia acquired in the community have a mixed infection caused by anaerobes and aerobic or microaerophilic streptococci, the patient who aspirates in the hospital may also have a mixed infection involving enteric gram-negative rods. In a study on the microbiology of severe aspiration pneumonia in institutionalized elderly patients, gram-negative bacilli were cultured in 49% of cases (with an anaerobe also recovered in 14% of this group), anaerobes in 16%, and S. aureus in 12%.
This form of anaerobic pneumonitis is characterized by numerous small abscesses that spread to involve several pulmonary segments. The process can be indolent or fulminating. This syndrome is less common than either aspiration pneumonia or lung abscess and includes features of both types of infection.
These abscesses result from subacute anaerobic pulmonary infection. The clinical syndrome typically involves a history of constitutional signs and symptoms (including malaise, weight loss, fever, night sweats, and foul-smelling sputum), perhaps over a period of weeks (Chap. 257). Patients who develop lung abscesses characteristically have dental infection and periodontitis, but lung abscesses in edentulous patients have been reported. Abscess cavities may be single or multiple and generally occur in dependent pulmonary segments (Fig. 164-1). Anaerobic abscesses must be distinguished from lesions associated with tuberculosis, neoplasia, and other conditions. Oral anaerobes predominate and are found in 60–80% of cases. There is also an important role for microaerophilic streptococci such as S. milleri. S. aureus and enteric gram-negative bacilli may be found as well. Septic pulmonary emboli may originate from intraabdominal or female genital tract infections and can produce anaerobic pneumonia and abscess.
Chest radiograph of right-lower-lobe lung abscess in a 60-year-old alcoholic patient. [From GL Mandell (ed): Atlas of Infectious Diseases, Vol VI. Philadelphia, Current Medicine Inc, Churchill Livingstone, 1996; with permission.]
Empyema is a manifestation of long-standing anaerobic pulmonary infection. The clinical presentation, which includes foul-smelling sputum, resembles that of other anaerobic pulmonary infections. Patients may report pleuritic chest pain and marked chest-wall tenderness.
Empyema may be masked by overlying pneumonitis and should be considered especially in cases of persistent fever despite antibiotic therapy. Diligent physical examination and the use of ultrasound to localize a loculated empyema are important diagnostic tools. The collection of a foul-smelling exudate by thoracentesis is typical. Cultures of infected pleural fluid yield an average of 3.5 anaerobic and 0.6 facultative or aerobic bacterial species. Drainage is required. Defervescence, a return to a feeling of well-being, and resolution of the process may require several months.
Extension from a subdiaphragmatic infection may also result in anaerobic empyema.
Intraabdominal infections—mainly peritonitis and abscesses—are usually polymicrobial and represent the normal intestinal (especially colonic) flora. These infections usually follow a breach in the mucosal barrier resulting from appendicitis, diverticulitis, neoplasm, inflammatory bowel disease, surgery, or trauma. On average, four to six bacterial species are isolated per specimen submitted to the microbiology laboratory, with a predominance of enteric aerobic/facultative gram-negative bacilli, anaerobes, and streptococci/enterococci. The most common isolates are Escherichia coli (found in ⩾50% of patients) and B. fragilis (30–50%). Disease originating from proximal-bowel perforation reflects the flora of this site, with a predominance of aerobic and anaerobic gram-positive bacteria and Candida.
Enterotoxigenic B. fragilis has been associated with watery diarrhea in a few young children and adults. In case-control studies of children with undiagnosed diarrheal disease, enterotoxigenic B. fragilis was isolated from significantly more children with diarrhea than children in the control group. Neutropenic enterocolitis (typhlitis) has been associated with anaerobic infection of the cecum but—in the setting of neutropenia (Chap. 86)—may involve the entire bowel. Patients usually present with fever; abdominal pain, tenderness, and distention; and watery diarrhea. The bowel wall is edematous with hemorrhage and necrosis. The primary pathogen is thought by some authorities to be Clostridium septicum, but other clostridia and mixed anaerobes have also been implicated. More than 50% of patients developing early clinical signs can benefit from antibiotic therapy and bowel rest. Surgery is sometimes required to remove gangrenous bowel. See Chap. 127 for a complete discussion of intraabdominal infections.
The vagina of a healthy woman is a major reservoir of anaerobic and aerobic bacteria. In the normal flora of the female genital tract, anaerobes outnumber aerobes by a ratio of ∼10:1 and include anaerobic gram-positive cocci and Bacteroides species (Table 164-1). Anaerobes are isolated from most women with genital tract infections that are not caused by a sexually transmitted pathogen. The major anaerobic pathogens are B. fragilis, P. bivia, P. disiens, P. melaninogenica, anaerobic cocci, and Clostridium species. Anaerobes are frequently encountered in Bartholin gland abscess, salpingitis, tuboovarian abscess, septic abortion, pyometra, endometritis, and postoperative wound infection, particularly following hysterectomy. These infections are often of mixed etiology, involving both anaerobes and coliforms; pure anaerobic infections without coliform or other facultative bacterial species occur more often in pelvic than in intraabdominal sites. Suppurative thrombophlebitis of the pelvic veins may complicate the infections and lead to repeated episodes of septic pulmonary emboli. See Chap. 130 for a complete discussion of pelvic inflammatory disease.
Anaerobic bacteria have been thought to be contributing factors in the etiology of bacterial vaginosis. This syndrome of unknown etiology is characterized by a profuse malodorous discharge and a change in the bacterial ecology that results in replacement of the Lactobacillus-dominated normal flora with an overgrowth of bacterial species including Gardnerella vaginalis, Prevotella species, Mobiluncus species, peptostreptococci, and genital mycoplasmas. A study based on 16S rRNA identification found other anaerobes that were predominant in cases but not in controls: Atopobium, Leptotrichia, Megasphaera, and Eggerthella. Pelvic infections due to Actinomyces species have been associated with the use of intrauterine devices (Chap. 163).
Skin and Soft Tissue Infections
Injury to skin, bone, or soft tissue by trauma, ischemia, or surgery creates a suitable environment for anaerobic infections. These infections are most frequently found in sites prone to contamination with feces or with upper airway secretions—e.g., wounds associated with intestinal surgery, decubitus ulcers, or human bites. Moreover, anaerobes have been isolated from cutaneous abscesses, rectal abscesses, and axillary sweat gland infections (hidradenitis suppurativa). Anaerobes are also frequently cultured from foot ulcers of diabetic patients. The deep soft-tissue infections associated with anaerobic bacteria are crepitant cellulitis, synergistic cellulitis, gangrene, and necrotizing fasciitis (Chaps. 125 and 142).
These soft tissue or skin infections are usually polymicrobial. A mean of 4.8 bacterial species are isolated, with an anaerobe-to-aerobe ratio of ∼3:2. The most frequently isolated organisms include Bacteroides, Peptostreptococcus, Clostridium, Enterococcus, and Proteus species. The involvement of anaerobes in these types of infections is associated with a higher frequency of fever, foul-smelling lesions, gas in the tissues, and visible foot ulcer.
Anaerobic bacterial synergistic gangrene (Meleney's gangrene), a rare infection of the superficial fascia, is characterized by exquisite pain, redness, and swelling followed by induration. Erythema surrounds a central zone of necrosis. A granulating ulcer forms at the original center as necrosis and erythema extend outward. Symptoms are limited to pain; fever is not typical. These infections usually involve a combination of Peptostreptococcus species and S. aureus; the usual site of infection is an abdominal surgical wound or the area surrounding an ulcer on an extremity. Treatment includes surgical removal of necrotic tissue and antimicrobial administration.
Necrotizing fasciitis, a rapidly spreading destructive disease of the fascia, is usually attributed to group A streptococci (Chap. 136) but can also be a mixed infection involving anaerobes and aerobes, usually after surgeries and in patients with diabetes or peripheral vascular disease. The most frequently isolated anaerobes in these infections are Peptostreptococcus and Bacteroides species. Gas may be found in the tissues. Similarly, myonecrosis can be associated with mixed anaerobic infection. Fournier's gangrene consists of cellulitis involving the scrotum, perineum, and anterior abdominal wall, with mixed anaerobic organisms spreading along deep external fascial planes and causing extensive loss of skin.
Bone and Joint Infections
Although actinomycosis (Chap. 163) accounts on a worldwide basis for most anaerobic infections in bone, organisms including peptostreptococci or microaerophilic cocci, Bacteroides species, Fusobacterium species, and Clostridium species can also be involved. These infections frequently arise adjacent to soft tissue infections. Hematogenous seeding of bone is uncommon. Prevotella and Porphyromonas species are detected in infections involving the maxilla and mandible, whereas Clostridium species have been reported as anaerobic pathogens in cases of osteomyelitis of the long bones following fracture or trauma. Fusobacteria have been isolated in pure culture from sites of osteomyelitis adjacent to the perinasal sinuses. Peptostreptococci and microaerophilic cocci have been reported as significant pathogens in infections involving the skull, mastoid, and prosthetic implants placed in bone. In patients with osteomyelitis (Chap. 126), the most reliable culture specimen is a bone biopsy sample free of normal uninfected skin and subcutaneous tissue. In patients with anaerobic osteomyelitis, a mixed flora is frequently isolated from a bone biopsy specimen.
In cases of anaerobic septic arthritis, the most common isolates are Fusobacterium species. Most of the patients involved have uncontrolled peritonsillar infections progressing to septic cervical venous thrombophlebitis (Lemierre's syndrome) and resulting in hematogenous dissemination with a predilection for the joints. Unlike anaerobic osteomyelitis, anaerobic pyoarthritis in most cases is not polymicrobial and may be acquired hematogenously. Anaerobes are important pathogens in infections involving prosthetic joints; in these infections, the causative organisms (such as Peptostreptococcus species and P. acnes) are part of the normal skin flora.
Transient bacteremia is a well-known event in healthy individuals whose anatomic mucosal barriers have been injured (e.g., during dental extractions or dental scaling). These bacteremic episodes, which are often due to anaerobes, have no pathologic consequences. However, anaerobic bacteria are found in cultures of blood from clinically ill patients when proper culture techniques are used. Anaerobes have accounted for 2–5% of all bacteremias, depending on the institution. B. fragilis is the single most common anaerobic isolate from the bloodstream, accounting for 35–80% of anaerobic bacteremias. The rate decreased from the 1970s through the early 1990s. This change may be related to the administration of antibiotic prophylaxis before intestinal surgery, the earlier recognition of localized infections, and the empirical use of broad-spectrum antibiotics for presumed infection. However, anaerobic bacteremia may be reemerging. Comparing two periods (1993–1996 and 2001–2004), investigators at the Mayo Clinics found a 74% increase in the incidence of anaerobic bacteremias per 100,000 patient-days; this finding contrasts with a 45% decrease in incidence from 1977 to 1988 at the same institution.
Once the organism in the blood has been identified, both the portal of bloodstream entry and the underlying problem that probably led to seeding of the bloodstream can often be deduced from an understanding of the organism's normal site of residence. For example, mixed anaerobic bacteremia including B. fragilis usually implies colonic pathology with mucosal disruption from neoplasia, diverticulitis, or some other inflammatory lesion. The initial manifestations are determined by the portal of entry and reflect the localized condition. When bloodstream invasion occurs, patients can become extremely ill, with rigors and hectic fevers. The clinical picture may be quite similar to that seen in sepsis involving aerobic gram-negative bacilli. Although complications of anaerobic bacteremia (e.g., septic thrombophlebitis and septic shock) have been reported, their incidence in association with anaerobic bacteremia is low. Anaerobic bacteremia is potentially fatal and requires rapid diagnosis and appropriate therapy. The mortality rate appears to increase with the age of the patient (with reported rates of >66% among patients >60 years old), with the isolation of multiple species from the bloodstream, and with the failure to surgically remove a focus of infection. The attributable mortality rate for bacteremia associated with the B. fragilis group was examined in a matched case-control study. Patients with B. fragilis–group bacteremia had a significantly higher mortality rate (28% vs 8%), with an attributable mortality rate of 19.3% and a mortality risk ratio of 3.2.
Endocarditis and Pericarditis
(See also Chap. 124) Endocarditis due to anaerobes is uncommon. However, anaerobic streptococci, which are often classified incorrectly, are responsible for this disease more frequently than is generally appreciated. Gram-negative anaerobes are unusual causes of endocarditis. Signs and symptoms of anaerobic endocarditis are similar to those of endocarditis due to facultative organisms. Mortality rates of 21–43% have been reported for anaerobic endocarditis.
Anaerobes, particularly B. fragilis and Peptostreptococcus species, are uncommonly found in infected pericardial fluids. Anaerobic pericarditis is associated with a mortality rate of >50%. Anaerobes can reach the pericardial space by hematogenous spread, by spread from a contiguous site of infection (e.g., heart or esophagus), or by direct inoculation arising from trauma or surgery.
There are three critical steps in the diagnosis of anaerobic infection: (1) proper specimen collection; (2) rapid transport of the specimens to the microbiology laboratory, preferably in anaerobic transport media; and (3) proper handling of the specimens by the laboratory. Specimens must be collected by meticulous sampling of infected sites, with avoidance of contamination by the normal flora. When such contamination is likely, the specimen is unacceptable. Examples of specimens unacceptable for anaerobic culture include sputum collected by expectoration or nasal tracheal suction, bronchoscopy specimens, samples collected directly through the vaginal vault, urine collected by voiding, and feces. Specimens appropriate for anaerobic culture include sterile body fluids such as blood, pleural fluid, peritoneal fluid, cerebrospinal fluid, and aspirates or biopsies from normally sterile sites. As a general rule, liquid or tissue specimens are preferred; swab specimens should be avoided.
Because even brief exposure to oxygen may kill some anaerobic organisms and result in failure to isolate them in the laboratory, air must be expelled from the syringe used to aspirate the abscess cavity, and the needle must be capped with a sterile rubber stopper. It is also important to remember that prior antibiotic therapy reduces cultivability of these bacteria. Specimens can be injected into transport bottles containing a reduced medium or taken immediately in syringes to the laboratory for direct culture on anaerobic media. Delays in transport may lead to a failure to isolate anaerobes due to exposure to oxygen or overgrowth of facultative organisms, which may eliminate or obscure any anaerobes that are present. All clinical specimens from suspected anaerobic infections should be Gram-stained and examined for organisms with characteristic morphology. It is not unusual for organisms to be observed on Gram's staining but not isolated in culture.
Because of the time and difficulty involved in the isolation of anaerobic bacteria, diagnosis of anaerobic infections must frequently be based on presumptive evidence. There are few clinical clues to the probable presence of anaerobic bacteria at infected sites. The involvement of certain sites with lowered oxidation-reduction potential (e.g., avascular necrotic tissues) and the presence of an abscess favor the diagnosis of an anaerobic infection. When infections occur in proximity to mucosal surfaces normally harboring an anaerobic flora, such as the gastrointestinal tract, female genital tract, or oropharynx, anaerobes should be considered as potential etiologic agents. A foul odor is often indicative of anaerobes, which produce certain organic acids as they proliferate in necrotic tissue. Although these odors are nearly pathognomonic for anaerobic infection, the absence of odor does not exclude an anaerobic etiology. Because anaerobes often coexist with other bacteria to cause mixed or synergistic infection, Gram's staining of exudate frequently reveals multiple morphotypes suggestive of anaerobes. Sometimes these organisms have morphologic characteristics associated with specific species.
The presence of gas in tissues is highly suggestive, but not diagnostic, of anaerobic infection. When cultures of obviously infected sites or purulent material yield no growth, streptococci only, or a single aerobic species (such as E. coli) and Gram's staining reveals a mixed flora, the involvement of anaerobes should be suspected; the implication is that the anaerobic microorganisms failed to grow because of inadequate transport and/or culture techniques. Failure of an infection to respond to antibiotics that are not active against anaerobes (e.g., aminoglycosides and—in some circumstances—penicillin, cephalosporins, or tetracyclines) suggests an anaerobic etiology.
Treatment: Anaerobic Infections
Successful therapy for anaerobic infections requires the administration of a combination of appropriate antibiotics, surgical resection, debridement of devitalized tissues, and drainage either surgically or percutaneously (guided by an imaging technique such as CT, MRI, or ultrasound). Any anatomic breach must be closed promptly, closed spaces drained, tissue compartments decompressed, and an adequate blood supply established. Abscess cavities should be drained as soon as fluctuation or localization occurs.
Antibiotic Therapy and Resistance
Decisions about the treatment of anaerobic infections with antibiotics are usually based on known resistance patterns in certain species, on the likelihood of encountering a given species in the case at hand, and on Gram's stain findings. Antibiotics active against clinically relevant anaerobes can be grouped into four categories on the basis of their predicted activity (Table 164-2). (Nearly all the drugs listed have toxic side effects, which are described in detail in Chap. 133.) In many infections, anaerobes are mixed with coliforms and other facultative organisms. The best therapeutic regimens, therefore, are usually those active against both aerobic and anaerobic bacteria. The choice of empirical antibiotics for the anaerobes in mixed infections can nearly always be made reliably, since patterns of antimicrobial susceptibility are usually predictable (Chap. 133 and Table 164-2).
Table 164-2 Antimicrobial Therapy for Infections Involving Commonly Encountered Anaerobic Gram-Negative Rods |Favorite Table|Download (.pdf)
Table 164-2 Antimicrobial Therapy for Infections Involving Commonly Encountered Anaerobic Gram-Negative Rods
|Category 1 (<2% Resistance)||Category 2 (<15% Resistance)||Category 3 (Variable Resistance)||Category 4 (Resistance)|
Carbapenems (imipenem, meropenem, doripenem)
β-Lactam/β-lactamase inhibitor combination (ampicillin/sulbactam, ticarcillin/clavulanic acid, piperacillin/tazobactam)
High-dose antipseudomonal penicillins
Antibiotic susceptibility testing of anaerobic bacteria has been difficult and controversial. Owing to the slow growth rate of many anaerobes, the lack of standardized testing methods and of clinically relevant standards for resistance, and the generally good results obtained with empirical therapy, there has been limited interest in testing these organisms for antibiotic susceptibility. However, one study of antibiotic-treated patients with Bacteroides isolates from blood found mortality rates of 45% among those whose isolates were deemed resistant to the agent used and 16% among those whose isolates were deemed sensitive. These figures suggest that in vitro susceptibility testing should be performed for Bacteroides isolates from hospitalized patients with bacteremia and that the results of this testing should guide treatment. In general, cure rates of >80% can be attained among Bacteroides-infected patients with appropriate antimicrobial therapy and drainage. Of the drugs active against most clinically relevant anaerobes, metronidazole, β-lactam/β-lactamase inhibitor combinations, and carbapenems are preferred.
Antibiotic resistance in anaerobic bacteria is an increasing problem. Resistance rates vary with the institution and the geographic region. In recent years, the activity of clindamycin, cefoxitin, cefotetan, and moxifloxacin has decreased against B. fragilis and related strains (B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. vulgatus). Nearly all organisms in the B. fragilis group (>97%) are resistant to penicillin G. Rates of resistance to β-lactam agents among anaerobes other than Bacteroides are lower but highly variable. β-Lactam/β-lactamase inhibitor combinations such as ampicillin/sulbactam, ticarcillin/clavulanic acid, and piperacillin/tazobactam are usually a good therapeutic option, but decreased susceptibility in up to 10% of B. fragilis–group isolates has been observed in a study from Belgium. Rates of resistance to the cephamycins (cefoxitin and cefotetan) have varied between 8% and 33% in different surveys. Metronidazole is active against gram-negative anaerobes, including the B. fragilis group; resistance is rare but has been reported. Resistance to metronidazole is more common among gram-positive anaerobes, including P. acnes, Actinomyces species, lactobacilli, and anaerobic streptococci. In the United States, rates of clindamycin resistance among isolates of the B. fragilis group increased from 3% in 1982 to 16% in 1996 and 26% in 2000, with figures as high as 44% in some series. Rates of resistance to clindamycin among non-Bacteroides anaerobes are much lower (<10%). Carbapenems (ertapenem, doripenem, meropenem, and imipenem) are equally active against anaerobes, with <1% of B. fragilis strains showing resistance. Tigecycline is active against some anaerobic bacteria, including Peptostreptococcus, Propionibacterium, Prevotella, Fusobacterium, and most Bacteroides species. Its efficacy for treatment of intraabdominal infections was comparable to that of imipenem in two phase 2 clinical trials. Low resistance rates (∼4%) have been observed. High rates of resistance to moxifloxacin among Bacteroides and Prevotella species have been reported, ranging up to 32% in a recent survey from Greece.
If a patient fails to respond to one of the category 1 or category 2 drugs (Table 164-2), consideration should be given to alternative therapy and to determination of the resistance patterns among Bacteroides isolates. Although in vitro resistance of Bacteroides species to chloramphenicol has not been reported, this drug may not be as effective as other category 1 drugs.
Infections at Specific Sites
In clinical situations, specific regimens must be tailored to the initial site of infection. The duration of therapy also depends on the infection site; the reader is referred to specific chapters on sites of infection for recommendations.
Infections above the diaphragm usually reflect the orodental flora, which does not include the B. fragilis group. β-Lactamase production has been reported in anaerobic strains that are usually isolated from infections originating above the diaphragm. Up to 60% of clinical isolates classified as Prevotella or Porphyromonas species, non–B. fragilis species of Bacteroides, or Fusobacterium species reportedly produce β-lactamase; thus all β-lactam drugs (penicillins and cephalosporins) are poor options. Because most of these infections have a mixed etiology that includes microaerophilic and aerobic streptococci, antibiotics that cover both aerobic and anaerobic bacteria are recommended. 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.
Although many oral anaerobic infections and most cases of anaerobic pneumonia still respond to penicillin therapy, some infections due to oral organisms fail to respond to this drug, and in these cases the use of a drug that is effective against penicillin-resistant anaerobes is recommended (Table 164-2). Life-threatening infections involving the anaerobic flora of the mouth, such as space infections of the head and neck, should be treated empirically as if penicillin-resistant anaerobes are involved. Less serious infections involving the oral microflora can be treated with penicillin alone; metronidazole can be added (or clindamycin can be substituted) if the patient responds poorly to penicillin therapy. Bronchoscopy in lung abscess is indicated only to rule out airway obstruction and does not enhance drainage; in any event, it should be delayed until the antimicrobial regimen has begun to affect the disease process so that the procedure does not spread the infection. Surgery is almost never indicated because of the danger of spilling the abscess contents into the lungs.
Chloramphenicol has been used successfully against anaerobic CNS infections at doses of 30–60 mg/kg per day, with the exact dose depending on the severity of illness. However, penicillin G and metronidazole also cross the blood-brain barrier and are bactericidal for many anaerobic organisms (Chap. 381).
Anaerobic infections arising below the diaphragm (e.g., colonic and intraabdominal infections) must be treated specifically with agents active against Bacteroides species (Table 164-2). In intraabdominal sepsis (Chap. 127), the use of antibiotics effective against penicillin-resistant anaerobes has clearly reduced the incidence of postoperative infections and serious infectious complications. Specifically, a drug from category 1 (Table 164-2) must be included for broad-spectrum coverage. Recommended doses for commonly used category 1 drugs are given in Table 164-3. Therapy for intraabdominal sepsis must also include drugs active against the gram-negative aerobic flora of the bowel. If the involvement of gram-positive bacteria such as enterococci is suspected, either ampicillin or vancomycin should be added. A meta-analysis of 40 randomized or quasi-randomized controlled trials of 16 antibiotic regimens for secondary peritonitis showed equivalent clinical success for all regimens.
Table 164-3 Doses and Schedules for Treatment of Serious Infections Due to Commonly Encountered Anaerobic Gram-Negative Rods |Favorite Table|Download (.pdf)
Table 164-3 Doses and Schedules for Treatment of Serious Infections Due to Commonly Encountered Anaerobic Gram-Negative Rods
|Ticarcillin/clavulanic acid||3.1 g||q4h|
Cases of anaerobic osteomyelitis in which a mixed flora is isolated from a bone biopsy specimen should be treated with a regimen that covers all the isolates. When an anaerobic organism is recognized as a major or sole pathogen infecting a joint, the duration of treatment should be similar to that used for arthritis caused by aerobic bacteria (Chap. 334). Therapy includes the management of underlying disease states, the administration of appropriate antimicrobial agents, temporary joint immobilization, percutaneous drainage of effusions, and (usually) the removal of infected prostheses or internal fixation devices. Surgical drainage and debridement procedures such as sequestrectomy are essential for the removal of necrotic tissue that can sustain anaerobic infections.
The outcome of anaerobic bacteremia is significantly better in patients either initially given or switched to appropriate therapy based on known antibiotic susceptibilities.
Anaerobic infections that fail to respond to treatment or that relapse should be reassessed. Consideration should be given to additional surgical drainage or debridement. Superinfections with resistant gram-negative facultative or aerobic bacteria should be ruled out. The possibility of drug resistance must be entertained; if resistance is involved, repeated cultures may yield the pathogenic organism.
Other supportive measures in the management of anaerobic infections include careful attention to fluid and electrolyte balance (since extensive local edema may lead to hypoalbuminemia), hemodynamic support for septic shock, immobilization of infected extremities, maintenance of adequate nutrition during chronic infections by parenteral hyperalimentation, relief of pain, and anticoagulation with heparin for thrombophlebitis. For patients with severe anaerobic infections of soft tissues, hyperbaric oxygen therapy is advocated by some experts, but its value has not been proven in controlled trials.