Anthony W. Chow MD, FACP, FRCPC1
1Professor and Directory, Department of Medicine MD/PHD Program, University of British Columbia Faculty of Medicine
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
April 2005
General Considerations
ANAEROBIC BACTERIA AND OXYGEN TOLERANCE
Obligate anaerobes require reduced oxygen tension (< 10%) for growth; they do not survive as surface growths on solid medium in ambient air (i.e., 20% oxygen). In contrast, facultative bacteria can grow in air with or without 10% carbon dioxide, whereas microaerophilic or capnophilic bacteria grow poorly in ambient air, but they grow better in air with reduced oxygen tension (i.e., 10% oxygen and 10% carbon dioxide). Obligate anaerobes vary greatly in their sensitivity to oxygen. Extremely oxygen-sensitive anaerobes, such as spirochetes and some Clostridium species, cannot tolerate even 0.5% oxygen. As a general rule, clinical isolates commonly recovered from anaerobic infections are relatively aerotolerant, able to survive in 2% to 8% oxygen.
OBLIGATE ANAEROBES IN THE NORMAL FLORA
Quantitatively, obligate anaerobes are the predominant normal flora on mucocutaneous surfaces—especially the oral cavity, skin, and gastrointestinal and genital tracts—where they outnumber facultative bacteria by a factor of 10 to 103 [see Table 1]. The major genera of obligate anaerobes and their distribution in the normal flora vary according to body site [see Table 2]. These indigenous bacteria have unique ecologic niches at different body sites. For example, in the oral cavity, Actinomyces viscosus (along with the aerobes Streptococcus sanguis, S. mutans, and S. mitis) preferentially colonizes the tooth surface; in contrast, Veillonella parvula and S. salivarius have a predilection for the tongue and buccal mucosa.1 Bacteroides vulgatus, B. thetaiotaomicron, B. fragilis, and B. distasonis are primarily indigenous in the colon2; Prevotella bivia and P. disiens are primarily resident in the female genital tract.3 In addition, this ecosystem is readily influenced by a variety of physiologic and other host factors, such as age, pregnancy, menses, diet, underlying disease, hospitalization, and antimicrobial therapy [see Table 3].
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Table 1 The Predominant Normal Flora at Various Body Sites |
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Table 2 Classification of Anaerobic Bacteria and Their Distribution in Normal Flora and in Infection |
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Table 3 Effect of Host Conditions on the Indigenous Microflora at Various Body Sites |
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PATHOGENESIS OF ANAEROBIC INFECTIONS
Host Conditions
Anaerobic infections characteristically are polymicrobial (mixed) and include both anaerobic and facultative organisms. The organisms tend to be acquired endogenously. The particular mix of pathogens reflects the combined influence of the complex commensal flora at a specific body site and the unique microbiota of the underlying conditions. Because these organisms are generally of low pathogenicity, anaerobic or mixed infections generally develop as a consequence of either structural alterations in the normal mucosal barrier or tissue ischemia with lowered oxidation-reduction potential. Knowledge of the anatomic location of the primary source of infection and the underlying condition of the host, therefore, is essential in predicting the probable organisms causing anaerobic and mixed infections associated with the indigenous microflora.
Microbial Synergy
Two thirds of anaerobic infections involve both anaerobes and facultative bacteria. The infectivity of obligate anaerobes in these instances is often facilitated by the coexistence of facultative organisms. Such examples of microbial synergy are particularly well demonstrated in periodontal infection and in various animal models of intra-abdominal and subcutaneous abscesses.4,5 For example, microbial synergy is common between Bacteroides species and aerobic bacteria or anaerobic cocci and between most Peptostreptococcus species andPseudomonas aeruginosa or Staphylococcus aureus. Anaerobes may require symbiotic facultative bacteria for providing necessary growth factors, lowering the oxidation-reduction potential of the environment, or impairing local host defenses. Conversely, the presence of obligate anaerobes may benefit coexisting facultative bacteria by growth enhancement,6 protection from phagocytosis (e.g., succinic acid production by Bacteroides species),7 or protection from β-lactam antibiotics (e.g., β-lactamase production).8 Infective synergy between anaerobes and facultative bacteria is best demonstrated within tissues in which bacterial clearance is normally slow (e.g., subcutaneous abscesses or fibrin clot in intraperitoneal infection) or is hampered by underlying disease. An understanding of the dynamic interactions between different components of a complex flora in mixed infections has important therapeutic implications. Microorganisms in mixed infections may respond to antimicrobial agents differently than do those in monomicrobial infections, and it may not be necessary to eradicate every bacterial species in mixed infection to achieve a cure.
Virulence Factors
A number of microbial virulence factors are considered important in the pathogenesis of anaerobic infections [see Table 4].
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Table 4 Microbial Virulence Factors Important in Mixed Anaerobic Infections |
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Extracellular or membrane-bound enzymes
Obligate an-aerobes possess a number of extracellular or membrane-bound enzymes that promote tissue destruction. These include lipases, proteases, nucleases, and heparinases.9 Membrane-bound enzymes, such as superoxide dismutase10 and β-lactamases,8 may be important for protecting virulent organisms from the toxic effects of oxygen and β-lactam antibiotics, respectively. Catalase may serve a function similar to that of superoxide dismutase. Organisms lacking these enzymes are susceptible to killing by toxic oxygen radicals and common antibiotics in the environment.
Capsular polysaccharide
Lipopolysaccharide
Like their aerobic counterparts, anaerobic gram-negative bacteria possess lipopolysaccharides (LPS) in their outer cell membrane. However, the structure and biologic activity of LPS from several anaerobic bacteria are distinctly different from those of the classic LPS of Enterobacteriaceae. For example, LPS of B. fragilis and P. intermedia lack 2-keto-3-deoxyoctanoic acid and L-glycero-D-mannoheptose, and they have little endotoxic potency.14 The LPS of F. nucleatum and V. parvula, on the other hand, have biochemical and biologic properties similar to those of classic endotoxin.
Fatty acids and other metabolites
Toxins
Several Clostridium species produce potent exotoxins. The most important of these is C. perfringens α-toxin, which is a lecithinase that exhibits hemolytic, necrotizing, and lethal properties.16 α-Toxin disrupts membranes containing phospholipid-lecithin complexes, including human cell and mitochondrial membranes, and has direct myocardial depressant properties. A second clostridial exotoxin, β-toxin, is a potent cytotoxin that has cytolytic activity, particularly against endothelial cells. Toxin production at a site of injury allows rapid invasion and destruction of healthy tissues. The paucity of leukocytes in the exudate of clostridial myonecrosis may reflect the presence of these cytotoxins.
Tetanus toxin (tetanospasmin) is produced in a tetanus-infected wound and is transported intra-axonally along motor nerves to the spinal cord. Here, the toxin alters normal control of the reflex arc by suppressing the inhibitory neurotransmitter γ-aminobutyric acid (GABA), producing severe muscle spasms. Like tetanospasmin, botulinum toxin also binds irreversibly to presynaptic nerve endings of cranial and peripheral nerves. Once bound, botulinum toxin prevents the release of the neurotransmitter acetylcholine, producing flaccid paralyses.
Specific Anaerobic Infections
Anaerobic bacteria can cause infections throughout the body. These infections can be conveniently divided into three categories on the basis of unique clinical, microbiologic, and epidemiologic features. These include infections caused by (1) Bacteroides and other mixed anaerobes, (2) Actinomyces species, and (3) Clostridium species.
INFECTIONS CAUSED BY BACTEROIDES AND OTHER MIXED ANAEROBES
Epidemiology
Anaerobic infections caused by Bacteroides and mixed anaerobes may involve any organ and may occur in persons of all ages. Obligate anaerobes are particularly prevalent in infections of the head and neck, lung and pleural space, intra-abdominal organs, the female genital tract, and necrotic skin and soft tissues. Predisposition to these infections is increased by local ischemia or tissue necrosis, such as from trauma, bites, surgical manipulation, irradiation, or neoplasm.
Etiology
The predominant obligate anaerobes commonly isolated from anaerobic or mixed infections at different anatomic sites include Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Peptostreptococcus, Actinomyces, and Clostridium [see Table 5]. All members of the genusBacteroides are thin, pleomorphic, gram-negative bacilli that are nonmotile and nonsporulating. The B. fragilis group dominates in the colonic microflora, whereas Porphyromonas and Prevotella species reside primarily in the oropharynx. B. fragilis [see Figure 1, part a], the encapsulated member of the B. fragilis group, is by far the most common in anaerobic infections. Other members of this group include B. ovatus, B. thetaiotaomicron, B. distasonis, and B. vulgatus.
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Table 5 Anaerobic Bacteria Associated with Specific Infections56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86 |
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Figure 1. Gram Stains of Anaerobes Gram stains of representative obligate anaerobes commonly isolated in anaerobic infections (magnification: × 1,000). (a) Bacteroides fragilis from a pelvic abscess. (b) Fusobacterium nucleatum from an anaerobic pleuropulmonary infection. (c) Clostridium perfringensfrom myonecrosis. (d) Actinomyces israelii from cervicofacial actinomycosis. |
Prevotella melaninogenica (formerly B. melaninogenicus) is recognized in the laboratory by the production of a dark pigment. The most prevalent Porphyromonas species isolated from oral and periodontal infections are P. gingivalis and P. asaccharolyticus.
Fusobacterium species are gram-negative bacilli with typically pointed ends. They generally reside in the oropharynx or the gastrointestinal tract. Among these, F. nucleatum [see Figure 1, part b] is the most important species in head and neck and pleuropulmonary infections.
Peptostreptococcus species are small gram-positive cocci that are common in mixed infections at all body sites but particularly the oral cavity and the female genital tract. Veillonella species are anaerobic gram-negative cocci that are occasionally isolated from mixed infections, but their pathogenicity is uncertain.
Among the nonsporulating anaerobic gram-positive bacilli, Propionibacterium acnes is occasionally isolated in blood cultures but almost always as a skin contaminant. Another nonsporulating anaerobic gram-positive bacillus with low pathogenicity is Lactobacillus, a dominant member of the normal vaginal flora. Lactobacillus species occasionally can cause serious infections, including bacteremia.19 Clinically important Actinomyces and Clostridium species are discussed separately (see below).
Clinical Presentations
Head and neck infections
Orofacial anaerobic infections are commonly odontogenous in origin and include periapical abscesses, gingival and periodontal infections, and orofacial fascial space infections.1 The clinical manifestations of these infections are largely dictated by the anatomic location and the extent and routes of spread. An aggressive form of gingivitis is Vincent angina, or trench mouth. This is a fulminant form of necrotizing, ulcerative gingivitis associated with severe pain, tissue destruction, foul breath, and a putrid discharge. Masticator-space infection generally originates from a molar or premolar tooth of the mandible and is characterized by pain and swelling at the angle of the jaw and by severe trismus. Extension of infection into the sublingual and submandibular spaces bilaterally may cause swelling of the base of the tongue and potential airway obstruction (Ludwig angina).20 Extension of infection into the posterior compartment of the lateral pharyngeal space may be complicated by thrombophlebitis of the jugular vein (Lemierre syndrome).
Obligate anaerobes are also commonly present in chronic sinusitis, otitis media and mastoiditis, and tonsillar and peritonsillar abscesses. Acute sinusitis is seldom caused by anaerobic organisms unless it is associated with a dental infection. Fusobacterium and anaerobic gram-positive cocci are also commonly isolated in chronic or recurrent maxillary sinusitis. Fusobacterium necrophorum and P. melaninogenica are most frequently recovered from tonsillar and peritonsillar abscesses.
Intracranial infections
Anaerobic bacteria are frequent pathogens in intracranial infections, particularly brain abscess caused by hematogenous dissemination from chronic and suppurative pulmonary foci; they are also frequently isolated in patients with cyanotic congenital heart disease. Contiguous spread from chronic otitis media, mastoiditis, or sinusitis may result in subdural empyema, epidural abscess, or suppurative thrombophlebitis of cortical vessels or venous sinuses. Purulent meningitis seldom involves anaerobic bacteria except in the newborn. Cerebral abscesses of sinus or dental origin are more probably caused by S. milleri, either alone or in mixed culture with other oropharyngeal aerobes and anaerobes. Otogenic cerebral abscesses, on the other hand, frequently involve B. fragilis, Proteus species, and streptococci.
Pleuropulmonary infections
Anaerobic pleuropulmonary infections include aspiration pneumonitis, putrid lung abscess, necrotizing pneumonia, and empyema. Pneumonitis is usually the initial lesion; related symptoms in the early phases may be indistinguishable from symptoms of acute bacterial pneumonia of other causes. If the initial lesion remains untreated, however, pulmonary abscess may ensue after 8 to 14 days. Approximately one half of patients with lung abscess develop putrid-smelling expectorations. The subsequent clinical course depends largely on the nature of the underlying pulmonary pathologic condition. About 10% of patients with anaerobic infections of the lung parenchyma develop empyema. Necrotizing pneumonia is characterized by multiple small cavities within a pulmonary segment or lobe. The course is often fulminant, with rapid extension into adjacent segments. Anaerobic pleuropulmonary infections are typically polymicrobial. Predominant anaerobic isolates include Peptostreptococcus species, F. nucleatum, and the saccharolytic black-pigmented anaerobic gram-negative bacilli (P. melaninogenica and P. intermedia). Aerobic and microaerophilic streptococci (e.g., S. intermedius) are also frequently isolated. Aerobes such as S. aureus, Escherichia coli, Klebsiella pneumoniae, and P. aeruginosa are more likely to be isolated along with anaerobic bacteria in hospital-acquired infections than in community-acquired aspiration pneumonia.
Intra-abdominal infections
Intra-abdominal sepsis most commonly results from bacterial contamination of intraperitoneal or retroperitoneal spaces after intestinal perforation. The initial event is peritonitis, either generalized or localized, with subsequent abscess formation. Common predisposing conditions include penetrating trauma, perforated appendicitis or diverticulitis, inflammatory bowel disease, intestinal malignancy with strangulation or obstruction, and anastomotic leak after intestinal surgery. Although a multiplicity of anaerobic and facultative bacteria may be isolated in intra-abdominal infections—particularly B. fragilis, Peptostreptococcus species, Clostridium species, Enterobacteriaceae, andEnterococcus faecalis—it is not always clear which components are the primary pathogens and which are merely symbionts or commensals. Animal studies of experimental peritonitis simulating intestinal perforation suggest that such infections follow a biphasic process21 [seeFigure 2]. Early peritonitis and bacteremia are related to aerobic coliform bacteria, whereas late abscesses are caused by anaerobes, often in synergy with facultative bacteria. The therapeutic implications of these studies are clear: both microbial components of intra-abdominal sepsis should receive appropriate antimicrobial attention.
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Figure 2. Mixed Infection in Intra-abdominal Sepsis Biphasic disease model of mixed infection in intra-abdominal sepsis.25 |
Female genital tract infections
Mixed aerobes and anaerobes are particularly important in closed-space infections such as vulvovaginal, adnexal, or tubo-ovarian abscesses and in postsurgical and postpartum infections. Other common gynecologic and obstetric infections involving mixed aerobic and anaerobic flora include acute and chronic salpingitis, infections associated with contraceptive intrauterine devices, postpartum or post-cesarean section wound infections, endometritis, and amnionitis. The most common anaerobes found include Prevotella species (especially P. bivia, P. disiens, and P. melaninogenica), Peptostreptococcus species, and Actinomyces species. The most common facultative pathogens are Enterobacteriaceae, especially E. coli, and aerobic or microaerophilic streptococci. B. fragilis is not a common organism in the normal vagina, but its prevalence is increased in posthysterectomy and post-cesarean section infections and in pelvic infections associated with malignancy and immunosuppressive therapy. Bacterial vaginosis also appears to be a polymicrobial infection involving both aerobes and anaerobes.22 In addition to Gardnerella vaginalis, high concentrations of Prevotella, Peptostreptococcus, and Mobiluncus (a motile anaerobic curved gram-negative bacillus) can be regularly isolated from vaginal secretions.
Necrotic skin and soft tissue infections
Necrotic wound and soft tissue infections are especially likely to develop in areas that are regularly exposed to fecal or oral contamination and that have been injured by trauma, ischemia, or surgery. Obligate anaerobes are particularly prevalent in infected pressure ulcers, diabetic foot infections, human bites, and infected pilonidal cysts. Clinical manifestations include crepitant cellulitis, synergistic necrotizing cellulitis or gangrene, myonecrosis, and necrotizing fasciitis. The range of bacterial isolates in such infections is enormous. Anaerobes, including Bacteroides, Peptostreptococcus, and Clostridium species, are almost universally present in mixed cultures.
Anaerobic bacteremia and endocarditis
Polymicrobial bacteremia is particularly prevalent in infections of the gastrointestinal tract and the female genital tract, as well as infections of dental origin. Anaerobic bacteremia originating from the female genital tract and odontogenous sources tends to be transient and self-limited. In contrast, anaerobic bacteremia originating from the gastrointestinal tract or from necrotic soft tissue tends to be recurrent and persistent in the absence of surgical drainage. The clinical manifestations of anaerobic bacteremia and the specific organisms involved depend to a large extent on the portal of entry and the nature of the underlying disease. For example, B. fragilis is most common in bacteremia of gastrointestinal and necrotic soft tissue origin.23 Bacteroidaceae bacteremia of the female genital tract and of odontogenous origin rarely involves B. fragilis; more commonly, Peptostreptococcus is isolated. Fusobacterium, when isolated, is usually oropulmonary or pelvic in origin. Several clinical features are particularly distinctive in anaerobic bacteremia. Excessive jaundice with hyperbilirubinemia has been noted in 10% to 40% of cases.24 Suppurative thrombophlebitis may be present in 5% to 12% of cases, primarily involving the pelvic, hepatic, mesenteric, and portal veins. Although anaerobic bacteria can cause endocarditis, such infections appear to be exceedingly rare.
INFECTIONS CAUSED BY ACTINOMYCES
Epidemiology
Actinomycosis is a relatively rare condition but has a worldwide distribution with no predilection for age, race, season, or occupation. However, a male-to-female predominance of 1.5:1 to 3:1 has been reported in many series. Predisposing factors include dental caries and extractions, gingivitis and gingival trauma, diabetes mellitus, immunosuppression, malnutrition, and local tissue damage caused by neoplastic disease or irradiation. In children, the development of actinomycosis should arouse suspicion of an underlying immunodeficiency state, particularly chronic granulomatous disease.
Etiology
Actinomyces species are nonsporulating strict or facultative anaerobes with a variable cellular morphology that ranges from diphtheroidal forms to coccoid filaments [see Figure 1, part c]. They are normal constituents of the oral, gastrointestinal, and genital flora. The term actinomycosis literally translates as “ray fungus,” which reflects the organism's characteristic filamentous, funguslike appearance in infected tissues. However, Actinomyces species are true bacteria with filaments that are much narrower than fungal hyphae. They require an enriched culture medium, such as brain-heart infusion broth, for growth; cultures should be observed for at least 14 to 21 days to allow adequate detection. Human actinomycosis is primarily caused by A. israelii. Other species known to cause human disease include A. odontolyticus, A. naeslundii, and A. graevenitzii. A. bovis causes the disease known as lumpy jaw in cattle but does not cause human disease. Actinomycosis is typically a polymicrobial infection; A. actinomycetemcomitans and Haemophilus aphrophilus are the most common coisolates. However, the significance of these coexisting bacteria in the pathogenesis of actinomycosis remains unclear.
Clinical Presentation
Actinomycosis is a chronic disease characterized by abscess formation, draining sinus tracts, fistulas, and tissue fibrosis. It can mimic a malignancy or granulomatous disease. A hallmark of actinomycosis is the tendency to spread without regard for anatomic barriers, including the fascial planes or the lymphatics; the development of multiple sinus tracts is also characteristic. Pain is generally an uncommon feature, particularly in chronic cases. Another characteristic is the presence of sulfur granules within infected tissue. The granules are 100 to 1,000 B5m in diameter and are hard in consistency. They are often visible to the naked eye or by microscopy with low magnification [see Figure 3, part a]. The granules are composed of an internal tangle of mycelial fragments and a rosette of peripheral clubs [see Figure 3, part b]. Filaments within a granule are often visible on Gram or methenamine-silver stain, though more calcified granules may be difficult to identify. Cervicofacial involvement is the most common manifestation, accounting for 50% of all cases; thoracic, abdominal, pelvic, and disseminated infections occur less frequently.
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Figure 3. Actinomyces Infection Sulfur granules are a characteristic feature of Actinomyces infection. (a) Gross appearance in exudates. (b) Histologic appearance in infected tissue. |
Cervicofacial actinomycosis
Fistulization from the perimandibular region is the most easily recognized manifestation of cervicofacial actinomycosis. Characteristic lesions usually develop slowly, over weeks to months, with adherence to overlying skin giving it a bluish or reddish appearance. This is often mistaken for cellulitis but, in fact, more likely represents venous congestion. Over time, sinus tracts invariably form on the skin surface or oral mucosae, eventually erupting to express a thick yellow or serous exudate, which yields the characteristic sulfur granules. A characteristic inflammatory, cicatricial scarring eventually results. Less commonly, actinomycosis may present as an acute suppurative infection with a rapidly progressive, fluctuant, and pyogenic mass. At this stage, the patient may experience pain and trismus that appear disproportionate to the local (visible) inflammation.
Thoracic actinomycosis
Pulmonary actinomycosis usually results from aspiration of organisms from the oropharynx. The disease has an insidious onset and a subacute course. Typical symptoms include cough, hemoptysis, chest wall discomfort, fever, and weight loss. Pulmonary osteoarthropathy is less common. The radiographic findings are variable and include patchy infiltrates, mass lesions, or cavitation. The infection may extend directly into the pleural space, ribs, and chest wall to produce empyema, osteomyelitis, and draining fistulous tracts. Less frequently, thoracic actinomycosis can extend to the mediastinum and present as pericarditis. The differential diagnosis includes carcinoma, tuberculosis, nocardiosis, and systemic mycosis. Because A. israelii is part of the normal oral flora, culturing the organism from sputum or bronchoscopic washings per se is not diagnostic of infection. Definitive diagnosis requires percutaneous needle aspiration, bronchoscopic biopsy, or open lung biopsy.
Abdominal actinomycosis
Gastrointestinal actinomycosis generally originates from damaged intestinal mucosa. Any portion of the intestinal tract may be involved, but ileocecal infection is most frequent. The disease can spread to the omentum, mesenteric lymph nodes, and intra-abdominal viscera and can produce fistulous invasions of the abdominal wall or perineum. Presenting manifestations include pain and fever, palpable mass lesions, and draining sinus tracts. Carcinoma, tuberculosis, and Crohn disease are prominent considerations in the differential diagnosis. Unless draining sinus tracts are present, surgery is required for definitive diagnosis. If the bladder is involved, sulfur granules may be present in the urine. A careful search for the characteristic histopathology may be needed to establish the diagnosis, even when excisional biopsy is performed. It is important to confirm the diagnosis, because actinomycosis requires postsurgical administration of antibiotics to prevent recurrent disease.
Pelvic actinomycosis
Pelvic actinomycosis is often associated with the use of intrauterine devices (IUDs) for contraception.25 The pathogenesis of pelvic actinomycosis is not certain, but the disease likely results from upward spread of organisms from the perineum via the intestinal tract. Clinically, pelvic actinomycosis may present as endometritis, salpingo-oophoritis, or tubo-ovarian abscess; bladder invasion or systemic infection arising from a vaginal focus is rare. Optimal management of asymptomatic women with chronic Actinomyces colonization is uncertain. Removal of IUDs has been suggested, but the role of antibiotics is unclear. Pelvic inflammatory disease is the major consideration in the differential diagnosis. Surgery is generally required to establish the diagnosis. Actinomycosis of the male genitourinary tract is rare, but infections of the prostate have been reported.
Disseminated infection
Disseminated actinomycosis most often occurs by hematogenous spread from a pulmonary focus. Any body site can be involved, including soft tissues, bone, the brain, and visceral organs.
INFECTIONS CAUSED BY CLOSTRIDIA
Clostridia are sporulating gram-positive bacilli; all species are obligate anaerobes, but some (e.g., C. perfringens) are relatively aerotolerant. Clinically important Clostridium species can be categorized into three major groups: histotoxic species (C. perfringens, C. novyi, C. septicum, C. bifermentans, and C. sordellii), enterotoxigenic species (C. perfringens and C. difficile), and neurotoxic species (C. tetani and C. botulinum).
Diseases from Histotoxic Clostridia
Most invasive infections caused by histotoxic clostridia originate from the gastrointestinal tract and are precipitated by trauma or underlying intestinal disorders. C. perfringens is the species that most commonly causes human disease [see Figure 1, part d], but isolation of C. perfringens may simply represent contamination of a wound surface. The spectrum of disease produced by C. perfringens and other histotoxic clostridia is broad, ranging in severity from relatively benign and localized conditions (e.g., a Welch abscess within a wound cavity) to fulminant infections associated with sepsis and high mortality (e.g., clostridial myonecrosis or parturient endometritis). C. septicum infections are particularly likely to occur in patients with underlying malignancies. C. tertium bacteremia occurs especially in neutropenic patients.
Soft tissue infections
Clostridial crepitant cellulitis is a moderately serious gas-forming infection of the skin and subcutaneous tissues that does not involve muscle or produce a toxemic state, as does clostridial gas gangrene (clostridial myonecrosis; see below). It develops primarily in devitalized tissue in inadequately debrided wounds. The infection extends gradually through tissue planes and is accompanied by the formation of large quantities of gas, which is easily palpated as crepitus (more than is usually evident in cases of clostridial myonecrosis). A thin, dark, gray-brown, foul exudate is produced. There is relatively little local pain or change in the overlying skin. Diagnosis is usually based on a Gram stain revealing plump, gram-positive bacilli (without spores) and variable numbers of polymorphonuclear leukocytes. Of note, crepitant cellulitis is more commonly caused by non-spore-forming anaerobes than by clostridia [see Necrotic Skin and Soft Tissue Infections, above]. A more serious complication is necrotizing fasciitis caused by C. sordellii with toxic-shock manifestations in black tar heroin users.26
Clostridial myonecrosis
Clostridial myonecrosis (i.e., gas gangrene or clostridial myositis) is a fulminant and rapidly progressive infection caused by C. perfringens. It initially involves injured or devitalized muscle and then aggressively invades contiguous normal muscle. Predisposing conditions include penetrating war wounds, surgery on the biliary tract or colon, infarcted bowel from an incarcerated hernia, arterial disease, and intramuscular injection of epinephrine. Spontaneous nontraumatic cases have also been reported. The incubation period is short, ranging from 8 to 72 hours. Onset is acute. Local pain is the earliest symptom, followed by pallor, apprehension, marked tachycardia, moderate fever, and lethargy. Hypotension, shock, and oliguria quickly supervene. There is extensive intravascular hemolysis, evidenced by the appearance of so-called port-wine urine. The overlying skin is swollen and exquisitely tender and becomes dark yellow or bronze. In an involved extremity, the skin is pale and cold because of ischemia. Crepitus is present but not prominent. A thin, brownish discharge with a foul odor is evident; tense blebs containing dark, thin fluid often develop. The overall mortality in gas gangrene is 15% to 30%. Gas gangrene of the abdominal wall has a mortality of 50%.
Uterine infection and septic abortion
Almost all cases of clostridial uterine infection are caused by C. perfringens, which is present in the genital tract in 5% of healthy women. Infection occurs in the setting of incomplete abortion, premature rupture of membranes, or operative termination of pregnancy. The organisms may enter and remain confined to the myometrium, or they may spread hematogenously, as occurs in the septicemic form of clostridial uterine infection. The incubation period is short, usually 12 to 72 hours, and is followed by vaginal bleeding, low-grade fever, and lower abdominal pain. The onset of systemic symptoms, such as vomiting, diarrhea, marked tachycardia, high fever, and chills, is abrupt. A foul-smelling vaginal discharge is present, the uterus and adnexa are tender, and perforation of the uterus may lead to pelvic peritonitis. Jaundice and hemoglobinemia may result from massive intravascular hemolysis. Hypotension, shock, and renal shutdown are common in such cases. Mortality in patients with intravascular hemolysis from postabortal C. perfringens uterine infection is approximately 50%. A variant of this infection is fulminant endometritis caused by C. sordellii in parturient young women, which is marked by profound leukocytosis and shock and which produces significant mortality.27
Diseases from Enterotoxigenic Clostridia
Food poisoning
Enteritis necroticans
In developing countries, intestinal infection with C. perfringens type C can produce a β-toxin that causes a severe hemorrhagic, inflammatory, or ischemic necrosis of the jejunum known as enteritis necroticans or pigbel.29 The infection primarily affects chronically ill persons who consume pig intestines (chitterlings).
At least 300,000 cases of C. difficile-associated diarrhea (CDAD) occur in the United States every year.30 Patients receiving tube feedings are at particular risk. CDAD was first observed in patients receiving clindamycin, but many other antibiotics can cause diarrhea. The risk is highest from clindamycin, the cephalosporins, and ampicillin and lowest for vancomycin, metronidazole, and the aminoglycosides. There is also an increased risk of CDAD associated with the use of proton pump inhibitors in hospital inpatients.31 In rare instances, CDAD may develop in patients who have not been hospitalized or exposed to antibiotics. For example, cancer chemotherapy predisposes to C. difficileinfection even in the absence of antibiotic therapy.
The clinical presentation of CDAD is quite variable. The symptoms range from mild diarrhea to severe colitis with fever, leukocytosis, abdominal cramps, and bloody diarrhea. The onset may be within the first few days of antibiotic therapy or as late as 6 weeks after antibiotics have been discontinued. Endoscopy reveals pseudomembrane formation in about half of cases. Toxic megacolon may occur in severe cases, particularly in patients who have received antimotility agents. Intestinal perforation may occur but is uncommon.
Diseases from Neurotoxic Clostridia
Tetanus
All of the clinical features of tetanus are caused by a potent neurotoxin—tetanospasmin—produced by C. tetani. The toxin travels to the spinal cord and suppresses the inhibitory neurotransmitter GABA in the neuromuscular junction, resulting in severe muscle spasms.
Tetanus is now rare in industrialized countries because of widespread immunization. In the United States, fewer than 50 cases are reported annually, mostly in inadequately immunized older adults.32 In developing countries, tetanus is still a major problem, causing the deaths of an estimated one million persons annually, half of whom are newborns. C. tetani is commonly found in the soil, in the intestines of domestic animals, and occasionally in human feces. The organism is commonly introduced by a laceration or puncture wound that is usually sustained outdoors. Tetanus may also occur in association with pregnancy (postpartum and postabortion tetanus), injection of illicit narcotics, surgery (postoperative tetanus), burns, vaccination, intramuscular injections, chronic skin ulcers, dog bites, and umbilical stump infection in newborns (neonatal tetanus). In 10% to 20% of patients with tetanus, there is no history of injury or evidence of an infected lesion.
The disease is characterized by generalized rigidity and intermittent, intense muscle spasms. The incubation period ranges from 1 to 55 days, but onset of symptoms occurs within 14 days after the initial injury in over 80% of patients. The usual presenting symptoms are restlessness; pain caused by muscle spasm; and stiffness of the back, neck, thighs, and abdomen. When muscle spasms occur, the characteristic clinical features are determined by the relative strengths of the opposing muscles: the greater strength of the masseter over the opposing digastricus and mylohyoid results in trismus; the greater strength of the extensor groups over the flexors in the lower extremities produces characteristic extension at the hips and knees; and the greater strength of the biceps results in flexion of the forearms. This combination of flexion of the upper extremities and extension of the lower extremities is termed opisthotonos [see Figure 4].
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Figure 4. Tetus Spasms Spasms in a wounded soldier with tetanus are illustrated in this drawing by Scottish surgeon and anatomist Sir Charles Bell in his bookThe Anatomy and Philosophy of Expression, published in 1832. The classic signs of tetanus—risus sardonicus, trismus, and opisthotonos—are shown. |
Difficulty in opening the mouth (trismus, or lockjaw) is the first symptom in more than 50% of patients. Dysphagia, caused by spasm of pharyngeal muscles, may be an early symptom. Deep tendon reflexes are hyperactive, but the plantar responses are flexor. As the process progresses, violent spasms of the paraspinal, abdominal, and limb musculature occur, but the patient remains conscious. Trismus and stiffness of the facial muscles produce risus sardonicus, a characteristic sneering expression. Sudden stimuli (e.g., bright light or noise) can precipitate tonic seizure accompanied by diaphragmatic, intercostal, glottal, or laryngeal spasm; such spasms can result in hypoxia and respiratory arrest. Fever may be caused by the marked muscular rigidity and spasms alone. Severe sympathetic hyperactivity, evidenced by labile hypertension or hypotension, tachypnea, tachycardia, arrhythmias, profuse sweating, and marked intermittent vasoconstriction, may occur singly or in varying combinations. After the manifestations of tetanus have peaked, they persist at the same level for about a week and then gradually diminish over several weeks. Residual stiffness may persist for several more weeks. In patients who have survived moderate to severe tetanus, respiratory assistance has been required for 2 to 4 weeks; the average hospital stay has been 5 to 8 weeks. The major complications of tetanus are respiratory arrest secondary to tetanic spasms, pneumonia secondary to aspiration, pulmonary emboli, cardiac problems related to sympathetic overactivity or to cardiomyopathy, and fractures of thoracic vertebrae caused by violent spasms.
Botulism
About 100 cases of botulism are reported in the United States each year, but a surge in cases associated with black tar heroin and the threat of international bioterrorism have renewed interest in a disease that was first recognized in the early 17th century.33
As with tetanus, all the clinical manifestations of botulism are caused by a potent neurotoxin produced by C. botulinum. The organism has been isolated from soil everywhere in the world. The spores are very hardy, resisting dryness and extremes of temperature. Spores that are introduced into food, wounds, or the human intestinal tract can germinate and elaborate botulinum toxin. Although seven antigenically distinct forms of the toxin (serotypes A through G) have been identified, just three types (A, B, and E) account for nearly all human disease. Botulism occurs in three main forms: food-borne botulism, wound botulism, and infant botulism.
Food-borne botulism results from the ingestion of home-processed foods that are improperly cooked or refrigerated. The vegetative organisms produce the toxin, which is heat labile and can be destroyed by boiling for 10 minutes or by heating to 80° C for 30 minutes. However, if contaminated food is not heated sufficiently, the toxin resists gastric acid and intestinal trypsin and is absorbed from the intestinal tract. About half the cases of food-borne botulism are caused by type A toxin; the rest are divided evenly between types B and E.
Wound botulism typically follows severe trauma, such as a crush injury involving an extremity. However, heroin use has become the leading predisposing factor in the United States; most cases have occurred in California after subcutaneous injection of black tar heroin from Mexico. About 80% of wound botulism is caused by type A toxin; most of the rest is caused by type B toxin.
Infant botulism is caused by the ingestion of C. botulinum spores rather than preformed toxin. The spores then germinate, colonizing the intestinal tract with toxin-producing organisms. Although the source of the spores eludes detection in most cases, honey has been implicated in about 15% of cases. Toxin type A and type B each accounts for about half the cases of infant botulism.
The symptoms of food-borne botulism usually begin 18 to 36 hours after ingestion of the toxin; the incubation period for wound botulism is typically longer. Although food-borne botulism may be heralded by gastrointestinal symptoms such as nausea, vomiting, abdominal cramps, and diarrhea (earlier stage) or constipation (later stage), neurologic manifestations soon predominate. In wound botulism, gastrointestinal symptoms are absent and the wound may appear surprisingly benign. Cranial nerve symptoms such as blurred vision and diplopia are usually the earliest neurologic complaints, followed by dysphagia, dysarthria, and dry mouth. Symmetrical motor paralysis ensues, characteristically progressing in a descending fashion that begins with the arms and then involves the respiratory muscles and lower body. Autonomic dysfunction can produce constipation, urinary retention, and orthostatic hypotension. Sensory deficits are absent, and mentation is normal. Respiratory arrest occurs in severe cases; mechanical ventilation and respiratory support may be required for weeks to months before full recovery. Infant botulism presents as lethargy, constipation, poor feeding, and floppiness, typically in the second month of life.
NEWLY RECOGNIZED ANAEROBES
Molecular tools such as 16S ribosomal DNA sequencing are continuing to identify new genera and species of clinically relevant anaerobic bacteria.34,35 For example, the anaerobic gram-negative bacillus Bilaphila wadsworthia is now known to be an important pathogen and is frequently isolated from gangrenous appendicitis.36 Newly described anaerobic cocci, gram-positive non-spore-forming rods, and clostridia have also been isolated from various infections.35,37
Diagnosis of Anaerobic Infections
CLINICAL CLUES TO ANAEROBIC INFECTIONS
Apart from actinomycosis and clostridial myonecrosis, infections involving obligate anaerobes are generally indistinguishable from infections caused by other pathogens. Clinical manifestations are largely determined by the organ system involved and by the extent and chronicity of the infection. The two most helpful clinical clues are the presence of local tissue ischemia or necrosis and the proximity of infection to mucosal surfaces where obligate anaerobes normally reside. A putrid, foul-smelling discharge is virtually diagnostic of infection involving anaerobes, although the absence of foul odor does not rule out this possibility. Similarly, crepitus or black discoloration of affected tissue is only suggestive evidence.
MICROBIOLOGIC DIAGNOSIS OF ANAEROBIC INFECTIONS
A well-performed Gram stain of appropriately collected clinical material is a very useful diagnostic tool. Anaerobic infections are typically polymicrobial, and the characteristic cellular morphology of certain anaerobic pathogens may be recognized by an accomplished microscopist [see Figure 1]. The finding of so-called sterile pus by conventional culture methods in the face of a positive Gram stain should be considered presumptive evidence of an anaerobic infection. In the final analysis, however, the accurate diagnosis of anaerobic infection depends on the ability of the laboratory to isolate these fastidious organisms from clinical material likely to yield meaningful bacteriologic data.
Specimen Collection and Transport
One of the major handicaps in the recovery of anaerobic bacteria is improper specimen collection and transport. Care must be taken to avoid specimens that may be contaminated by commensal flora of mucocutaneous surfaces where anaerobes normally reside (e.g., throat swabs, expectorated sputum, voided urine, bronchoscopic and nasotracheal aspirates, vaginal secretions, feces, colostomy effluent, or superficial wound swabs). Blood and other body fluids that are normally sterile and aseptically obtained should be routinely cultured for anaerobic bacteria. Other clinical materials likely to yield meaningful bacteriologic data for anaerobic infections include specimens from tissue biopsy or curettage or from deep wounds during surgery.
Proper specimen transport to preclude aeration is critical for microbiologic confirmation of an anaerobic infection. Many fastidious organisms are extremely oxygen sensitive and cannot withstand even a brief moment of exposure to air. Furthermore, in mixed infections, the presence of facultative organisms that grow faster than anaerobes frequently precludes recovery of the latter. Several commercially available systems for anaerobic transport of clinical specimens have been evaluated and have been shown to provide excellent recovery of fastidious anaerobes.38 If commercial anaerobic transport vials are not available, specimens should be collected with a sterile needle and syringe. Air in the syringe is carefully expelled. The needle is capped to minimize aeration, and the specimen should be promptly delivered to the clinical laboratory. If swabs are to be used, they should be prepared, stored, and transported in gas-filled containers under anaerobic conditions. Immediate processing of specimens by the laboratory also improves recovery, but in practice, this is often not feasible.
RADIOLOGIC AND IMAGING STUDIES
Noninvasive tests such as computed tomography, magnetic resonance imaging, ultrasonography, and gallium or indium scanning are most useful for localization of suppurative infections in the central nervous system and in intra-abdominal and pelvic organs. The sensitivity and specificity of these tests in the detection of abscess and the differentiation from tumor, hematoma, and other noninflammatory space-occupying lesions in various sites remain to be determined by careful prospective study. In general, it may be said that a positive scan is highly suggestive, particularly when supported by the clinical picture; however, a negative scan is much less useful in ruling out infection.
SPECIFIC ANAEROBIC INFECTIONS
Actinomycosis
The diagnosis of actinomycosis depends on identification of the organism by smear or culture and by characteristic histopathology from tissue biopsy. The identification of sulfur granules establishes the diagnosis of actinomycosis [see Figure 3]; however, sulfur granules may constitute no more than 1% of total tissues in a given lesion and, hence, are easily missed by routine tissue staining. Similar granules may be seen with other microorganisms, notably Nocardia brasiliensis and Streptomyces madurae (both of which can cause mycetoma), as well as S. aureus (a cause of botryomycosis). However, these other granules do not have peripheral clubs, which appear to be specific toActinomyces species. Not all Actinomyces species form sulfur granules (e.g., A. odontolyticus does not), and a peripheral fringe of clubs may be absent in certain instances, such as in a tonsillar crypt infection or in pelvic actinomycosis associated with an IUD. Additionally,Actinomyces species can be morphologically differentiated from Nocardia; moreover, Nocardia is acid fast in modified acid-fast stains, whereas Actinomyces is not.
Clostridial Myonecrosis versus Crepitant Cellulitis
Surgical exploration is necessary to distinguish myonecrosis from anaerobic cellulitis. In gas gangrene, the involved muscle looks cooked and lacks contractility, whereas in clostridial cellulitis, the muscle is visibly healthy. A presumptive diagnosis is based on a typical Gram stain of the wound drainage or aspirate that reveals many clostridia but few leukocytes. The presence of gas in subcutaneous tissue is not pathognomonic of clostridial infection. Patients with diabetes mellitus are particularly prone to crepitant cellulitis caused by enteric bacteria or Bacteroides species. Perineal phlegmons, which result from extension of perirectal abscesses caused by mixed anaerobic and facultative organisms, may also involve subcutaneous gas formation. Crepitus from trapped air after traumatic injury can usually be distinguished from anaerobic cellulitis or myonecrosis by the fact that the former does not spread.
The diagnosis of CDAD is established by demonstrating the toxins of C. difficile in stool specimens by immunoassays. Toxins A and B can be detected using specific antibodies. In approximately 5% to 20% of patients, more than one stool specimen is required to detect C. difficiletoxin. Consequently, when enzyme-linked immunosorbent assay results are negative but clinical suspicion is high, tests should be repeated using the tissue culture cytotoxicity assay. Some clinical laboratories utilize screening tests that detect the presence of C. difficile in fecal specimens, either by culture or by detecting the presence of glutamate dehydrogenase, a metabolic enzyme expressed at high levels by all strains of C. difficile, both toxigenic and nontoxigenic.39 Although these rapid screening tests may be cost-effective in some instances where large volumes of fecal specimens are processed, they are more suitable for excluding rather than establishing the diagnosis of CDAD because of their high negative (approximately 98%) but low positive (approximately 60%) predictive values.
Tetanus
The diagnosis of fully developed tetanus presents little difficulty. Acute strychnine poisoning is the only disease that resembles tetanus. A greater problem in the differential diagnosis occurs earlier in the course of the illness, when trismus is the principal manifestation. Trismus may occur in patients with intraoral disease, especially dental or jaw infections, and is occasionally seen in patients with trichinosis. Hepatic encephalopathy is sometimes associated with prominent muscle stiffness and rigidity. However, the associated liver disease is usually obvious. Furthermore, a sudden stimulus, such as jarring a bed rail, is likely to cause spasms in a patient with tetanus but not in a patient with hepatic encephalopathy. Trismus may also develop as an acute reaction to phenothiazines (the so-called grimacing syndrome). Unlike trismus from tetanus, the masseter muscle spasm in this drug reaction is painful and intermittent, and to some degree it can be overcome voluntarily. This drug reaction is readily reversed with intravenous diphenhydramine.
Botulism
Because botulism is uncommon, the diagnosis may not be entertained despite characteristic clinical findings. Clustering of cases in a family or community and a history of eating home-canned or spoiled foods may be important clues. The differential diagnosis includes Guillain-Barré syndrome, Eaton-Lambert syndrome, myasthenia gravis, cerebrovascular accidents, tick paralysis, and chemical intoxication. In patients with botulism, results of complete blood counts, blood chemistries, CNS imaging studies, and cerebrospinal fluid analysis are all normal. Rapid repetitive electromyography, however, is highly suggestive of botulism if it demonstrates a pattern of facilitation. A positive diagnosis can be established by demonstrating botulinum toxin in serum or stool specimens; the toxin may also be detected in food samples.
Management of Anaerobic Infections
Successful treatment of anaerobic infections requires rational antibiotic selection in conjunction with judicial surgical resection and drainage. The choice of antibiotics should be guided by culture results and antibiotic susceptibility data.
Several methods for antimicrobial susceptibility testing of obligate anaerobes have been validated by the National Committee for Clinical Laboratory Standards.40 Both agar dilution and microbroth testing methods are appropriate, whereas the E-test, which utilizes a predefined gradient of antibiotic concentrations on a plastic strip, offers a more expensive but practical and fairly accurate alternative for susceptibility testing of individual anaerobic isolates. In light of the growing concern of emerging antibiotic resistance among anaerobic bacteria, the need for more regular susceptibility testing of clinical isolates of anaerobic bacteria has become evident.41 Susceptibility testing is particularly important in clinical settings where there has been a suboptimal response to empirical antibiotic regimens. Certainly, antimicrobial susceptibility testing should be routinely performed on organisms that are frequently resistant to antibiotics commonly used as empirical therapy, such as members of the B. fragilis group; pigmented Prevotella, including P. bivia and P. disiens; and certain Fusobacteriumspecies. In the absence of specific culture or susceptibility data, initial antibiotic therapy must be chosen empirically and directed against the pathogens most likely to be present in a particular clinical setting [see Table 5], in accordance with predicted in vitro susceptibility patterns [see Table 6].
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Table 6 Predicted in Vitro Susceptibility of Clinically Important Anaerobes to Major Classes of Antimicrobial Agents |
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PREDICTED ANTIMICROBIAL SUSCEPTIBILITY
Although penicillin G has been considered the agent of choice for a number of mixed infections at various sites above the diaphragm (particularly oropulmonary and head and neck infections), β-lactamase production and treatment failure have been increasingly reported.42β-lactamase production is increasingly recognized in oral isolates of P. intermedia, F. nucleatum, and Peptostreptococcus micros.42,43 Among the cephalosporins, only cefoxitin, cefotetan, and ceftizoxime have an enhanced antianaerobic spectrum. These agents appear to have comparable activity against B. fragilis, with resistance rates ranging from 10% to 20%; none are as active as clindamycin or metronidazole. Among the penems, imipenem-cilastatin, meropenem, and erzapenem are the most broadly active.44 The monobactam aztreonam is inactive against anaerobes, as well as gram-positive aerobes.
All strains of B. fragilis produce β-lactamases and are resistant to penicillin, but extended-spectrum penicillins in combination with β-lactamase inhibitors (e.g., ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam) are active against most strains. Increasing resistance of B. fragilis to cefoxitin and clindamycin has also been reported, and they are no longer the agents of choice in intra-abdominal infections.45 Cefotetan, ceftizoxime, piperacillin-tazobactam, imipenem, and meropenem remain active. Antibiotic susceptibilities of the non-fragilis species of the B. fragilis group are more variable than those of B. fragilis. Only metronidazole, imipenem, and chloramphenicol are predictably active against nearly all isolates.46
Erythromycin and ketolides are relatively inactive against Fusobacterium species and most B. fragilis strains. Similarly, the first- or second-generation quinolones (e.g., norfloxacin, ciprofloxacin, enoxacin, ofloxacin, and levofloxacin) are relatively inactive as single-agent therapy for anaerobic or mixed infections. However, the third-generation quinolones moxifloxacin and gatifloxacin have good in vitro activity against most anaerobes, including B. fragilis,47 whereas gemifloxacin is less active.48
Metronidazole has excellent activity against B. fragilis, Fusobacterium species, and Clostridium perfringens. Peptostreptococcus andBacteroides species other than B. fragilis are only moderately sensitive, whereas nonsporulating gram-positive bacilli are relatively resistant. Metronidazole lacks activity against aerobic bacteria and should not be used as a single agent for empirical therapy, because most infections involving anaerobic bacteria are in fact mixed infections. On the other hand, metronidazole is the only agent with consistent bactericidal activity against B. fragilis. Metronidazole crosses the blood-brain barrier well, so it is particularly useful for treating anaerobic brain abscess or infective endocarditis.
Tetracycline and its analogues can no longer be recommended for the empirical treatment of anaerobic infections because of the substantial resistance acquired by B. fragilis and virtually all classes of other anaerobic bacteria. Tetracycline remains useful in the treatment of actinomycosis, however. Trimethoprim-sulfamethoxazole has only limited activity against anaerobic bacteria. Vancomycin is effective against some gram-positive anaerobes (particularly C. difficile), but it has no activity against gram-negative anaerobes. Aminoglycosides are uniformly inactive against obligate anaerobes.
EMPIRICAL ANTIMICROBIAL THERAPY
The recommended regimens for empirical therapy for various anaerobic or mixed infections vary according to the site of infection [see Table 7]. In general, therapy should be directed at both the aerobic and anaerobic components of the suspected microflora. Monotherapy with a broad-spectrum single agent (e.g., ceftizoxime, cefotetan, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam, imipenem-cilastatin, meropenem, or ertapenem) may be used to minimize toxicity and reduce cost. Parenteral administration, relatively high dosages, and prolonged duration of treatment (3 to 6 weeks) are usually required because of the extent of tissue necrosis and the tendency for relapse with these infections. There are insufficient published data to evaluate the efficacy of empirical therapy with the newer quinolones (e.g., moxifloxacin and gatifloxacin) against severe anaerobic or mixed infections, despite their favorable in vitro susceptibility profiles.
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Table 7 Empirical Antimicrobial Regimens for Suspected Anaerobic or Mixed Infections |
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SURGICAL DRAINAGE
Surgical drainage of abscesses and resection of necrotic tissue may be the decisive therapeutic modality for most suppurative anaerobic infections. However, several exceptions are noteworthy. In lung abscess, nonsurgical treatment alone is often effective, perhaps because of spontaneous drainage and expectoration of abscess contents through the tracheobronchial tree. Certain cerebral abscesses, even when well encapsulated, may also respond to antibiotics alone. A similar favorable experience has been noted with hepatic and tubo-ovarian abscesses. Although abscesses do not always require drainage, it is not clear what factors reliably predict a favorable response to antibiotics alone. When necrotic tissue is present, however, surgical excision is invariably required.
HYPERBARIC OXYGEN AND OTHER ADJUNCTIVE MEASURES
Hyperbaric oxygen therapy, consisting of 100% oxygen at 2 to 3 atm administered for approximately 2 hours, has been used as an adjunct to surgical debridement and antibiotics in the treatment of clostridial gas gangrene and other necrotizing soft tissue infections. Despite enthusiasm for hyperbaric oxygen therapy, there have been no controlled trials of its use in humans, and its precise role in the management of these infections remains to be defined. Nevertheless, hyperbaric oxygen therapy has been recommended for selected cases of necrotic soft tissue infections and for recalcitrant anaerobic osteomyelitis of the maxilla or mandible. Other adjunctive measures useful for the management of anaerobic infections include topical wound irrigation with 3% hydrogen peroxide solution to control foul-smelling discharge and administration of fibrinolytic agents (e.g., trypsin) to prevent intra-abdominal abscess formation postoperatively.49
TREATMENT OF SPECIFIC ANAEROBIC INFECTIONS
Actinomycosis
High-dose penicillin remains the drug of choice for actinomycosis. For severe infections, a 4- to 6-week course of intravenous penicillin G should be followed by oral penicillin V (2 to 4 g/day in four divided doses) for 6 to 12 months. For mild infections, a 2-month course of oral penicillin V is generally appropriate. Oral amoxicillin (500 mg three times daily) is equally effective. Acceptable alternatives to penicillin include the tetracyclines, erythromycin, and clindamycin. Agents generally deemed to have poor activity against Actinomyces species include oral cephalexin; oxacillin and dicloxacillin; the first- and second-generation fluoroquinolones; metronidazole; aminoglycosides; and aztreonam.50 For patients with penicillin allergy, tetracycline probably offers the best alternative, especially in milder disease. Therapy does not need to be directed against other commensal flora that are recovered along with Actinomyces species, because antibiotic regimens effective against Actinomyces alone are usually curative. Surgical intervention may be necessary in more complicated cases.
Clostridial Myonecrosis
Aggressive surgical debridement is mandatory for suspected gas gangrene to determine the extent of infection and to eliminate all necrotic tissue. The procedure includes multiple incisions for drainage; fasciotomy for decompression of muscle compartments; and excision of necrotic muscle. If the process is extensive and if irreversible changes have occurred in an extremity, amputation becomes necessary. Early use of hyperbaric oxygen therapy may limit the zone of frank muscle necrosis, reducing the extent of the surgical debridement. Simple drainage, with fasciotomy where indicated, is usually sufficient for treating clostridial cellulitis. Antibiotic therapy is required to treat bacteremia and prevent the spread of infection. The combination of penicillin G and clindamycin is recommended, because the latter rapidly inhibits toxin synthesis. When a Gram stain indicates a polymicrobial infection, monotherapy with broad-spectrum agents, such as piperacillin-tazobactam, imipenem, or meropenem, is indicated. Alternatively, an aminoglycoside (e.g., gentamicin), a newer cephalosporin (e.g., cefotaxime), or a fluoroquinolone (e.g., ciprofloxacin) may be added initially.
Symptomatic patients should receive oral metronidazole or vancomycin. Either agent, given at a dosage of 500 mg three times daily for 10 days, produces a clinical cure in 94% of patients. Metronidazole is considerably less expensive, but some C. difficile strains are resistant to the drug. Because vancomycin is active against all isolates and is not absorbed in the upper gastrointestinal tract, it may be preferable for severely ill patients. Orally administered bacitracin alleviates symptoms as effectively as metronidazole or vancomycin but is less effective in eradicating C. difficile and its toxins from the stools. For patients with CDAD who cannot tolerate oral therapy, intravenous therapy with vancomycin plus metronidazole or intravenous therapy with metronidazole alone has been recommended.
Regardless of the treatment regimen, symptoms recur in about 20% of patients.51 Relapse is less likely to occur in patients who mount a serum antibody response to toxin A during the initial episode. Patients with recurrent symptoms should be retreated with oral metronidazole or vancomycin. Various regimens, including prolonged and tapering courses of vancomycin, have been suggested.52 Cholestyramine resin, which binds the toxin in the intestine, may be useful for some patients. It is administered in conjunction with oral vancomycin for 1 to 2 weeks (4 g three or four times daily). Administration of the yeast Saccharomyces boulardii may improve the results of antibiotic therapy in some patients who experience relapses of C. difficile colitis.53 Attempts to reconstitute the normal colonic flora by the administration of donated stool directly through a colonoscope have also been tried, with some success.51 Prevention of antibiotic-associated diarrhea by the coadministration of Lactobacillus GG was evaluated in one randomized clinical trial but was unsuccessful during 21 days of follow-up.54
Tetanus
Treatment of tetanus is aimed at controlling muscle spasms, managing dysautonomia, neutralizing circulating toxin, eliminating the continuing source of the toxin, and preventing respiratory complications. Patients with tetanus should be monitored in an intensive care unit. External stimuli (e.g., noise or bright lights) that may precipitate muscle spasms must be kept to a minimum. A urinary catheter is required. Because of the danger of precipitating pharyngeal or laryngeal spasms by oral feedings, fluids and electrolytes are initially administered intravenously. Later, when the danger of aspiration is reduced, a nasojejunal tube may be used, provided that a cuffed endotracheal tube or tracheostomy tube is in place. Antitoxin treatment with human tetanus immune globulin (500 to 1,000 units) is administered intramuscularly; it neutralizes circulating toxin only.
The use of muscle relaxants is essential. Intravenous diazepam (40 to more than 200 mg a day, titrated according to need) is the drug of choice because it acts rapidly as a muscle relaxant and produces a sedative effect without inducing depression. If severe spasms cannot be controlled by diazepam, assisted ventilation and neuromuscular blockade may be necessary. Beta blockers, such as propranolol and labetalol, are used to control sympathetic overactivity.
The value of antimicrobial agents in the treatment of tetanus is doubtful. The only beneficial effect would be to clear the wound of vegetative cells of C. tetani that could produce additional toxin. Penicillin has been the traditional drug of choice, but metronidazole is now preferred. If feasible, wound debridement is carried out to eliminate the site of toxin elaboration. Surgical wound care should be performed only after the initial doses of tetanus immune globulin and antibiotics have been administered and after muscle spasms have been controlled. The wound should be thoroughly irrigated and left open. Because clinical tetanus does not establish natural immunity, the patient should be immunized with the first dose of adsorbed tetanus toxoid before discharge.
Botulism
Antitoxin should be administered promptly to neutralize any circulating botulinum toxin before it binds to cholinergic synapses. The currently recommended dose is one vial of intravenous trivalent (types A, B, and E) antitoxin, which is of equine origin and available from the Centers for Disease Control and Prevention (404-639-2206 during business hours; 404-639-2888 at other times). Hypersensitivity reactions can occur in up to 7% of recipients; such reactions may be severe. A human botulism immune globulin is being developed for the treatment of infant botulism. Wound botulism should be managed with surgical debridement and intravenous penicillin. Patients with severe botulism require mechanical ventilation and metabolic support.
Prevention
SURGICAL PROPHYLAXIS FOR POSTOPERATIVE WOUND INFECTIONS
Anaerobic infections can be prevented by avoiding conditions that predispose to tissue invasion by commensal microflora. In traumatic wounds, the most effective prophylaxis is thorough debridement and cleansing of the wound, elimination of foreign bodies and dead space, and the reestablishing of good circulation. Preoperative mechanical cleansing of the bowel with a low-residue or liquid diet followed by cathartics, enemas, and luminal antibiotics can reduce the incidence of postoperative wound infections after colorectal surgery. Parenteral perioperative antibiotics are used in gastrointestinal and gynecologic surgery when there is heavy contamination with normal microflora at the operative site; examples of such surgeries include elective colorectal surgery, cesarean section after premature rupture of membranes, vaginal hysterectomy in a premenopausal woman, and radical pelvic or head and neck surgery for malignancy. Several studies have shown significant reduction in the frequency of postoperative infections, from about 20% to 30% down to 4% to 8%. Cefoxitin is the agent of choice for prophylaxis of postsurgical intra-abdominal wound infections.55 A first-generation cephalosporin, such as cefazolin, is as effective as some second- or third-generation cephalosporins. In surgery on contaminated or so-called dirty sites, early treatment rather than prophylaxis is essential for reducing the incidence of postoperative morbidity.
INFECTION CONTROL MEASURES FOR C. DIFFICILE-ASSOCIATED DIARRHEA
Enteric precautions, strict adherence to hand washing, and restrictions on the use of antibiotics are necessary to control the intrahospital spread of CDAD. The use of environmental disinfectants containing hypochlorite can reduce the incidence of C. difficile acquisition and the subsequent development of disease. However, antibiotic therapy for asymptomatic carriers is not beneficial.
WOUND CARE AND ACTIVE IMMUNIZATION FOR TETANUS
About two thirds of tetanus cases in the United States occur after puncture wounds, lacerations, and other penetrating trauma. Prompt and thorough wound debridement is of paramount importance in preventing trauma-induced tetanus. Prophylactic antibiotics do not reliably prevent the development of tetanus. The United States Public Health Service has issued specific recommendations for wound management and tetanus prophylaxis56 [see Table 8]. Active immunization should be promoted for the general public. Infants should receive diphtheria-pertussis-tetanus (DPT) vaccine at 2 months of age. Two additional doses are given at 4 and 6 months of age. A booster injection of DPT is given at 18 months of age and again 4 years later. At 16 years of age, a booster dose of combined adult-type tetanus and diphtheria toxoids is administered. Thereafter, immunity is maintained by booster injections every decade. About 70% of Americans have protective levels of tetanus antibodies (> 0.15 IU/ml). Nearly 90% of children are protected, but the rate declines rapidly after 40 years of age, decreasing to less than 30% after 70 years of age. Adults who have not been immunized should receive two doses of alum-precipitated tetanus toxoid intramuscularly, 1 month apart, followed by a booster dose after 1 year. Thereafter, immunity is maintained by booster injections every decade.
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Table 8 Recommendations for Tetanus Prophylaxis in Routine Wound Management |
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Acknowledgment
Figure 3 Reproduced with permission from Finegold SM, Sutter VL: Anaerobic Infections, 4th ed. Scope Publications, Kalamazoo, Michigan, 1982
References
Editors: Dale, David C.; Federman, Daniel D.