Anaerobic Infections Part 2

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, Peptostrepto-coccus, Actinomyces, and Clostridium [see Table 5]. All members of the genus Bacteroides 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 1a], 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. distaso-nis, and B. vulgatus.

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 pe-riodontal 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 1b] is the most important species in head and neck and pleuropul-monary 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 nonsporulat-ing 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 fas-cial 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 peritonsil-lar abscesses. Acute sinusitis is seldom caused by anaerobic organisms unless it is associated with a dental infection. Fusobac-terium 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.

Gram stains of representative obligate anaerobes commonly isolated in anaerobic infections (magnification: x 1,000). (a) Bacteroides fragilis from a pelvic abscess. (b) Fusobacterium nucleatum from an anaerobic pleuropulmonary infection. (c) Clostridium perfringens from myonecrosis. (d) Actinomyces israelii from cervicofacial actinomycosis.

Figure 1 Gram stains of representative obligate anaerobes commonly isolated in anaerobic infections (magnification: x 1,000). (a) Bacteroides fragilis from a pelvic abscess. (b) Fusobacterium nucleatum from an anaerobic pleuropulmonary infection. (c) Clostridium perfringens from myonecrosis. (d) Actinomyces israelii from cervicofacial actinomycosis.

Intracranial infections Anaerobic bacteria are frequent pathogens in intracranial infections, particularly brain abscess caused by hematogenous dissemination from chronic and sup-purative 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 saccha-rolytic black-pigmented anaerobic gram-negative bacilli (P. melaninogenica and P. intermedia). Aerobic and microaerophilic streptococci (e.g., S. intermedius) are also frequently isolated. Aer-obes 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.

Biphasic disease model of mixed infection in intraabdominal sepsis.

Figure 2 Biphasic disease model of mixed infection in intraabdominal sepsis.

Intra-abdominal infections Intra-abdominal sepsis most commonly results from bacterial contamination of intraperi-toneal or retroperitoneal spaces after intestinal perforation. The initial event is peritonitis, either generalized or localized, with subsequent abscess formation.Although a multiplicity of anaerobic and facultative bacteria may be isolated in intra-abdominal infections— particularly B. fragilis, Peptostreptococcus species, Clostridium species, Enterobacteriaceae, and Enterococcus 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 [see Figure 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 in-tra-abdominal sepsis should receive appropriate antimicrobial attention.

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 postsur-gical 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-ce-sarean section wound infections, endometritis, and amnionitis. The most common anaerobes found include Prevotella species (especially P. bivia, P. disiens, and P. melaninogenica), Peptostrepto-coccus 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 anaer-obes.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, syner-gistic necrotizing cellulitis or gangrene, myonecrosis, and necro-tizing 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 bac-teremia is particularly prevalent in infections of the gastrointestinal tract and the female genital tract, as well as infections of dental origin.


Sulfur granules are a characteristic feature of Actinomyces infection. (a) Gross appearance in exudates. (b) Histologic appearance in infected tissue.

Figure 3 Sulfur granules are a characteristic feature of Actinomyces infection. (a) Gross appearance in exudates. (b) Histologic appearance in infected tissue.

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. Fusobac-terium, 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 1c]. 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. Actin-omycosis is typically a polymicrobial infection; A. actinomycetem-comitans 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 pm in diameter and are hard in consistency. They are often visible to the naked eye or by microscopy with low magnification [see Figure 3a]. The granules are composed of an internal tangle of mycelial fragments and a rosette of peripheral clubs [see Figure 3b]. Filaments within a granule are often visible on Gram or methe-namine-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.

Cervicofacial actinomycosis Fistulization from the peri-mandibular 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 contracep-tion.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. perfrin-gens, C. novyi, C. septicum, C. bifermentans, and C. sordellii), entero-toxigenic 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 1d], 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 tox-emic state, as does clostridial gas gangrene (clostridial my-onecrosis; 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 polymorphonu-clear 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.

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, in-farcted bowel from an incarcerated hernia, arterial disease, and intramuscular injection of epinephrine. Spontaneous nontrau-matic 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 he-moglobinemia may result from massive intravascular hemoly-sis. 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.

Diseases from Enterotoxigenic Clostridia

Food poisoning C. perfringens ranks second only to S. aureus in causing outbreaks of food poisoning in the United States.28 Most strains of C. perfringens that are associated with food poisoning are heat-resistant type A organisms. The vehicle is usually a meat product that has been stewed or boiled and then left for a few hours before serving or rewarming. The initial cooking kills contaminating vegetative forms but not heat-resistant spores of C. perfringens. During cooling, the spores germinate and multiply in the anaerobic environment. Large numbers of viable organisms are then ingested. These organisms multiply and sporu-late in the small intestine. Sporulation is associated with the elaboration of an enterotoxin that produces ileal fluid accumulation and diarrhea. Abdominal cramps and diarrhea develop about 8 to 12 hours after ingestion of contaminated food. Nausea occurs occasionally, but vomiting does not occur. Fever, headache, and systemic symptoms are absent. The illness is mild and runs its course in 24 hours.

Enteritis necroticans In developing countries, intestinal infection with C. perfringens type C can produce a p-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).

C. difficile-associated diarrhea and colitis C. difficile accounts for about 25% of all cases of diarrhea in patients receiving antibiotics. C. difficile is acquired in the gastrointestinal tract early in infancy, often in neonatal nurseries. Up to 78% of neonates harbor the organism, but the carrier rate declines to less than 50% in older children and to about 5% in healthy adults. Despite the high carrier rate, infants and young children are highly resistant to the effects of C. difficile toxins, possibly because their intestinal mucosa is relatively immature and lacks toxin receptors. The carrier rate is much higher in debilitated adults, and the organism is transmitted person-to-person in health care facilities. About 20% of all hospitalized patients acquire the organism, but two thirds remain asymptomatic.

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. difficile infection 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.

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