INTRODUCTION	Section 2 of 9
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Background: This monograph describes infections caused by the Bacteroides fragilis group and other anaerobic gram-negative bacilli (AGNB) that were previously included in the Bacteroides species but are now included in the Prevotella and Porphymonas species. Infections due to AGNB are common, yet the specific identification of AGNB in these infections is difficult.

Bacteroides species are anaerobic bacteria that are predominant components of the bacterial florae of mucous membranes and, therefore, are a common cause of endogenous infections. Bacteroides infections can occur in all body sites, including the CNS, the head, the neck, the chest, the abdomen, the pelvis, the skin, and the soft tissues. Inadequate therapy against these anaerobic bacteria may lead to clinical failures. Because of their fastidiousness, they are difficult to isolate and are often overlooked. Their isolation requires appropriate methods of collection, transportation, and cultivation of specimens. Treatment is complicated by 3 factors: slow growth, increasingly encountered resistance to antimicrobials, and the polymicrobial nature of the infection.

The B fragilis group, a member of the Bacteroidaceae family, includes B fragilis (occurs with the greatest frequency in clinical infections), Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, and Bacteroides vulgatus. These bacteria are resistant to penicillins, mostly through the production of beta-lactamase. They are part of the normal GI florae and predominate in intra-abdominal infections and infections originating from those florae (eg, perirectal abscesses, decubitus ulcers). Enterotoxigenic B fragilis (ETBF) are also a potential cause of diarrhea.

Pigmented Prevotella, such as Prevotella melaninogenica and Prevotella intermedia (which were previously called the Bacteroides melaninogenicus group), Porphyromonas (eg, Porphyromonas asaccharolytica), and nonpigmented Prevotella (eg, Prevotella oralis, Prevotella oris) are part of the normal oral and vaginal florae and are the predominant AGNB isolated from respiratory tract infections and their complications, including aspiration pneumonia, lung abscess, chronic otitis media, chronic sinusitis, abscesses around the oral cavity, human bites, paronychia, brain abscesses, and osteomyelitis. Prevotella bivia and Prevotella disiens (previously called Bacteroides) are important in obstetric and gynecologic infections.

Pathophysiology: Most infections due to AGNB originate from the endogenous mucosal membrane florae. Knowledge of the common mode of distribution allows for a logical choice of antimicrobial therapy for infections in these sites.

AGNB infections are generally polymicrobial. The number of isolates can reach 5-10 organisms. The type of copathogens depends on the infection site and the circumstances of the infection. Antimicrobial therapy should be directed at all major aerobic and anaerobic pathogens. AGNB promote infection through synergy with their aerobic and anaerobic counterparts and with each other.

An indirect pathogenic role of AGNB is their ability to produce the enzyme beta-lactamase, which allows them to protect themselves and other penicillin-susceptible organisms from the activity of penicillins.

Frequency:

• In the US: The exact frequency of AGNB infection is difficult to calculate because of inappropriate methods of collection, transportation, and cultivation of specimens. AGNB are more commonly found in chronic infections. Their rate of recovery in blood cultures is 2-5% and is higher in association with patients who have predisposing conditions.

• Internationally: The frequency of these infections appears to be higher in developing countries, where therapy is often inadequate or delayed.

Mortality/Morbidity: The mortality rate has decreased over the past 3 decades because of early recognition and initiation of proper prophylactic and therapeutic antimicrobial therapies.

Age: AGNB infections can occur in patients of all ages; however, the frequency of head and neck infections is higher in pediatric patients than in other patients.

	CLINICAL	Section 3 of 9
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History: AGNB infections occur more often in chronic infections and in association with the predisposing conditions discussed below. However, they can also cause acute infections (ie, maxillary sinusitis associated with dental infections, intra-abdominal infections following perforation).

• CNS infections

• AGNB can cause a variety of intracranial infections, including brain abscess, subdural empyema, epidural abscess, and meningitis (usually from contiguous spread from adjacent foci of infection). Brain abscesses are commonly caused by chronic infections in the ears, the mastoids, the sinuses, the oropharynx, the teeth, or the lungs.

• Hematogenous spread can occur after dental, oropharyngeal, pulmonary, or intra-abdominal infection. Rarely, bacteremia of another origin or endocarditis can lead to such infection.

• Head and neck infections: Anaerobes, including AGNB, are recovered from a variety of infections, especially in their chronic form. Head and neck infections include chronic otitis media; sinusitis; mastoiditis; tonsillar, peritonsillar, and retropharyngeal abscesses; cervical lymphadenitis; all deep neck space infections; thyroiditis; odontogenic infections; and postsurgical and nonsurgical head and neck wounds and abscesses.

• Sinusitis is complicated by anaerobes, including AGNB, when it turns chronic and oxygen levels decline. Anaerobes are isolated from 10% of patients with acute maxillary sinusitis (mostly secondary to odontogenic infection), but they are found in as many as 67% of chronic infections of the maxillary, ethmoid, frontal, and sphenoid sinuses. The infection may spread via anastomosing veins or contiguously to the CNS. Complications include orbital cellulitis, meningitis, cavernous sinus thrombosis, and epidural and subdural brain abscesses.

• Tonsillitis, whether acute or chronic, may have AGNB involvement. AGNB can also be involved with tonsillitis complications, including internal jugular vein thrombophlebitis, which often causes postanginal sepsis. Prevotella species and other anaerobes are recovered from tonsillar or retropharyngeal abscesses without any aerobic bacteria, and they are isolated in cases of Vincent angina.

• Pleuropulmonary infections: Aspiration of oropharyngeal or gastric secretions and periodontal or gingival disease are risk factors for developing anaerobic pleuropulmonary infection due to AGNB and to other anaerobes. The infection can progress from pneumonitis to necrotizing pneumonia and lung abscess, with or without empyema.

• Intra-abdominal infections

• Secondary peritonitis and abdominal abscesses generally occur after entry of enteric organisms into the peritoneal cavity through perforation of the intestine or other viscus as a result of obstruction, infarction, or trauma.

• The more distal the perforation, the more numerous the types and number of organisms that gain access into the peritoneal cavity (ie, perforations in the descending colon are associated with spillage of more organisms than perforations in proximal parts of the colon).

• Enterotoxigenic B fragilis are considered an emerging enteropathogen-causing diarrhea.

• Female genital tract infection: These infections include bacterial vaginosis; soft tissue perineal, vulvar, and Bartholin gland abscesses; endometritis; pyometra; salpingitis; tubo-ovarian abscesses; adnexal abscess; pelvic inflammatory disease, which may include pelvic cellulitis and abscess; amnionitis; septic pelvic thrombophlebitis; intrauterine device–associated infection; septic abortion; and postsurgical obstetric and gynecologic infections.

• Skin and soft tissue infections

• Infections involving AGNB include superficial infections, such as infected cutaneous ulcers, cellulitis, secondary diaper rash, gastrostomy or tracheostomy site wounds, infected subcutaneous sebaceous or inclusion cysts, eczema, scabies or kerion infections, paronychia, hidradenitis suppurativa, and pyoderma.

• Subcutaneous tissue infections and postsurgical wound infections that may also involve the skin include cutaneous and subcutaneous abscesses, decubitus ulcers, infected diabetic (vascular or trophic) ulcers, breast abscesses, bite wounds, anaerobic cellulitis and gas gangrene, bacterial synergistic gangrene, infected pilonidal cyst or sinus, Meleney ulcer, and burn wound infection.

• Deeper anaerobic soft tissue infections are necrotizing fasciitis, necrotizing synergistic cellulitis, gas gangrene, and crepitus cellulitis. These infections can involve only the fascia and/or the muscle surrounded by the fascia, inducing myositis and myonecrosis.

• Anaerobic infections, such as decubitus ulcers or diabetic foot ulcers, are generally polymicrobial and are often complicated by osteomyelitis or bacteremia.

• Deep tissue infections, such as necrotizing cellulitis, fasciitis, and myositis, often involve clostridial organisms and Staphylococcus pyogenes. They may be polymicrobic; may contain gas and gray, thin, putrid pus; and are associated with bacteremia and mortality.

• Osteomyelitis and septic arthritis: Osteomyelitis in the long bones and the cranial and facial bones is frequently polymicrobic and may be associated with anaerobes in patients with peripheral vascular disease and decubitus ulcers.

• Bacteremia

• The prevalence of anaerobes, including AGNB, in bacteremia was 5-15%. However, rates have declined in the last decade to 2-6%. Which organisms are involved depends on their portal of entry and the underlying disease. The common isolates are the B fragilis group (60-75% of isolates).

• The B fragilis group and clostridial organisms are associated with a GI source.

• Pigmented Prevotella, Porphyromonas, and Fusobacterium are associated with the oropharynx and a pulmonary source.

• Fusobacterium species involve the female genital tract.

• Propionibacterium acnes is associated with a foreign body.

• Peptostreptococcus species are associated with all sources but especially with oropharyngeal, pulmonary, and female genital tract sources.

• Predisposing factors include neoplasms; hematologic disorders; organ transplantation; intestinal obstruction; decubitus ulcers; dental extraction; diabetes mellitus; postsplenectomy; use of cytotoxic agents or corticosteroids; total body irradiation; and recent GI, obstetric, or gynecologic surgery.

• Features typical of bacteremia due to anaerobes include metastatic lesions, hyperbilirubinemia, and suppurative thrombophlebitis.

• The mortality rate is 15-30% and improves with early appropriate antimicrobial therapy and resolution of the primary infection.

Causes:

• Conditions predisposing patients to AGNB infections include the exposure of sterile sites to a high inoculum of indigenous mucous membrane florae; use of antibiotics that are ineffective against AGNB; reduced blood supply; and tissue necrosis, which lowers the oxidation-reduction potential and favors the growth of anaerobes. Conditions that lower the blood supply include trauma, foreign body, malignancy, surgery, edema, shock, colitis, and vascular disease.

• Infection with aerobic bacteria can make the local tissue conditions more favorable for the growth of anaerobes. The host defenses can become impaired by anaerobic conditions and anaerobic bacteria.

• Anaerobic infection is often manifested by suppuration, thrombophlebitis, abscess formation, and gangrenous destruction of tissue associated with gas.

• Anaerobes, including AGNB, are common in chronic infections. Therapy with antimicrobials, such as aminoglycosides, trimethoprim-sulfamethazine, and older quinolones, often does not eradicate anaerobes.

• Certain infections that often involve anaerobes include brain abscess, oral or dental infections, human or animal bites, aspiration pneumonia, lung abscesses, amnionitis, endometritis, septic abortions, pelvic inflammatory disease, tubo-ovarian abscess, peritonitis following viscus perforation, abscesses in and around the oral and rectal areas, and pus-forming necrotizing infections of soft tissue or muscle.

• Some tumors, such as colonic, uterine, and bronchogenic carcinomas and necrotic tumors of the head and the neck, can become infected with anaerobes.

	WORKUP	Section 4 of 9
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Lab Studies:

• Collection of specimens of anaerobic bacteria is important because documentation of an anaerobic infection is through culture of organisms from the infected site. Appropriate documentation of anaerobic infection requires proper collection of appropriate specimens, expeditious transportation, and careful laboratory processing.

• Specimens must be obtained free of contamination. Inadequate techniques or media can lead to missing the presence of anaerobic bacteria or the assumption that only aerobic organisms are present in a mixed infection.

• Because anaerobes are present on skin and mucous membranes, even minimal contamination with normal florae can be misleading.

• Unacceptable or inappropriate specimens can yield normal florae and, therefore, have no or little diagnostic value.

• Appropriate materials should be obtained by using techniques that bypass the normal florae.

• Direct-needle aspiration is the best method of obtaining a culture; the use of swabs is much less desirable.
  • Specimens obtained from normally sterile sites, such as blood or spinal, joint, or peritoneal fluids, are collected after thorough skin decontamination.

  • Two approaches are used to culture the maxillary sinus following sterilization of the canine fossa or the nasal vestibule, via either the canine fossa or the inferior meatus.

  • Urine is collected by percutaneous suprapubic bladder aspiration.

  • Other specimens can be collected from abscess contents, from deep aspirates of wounds, and by special techniques, such as transtracheal aspirates or direct lung puncture.

  • Specimens of the lower respiratory tract are difficult to obtain without contamination with indigenous florae. Double-lumen catheter bronchial brushing and bronchoalveolar lavage, cultured quantitatively, can be useful.

  • Culdocentesis fluid obtained after decontamination of the vagina is acceptable.

• Transportation of specimens should be prompt unless transport devices are available. Transport devices generally contain oxygen-free environments provided by a mixture of carbon dioxide, hydrogen, and nitrogen, plus an aerobic condition indicator. Specimens should be placed into an anaerobic transporter as soon as possible.

• Liquid or tissue specimens are always preferred to swabs.

• Liquid specimens are inoculated into an anaerobic transport vial or a syringe and a needle.

• All air bubbles are expelled from the syringe. Insertion of the needle tip into a sterile rubber stopper is no longer recommended. Because air gradually diffuses through the plastic syringe wall, specimens should be processed in less than 30 minutes.

• Swabs are placed in sterilized tubes containing carbon dioxide or prereduced anaerobically sterile Carey and Blair semisolid media.

• Tissue specimens can be transported in an anaerobic jar or in a sealed plastic bag rendered anaerobic.

• Gram stain of a smear of the specimen provides important preliminary information regarding the types of organisms present, suggests appropriate initial therapy, and serves as a quality control.

• Cultures should be immediately placed under anaerobic conditions and should be incubated for 48 hours or longer. An additional 36-48 hours is generally required for species- or genus-level identification by using biochemical tests. Kits containing these tests are commercially available.

• A rapid enzymatic test enables identification after only 4 hours of aerobic incubation.

• Gas-liquid chromatography of metabolites is often used.

• Nucleic acid probers and polymerase chain reaction methods are also being developed for rapid identification.

• Detailed procedures of laboratory methods can be found in microbiology manuals.

• Antimicrobial susceptibility testing of AGNB has become less predictable because their resistance to several antimicrobials has increased. Screening of AGNB isolates for beta-lactamase activity may be helpful. However, occasional strains may resist beta-lactam antibiotics through other mechanisms.

• Routine susceptibility testing is time-consuming and often unnecessary. However, testing the susceptibility of isolates recovered from sterile body sites and/or those that are clinically important (ie, blood cultures, bone, CNS, serious infections) and have variable susceptibilities, especially those isolated in pure culture from properly collected specimens, is important.

• Antibiotics that should be tested include penicillin, a broad-spectrum penicillin, a penicillin plus a beta-lactamase inhibitor, clindamycin, chloramphenicol, a second-generation cephalosporin (eg, cefoxitin), newer quinolones, metronidazole, and a carbapenem.

• The recommended methods include agar microbroth and macrobroth dilution.

• Newer methods include the E-test and the spiral gradient end point system.

Imaging Studies:

• Radiologic or imaging studies are helpful. The presence of gas in the infected site is highly suggestive of anaerobic infection.