Anaerobic Bacteria

Authors: Maria Hedberg, Ph.D. , Carl Erik Nord, M.D., Ph.D.

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Microbiology

Anaerobic Gram-positive Non-sporeforming Rods and Anaerobic Gram-positive Cocci

The anaerobic Gram-positive cocci and anaerobic Gram-positive non-sporeforming rods such as Anaerobic+bacteria, Bifidobacterium, Eubacterium, Lactobacillus and Propionibacterium species are, for the most part, components of the normal flora of the mucosal surfaces and, to a lesser extent, the skin. They are generally considered to be of relatively low virulence and are especially prevalent in infections associated with predisposing or underlying conditions such as previous surgery, malignancy, immunodeficiency, diabetes and presence of foreign bodies. These opportunistic pathogens are seldom recovered as single isolates (13). They are often mixed with other anaerobic or aerobic bacteria. The infections in which this group of microorganisms most often has been recovered are skin and soft tissue infections, chronic otitis media and sinusitis, aspiration pneumonia, intra-abdominal infections, gynecological infections, and dental infections (13, 43).

Actinomycosis is an uncommon bacterial infection that has a characteristic chronic indolent course. Anaerobic+bacteria species are relatively often recovered from female genital tract infections, especially in women using intrauterine contraceptive device. Although most cases of pelvic actinomycosis are associated with long term use of an intra-uterine device, also other foreign bodies may cause similar pathogenesis. Recently a case was reported where retained intrauterine fetal bone was detected and the agent of infection was identified as Anaerobic+bacteria israelii (86). Pelvic actinomycosis associated with intrauterine device might mimic pelvic malignancy and A. israelii may cause localized tumor-like infections. This species has been reported in a case of renal actinomycosis mimicking renal carcinoma (24). If the diagnosis of actinomycosis can be obtained preoperatively, antibiotic treatment may lead to complete resolution (24, 34, 60, 86). Anaerobic+bacteria species are also isolated from patients with dental infections, anaerobic pleuropulmonary infections, from skin and soft-tissue abscesses in intravenous drug abusers (A. odontolyticus) and nonintravenous drug abusers (Anaerobic+bacteria sp.) (33). A. radicidentis, has been associated with failed endodontic treatment (44). Infections caused by Anaerobic+bacteria sp. may also involve the eyes. A. neuii subspecies anitratus has been isolated from chronic endophthalmitis after cataract surgery (68) and A. israelii was identified from a case of bilateral blepharokeratoconjunctivitis (36). Both cases were successfully cured by antimicrobial therapy. The rare species A. turicensis and A. radingae have been isolated from two cases of breast abscess. Both infections displayed chronicity and required recurrent aspirations and drainage in combination with prolonged antimicrobial therapy to cure (2).

Bifidobacteria are seldom encountered in clinical materials. Bifidobacterium dentium seems to be the major Bifidobacterium with pathogenic potential. It has been isolated from dental caries, feces and vagina from humans and from lower respiratory tract specimens. It has also been isolated from a case of peritonsillar abscess together with several other anaerobes (22). Bifodobacterium sp. was among other anaerobic bacteria reported in a recent study on anaerobes in pleural empyema (9). B. longum and B. breve are occasionally found in clinical materials. Sepsis caused by B. longum after acupuncture therapy (37) and neonatal meningitis caused by B. breve has been reported (62).

The genus Eubacterium currently comprises a heterogeneous group of bacteria and recent taxonomic studies have led to the suggestion of new genera to include species originally placed in the genera Eubacterium. Eubacteria are not frequently isolated from clinical specimens. They have been reported from anaerobic pleuropulmonary infections and intrauterine contraceptive device-associated infections (9, 33), in mixed cultures from abscesses, wounds and infections at different sites such as head and neck, thorax, bone, skin, peritoneal fluid (43) and dental infections (25, 48).

The pathogenic potential of lactobacilli is very low and infections caused by these bacteria are rare, in spite of their ubiquitous presence in the gastrointestinal tract and their widespread consumption in fermented milk. In a study of lactobacilli and bacteremia by Saxelin et al. (74), lactobacilli were identified in eight patients among 3,317 blood culture isolates. There was no evidence that any particular species or subspecies of Lactobacillus was the cause of the infections. Lactobacillus sp. are occasionally recovered from anaerobic pleuropulmonary infections (9, 33). They may also be involved in other human diseases such as dental caries, rheumatic vascular disease, septicemia and infective endocarditis (48). In infective endocarditis L. rhamnosus and L. paracasei subsp. paracasei are quite frequently isolated which suggests that they may have a greater pathogenic potential than other Lactobacillus species, or it is just a reflection of their relative high numbers in the oral cavity (4, 39). L. rhamnosus has also been isolated from a liver abscess (69).

Propionibacterium species are colonizing the human skin and mouth and are frequently recovered from mixed infections of the skin and soft tissue, acne vulgaris and infections linked to operative procedures or foreign bodies (13, 48). Propionibacteria are dominating in conjunctival cultures from children and adults and have been reported from cases of chronic infectious endophthalmitis following extracapsular cataract extraction (38). Although serious infections due to P. acnes are rarely reported it is increasingly recognized in severe infections like blood stream infections, prosthetic joint infections, osteomyelitis, meningitis and endocarditis (23, 49, 66). Propionibacteria has also been isolated from pleural empyema (9).

The Gram-positive anaerobic cocci are a heterogeneous group of bacteria that form a part of the normal human microflora of the skin, oral cavity, gut and urogenital tract. Taxonomical changes are ongoing in this group of microorganisms and it has been suggested that the genus Peptostreptococcus should consist ofPeptostreptococcus anaerobius and P. stomatis. The other species formerly belonging to this genus have been proposed to be reclassified into new genera that will be used in this chapter (29,76,77,80). Gram-positive anaerobic cocci are isolated from clinical specimens more often than any group of anaerobic bacteria exceptBacteroides sp. They are seen particularly in dental infections, head and neck infections, and other infections related to the oropharyngeal flora, as well as in female genital tract infections where they are the most common anaerobic isolates. They also seem to have a potential role in mediating impaired wound healing (85). The most frequent species of gram-positive anaerobic cocci isolated from clinical specimens are Finegoldia magna, Parvimonas micra and Peptinophilus harei (12) and F. magnais considered as the most pathogen species (76). Gram-positive anaerobic cocci are also one of the major groups isolated from patients with pulmonary (P. micra, F. magna and Peptostreptococcus anaerobius) (9) and intra-abdominal infections (P. micra). It has been demonstrated that the predominant anaerobic microorganisms isolated from diabetic foot infections are F. magna, Peptoniphilus asaccharolyticus, P. anaerobius, and Anaerococcus prevotii (20, 31, 33). The three species of gram-positive anaerobic cocci most commonly seen in clinical specimens from the intestinal and genital tracts are F. magna, P. anaerobius and P. asaccharolyticus. A. prevotii and A. tetradius are also clinically important Gram-positive anaerobic cocci. P. micra is frequently found in periodontal and peritonsillar infections (56, 57, 82) and F. magna has been identified as the cause of infection in five cases of endocarditis (6). P. asaccharolyticus has been isolated from a renal abscess in a pediatric patient (18). Renal abscess is uncommon in pediatrics and is rarely a cause of fever of unknown origin, as it was in this special case.

Anaerobic Gram-negative Rods Excluding Bacteroides sp.

Gram-negative anaerobic bacilli are the anaerobes most commonly encountered in clinical infections. Pigmented and non-pigmented Prevotella species are, after the B. fragilis group and Gram-positive anaerobic cocci, one of the most commonly encountered group of anaerobic bacteria in human infections.

The pigmented anaerobic Gram-negative rods are composed of species of the genera Prevotella, Porphyromonas and Alistipes finegoldii (19). Several species of these genera are found in human clinical material and eight of them originate mostly from the oral cavity (Prevotella corporis, Pr. denticola, Pr. intermedia, Pr. loeschii, Pr. melaninogenica, Pr. nigrescens, Porphyromonas endodontalis and Po. gingivalis) while Po. asaccharolytica and Po. levii-like organisms are prevalent in the urogenital and intestinal tracts (43). A. finegoldii has been isolated from appendicitis specimens (19).

Some of the pigmented Porphyromonas and Prevotella species are important pathogens in dental and bite wound infections (43). They are also isolated from infections of the head, neck, lower respiratory tract and gynecological infections. Pr. corporis, Pr. intermedia and Po. asaccharolytica have been reported in peritonsillar abscesses, suggesting that these species may have a role in the pathogenesis of this type of infection. Eighty-four percent of the positive cultures in peritonsillar abscesses have been reported to contain anaerobic bacteria (57) and similar results were described in a study of pleural empyema where anaerobes were isolated from 74 % of the cases (9). Periodontal diseases are often associated with a subgingival microflora comprising of specific potentially pathogenic microorganisms. Among the most important periodontal pathogens associated with adult periodontitis are considered to be the black pigmented Po. gingivalis and Pr. intermedia (54, 59, 82). Prevotella spp are common isolates in endodontic infections. Pr. bivia and Pr. disiens are non-pigmented and often isolated from female genital tract infections and less frequently in oral and respiratory tract infections. The non-pigmented species Pr. oris and Pr. buccae are found in different oral, pleuropulmonary and other infections (19, 43).

The fusobacteria are normally found in the oropharyngeal and the intestinal tracts. They are often isolated from severe infections such as peritonsillar abscesses, head and neck infections, brain abscesses, meningitis, gynecological infections and intra-abdominal abscesses. F. nucleatum is the Fusobacterium species most commonly encountered in clinical infections. F. necrophorum, F. varium and F. mortiferum are also common clinical isolates (43, 72). F. necrophorum is a very virulent species causing infections, most often in children or young adults, often originating from pharyngotonsillitis and it has also been encountered in peritonsillar abscesses in pure cultures (57, 71). It was stated by Bartlett and Gorbach (5) that “F. necrophorum is another normal cohabitant of the upper airways”, but this has been questioned since no convincing culture evidence exists to confirm this statement (71). Lemierre’s syndrome is a severe, septicemic illness most commonly caused by F. necrophorum and it is characterized by an acute oropharyngeal infection, with secondary septic thrombophlebitis of the internal jugular vein and frequent metastatic infections (11, 71). The microorganism is encountered frequently in mixed infections and, therefore, synergism between F. necrophorum and other pathogens may play an important role in infections. An association of fusobacterial infections and infectious mononucleosis has been observed, but more investigations are needed to clarify the correlation between Epstein-Barr virus and fusobacteria (16, 11). A case of orbital cellulitis caused by F. necrophorum in a previously healthy young female was reported by Escardo et al. (28). The patient required three sinus debridement operations and 30 days of intravenous antibiotics, but her vision did not fully recover. Fusobacteria are involved in endodontic infections and are also associated with refractory and recurrent periodontitis (50, 54, 57, 82). Three chemotherapy-induced neutropenic hematologic patients with severe systemic infection by F. nucleatum, has been reported (51). The infection was considered to be promoted by a combination of chemotherapy-induced mucositis, which served as a portal entry for the systemic infection, and the antibiotic regimen (vancomycin) used in these patients. F. nucleatum has also been isolated from pyarthrosis of the hip, following a transient synovitis in an otherwise healthy boy (21). Anaerobic bacteria are uncommon pathogens in septic arthritis.

Anaerobic Gram-negative Cocci

Veillonella sp. are small, nonmotile Gram-negative cocci present as commensals in the oropharynx, gastrointestinal tract and female genital tract. Infections caused by these bacteria are seldom reported, as they in most cases are regarded as normal flora or non-pathogenic microorganisms. They have been isolated from head and neck infections, skin and soft tissue infections and infections in the respiratory tract, peritoneal fluid and blood and also bite wound infections (43). The majority of Veillonella sp. from clinical specimens are V. parvula, but also V. dispar, V. atypica and the newly discovered species V. montpellierensis have been isolated from human specimens. Veillonella sp. may occur in severe infections such as meningitis and endocarditis (7, 55, 73).

Epidemiology

Anaerobic infections caused by bacteria described in this chapter are mainly endogenic infections, and are therefore not spread between individuals.

Clinical Manifestations

The clues listed in Table 1 are not specific except for the odor, but when two or more are present, anaerobic bacteria should be considered potential pathogens.

Laboratory Diagnosis

The most important factor in obtaining clinically relevant microbiology culture results is the quality of the specimen. Special precautions are needed in specimen collection and transport. Contamination by the normal mucosal flora at sampling must be avoided and the specimen should immediately be placed in a suitable anaerobic transport tube or pouch to avoid exposure to air. A short transport time to the laboratory is also of great value. The initial processing procedures include direct examination of the sample (macroscopic: e.g., foul odor, and microscopic: Gram-stain) and inoculation onto appropriate agar media and liquid anaerobic medium. If possible, specimen processing should be done in an anaerobic chamber to minimize aeration. In the case no such equipment is available, the sample should be processed within 15 minutes and incubated in an anaerobic environment. The culture should be incubated at 37oC for at least 48 hours. The Gram-stain is a useful tool since many anaerobes are unique morphologically. As culture results may not be available for several days this information is very important in deciding the initial therapy. The microscopic findings must always be correlated to the specimen source. It should also be taken into account that anaerobic bacteria can act synergistically with non-anaerobic bacteria in the mixed flora of anaerobic infections, or with each other. Preliminary grouping and even complete identification of some organisms are based on colonial and cellular morphology, Gram reaction, susceptibility to special potency antibiotic discs, catalase, indole and nitrate reactions. Gas-liquid chromatography is used to analyze the metabolic end products produced by anaerobic bacteria (43, 64).

Molecular methods (e.g. 16S rRNA PCR-RFLP, sequencing of special regions of 16S rRNA, DNA-DNA hybridization, PFGE) in the diagnostics of anaerobic bacteria may be useful tools in the everyday clinical microbiological practice as well as in special situations. Methods for species diagnostics to distinguish species that are otherwise difficult to differentiate, or to identify new species, detection of slow growing bacteria and non-cultivable microbes, detection of resistance genes and toxins are examples of areas where molecular methods are successfully used (61, 66). A high proportion of the human microflora cannot be grown in the laboratory and the cultivable microorganisms are not necessarily the most relevant species.

Despite attractive advantages for species identification, the nucleic acid based methodologies are less useful when polymicrobial infections are to be analyzed. When PCR-based methods are used, some bacterial species might be discriminated against others and as a result an incorrect proportion of pathogenic bacteria will be displayed. Such inaccuracy regarding the proportion of individual pathogens in a polymicrobial infection might hamper the decision of the most adequate therapy (41). In a recent report on detection of bacteria in placental tissues it was described that, although culture positive samples, no bacteria in the specimens could be detected by PCR. The negative PCR results were probably due to constituents in the chorionic plate of the placenta that rapidly degraded or blocked the detection of foreign DNA, thereby preventing identification of the foreign DNA by PCR (65).

Pathogenesis

Anaerobic infections may arise in different ways and have a variety of clinical presentations with abscess formation and tissue necrosis especially common. These infections are derived from the normal flora of the oropharynx, skin, intestinal or female genital tract. Anaerobic bacteria are generally considered to be of relatively low virulence and are especially prevalent in infections associated with predisposing or underlying conditions such as trauma or previous surgery, thus affording an opportunity to penetrate deeper tissues and to set up infection. Other predisposing factors are tissue necrosis, poor blood supply, malignancy, immunodeficiency, diabetes and presence of foreign bodies. In aspiration pneumonia anaerobic bacteria from a site of normal carriage (oropharynx) may move into another area normally free of organisms to produce infection at that site. These opportunistic pathogens are seldom recovered as single isolates. They are often mixed with other anaerobic or aerobic bacteria. The three major virulence factors in anaerobes are the ability to adhere to or invade epithelial surfaces, the production of toxins or enzymes that play a pathogenic role, and surface constituents of the organism such as capsular polysaccharide or lipopolysaccharide (11, 13, 30).

SUSCEPTIBILITY IN VITRO AND IN VIVO

During several years, an increasing resistance to different antimicrobial agents in anaerobic bacteria has been observed. Anaerobic bacteria are naturally resistant to certain antibiotics, including the aminoglycosides and the earlier quinolones, and many anaerobes now exhibit resistance to several β-lactam agents as well. Resistance to β-lactam agents is most often caused by production of β-lactamases, enzymes that inactivate β-lactam compounds by hydrolysis. Changes in the penicillin-binding proteins (PBP) or blocked penetration of drug into the active site via alteration of the bacterial outer membrane pores are also decreasing the susceptibility to β-lactam agents. Resistance is more common in Gram-negative than in Gram-positive anaerobic isolates. Patterns of susceptibility vary in different geographic areas and even in different hospitals in the same city, depending on antibiotic-prescribing practices. Four groups of drugs are active against almost all anaerobic bacteria of clinical significance: nitroimidazoles, carbapenems, chloramphenicol, and combinations of β-lactam drugs with a β-lactamase inhibitor (ampicillin/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam) (Table 2).

The antimicrobial activity of clindamycin is directed against most anaerobic bacteria and clindamycin is therefore often used for treatment of anaerobic infections. The drug penetrates into bones and joints but does not efficiently cross the blood-brain barrier and should not be administered in CNS infections (17). It is not active against enterococci and aerobic Gram-negative rods. Periorally administered clindamycin causes marked ecological disturbances in the normal oropharyngeal and intestinal microflora and resistant clostridia and enterococci are frequently isolated during and after treatment (53).

Metronidazole is an antimicrobial agent that is often used for treatment and prophylaxis of anaerobic infections. Anaerobic bacteria sensitive to metronidazole include peptostreptococci, clostridia, bacteroides, fusobacteria, prevotella and porphyromonas. A few clinical anaerobic isolates, other than B. fragilis, resistant to metronidazole have been reported (58, 67, 82).

Chloramphenicol is a bacteriostatic, highly effective broad-spectrum antimicrobial agent. The drug is very active against many Gram-positive and Gram-negative bacteria and has an excellent activity against anaerobic bacteria. Chloramphenicol is specially indicated for use in seriously ill patients when the nature and susceptibility of the infecting bacteria are unknown and in CNS infections (17). The major side effect is bone marrow toxicity, which complicates the use of chloramphenicol.

Since the bacteria in anaerobic infections are often mixed with aerobic microorganisms, combinations of two antimicrobial agents may be used in the treatment of these infections, where the microbiological analyses reveal two or more pathogenic species with different susceptibility patterns. In certain situations, the pharmacologic properties of the drugs and whether or not they are bactericidal are important considerations. In central nervous system infections, a drug that crosses the blood-brain barrier well must be used. In such infections and in endocarditis, the bactericidal activity is important (17, 32). Most of the drugs that are active against anaerobes have good bactericidal activity, except chloramphenicol. Prescription of antimicrobial agents must always be based on distinct clinical and microbiological diagnoses and the clinical benefits must always be expected to outweigh the potentially ecological disadvantages and other side effects of the treatment.

Most Gram-positive anaerobic cocci (>90%) isolates are susceptible to β-lactam agents, although cephalosporins may be less effective (10, 12, 76). In a study by Duerden (26), all except two of 25 Gram positive anaerobic cocci isolates were susceptible to penicillin. The two resistant strains had MIC values >16 mg/L and neither strain were susceptible to amoxicillin/clavulanate. Aldridge et al. have also reported similar results in a multicenter surveillance study from the US, where 49 isolates of Gram-positive anaerobic cocci were examined (1). β-Lactam resistance in Gram-positive cocci seems not to be due to β-lactamase production, but rather to modifications in the PBPs that frequently involve cross-resistance to cefoxitin and β-lactamase inhibitor combinations. Macrolide-lincosamide resistance has been shown to be inducible in Gram-positive anaerobic cocci strains and highly resistant populations in Po. asaccharolytica (MIC>8 mg/L) to erythromycin (30 % resistant strains) and clindamycin (22 % resistant strains) have also been documented (70). Recent multicenter studies have reported resistance to clindamycin in Gram-positive anaerobic cocci Prevotella, Porphyromonas and Fusobacterium sp. varying between 4 and 33 % (1, 10, 12, 20, 35, 67).

The information on antimicrobial susceptibility of anaerobic non-sporeforming Gram-positive rods is limited compared with the information available on the other anaerobic bacterial groups. In general, members of this bacterial group are susceptible to benzylpenicillin, carbenicillin and chloramphenicol. With few exceptions clindamycin, erythromycin and tetracycline are active against 60-94 % of isolates tested in this group of bacteria and the rods are commonly resistant to nitroimidazoles (20, 66, 87). In a recent European surveillance study on antibiotic susceptibility of P. acnes, resistance to clindamycin varied between 0 and 67% depending on region of isolation (66).

Resistance is increasingly common among anaerobic Gram-negative rods. Approximately two-thirds of Prevotella species are β-lactamase producers (8, 40, 67,84, 87) and β-lactamase production among oral pigmented Prevotella species is also frequently present in young children. β-Lactamase production has been studied among different ribotypes of Pr. melaninogenica isolated from the oral cavity of young children and their mothers. Seventy-six percent of the strains isolated from the children and 69% of the strains isolated from their mothers were β-lactamase producers (46). Most strains are still susceptible to clindamycin and metronidazole, while resistant strains to tetracycline have been reported. In a recent study on antimicrobial resistance in anaerobic bacteria isolated from periodontal infections three of 39Prevotella sp. strains were reported resistant to moxifloxacin (MIC >32 mg/L) (59).

The fusobacteria have become more resistant to antimicrobial agents during the last years. Penicillin-resistant strains due to β-lactamase production have been found and also clindamycin-resistant strains. The fusobacterial isolates are still susceptible to β-lactam agents combined with β-lactamase inhibitors. Metronidazole is also active against most strains (1, 33, 9, 82, 87). Most anaerobic Gram-negative rods are susceptible to metronidazole but there are exceptions: It has been demonstrated in a Colombian population that metronidazole lacked activity against Fusobacterium strains (45% resistant strains), Prevotella strains and Porphyromonasstrains (25% resistant strains) isolated from patients with periodontitis (56). The clinical implication of these findings is unknown.

ANTIMICROBIAL THERAPY

Drugs of Choice

The anaerobic Gram-positive non-sporeforming rods are susceptible to β-lactam agents including penicillins, cephalosporins, carbapenems and β-lactam/β-lactamase inhibitor combinations which are used for the treatment of infections caused by these microorganisms. Clindamycin can be given to patients allergic to β-lactam agents while metronidazole is inactive against the majority of isolates. All strains are susceptible to chloramphenicol.

Most Gram-positive anaerobic cocci are normally susceptible to penicillins and β-lactam/β-lactamase inhibitor combinations. Clindamycin and metronidazole are less active against Gram-positive anaerobic cocci but can be used in most infections (17). Gram-positive anaerobic cocci resistant to metronidazole might be microaerophilic species. In two recent surveillance studies on antimicrobial susceptibility of Gram-positive anaerobic cocci, 4-7 % of the isolates were reported resistant to penicillin and 4-7 % to clindamycin. No metronidazole resistance was described in these extensive surveys (10, 12). In another recent report by Boyanova et al. resistance to penicillin and clindamycin in Gram-positive anaerobic cocci was accounted to 21 and 15 % respectively and metronidazole resistance was found in 16 % of the tested strains (9).

About 70 % of Prevotella strains and 20% of Porphyromonas strains produce β-lactamases making penicillin inactive. The combination of a β-lactam agent together with a β-lactamase inhibitor is active against these strains (1, 33, 84). In an antimicrobial susceptibility study by King et al., 68% of the P. bivia strains tested were reported resistant to penicillin. Among the isolates of P. melaninogenica 60% were resistant, P. denticola 41% and P. oralis 53% (45).

Fusobacterium strains have also been reported to produce β-lactamases. Resistance to β-lactam agents is relatively frequent among fusobacteria, about 13-30% in Europe and 10-40% in the US (1, 8, 35, 47). β-Lactam-resistant strains of F. nucleatum are most often seen, but resistant F. varium and F. mortiferum strains have also been isolated. Some strains of these species produce β-lactamases. β-Lactamase producing F. nucleatum strains has been isolated from the tonsils during penicillintreatment (81). In a study by Könönen et al., 10 of 20 children ranging in age from 2 to 3.4 years harbored β-lactamase producing F. nucleatum isolates. They had not received antimicrobial treatment within the last month preceding the specimen collection (47). As Fusobacterium species are intrinsically resistant to erythromycin, which is often the alternative antibiotic for the treatment of upper respiratory tract infections in patients allergic to penicillin, a combination of erythromycin or penicillin with metronidazole will provide protection against both the aerobic and anaerobic pathogens. Alternatively clindamycin, chloramphenicol, imipenem or a β-lactam agent in combination with a β-lactamase inhibitor can be effective (11).

Special Infection

Anaerobic Endocarditis

Anaerobic endocarditis is a rare but serious infection with a mortality rate of 21-43 % and it accounts for 2-16 % of all cases of infective endocarditis (15). Gram-positive anaerobic cocci and Bacteroides fragilis are most often causing anaerobic endocarditis. In patients with prosthetic heart valves, vascular grafts or intravascular prosthesis, endovascular infections caused by lactobacilli, propionibacteria and bifidobacteria have been reported. Benzylpenicillin is considered to be the agent of choice for treatment of endocarditis caused by Gram-positive anaerobic cocci, lactobacilli, propionibacteria and bifidobacteria (33). In a report of endocarditis caused by F. magna it was concluded that the diagnosis seems to be depending on the blood culture system used, as some of these patients had several negative blood cultures before the infecting microorganism finally was detected (6). The incidence of infective endocarditis caused by Propionibacterium sp. is low, a fact that limits the understanding of the disease. The diagnosis of Propionibacteriumendocarditis is often missed or delayed due to the prolonged incubation (7-14 days) required for isolation of these bacteria from blood cultures, as well as the difficulty to differentiate whether the positive cultures represent skin contamination or a true bacteremia. A large multinational study of Propionibacterium infective endocarditis was recently conducted to examine clinical features, complications and outcomes of 15 cases, using prospectively collected data. Prosthetic valve endocarditis occurred in 13 of 15 patients and clinical findings included valvular vegetation in nine cases and cardiac abscesses in three cases. Ten of 15 patients underwent valve replacement surgery and two died (49). The infections indolent clinical course and negative blood cultures may delay appropriate therapy and contribute to abscess formation. P. acnes is the most frequently reported species in Propionibacterium endocarditis and the most common antimicrobial therapy is penicillin alone or in combination with an aminoglycoside (23).

Anaerobic Pericarditis

Anaerobic bacteria have only rarely been isolated from pericardial fluid. In a review by Skiest et al. 30 cases of pericarditis were reported, in which at least one specific type of anaerobic bacteria was implicated (75). The anaerobes were isolated from the pericardial fluid in 27 cases and from the blood in three cases. In these three cases the cultures of purulent pericardial fluid were sterile. The following anaerobic organisms were isolated: Bacteroides species (includingPrevotella species), "anaerobic streptococci", peptostreptococci, Clostridium species, Fusobacterium species and Bifidobacterium species. The mortality rate was 52%. No firm conclusion concerning the impact of treatment on outcome could be drawn because of the small number of cases. Cases due to Anaerobic+bacteria were excluded from the review. For patients with odontogenic infections, esophageal diseases, anaerobic pleuropulmonary infections, intraabdominal infections, or pelvic infections, purulent pericarditis may be caused by anaerobic bacteria. In all cases of pericarditis there should be a search for the source of the organism infecting the pericardium and initial antimicrobial therapy should include antibiotics directed against anaerobic bacteria (75).

Anaerobic Meningitis

Anaerobic bacteria are uncommon as the etiology of meningitis. Anaerobic bacterial meningitis occurs in older children and adults with chronic sinusitis, chronic otitis media or bowel diseases. Benzylpenicillin is recommended for treatment of meningitis due to Gram-positive anaerobic cocci and propionibacteria (33). Chloramphenicol has also been used. Recently meropenem has shown to be useful for treatment of pneumococcal meningitis. It may therefore also be used for Gram-positive anaerobic cocci meningitis (63). Meningitis caused by F. necrophorum has high mortality (33 %) and morbidity (60 %). Two cases of fatal meningitis in children (4 and 5 years old) due to F. necrophorum were recently reported by Veldhoen et al. The children were previously healthy and a few weeks before admission they were both diagnosed with otitis media for which they were treated with antimicrobials, one of them with amoxicillin and the other with neomycin. At admission they were acutely ill with symptoms like high-grade fever, headache and vomiting. In the first case computed tomography scan (CT-scan) revealed no abnormalities at admission, but cerebrospinal fluid examination indicated leukocytosis and ceftriaxone was immediately initiated. A new CT-scan 12 hours later showed mastoiditis and suggestive pus in the ventricular system. Gram-negative rods identified as F. necrophorum was grown from blood and cerebrospinal fluid within 12 hours and the antibiotic was changed to meropenem. The F. necrophrum infection was rapidly progressing and a CT-scan made 12 hours after the second one revealed multiple hypodense areas, probably ischemic zones, and eight hours later the child was declared clinically brain dead. In the second case initial findings by CT-scan indicated mastoiditis and Pseudomonas was at first suspected as the infecting agent. The patient’s neurologic condition deteriorated rapidly during the next six hours despite meropenem therapy. A new CT-scan displayed among other findings, multiple cerebral infarcts and jugular vein thrombosis. A few days later the child was declared brain dead and F. necrophorum was grown from blood and cerebrospinal fluid. Microbiological diagnosis can be easily missed or delayed as F. necrophorum can only be isolated under strict anaerobic conditions and may require prolonged incubation (83). Meningitis caused by V. parvula was recently reported by Bhatti and Frank. A predisposing factor in this case was probably a chronic sinusitis. The V. parvula isolate was grown from spinal fluid, while blood cultures from the day of admission yielded P. intermedia and P. anaerobius and a culture of fluid from the right sphenoid grew Enterobacter cloacae and P. acnes. The patient was cured after a 6-week course of ceftriaxone and metronidazole (7).

Anaerobic Liver Abscess

From liver abscesses the following anaerobic bacteria are most often isolated: Gram-positive anaerobic cocci, bacteroides and fusobacteria. The most common sources are biliary tract and other intraabdominal infections. A few cases of liver abscesses due to Lactobacillus spp. have been reported. In one case L. rhamnosus was isolated from a 74-year woman with a several year history of hypertension and non-insulin-dependant diabetes mellitus. The bacterium was indistinguishable from L. rhamnosus strain GG, which is used in diary products in Finland. Four months before her symptom onset, she had a daily intake of one-half litre dairy drinks containing L. rhamnosus strain GG, to relieve abdominal discomfort (69). Successful treatment of liver abscess requires drainage of the abscess and appropriate antimicrobial therapy. If the underlying source of infection such as bowel perforation or bile duct obstruction must be controlled, surgical drainage is indicated. Empiric antimicrobial treatment is recommended to start before the surgical drainage. A combination with an aminoglycoside plus metronidazoleor clindamycin will give an optimal coverage for the aerobic and anaerobic bacteria involved. Carbapenems like imipenem and meropenem have also been used successfully for treatment of these infections (63).

Anaerobic Discitis

Staphylococcus aureus or other aerobic and facultative microorganisms generally cause diskitis, an inflammation of the invertebral disk. Anaerobic bacteria have been isolated from adults with spondylodiscitis, but this has not been reported in children. The recovery of anaerobic bacteria in two children with diskitis was recently published. One patient was a 10-year old boy. The blood culture showed no growth, but a Gram stain from the infected site revealed Gram-positive cocci in chains. Anaerobic cultures yielded heavy growth of F. magna, which was susceptible to penicillin, clindamycin and vancomycin (14). The other patient was an 8-year old boy. One month earlier he had an upper respiratory tract infection with sore throat, for which he had no therapy. Aspirated material from the disc space was sent for aerobic and anaerobic cultures. Gram stain showed fusiform Gram-negative bacilli and the anaerobic culture showed light growth of F. nucleatum. The strain produced β-lactamase and was susceptible to ticarcillin-clavulanate, clindamycin, metronidazole and imipenem (14). Veillonella sp. has also been identified as a cause of anaerobic diskitis. A 27-year-old man was admitted to the hospital after a 3-week history of low back pain. The onset of pain was abrupt with no identifiable precipitating factor. Spinal motion was limited in all planes and a CT-scan revealed a disk herniation. The pain persisted and at the 33rd hospital day laboratory tests disclosed worsening inflammation and findings from magnetic resonance imaging of the lumbar spine suggested diskitis. Culture from a fine needle biopsy of the disk grew Veillonella sp. No portal of entry could be located, the patient was treated with amoxicillin for 11 weeks and was finally cured (42). A similar situation withveillonella-diskitis was reported by Marriott et al., although in this case the predisposing factor probably was a routine endoscopy that the patient underwent two months earlier. The initial antimicrobial treatment for the infection was flucloxacillin and ceftriaxone, but despite the therapy fever and pain worsened. Six days after admission V. parvula was isolated from disk aspirate and blood. The antibiotic was changed to cefotaxime and later on to amoxicillin-clavulanic acid that completed a total of 3 months successful antimicrobial therapy (55). In many cases no bacterial growth is obtained from infected invertebral discs, which might be caused by improper methods for their collection, transport and cultivation. Proper choice of antimicrobial therapy of diskitis can be accomplished only by identification of the causative organisms and its antimicrobial susceptibility. This is particular important in infections caused by anaerobic bacteria that are often resistant to antimicrobial agents used to empirically treat diskitis (14).

Underlying Diseases

Anaerobic infections are often associated with predisposing or underlying conditions where host defenses are impaired, such as previous surgery, impaired blood supply, malignancy, immunodeficiency, diabetes and presence of foreign bodies. Tissue necrosis or poor blood supply lowers the oxidation-reduction potential, favoring the growth of anaerobic organisms. To cure the infection underlying factors should be traced and eliminated if possible. In a study by Lark et al., F. nucleatumand Leptotrichia buccalis were reported as the most frequently isolated anaerobic bacteria from bloodstream infections in patients who underwent bone marrow transplantation (52). In elderly and immunocompromised patients Lactobacillus sp. have been identified as potential emerging pathogens, particularly in those patients receiving broad spectrum antibiotic therapy (3).

Alternative Therapy

Moxifloxacin, a methoxyfluoroquinolone, has a broad spectrum of antibacterial activity and has been shown to be useful in mixed aerobic and anaerobic infections. The compound has good activity against anaerobes in addition to enhanced activity against Gram-positive bacteria as compared to earlier quinolones, like ciprofloxacin, ofloxacin and norfloxacin. Moxifloxacin is particularly active against microorganisms causing respiratory tract infections and skin and soft tissue infections (79). However, resistance to this agent seems to increase among several genera of anaerobic bacteria such as the B. fragilis group (20, 79, 87).

Linezolid belongs to a class of synthetic antimicrobial agents called oxazolidinones. The agent is active against many clinically important Gram-positive bacteria including methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant pneumococci. This compound does generally not inhibit Gram-negative aerobic bacteria. Linezolid has excellent activity against Gram-positive anaerobic microorganism, and exhibits also activity against Gram-negative anaerobic bacteria (27). Linezolid may be used for treatment of anaerobic infections. Sporadic isolates of Prevotella sp., anaerobic cocci and anaerobic Gram-positive rods resistant to linezolid have recently been reported (87).

Tigecycline is the first glycycline antibiotic to be approved by the US Food and Drug Administration. The compound is active against a wide range of bacteria: e.g. Gram-positive and Gram-negative bacteria, methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci and extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae as well as several anaerobic bacteria but lacks activity against Pseudomonas aeruginosa. The drug is unique for its ability to be used as monotherapy for empirical coverage of various drug resistant pathogens and polymicrobial infections. Because of poor oral absorption, tigecycline should be given parenterally (78). Resistance to tigecycline among anaerobes has been reported in the Bacteroides fragilis group (19 %) and a few isolates of clostridia but not in other anaerobes (87).

VACCINES

At present, no vaccines against anaerobic bacteria are available. The anaerobic bacteria consist a great part of the normal microflora and the immune response is therefore low.

ADJUNCTIVE THERAPY

The two key approaches to treatment of infections involving anaerobic bacteria are surgery and antimicrobial therapy. In most anaerobic infections (except pulmonary), surgical drainage and debridement are necessary for a favorable outcome. Failure to carry out essential surgical therapy may lead to poor or no response to appropriate antimicrobial agents. Other modes of therapy such as hyperbaric oxygen (HBO) and hydrogen peroxide occasionally may be useful in selected circumstances (30, 33).

PREVENTION

Most of the anaerobic bacteria involved in infection are present as normal flora at various sites in the human body, which makes prevention of anaerobic infections difficult.

CONCLUSIONS

Anaerobic bacteria are important pathogens in many different infections. During the last years, resistance to several antimicrobial agents in anaerobic bacteria has been more frequently described (1, 10, 12, 20, 35, 45, 59, 66, 67, 87). While other groups of anaerobic bacteria have remained substantially stable in their susceptibility patterns, the Bacteroides genus and the genera Prevotella and Porphyromonas have become increasingly resistant to many anti-anaerobic agents such as penicillins and cephalosporins. Antimicrobial agents commonly used in the treatment of anaerobic infections are ß-lactam antibiotics (carbapenems), metronidazole and ß-lactam compounds (ampicillin, amoxicillin, ticarcillin and piperacillin) in combination with a ß-lactamase inhibitor, such as clavulanic acid, sulbactam, or tazobactam. The broad-spectrum quinolones moxifloxacin and gatifloxacin have potential to treat mixed aerobic and anaerobic infections, however resistance to these agents seems to increase among several genera of anaerobic bacteria (20, 79, 87). New antimicrobial agents such as linezolid and tigecycline may be an alternative in the therapy of anaerobic infections. The treatment of anaerobic infections must be individualized, taking into account the site, type, extent and severity of the infection. Empiric antimicrobial therapy is frequently used in the treatment of anaerobic infections as it might take several days for bacterial cultures to grow and, in many cases, the patient needs care without delay. The antibiotic resistance patterns are no longer predictable in anaerobic bacteria and the first choice of antibiotic might not be sufficient. Antimicrobial susceptibility testing of the infecting microorganisms will give essential information of the alternatives for treatment. The patient’s condition and the nature of the infecting microorganisms are of extreme importance.

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Tables

Table 1. Major Clues to Anaerobic Infection

Foul-smelling discharge

Infection in proximity to a mucosal surface

Tissue necrosis, gangrene

Gas in tissues or discharges

Infection associated with malignancy

Infections secondary to human or animal bite

Infection related to the use of aminoglycosides, quinolones, trimethoprim/sulfamthoxazole, monobactams, or cefalosprins with poor activity against anaerobes

Classical clinical picture such as gas gangrene and actinomycosis

Infections which are primarily of anaerobic etiology (e.g., brain abscess, lung abscess)

Septic trombophlebitis

Unique morphology of Gram stain of exudates

No growth on routine culture – “sterile pus”

Black discoloration of blood-containing exudates; these exudates may fluoresce red under ultraviolet light (infections involving pigmented Prevotella andPorphyromonas)

Adapted from Finegold et al. 1992 (30) and Finegold 1995 (32)

Table 2.In vitro Susceptibility to Antimicrobial Agents of Anaerobic Bacteria (not including Bacteroides sp. and Clostridium sp.)a

Bacteria	Antimicrobial Agent
	PcV	Amox	Amox/ clav	Cefox	Imip	Clinda	Metro	Chloram	Moxi
Gram-positive bacteria
Anaerobic+bacteria sp.	S	S	S	S	S	S	R	S	S
Bifidobacteria	S	S	S	S	S	S	R	S	S
Eubacteria*	S	S	S	S	S	S	R	S	S
Lactobacilli	S	S	S	S	S	S	R	S	S
Propionibacteria	S	S	S	S	S	V	R	S	S
Anaerobic Gram-positive cocci	S/V	S/V	S/V	S	S	V	V	S	S
Gram-negative bacteria
Fusobacteria	V	V	S	S	S	S/V	S	S	S
Porphyromonas sp.	V	V	S	S	S	S/V	S	S	S
Prevotella sp.	V	V	S	S	S	S/V	S	S	S/V
Veillonella sp.	V	S	S	S	S	S/V	S	S	S