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Anaerobe 16 (2010) 183–189

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Review

The role of anaerobic bacteria in bacteremia Itzhak Brook* Georgetown University, Schools of Medicine, 4431 Albemarle st NW, Washington, DC 20016, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 November 2008 Received in revised form 12 August 2009 Accepted 7 December 2009 Available online 16 December 2009

Anaerobic bacteria remain an important cause of bloodstream infections and account for 1–17% of positive blood cultures. This review summarizes the epidemiology, microbiology, predisposing conditions, and treatment of anaerobic bacteremia (AB) in newborns, children, adults and in patients undergoing dental procedures. The majority of AB are due to Gram-negative bacilli, mostly Bacteroides fragilis group. The other species causing AB include Peptostreptococcus, Clostridium spp., and Fusobacterium spp. Many of these infections are polymicrobial. AB in newborns is associated with prolonged labor, premature rupture of membranes, maternal amnionitis, prematurity, fetal distress, and respiratory difficulty. The predisposing conditions in children include: chronic debilitating disorders such as malignant neoplasm, hematologic abnormalities, immunodeficiencies, chronic renal insufficiency, or decubitus ulcers and carried a poor prognosis. Predisposing factors to AB in adults include malignant neoplasms, hematologic disorders, transplantation of organs, recent gastrointestinal or obstetric gynecologic surgery, intestinal obstruction, diabetes mellitus, post-splenectomy, use of cytotoxic agents or corticosteroids, and an undrained abscess. Early recognition and appropriate treatment of these infections are of great clinical importance. Ó 2009 Elsevier Ltd. All rights reserved.

Keywords: Bacteremia Anaerobes Bacteroides fragilis Clostridium spp. Peptostreptococcus

1. Introduction Anaerobes can cause infections at virtually all anatomic sites as well as bacteremia. These organisms remain an important cause of bloodstream infections and account for 1–17% of positive blood cultures [1–7]. Early recognition and appropriate treatment of these infections are of great clinical importance. This review summarizes the epidemiology, microbiology, predisposing conditions, and treatment of anaerobic bacteremia (AB) in newborns, children, and adults. 2. Epidemology Anaerobes accounted for 10–20% of episodes of bacteremia in studies done up to the 1990th [6,8]. However, in the 1990th the incidence was lowered to approximately 4% (0.5–12%) of all cases of bacteremias (or approximately one case per 1000 admissions), with variation by geographic location, hospital patient demographics, and especially, patient age [6,8]. Increased awareness of the importance of anaerobes and enhanced recognition of the types of clinical infection caused by these organisms, along with

* Tel.: þ1 202 363 4253; fax: þ1 202 244 6809. E-mail address: [email protected] 1075-9964/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.anaerobe.2009.12.001

appropriate prophylaxis and treatment, were postulated as reasons that explain the decrease in the incidence of AB during 1974–1988 [8]. Recent studies, however, documented a resurgence in AB. A study from the Mayo Clinic (Rochester, MN) has reported that the mean incidence of AB increased from 53 cases/year during 1993– 1996 to 75 cases per year during 1997–2000 to 91 cases/year during 2001–2004 (an overall increase of 74%). The total number of cases of AB per 100,000 patient-days increased by 74% (p < 0.001). The number of anaerobic blood cultures per 1000 cultures performed increased by 30% (p ¼ 0.002) [9]. The study found that was a greater proportion of patients with AB with underlying malignancies in 2004 than during 1993–1994 [9]; however, no statistically significant difference was shown (46% vs. 39%, respectively; p ¼ 0.39). Hematologic malignancies were most common during both periods, followed by gastrointestinal, gynecological, and urogenital malignancies. 3. Microbiology The majority of ABs are due to Gram-negative bacilli, mostly Bacteroides fragilis group. B. fragilis is the most common blood isolate recovered from patients with AB; this organism and species of the B. fragilis group account for approximately half of ABs. B. fragilis bacteremia is associated with a mortality of about 20% with a mortality risk of 3.2; a 16-day increase in hospital stay; and often, intra-abdominal disease. Associated risks for mortality

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include chronic liver disease and congestive heart failure. The other species causing AB include Peptostreptococcus and Clostridium spp. (about 10% each), and Fusobacterium spp. (about 5%). Many of these infections are polymicrobial [10,11]. Propionibacterium acnes is a common isolate but is often a skin contaminate of blood cultures. However, it can be recovered from the blood of patients with shunt or vascular catheter bacteremia [12]. Studies documenting AB were performed in newborns, children, adults, and in patients undergoing dental procedures. The following sections present these studies. 3.1. Anaerobic bacteremia in newborns The awareness of the role of anaerobic bacteria in neonatal bacteremia and sepsis has increased in recent years. The incidence of recovery of anaerobes in neonatal bacteremia varies between 1.8% and 12.5% [13]. Of the 179 cases reported in the literature and reviewed by Brook [13], 73 were due to Bacteroides spp. (69 were the B. fragilis group), 57 Clostridium spp. (mostly Clostridium perfringens), 35 Peptostreptococcus spp., 5 P. acnes, 3 Veillonella spp., 3 Fusobacterium spp, and 2 Eubacterium spp. Multiple organisms, aerobic and anaerobic, were isolated from eight patients reported in one study [14], anaerobic co isolates from 6 (5 Peptostreptococcus spp., one Veillonella parvula,) and aerobic co isolates from only two (Escherichia coli and alpha-hemolytic streptococcus). In one patient, reported by Noel et al. [15], Bacteroides vulgatus was isolated from a single blood culture along with 4 aerobic bacteria (Streptococcus faecalis, E. coli, Streptococcus faecium and Klebsiella pneumoniae). Simultaneous isolation of the anaerobes from other sites was reported by several authors [14,16–21]. This was especially common with B. fragilis and Clostridium spp. Chow and co-workers [14] reported the simultaneous isolation of Bacteroides spp. from gastric aspirate in four instances, from the amniotic fluid or uterus at cesarean section in two cases, and from the maternal and fetal placental surfaces and the external auditory canal in one instance each. Brook et al. [22] reported the concomitant recovery of B. fragilis group from lung aspirates of two patients with pneumonitis; Harrod and Sevens [23] recovered B. fragilis from the inflamed placenta; Dysant and associates [19] and Brook et al. [22], Kasik et al. [18] and Webber and Tuohy [24] recovered B. fragilis from the cerebrospinal fluid of a total of four patients with meningitis. Brook [17] isolated B. fragilis from an occipital abscess that developed following neonatal monitoring with scalp electrodes. Ahonkhai et al. [25] described the concomitant isolation of C. perfringens in the placenta of a newborn. Kosloske et al. [26] recovered Clostridium spp., B. fragilis, and Eubacterium spp. from the peritoneal cavity of four patients with necrotizing enterocolitis. Brook et al. [20] isolated Clostridium difficile from the peritoneal cavity of a newborn with necrotizing enterocolitis. Spark and Wike [27] reported four cases of isolation of Clostridium spp. from omphalitis, and Heidemann et al. [21] recovered a gas forming C. perfringens in the cerebrospinal fluid of a newborn with meningitis [28]. 3.2. Anaerobic bacteremia in children AB has rarely been described in pediatric patients. Sanders and Stevenson [29] in a review of the literature in 1968 summarized 11 cases of Bacteroides bacteremias in children. Berry et al. recovered anaerobes from 6 of 34 children who required general anesthesia and nasotracheal intubation for dental repair [30]. Another study documented bacteremia in 28 children who were undergoing dental manipulations [31]. Among the 28 isolates recovered, 21

were anaerobes, Propionibacterium spp., 9; Veillonella alcalescens, 5; Prevotella melaninogenica, 3; Peptostreptococcus spp., 2; and Eubacterium spp. and Fusobacterium spp., one each. Brook et al. [32] reviewed their experience in recovery of anaerobes in the blood over a 12-month period in UCLA Medical Center in Los Angeles, California. Thirteen blood cultures were positive and contained 14 anaerobic bacteria: B. fragilis (5), Bacteroides spp. (3), Propionibacterium spp. (3), Fusobacterium spp. (2), and Peptostreptococcus spp. (1) In one instance two organisms were isolated from a blood culture: a Peptostreptococcus and a Fusobacterium spp. Dunkle et al. [33] recovered 14 anaerobes from blood cultures over a one-year study at St. Louis Children’s Hospital. The anaerobes recovered were Clostridium spp. (4), Fusobacterium nucleatus (3), Gram-positive cocci (3), and B. fragilis (2). Although 27 isolates of P. acnes were recovered, only three were associated with clinical infection. Thirmuoothi et al. [34] reviewed their experience over a period of 18 months in Detroit, Michigan, and reported 35 anaerobic isolates from 34 blood cultures. The predominant isolates were 4 each of Gram-positive cocci and Bacteroides spp. and 2 isolates each of Fusobacterium, Bifidobacterium, and Clostridium spp. Although Propionibacterium spp. were recovered in 18 instances, there was no apparent relationship between their recovery from the blood and the patients’ clinical illness. Brook and colleagues [35] summarized their experience in detecting of AB noted in 28 children at UCLA Medical Center and Children Hospital in Washington DC. Twenty-nine anaerobic isolates were recovered from 28 patients (age of 1 week–15 years). The isolates were Bacteroides spp. (14, including 11 B. fragilis group), Clostridium spp. (4), anaerobic Gram-positive cocci and P. acne (4 each), and Fusobacterium spp. (3). All of the patients with P. acnes bacteremia had clinical infection, and all but one responded to antimicrobial therapy. Furthermore, two patients had meningitis caused by this organism after installation of cardiovascular shunts. An important aspect of AB in children is that anaerobes frequently are present in cases of polymicrobial bacteremia [36] reflecting the fact that localized anaerobic infections are usually polymicrobial. Polymicrobial bacteremia involving anaerobes were reported by several authors. Frommell and Todd [37] reported 56 children with bacteremia with multiple bacterial isolates. Five anaerobes were isolated: 2 Bacteroides spp., two Peptostreptococcus spp. and one C. perfringens. Rosenfeld and Jameson [38] reported a 15-year-old child with polymicrobial bacteremia involving seven isolates (including four Bacteroides spp. and an anaerobic cocci) associated with pharyngotonsillitis. Seidenfeld et al. [39] reported an adolescent with a fatal bacteremia caused by Fusobacterium necrophorum and Peptostreptococcus spp. associated with peritonsillar abscess. Givner et al. [40] recovered Bacteroides capillosus with Corynebacterium hemolyticum from the blood of a child with primary Epstein–Barr virus infection who developed sinusitis. Caya and Truant summarized 65 non-infant pediatric clostridial bacteremia [41]. The predominant isolates were Clostridium septicum, C. perfringens and Clostridium tertium. Twenty-nine of the 63 children analyzed (46%) survived their episode of clostridial bacteremia. The presence of 3 clinical indices was shown to have a statistically significant negative impact on survival: hypotension, hemolysis, and lack of use of antibiotic therapy. Of the 36 patients with known underlying neoplastic disease, 27 had acute leukemia, 5 had sarcoma, 3 had a malignant lymphoproliferative disorder and 1 had glioblastoma multiforme. Twenty-three patients had no underlying neoplasia; 3 of those 23 patients had cyclic neutropenia; 2 were in sickle cell disease crisis; 2 had neutropenia associated with aplastic anemia; and one was mildly immunocompromised due to renal transplant ion.

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Brook reported the microbiology of 101 specimens obtained from 95 children with malignancy at several medical centers in Southern California and Washington DC hospitals [42]. A total of 17 patients had bacteremia. Four had E. coli, in one instance mixed with B. fragilis. B fragilis group isolates were recovered in 3 instances (two in patients with leukemia who had a perirectal abscess), Staphylococcus aureus in 3, Clostridium spp. in 2 (one C. perfringens and one C. septicum) and 2 Proteus spp. 3.3. Anaerobic bacteremia in adults Several studies reported the recovery of anaerobes in patients with bacteremia. Goldstein & Citron [43] isolated 45 anaerobes over one year period in a community hospital in Los Angeles California. They recovered 69 (64%) B. fragilis group isolates (19 were B. fragilis and 5 were Bacteroides thetaiotaomicron), 8 (18%) Clostridium spp., and 2 (4%) Fusobacterium spp. Brook [11] reviewed clinical and microbiologic data of 296 patients with AB seen over 12 years in two military hospitals in Greater Washington DC area. Anaerobes were isolated with aerobic or facultative bacteria in 23 instances. The B. fragilis group accounted for 148 (70%) of 212 isolates of Bacteroides spp. B. fragilis accounted for 78% and B. thetaiotaomicron for 14%. Among other species, there were 20 (6%) Fusobacterium organisms, 63 (18%), Clostridium isolates, and 53 (15%) anaerobic cocci. Seventy-five patients died: 40 had B. fragilis group isolates – B. fragilis, 28, and B. thetaiotaomicron, 8 - and 21 had Clostridium organisms isolated. The primary portals of entry were the gastrointestinal tract (42%), decubiti and gangrene (10%), the female genital tract (8%), and the oropharynx (7%). The gastrointestinal tract, decubiti, and gangrene were the predominant sources for B. fragilis and Clostridium organisms, the female genital tract and oropharynx for anaerobic cocci and Fusobacterium spp., and the oropharynx for pigmented Prevotella and Porphyromonas spp. Foreign body was associated with P. acnes and Clostridium spp. Factors predisposing to AB were abscesses, 53; malignancy, 51; surgery, 30; and intestinal obstruction or perforation, 27. Gransden et al. [44] recovered 250 anaerobic isolates between 1969 and 1990 in England. There were 138 (55%) B. fragilis group isolates, 18 (12%) Clostridium spp., 20 (8%) Peptostreptococcus spp., and 18 (7%) Fusobacterium spp. Summanen et al. [45] reported the recovery of 147 anaerobic isolates between 1984 and 1990 in a Veteran Administration Hospital in Los Angeles California. There were 63 (43%) B. fragilis group isolates (42 were B. fragilis and 7 were B. thetaiotaomicron), 56 (38%) Clostridium spp., 16 (11%), Peptostreptococcus spp., and 12 (8%) Fusobacterium spp. Peraino et al. [46] isolated 35 anaerobic isolates over one year period in a community hospital in Los Angeles California. There were 16 (45%) B. fragilis group isolates (6 were B. fragilis and 5 were B. thetaiotaomicron), 5 (13%) Clostridium spp., 3 (8%), Peptostreptococcus spp., and 2 (6%) Fusobacterium spp. Noriega et al. [47] reviewed 75 episodes of AB observed in cancer patients in Santiago, Chile. Gastrointestinal (22.7%), hematological (22.7%) and female genital tract (18.6%) cancers were the most common underlying malignant diseases. Among 84 strains of strict anaerobic bacteria recovered in the 75 patients, Gram-negative rods were isolated in 49 patients (58.3%), Gram-positive rods in 29 patients (34.5%) and Gram-positive cocci in 6 patients (8%). Bacteroides spp. and Clostridium spp. were the most frequent pathogens (85.7%). Twenty-one episodes of bacteremia were polymicrobial, and aerobic gram-positive cocci were the most frequently associated pathogens. The primary sites were the gastrointestinal tract (40%), the female genital tract (17.3%), skin and soft tissue (14.6%), the oropharynx (12%) and the lower

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respiratory tract (6.7%). The source remained unknown in 7 cases (9.3%). The overall survival (10 days after the occurrence of bacteremia) was 82.5%. There was no difference in mortality between patients with monomicrobial and polymicrobial bacteremia. Pulmonary complications were more frequent in patients with fatal outcome (31%) in comparison to patients who survived (5%). The mortality rate of the patients adequately treated was 10.3% compared to 41% for the patients not treated or treated inadequately (P ¼ 0.016, chi 2). Ramos et al. [48] evaluated 131 episodes over a period of six and a half years with AB in Madrid, Spain. The relative frequency of AB was 7.5% of 1750 bacteremia episodes. Clinical significance was found in 86 out of the 131 episodes (66%). The isolation of Bacteroides spp. was clinically significant in 89% while Clostridium spp. was so only in 33% (p < 0.001). Mortality related with AB was 32%. The factors considered related to bad prognosis statistical analysis (p < 0.05) were: (1) admission to medical wards, (2) rapid and fatal underlying disease, (3) presence of septic shock, (4) renal failure, (5) inappropriate antimicrobial treatment, and (6) the absence of drainage for the septic foci. Arzese et al. [49] found 225 anaerobic isolates in a nationwide survey of AB in Italy between 1991 and 1992. There were 63 (34%) B. fragilis group isolates (54 were B. fragilis and 13 were B. thetaiotaomicron), 28 (11%) Clostridium spp., 20 (8%) Peptostreptococcus spp., and 15 (6%) Fusobacterium spp. Salonen et al. [50] retrospectively studied the incidence of AB during 6 years (1991–1996) in Turku University Central Hospital, Finland. Cultures of blood from 81 patients yielded anaerobic bacteria (4% of all bacteremias). AB was clinically significant in 57 patients (0.18 cases/1000 admissions). Only half of these patients received appropriate and effective antimicrobial treatment before the results of blood cultures were reported; for 18 patients (32%), initially ineffective treatment was changed on the basis of the bacteriologic results, and for 11 patients (19%), the treatment was not changed. The mortality in these patient groups was 18%, 17%, and 55%, respectively. Empirical therapy may provide coverage for anaerobes in only half of the patients with AB, and failure to pay attention to the results of anaerobic blood cultures was associated with serious consequences for patients. Anuradha et al. [51] identified 17 cases of AB over two years in Mumbai India. Twelve grew anaerobes alone while five had a polymicrobial flora. Seven of these patients had pre-existing heart disease while others had history of prior surgery, diabetes mellitus or urinary tract infection. Oropharynx was the commonest portal of entry, followed by gastrointestinal tract. The anaerobes isolated were anaerobic streptococci, B. fragilis group and Bilophila and Eubacterium spp. Fifteen patients developed major complications such as congestive cardiac failure, systemic embolisation, and perforative peritonitis. The mortality rate among the cases with AB was 23.5%. Blairon et al. [5] evaluated AB over 62 months at Mont-Godinne University Hospital, Yvoir, Belgium. The proportion of positive blood cultures yielding obligate anaerobes was 3.3%. The overall incidence of clinically significant anaerobic bacteremia was 0.51 cases/1000 patient admissions (0.61 cases/10,000 hospital-days), but was significantly higher in patients with active hematological malignancies than in other groups (5.97/10,000 vs. 0.33/10,000 hospital-days; p < 0.05). B. fragilis group accounted for 61% of isolates, followed by Clostridium spp. (12.2%), Peptostreptococcus and Leptotrichia spp. (7.3% each) and Fusobacterium spp. (4.8%). The most common risk factors were gastrointestinal surgery (49%) and active hematological malignancies with chemotherapy and/or bone marrow graft (47%). One or more co-morbidities were present in 30 (77%) of 39 patients. The lower gastrointestinal tract (41%) and the oropharynx (23%) were the two most frequent presumed or proven sources for bacteremia, with the origin remaining unknown in

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eight (20.5%) cases. The overall mortality rate was 13%. Fatal outcome correlated with the severity of underlying diseases and the immunosuppressed status of the patients rather than with the causative pathogen or the effectiveness of antimicrobial therapy and there was no difference in the mortality rate between patients with monomicrobial and polymicrobial bacteremia. Muttaiyah et al. [52] studied AB over a 2-year period at Auckland City Hospital, Auckland., New Zealand. Anaerobes were isolated from 140 blood culture sets taken from 114 patients. The most likely source of infection was intra-abdominal, 26 (50%), mucositis associated with neutropaenia contributed to by cytotoxic therapy, 11 (19%), skin and soft tissue, 4 (8%), pelvic, 5 (9%) and oropharyngeal, 4 (8%). Thirty-five patients were on appropriate therapy prior to the availability culture results. Five patients died but only one death was directly attributable to AB. Lassmann et al. [9] presented their yearly experience in recovery of anaerobes from blood cultures from 1993 to 2004 in Mayo Clinic, Rochester, Minnesota. B. fragilis group was recovered from 26% to 43%, other anaerobic Gram-negative bacteria and other Bacteroides spp. from 8% to 25%, Gram-positive cocci from 35 to 20%, Clostridium spp. from 16% to 46%, non spore forming Gram-positive bacteria from 4% to 18%, and Prevotella and Porphyromonas spp. from 2% to 10%.

3.4. Anaerobic bacteremia after dental procedures The majority of bacterial species found in blood samples after dental treatment are anaerobic. Heimdahl et al. [53] evaluated patients after dental extraction, third-molar surgery, dental scaling, endodontic treatment, and bilateral tonsillectomy for bacteremia. Samples were obtained before, during, and 10 min after treatment. Bacteremia was observed in 100% of patients after dental extraction, 55% of patients after third-molar surgery, 70% of patients after dental scaling, 20% of patients after endodontic treatment, and 55% of patients after bilateral tonsillectomy. Anaerobes were isolated more frequently than aerobic microorganisms were, and viridans group streptococci were the most commonly isolated bacteria. Ten minutes after treatment, the frequency as well as the magnitude of bacteremia showed pronounced reduction. Okabe et al. [54] examined the factors that affect the occurrence of bacteremia associated with tooth extraction and the kinds of bacteria causing this bacteremia. Bacteremia was found in 132 (72.1%) of 183 patients who had one or more teeth extracted for various reasons. Bacteremia occurred more frequently when teeth were extracted because of inflammatory dental diseases. The occurrence of bacteremia also increased with the number of teeth extracted and the age of the patients. When the volume of blood lost during surgery was >50 ml and the time required for the operation exceeded 100 min, the occurrence of bacteremia was also higher. Anaerobes were isolated from 104 (78.8%) of the 132 cases of bacteremia. Of the 187 isolates obtained, three (1.6%) were aerobes, 51 (27.3%) were facultative anaerobes (including microaerophils), and 133 (71.1%) were anaerobes. Among facultative anaerobes and microaerophils, the most frequently isolated bacterial genera were Lactobacillus (15 isolates), Streptococcus (13), and Staphylococcus (12); and among anaerobes, Eubacterium (40), Peptostreptococcus (40), and Propionibacterium spp. (20). Rajasuo et al. [55] detected bacteremia in 16 of 18 (88%) patients following surgical extraction of mandibular third molars. Blood cultures contained 31 species (74% anaerobes), with 3.9  2.6 species isolated per subject. The predominate isolated anaerobes are Peptostreptococcus micros, Fusobacterium nucleatum, P. melaninogenica, Eubacterium timidum, Veillonella spp., Peptostreptococcus anaerobius, and Campylobacte rectus.

4. Pathogenesis AB is almost invariably secondary to a focal primary infection where the strain of anaerobic organisms recovered depended to a large extent on the portal of entry and the underlying disease [6,38]. 4.1. Anaerobic bacteremia in newborns Predisposing factors in newborns are perinatal maternal complications (especially premature rupture of membranes and chorioamnionitis), scalp abscess, prematurity, and necrotizing enterocolitis [13]. Organisms similar to those isolated in blood were concomitantly recovered in lung aspirates and cerebrospinal and peritoneal fluids. Salem and Thadepalli [56] studied the histology of the cord, placenta, and membranes and attempted to correlate the cord blood cultures with the neonatal outcome in 50 consecutive births. Blood cultures were positive for aerobic–anaerobic bacteria in 30% of the newborns soon after birth. Anaerobes were found in cord cultures in 9 samples (18%), Peptostreptococci dominating. An excellent correlation was found between the cord blood culture results and the morphotypes of the bacteria seen in the Gramstained sections of the placenta, cord, and membranes. Inflammation evidenced by leukocyte infiltration was rare, found in only one instance. It appears, therefore, that transplacental transmission of aerobic and anaerobic bacteria is a common, but fortunately benign feature of normal labor. In most instances it results from the contamination of the amniotic fluid with the cervical flora, followed by the transplacental influx of organisms created by the intrauterine pressure changes during active labor. Since amnionitis is generally a polymicrobial aerobic–anaerobic infection [57], newborns who are exposed to maternal amnionitis at term are at greater risk for AB. 4.2. Anaerobic bacteremia in children and adults AB in older children and adults has been most frequently related to an abdominal infection source (in 50–70% of cases), pelvic infections (in 5–20%), otolaryngological sites (in 5–20%), skin and soft tissue infections (in 5–20%) and lower respiratory tract 9 (in 5– 11%) [6]. The gastrointestinal tract accounted for half of AB and that the female genital tract is source of 20%. The gastrointestinal tract is the principal source of B. fragilis group and clostridial bacteremias and the female genital tract is the principal source of Peptostreptococcus and Fusobacterium spp. bacteremias [6,38]. The main origin of bacteremias due to B. fragilis group is the gastrointestinal tract, soft tissue wound infections, female genitourinary tract, lung infections and malignancies (genitourinary, gynecological, acute leukemia, and gastrointestinal) [58]. The ear, sinus, and oropharynx are the portals of entry for bacteremia with Peptostreptococcus and Fusobacterium spp. This is not surprising since these organisms are part of the oral flora and are involved in local infections. 5. Predisposing factors A review of the suspected portal of entry for 855 episodes of bacteremia involving anaerobes indicated an intra-abdominal source in 52 percent, the female genital tract in 20%, the lower respiratory tract in 6%, the upper respiratory tract in 5%, and soft tissue infections in 8% [59]. Elderly persons seem to be at increased risk for developing AB while young children (2–5 years of age) are at the least risk.

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AB in newborns is associated with prolonged labor, premature rupture of membranes, maternal amnionitis, prematurity, fetal distress, and respiratory difficulty [13]. The predisposing conditions in children include: chronic debilitating disorders such as malignant neoplasms, hematologic abnormalities, immunodeficiencies, chronic renal insufficiency, or decubitus ulcers and carried a poor prognosis [35]. Predisposing factors to AB in adults include malignant neoplasms, hematologic disorders, transplantation of organs, recent gastrointestinal or obstetric gynecologic surgery, intestinal obstruction, diabetes mellitus, post-splenectomy, use of cytotoxic agents or corticosteroids, and an undrained abscess [6,36]. Bacteremia caused by P. acnes is often associated with a foreign body (i.e. shunt, prosthetic valve). Recovering an organism from more than one blood sample strengthens the pathogenicity of the isolate. However, this is not always the case in many instances. The recovery of an isolate from another location or the presence of an infection that is often anaerobic in nature (i.e. gas gangrene and necrotizing fasciitis) is also helpful. Dental or oral surgery can also predispose to AB in adults and children due to oral flora anaerobes (i.e. Prevotella, Eubacterium, and Peptostreptococcus spp.) [6,36]. The recent report of AB at the Mayo Clinic [9] observed that the ‘‘typical’’ clinical contexts for AB was less predictable than it used to be the past. The data showed that 38% of patients with AB in 2004 had sources other than the genitourinary and gastrointestinal tracts. Internal review of unpublished data from the Mayo Clinic during 1995–1996 showed that, in 34.3% of patients, anaerobes would have not been suspected as the cause of bacteremia on the basis of ‘‘typical’’ clinical predictors [9]. The authors concluded that the sources of AB are now more varied than previously, especially among immunosuppressed patients and patients with complex underlying disease.

6. Clinical features and diagnosis The clinical features of AB are not much different from other types of bacteremia; however, a relatively longer period is generally needed before an etiologic diagnosis can be made. This can be a result of the longer time needed for growth and identification of anaerobic organisms. Diagnosis should include detection of the primary infection [36,59]. The clinical presentation of AB relates in part to the nature of the primary infection, which will typically include fever, chills, and leukocytosis. Anemia, shock, and intravascular coagulation also may be present. Bacteroides bacteremia generally is characterized by thrombophlebitis, metastatic infection, hyperbilirubinemia, and high mortality rate (up to 50%). C. perfringens bacteremia may present with hemolytic anemia, hemoglobinemia, hemoglobinuria, disseminated intravascular coagulation, bleeding tendency, bronze color skin, hyperbilirubinemia, shock, oliguria, and anemia [36,59]. Clostridial bacteria may, however, be transient and inconsequential. However, C. septicum infection may be a marker for a silent colonic or rectal malignancy [60]. Blood culture supporting the growth of anaerobic bacteria should be obtained from patients where an anaerobic infection is present or suspected clinically. It is. However, good practice to obtain such a culture routinely in all patients because anaerobic bacteria can cause bacteremia in settings where they may not be suspected. Inadequate methodology can lead to missing cases of AB. Susceptibility testing for the isolated organisms should be performed. Bacteremia by organisms that are part of the skin flora such as P. acnes requires correlation with the clinical settings.

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Detection of AB has become more important in recent years because of the emerging resistance in anaerobes to antimicrobials and the susceptibility of anaerobic bacteria to antimicrobial agents has become less predictable [61–63]. Resistance to several antimicrobial agents by B. fragilis group and other anaerobic gramnegative bacilli have increased over the past decade [61]. A decrease in susceptibility to penicillin of C. perfringens has been noted and the susceptibility of Clostridium species (other than C. perfringens) is variable and often unpredictable [62,63]. It is important therefore, to perform susceptibility testing to isolates recovered from the blood especially those that have variable or unique susceptibility.

7. Management Institution of early and prolonged effective therapy is important. The length of therapy depends on the type of organism isolated, primary infection and the patient co-morbidity. The primary source of infection, such as an abscess, should be drained. Selection of the appropriate antimicrobial therapy is of great importance. Nguyen et al. [61], who performed a prospective observational study of 128 cases of bacteremia involving the B. fragilis group, illustrated that mortality, microbial persistence, and clinical failure occurred more frequently among patients who did not receive an appropriate antibiotic agent to treat infection with resistant members of the B. fragilis group. Although isolation and identification are neither practical nor readily available for the individual patient, knowledge of the susceptibility of anaerobic antibiotics at individual hospitals may be important in the selection of empirical antimicrobial therapy when anaerobic blood culture results are positive. When anaerobes resistant to penicillin, such as the B. fragilis group, anaerobic Gram-negative bacilli (i.e. Pigmented Prevotella spp.) or Fusobacterium spp., are suspected or isolated, antimicrobials such as clindamycin, chloramphenicol, metronidazole, cefoxitin, a carbapenem, or the combination of a betalactamase inhibitor and a penicillin should be administered [62]. This is the case in both infections above and below the diaphragm. Local surveillance of antimicrobial susceptibility patterns can provide guidelines as to the choice of the best antimicrobial agent. The development of resistance to all known agents by anaerobes (i.e. clindamycin, cefoxitin), make the selection of reliable empirical therapy difficult. Many anaerobic species besides the B. fragilis group have developed beta-lactamase activity. Rarely, resistance to carbapenems, induced by metalloenzymes, and to metronidazole has been reported [63]. Consequently, one is not able to predict the susceptibility of some anaerobic isolates. Performing susceptibility testing is of great importance in treating AB. In the case of polymicrobial bacteremia coverage is needed against all pathogens aerobic and anaerobic. The choice of coverage against the aerobic or facultative co-pathogens depends on their susceptibility. A single antimicrobial can achieve coverage against all pathogens. However, a combination of antimicrobials may be required [62]. Empiric therapies depend on the predisposing condition, and the site of the potential primary infection site. The length of treatment with antimicrobial varies from 10 days to 3 month and depends of the source of the infection and ability to correct of the underlying pathology. Organisms identical to those causing AB often can be recovered from other infected sites. Extravascular infection sites may serve as a source of persistent bacteremia in some cases. Surgical correction and drainage of these sites are essential to prevent persistence of the bacteremia and can shorten the time required to treat it.

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Preventing bacteremia associated with dental or oral surgery can be accomplished by prophylactic administration of penicillin alone or with or metronidazole or clindamycin. 8. Complications and mortality The overall mortality noted in newborns is 26% [13] and is highest with B. fragilis group (34%). Inappropriate choice of antimicrobial therapy was often a contributory factor to mortality. Correction of underlying pathology, surgical drainage, and the use of proper antimicrobials are critical to successful resolution of the infection. Mortality remains high (15–35%) in older children and adults [6,36]. Risk factors for a fatal outcome include compromised status, malignancy, advanced age, inadequate or no surgical therapy, and the presence of polymicrobial sepsis. Often the patient’s compromised status (i.e. malignancy) accelerates the mortality caused by the AB. B. fragilis group bacteremia contributes significantly to morbidity and mortality. The mortality of associated with the B. fragilis group bacteremia was examined in a matched case-control study [64]. Patients with B. fragilis group bacteremia were matched to a control patient without bacteremia but with the same principal diagnosis or the same major surgical procedure. Those with B. fragilis group bacteremia had a significantly higher mortality rate compared to control patients (28 compared to 9%), and an attributable mortality rate of 19%(95% CI, 3.7–6.0). Certain other serious concomitant sites of infection can be present in patients with AB. Most of these sites serve as the source of the infection; however, others may represent a site of secondary hematogenous spread. These includes abscess (intracranial, splenic, hepatic, osteomyelitis, endocarditis). However, it is often difficult to ascertain if the infectious site are the source or the result of AB. 9. Conclusions Anaerobic bacteria remain an important cause of bloodstream infections at all age groups and are often missed. Most are due to Gram-negative bacilli, Peptostreptococcus, Clostridium spp., and Fusobacterium spp. Many of these infections are polymicrobial. The growing antimicrobial resistance of anaerobic bacteria made the management of AB more challenging. Their early recognition and the institution of medical and surgical therapy when indicated are essential in securing recovery and preventing complications. References [1] Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol 2003;41:3655–60. [2] Lark RL, McNeil SA, VanderHyde K, Noorani A, Uberti J, Chenoweth C. Risk factors for anaerobic bloodstream infections in bone marrow transplant recipients. Clin Infect Dis 2001;33:338–43. [3] Raymond NJ, Blackmore TK, Humble MW, Jones MR. Bloodstream infections in a secondary and tertiary care hospital setting. Intern Med J 2006;36:765–72. [4] Lombardi DP, Engleberg NC. Anaerobic bacteremia: incidence, patient characteristics, and clinical significance. Am J Med 1992;92:53–60. [5] Blairon L, De Gheldre Y, Delaere B, Sonet A, Bosly A, Glupczynski Y. A 62month retrospective epidemiological survey of anaerobic bacteraemia in a university hospital. Clin Microbiol Infect 2006;12:527–32. [6] Goldstein E. Anaerobic bacteremia. Clin Infect Dis 1996;23(Suppl. 1):S97–101. [7] Washington 2nd JA. Comparison of two commercially available media for detection of bacteremia. Appl Microbiol 1971;22:604–7. [8] Dorsher CW, Rosenblatt JE, Wilson WR, Ilstrup DM. Anaerobic bacteremia: decreasing rate over a 15-year period. Rev Infect Dis 1991;13:633–6. [9] Lassmann B, Gustafson DR, Wood CM, Rosenblatt JE. Reemergence of anaerobic bacteremia. Clin Infect Dis:895–900, http://www.journals.uchicago.edu/ CID/journal/issues/v44n7/41079/41079.text.html-fn1#fn1, 2007;44. [10] Brook I. Anaerobic infections in children. Microbes Infect 2002;4:1271–80.

[11] Brook I. Anaerobic bacterial bacteremia: 12-year experience in two military hospitals. J Infect Dis 1989;160:1071–5. [12] Brook I, Frazier EH. Infections caused by Propionibacterium species. Rev Infect Dis 1991;13:819–22. [13] Brook I. Bacteremia due to anaerobic bacteria in newborns. J Perinatol 1990;10:351–6. [14] Chow AW, Leake RD, Yamauchi T, Anthony BF, Guze LB. The significance of anaerobes in neonatal bacteremia: analysis of 23 cases and review of the literature. Pediatrics 1974;54:736–45. [15] Noel J, Laufer DA, Edelson PJ. Anaerobic bacteremia in a neonatal intensive care unit: an eighteen-year experience. Pediatr Infect Dis J 1988; 7:858–62. [16] Ohta S, Shimizu S, Fujisawa S, Tsurusawa M. Neonatal adrenal abscess due to Bacteroides. J Pediatr 1978;93:1063–4. [17] Brook I. Osteomyelitis and bacteremia caused by Bacteroides fragilis. Clin Pediatr 1980;19:639–40. [18] Kasik JW, Bolam DL, Nelson RM. Sepsis and meningitis associated with anal dilation in newborn infant. Clin Pediatr 1984;9:509–10. [19] Dysart NK, Griswold WR, Schanberger JE, Goscienki PJ, Chow AW. Meningitis due to Bacteroides fragilis in a newborn. J Pediatr 1976;89. p. 509–10. [20] Brook I, Avery G, Glasgow A. Clostridium difficile in pediatric infections. J Infect 1982;4:253–7. [21] Heidemann SM, Meest KL, Perrin E, Sarnaik AP. Primary meningitis in infancy. Pediatr Infect Dis J 1989;8:126–8. [22] Brook I, Martin WJ, Finegold SM. Neonatal pneumonia caused by members of the Bacteroides fragilis group. Clin Pediatr 1980;19:541–3. [23] Harrod JR, Stevens DA. Anaerobic infections in the newborn infant. J Pediatr 1974;85:399–402. [24] Webber SA, Tuohy P. Bacteroides fragilis meningitis in a premature infant successfully treated with metronidazole. Pediatr Infect Dis J 1988; 7:886–7. [25] Ahonkhai VI, Kim MH, Raziuddin K, Goldstein EJ. Perinatal Clostridium perfringens infection. Clin Pediatr 1981;20:532–3. [26] Kosloske AM, Ulrich JA. A bacteriologic basis for clinical presentation of necrotizing enterocolitis. J Pediatric Surg 1980;15:558–64. [27] Spark RP, Wike DA. Nontetanus clostridial neonatal fatality after home delivery. Ariz Med 1983;10:697–700. [28] Freedman S, Hollander M. Clostridium perfringens septicemia as a postoperative complication of the newborn infant. J Pediatr 1967;71:576–8. [29] Sanders DU, Stevenson J. Bacteroides infections in children. J Pediatr 1968;72:673–7. [30] Berry Jr FA, Yarbrough S, Yarbrough N, Russell CM, Carpenter MA, Hendley JO. Transient bacteremia during dental manipulation in children. Pediatrician 1973;51:476–9. [31] De Leo AA, Schoenknecht FD, Anderson MW, Peterson JC. The incidence of bacteremia following oral prophylaxis on pediatric patients. Oral Surg Oral Med Oral Pathol 1974;37:36–45. [32] Brook I, Martin WJ, Cherry JD, Sumaya CV. Recovery of anaerobic bacteria from pediatric patients: a one-year experience. Am J Dis Child 1979;133:1020–4. [33] Dunkle LM, Brotherton MS, Feigin RD. Anaerobic infections in children: a prospective study. Pediatrics 1976;57:311. [34] Thirmuoothi MC, Keen BM, Dajani AS. Anaerobic infections in children: a prospective study. J Clin Microbiol 1976;3:318–23. [35] Brook I, Controni G, Rodriguez WJ, Martin WJ. Anaerobic bacteremia in children. Am J Dis Child 1980;134:1052–6. [36] Finegold SM. Anaerobic bacteria in human disease. New York: Academic Press; 1977. [37] Frommell GT, Todd JK. Polymicrobial bacteremia in pediatric patients. Am J Dis Child 1984;138:266–9. [38] Rosenfeld RG, Jameson S. Polymicrobial bacteremia associated with pharyngotonsillitis. J Pediatr 1978;93:251–2. [39] Seidenfeld S, Sutker WL, Luby JP. Fusobacterium necrophorum septicemia following oropharyngeal infection. JAMA 1982;248:1348–50. [40] Givner LB, McGehee D, Taber LH, Stein F, Sumaya CV. Sinusitis, orbital cellulitis and polymicrobial bacteremia in a patient with primary Epstein-Barr virus infection. Pediatr Infect Dis 1984;3:254–6. [41] Caya JG, Truant AL. Clostridial bacteremia in the non-infant pediatric population: a report of two cases and review of the literature. Pediatr Infect Dis J 1999;18:291–8. [42] Brook I. Bacterial infection associated with malignancy in children. Int J Pediatr Hematol Oncol 1998;5:379–86. [43] Goldstein EJ, Citron DM. Annual incidence, epidemiology, and comparative in vitro susceptibilities to cefoxitin, cefotetan, cefmetazole, and ceftizoxime of recent community-acquired isolates of the Bacteroides fragilis group. J Clin Microbiol 1988;26:2361–6. [44] Gransden WR, Eykyn SJ, Phillips I. Anaerobic bacteremia: declining rate over a 15-year period. Rev Infect Dis 1991;13:1255–6. [45] Summanen P, Baron EJ, Citron DM, Strong C, Wexler HM, Finegold SM. Wadsworth anaerobic bacteriology manual. 5th ed. Belmont, CA: Star Publishing Co.; 1993. [46] Peraino VA, Cross SA, Goldstein EJ. Incidence and clinical significance of anaerobic bacteremia in a community hospital. Clin Infect Dis 1993;16(Suppl. 4):S288–91. [47] Noriega LM, Van der Auwera P, Phan M, Daneau D, Meunier F, Gerain J, et al. Anaerobic bacteremia in a cancer center. Support Care Cancer. 1993;1:250–5.

Author's personal copy

I. Brook / Anaerobe 16 (2010) 183–189 [48] Ramos JM, Garcı´a-Corbeira P, Ferna´ndez-Roblas R, Soriano F. Bacteremia caused by anaerobes: analysis of 131 episodes. Enferm Infecc Microbiol Clin 1994;12:9–16. [49] Arzese A, Trevisan R, Menozzi MG. Anaerobe-induced bacteremia in Italy: a nationwide survey. The Italian Anaerobe Study Group. Clin Infect Dis 1995;20(Suppl. 2):S230–2. [50] Salonen JH, Eerola E, Meurman O. Clinical significance and outcome of anaerobic bacteremia. Clin Infect Dis 1998;26:1413–7. [51] Anuradha DE, Saraswathi K, Gogate A. Anaerobic bacteraemia: a review of 17 cases. J Postgrad Med 1998;44:63–6. [52] Muttaiyah S, Paviour S, Buckwell L, Roberts SA. Anaerobic bacteraemia in patients admitted to Auckland City Hospital: its clinical significance. N Z Med J 2007;120(1265):U2809. [53] Heimdahl A, Hall G, Hedberg M, Sandberg H, So¨der PO, Tuner K, et al. Detection and quantitation by lysis-filtration of bacteremia after different oral surgical procedures. J Clin Microbiol 1990;28:2205–9. [54] Okabe K, Nakagawa K, Yamamoto E. Factors affecting the occurrence of bacteremia associated with tooth extraction. Int J Oral Maxillofac Surg 1995;24:239–42. [55] Rajasuo A, Perkki K, Nyfors S, Jousimies-Somer H, Meurman JH. Bacteremia following surgical dental extraction with an emphasis on anaerobic strains. J Dent Res 2004;83:170–4.

189

[56] Salem FA, Thadepalli H. Microbial invasion of the placenta, cord and membranes during normal labor. Clin Pediatr 1978;18:50–2. [57] Hagberg H, Wennerholm UB, Savman K. Sequelae of chorioamnionitis. Curr Opin Infect Dis 2002;15:301–6. [58] Fainstein V, Elting LS, Bodey GP. Bacteremia caused by non-sporulating anaerobes in cancer patients. A 12-year experience. Medicine (Baltimore) 1989;68:151–62. [59] Finegold SM, George WL, Mulligan ME. Anaerobic infections. Part I. Dis Mon 1985;31:1–77. [60] Caya JG, Farmer SG, Ritch PS, Wollenberg NJ, Tieu TM, Oechler HW, et al. Clostridial septicemia complicating the course of leukemia. Cancer 1986;57:2045–8. [61] Nguyen MH, Yu VL, Morris AJ, McDermott L, Wagener MW, Harrell L, et al. Antimicrobial resistance and clinical outcome of Bacteroides bacteremia: findings of a multicenter prospective observational trial. Clin Infect Dis 2000;30:870–6. [62] Brook I. Treatment of anaerobic infection. Expert Rev Anti Infect Ther 2007;5:991–1006. [63] Hecht DW. Anaerobes: antibiotic resistance, clinical significance, and the role of susceptibility testing. Anaerobe 2006;12:115–21. [64] Redondo MC, Arbo MD, Grindlinger J, Snydman DR. Attributable mortality of bacteremia associated with the Bacteroides fragilis group. Clin Infect Dis 1995;20:1492–6.