Bacteroides fragilis --- beware of Bacteroides!

Thirty to fifty percent of fecal matter is said to be B. fragilis! Bacteroides species are common in the terminal ileum, and prolific in the colon (10 ¹¹ organisms per gram). Bacteroides is the most frequent anaerobic pathogen in man (80% of anaerobic infections). Resistance to some antibiotics may be increasing. Infection can occur anywhere in the body, commonly associated with abscess formation. If documented B. fragilis infection is left untreated, the mortality rate is reported to be about 60%.

Significance to man

Benefits

• Bacteroides plays a key role in enterohepatic bile acid recirculation, and bile acid biotransformation.
• Bacteroides also probably compete with pathogenic micro-organisms for colonic resources - diminishing the food supply and receptor sites for agents such as Salmonellae and Shigellae, and making the environment unfavourable by deconjugating bile salts and changing the pH.
• Some vitamin K may be produced (menaquione, vitamin K2) - its relevance is unclear.
• Although anaerobic production of butyrate as well as acetate and propionate provides about 70% of the energy supply of the colonic enterocytes, butyrate is only occasionally produced by Bacteroides (the main contributors being organisms that possess butyryl-CoA:acetate CoA-transferase, such as Roseburia cecicola, Faecalibacterium prauznitzii and Eubacterium spp.)

Harm

Infections are often polymicrobial, and abscess formation is common. Anaerobic infections are commonly associated with an offensive odour.

• Especially common are intra-abdominal & pelvic abscesses (For Rx of these infections, regimens must cover B. frag. which is common in, for example, sub-phrenic abscesses. See [ J Chemother 1999 Dec;11(6):440-5 ] );
• Diarrhoea is commonly caused by this organism in children of 1-5 years old, and also seen in adults, possibly more often in those with inflammatory bowel disease - in one study, 13% of 83 patients with inflammatory bowel disease had enterotoxigenic B. fragilis in faeces, versus 2.9% of controls. None of those with inactive disease were positive for this organism !
• Anaerobic bacteraemia is associated with a 24% mortality rate. There was a recent article in J Postgrad Med [1998 Jul-Sep;44(3):63-6] although the number of cases studied was small.

Mechanisms of injury

There is often synergy with other bacteria, notably E. coli. There are numerous reported mechanisms:

1. The capsule may confer resistance to host defence mechanisms. Fibrin deposition and abscess formation can be stimulated by purified capsule alone! Surprisingly, the capsular antigens may cause more of a T-cell response than an antibody-mediated response. The capsule comprises 'Polysaccharides A and B' with oppositely charged groups that ionically link the two polysaccharides and seem to be important in abscess formation (Similar in charge, but not structure, to the capsular polysaccharide of S. pneumoniae type 1). Remarkably, vaccination with S. pneumoniae polysaccharide prevents intraperitoneal abscess formation subsequent to B. fragilis instillation, and this protection is not conferred if the charged groups are altered on the capsular vaccine!
2. Extracellular beta lactamase protects both the organism and others against penicillins.
3. Unidentified factors degrade host complement!
4. Neuraminidase may be produced, as well as hyaluronidase, DNase, 'phosphatase', and (very occasionally) fibrinolysins.
5. Heparinase may predispose to vascular thrombosis!
6. Zinc metalloproteases: The enterotoxin is a zinc metalloprotease (fragilysin); MW 20KD. It damages tight junctions and thus enterocytes (with cytotoxic effects and fluid secretion);

Identification and features

Underdiagnosis is common due to inappropriate sampling of tissues, and poor transport, although B. fragilis may survive up to 3 days of air exposure!

ID

The organism is an obligate anaerobe, saccharolytic with substantial production of acetate and succinate end products.

1. indole -, catalase +, esculin hydrolysis +, glucose fermenter +, lactose +
2. Note use of Bacteroides bile esculin agar (BBE).
3. Most B. fragilis can deconjugate bile acids, and are thus not inhibited by them!

Features

• An obligate anaerobic Gram-negative microorganism, a bit smaller than E coli (about 0.6 µm by 1.5 to 4.5 µm); the ends of the bacilli are rounded.
• Grows well on blood agar (anaerobically);
• May have large vacuoles resembling spores! B. fragilis does NOT form spores.
• Enormous capsule, NO cell membrane endotoxin.
• G+C 42% (40-48 for Bacteroides);
• contain HMP shunt enzymes; membranes contain sphingolipids; possess menaquiones; peptidoglycan contains meso-diaminopimelic acid.
• Some B. fragilis possess superoxide dismutase and are more oxygen tolerant as a result; the organism has 29 other oxygen-induced proteins.

Subtypes, Nomenclature and Relatives

There may be two phylogenetic divisions of B. fragilis identifiable based on gene analysis [ Microbiology 2000 146 1241-54 ]

For Bacteroides nomenclature, see Euzéby's list of names.

Related are other Bacteroides species, as well as Porphymonas, and Prevotella (previously Bacteroides melaninogenicus). Together these three form a major subgroup of the Cytophaga-Flavobacter-Bacteroides phylum.

Treatment

Treatment should be predicated by appropriate resuscitative measures, and drainage of abscesses as soon as is possible. Antibiotics include:

1. Metronidazole / Chloramphenicol / Carbapenems (active against 99%+) Metronidazole is probably the drug of choice
   [ Mayo Clin Proc 1999 Aug;74(8):825-33 ] Here's some information on metronidazole, and a shorter note.
2. Beta lactam + Beta lactamase inhibitor (active against 95%+) {resistance more common with other Bacteroides than with B fragilis}.
3. Clindamycin resistance may be increasing (while susceptibility to beta-lactams may even be greater, for unexplained reasons)! See [ Antimicrob Agents Chemother 1999 Oct;43(10):2417-22 ]. Susceptibility to clindamycin is currently 85 to 95%.
4. Susceptibility of B. fragilis to moxalactam, ceftriaxone, and clarithromycin is around 70-84%, and to cefoperazone, cefotaxime, ceftazidime, sparfloxacin, etc under 70%.

DO NOT USE 'Fourth generation' cephalosporins ; there is also inherent resistance to aminoglycosides. When tetracycines were first used, they were effective against Bacteroides, which is now almost universally resistant! For B. fragilis, cefoxitin resistance is about 3-6%, with far higher resistance rates in other Bacteroides species. Penicillin resistance is over 50%.

Resistance

Plasmids occur in about half of B. fragilis, and plasmid-mediated resistance occurs. Plasmids may be transferred to E. coli. Beta-lactamase resistance occurs, and is a common mechanism of resistance. Chromosomal resistance has also been reported.

Clindamycin and erythromycin resistance is conferred by three genes closely related to those providing macrolide resistance in gram positives.

Cautions

Be aware of anaerobes, which are often ignored to the detriment of the patient, especially with intra-abdominal sepsis.

Pictures

There are several good pictures in an article by S Finegold. (This is also an excellent general reference).

References

1. A Good page on Bacteroides infection.
2. A tiny webpage at Houston Medical School
3. There's a rather skeletal overview of Bacteroides fragilis at UFL.
4. Here's a more comprehensive one - actually a very interesting read, packed with information! There are a few typos. Also at the East Carolina University site is the Bacteroides sequence page.
5. (As an aside: a Good approach to antibiotics!)
6. Of general interest: Sacho & Schoub's notes on bacteraemia.

Thanks to Julian Marchesi for correcting an error about butyrate.

Web searches

Use Bacteroides fragilis as your main search term. For clinical information, perhaps metronidazole, imipenem, chloramphenicol AND clindamycin, AND possibly abscess. For metabolic information, try AND butyrate .