Continuing Education Activity

The human colon possesses the largest population of bacteria in the body, and the majority of these organisms are anaerobes; of these, about 25 percent are species of Bacteroides. Bacteroides fragilis is part of the normal microbiota of the human colon. Disruption of the mucosal surface either by inflammation, trauma, or surgery and spread of Bacteroides fragilis to the bloodstream or surrounding tissues results in clinically significant infection. This activity outlines the evaluation and treatment of Bacteroides fragilis infection and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology of Bacteroides fragilis infections and emergencies.
• Review the appropriate evaluation of Bacteroides fragilis infections.
• Describe the management options available for Bacteroides fragilis infections.
• Explain some interprofessional team strategies for improving care coordination and communication to advance the management of Bacteroides fragilis infections and improve outcomes.

Introduction

Anaerobes are bacteria that do not require oxygen to live. Anaerobes usually fit into two groups based on their gram stain into gram-positive and gram-negative and into cocci and bacilli based on their morphology. Of these, notable pathogenic gram-negative bacillus-shaped strains are Prevotella, Fusobacterium, Bacteroides, and Porphyromonas. Bacteroides species are important clinical pathogens and are present in most anaerobic infections, with an associated mortality of approximately 19%.[1] Bacteroides fragilis is an obligate anaerobic gram-negative bacillus. The human colon has the greatest population of bacteria in the body (over ten organisms per gram of wet weight), and the largest part of these organisms are anaerobes; of these, approximately 25% are species of Bacteroides.[2] Bacteroides fragilis is part of the normal microbiota of the human colon. Disruption of the mucosal surface either by inflammation, trauma, or surgery and spread of Bacteroides fragilis to the bloodstream or surrounding tissues results in clinically significant infection.

Etiology

Bacteroides fragilis is a part of the colonic microbiota, and Bacteroides thetaiotaomicron is more abundant than B. fragilis in the microbiota but has been less frequently identified as a pathogen. Humans acquire Bacteroides fragilis likely at birth. In the early months of life, the bacterial flora changes considerably, and by the age of one year, the intestinal microbiota converts toward an adult microbiota profile.[3] 

Bacteroides fragilis infection is one of the common organisms involved in intrabdominal infection. Disruption of tissue barriers and the spread of intestinal flora into adjacent tissue causes polymicrobial infection. That is why Bacteroides fragilis is seldom the solitary organism of infection and usually part of other anaerobic organisms and Enterobacteriaceae.

Epidemiology

Bacteroides fragilis are part of the normal human colon flora. In a longitudinal analysis of the stool specimens collected from 15 healthy adults, B. fragilis was cultured from 87% of the cohort.[4] Bacteroides fragilis plays an intricate role in the human colon and has a beneficial relationship with the host. Still, if there is a breach in the integrity of the mucosal lining either by surgery or trauma, it can cause significant morbidity.[1]

A review of surgical site infections in Japan showed that in 12.8%of cases, Bacteroides species were isolated.[5] An epidemiological review of anaerobic infection from Greece showed that patients with an infection due to B. fragilis were more frequent in patients with recent surgery. Total mortality was 10.9% and was associated with bacteremia or malignancy.[6]

Between January 1, 1969, and December 31, 2012, 20 episodes of Bacteroides periprosthetic joint infections were observed in 17 patients at the Mayo Clinic in Rochester, MN.[7]

Pathophysiology

Bacteroides fragilis is usually a commensal organism that, when the mucosal barrier becomes disrupted, results in abscess formation and bacteremia. Bacteroides species have involvement in the prolongation of the intrinsic pathway of clotting in human blood.[8] Both B. fragilis and B. thetaiotaomicron cause the release of significant levels of bradykinin in human plasma, a mechanism that will provide the bacteria with an opportunity to spread by inhibition of clot formation.[8] 

Bacteroides fragilis virulence is mostly by toxin production. Enterotoxigenic Bacteroides fragilis (ETBF) strains are strains of B. fragilis that secrete an enterotoxin termed the B. fragilis toxin (BFT) and may have a role in inflammatory diarrhea and flare-ups of inflammatory bowel disease.[9][10]

Outer-membrane vesicles (OMVs) are vesicles that bud out of the outer membrane of bacteria and are commonly produced by gram-negative bacteria and may play a role in trafficking bacterial biochemicals.[11]  Elhenawy et al. .demonstrated the preferential packing of acidic glycosidases and proteases into Bacteroide's outer membrane vesicles and proposed that OMVs contribute to the establishment and balance of the gut microbiota.[12]

Histopathology

In an experimental study evaluating mixed anaerobic infection, including Bacteroides and Fusobacterium species, acute inflammatory processes were noted in tissue samples occurring within hours postinfection. By 48 hours after infection, both acute and chronic inflammatory cells infiltrate the liver parenchyma. In 2 to 6 weeks after inoculation, Large intrahepatic abscesses were present.[13]

Experimental anaerobic maxillary sinusitis was induced in rabbits by inoculating Bacteroides fragilis in the nasal ostium. Moderate or severe inflammation appeared in all infected sinuses. The characteristic features were ciliary damage, desquamation, hyperplasia, and metaplasia of the epithelium.[14]

History and Physical

Predisposing factors for anaerobic infections include Bacteroides fragilis are recent surgery, trauma, and malignancy. Foul-smelling discharge and abscess formation are usually present on the clinical exam on anaerobic infections, including Bacteroides fragilis. Different clinical presentations depending on different tissues of involvement exist in the literature. Anaerobic bacteria, including Bacteroides fragilis, have been isolated from chronic pressure ulcers and diabetic foot ulcers. Enterotoxigenic Bacteroides fragilis may have involvement in inflammatory diarrhea. Bacteroides fragilis may also present in various clinical scenarios, such as necrotizing fasciitis and synergistic anaerobic infections. Bloodstream infection usually results from the spread of uncontrolled local infection into the bloodstream, or it could be a central line-associated bloodstream infection. In a review of anaerobic bacteremia, the Bacteroides fragilis group was the most common causative organism (41%), and the source was mostly intraabdominal infections.[15] The microbes involved in septic abortion are usually from the vaginal flora, but researchers also described septic abortion and bacteremia with distant abscess formation due to Bacteroides fragilis infection.[16] Anaerobic infection, including Bacteroides fragilis causing pyogenic arthritis of native joints, is a very infrequent presentation usually accompanied by bacteremia.[17][18] Bacteroides fragilis have also been an infrequent cause of periprosthetic joint infections. Necrotizing pancreatitis and anaerobic bacteremia are complications.[19] Anaerobic endocarditis is generally rare. Bacteroides fragilis endocarditis was present in a patient with Crohn disease.[20] Septic thrombophlebitis of the superior mesenteric vein has also occurred.[21] 

Evaluation

The proper collection of specimens is critical to avoid contamination with the normal microbial flora. The key to appropriate processing is prompt transport to the laboratory for immediate handling. Needle aspiration and tissue biopsy are the best materials for anaerobic cultures. Exudates, swabs from burns, wounds, and skin abscesses are generally unacceptable for anaerobic cultures due to colonization by normal flora. (Mendoza, M.D. (Phil J Microbiol Infect Dis 1998; 27(2):71-73). Bacteroides fragilis are also diagnosable by PCR amplification.[22]

Treatment / Management

Bacteroides fragilis is resistant to penicillin due to the production of beta-lactamase. Cefoxitin, moxifloxacin, and clindamycin have low levels of susceptibility for Bacteroides fragilis, whereas Piperacillin/tazobactam, meropenem, and metronidazole have high susceptibility rates.[23] Metronidazole is the antibiotic of choice for the management of infections caused by anaerobes. The reported rate of metronidazole-resistant B. fragilis ranges from 0.5% to 7.8% across many surveys.[24] In anaerobes, acquired resistance to metronidazole may be due to a combination of various and complex mechanisms. Among them, nim genes, possibly located on mobile genetic elements, encode nitro-imidazole-reductases responsible for the drug inactivation.[25] The non-fragilis Bacteroides group (including B. intestinalis, B. nordii, B. pyogenes, B. stercoris, B. salyersiae, and B. cellulosilyticus) were found to be resistant to meropenem (14%) and cefotetan (71%).[26] An imipenem-resistant Bacteroides fragilis strain was found in Croatia.[27] Bacteroides fragilis infection is usually a part of polymicrobial infection that happens due to a breach of natural barriers either by surgery, inflammation, or trauma and result commonly in intrabdominal infections. Antimicrobial therapy of intraabdominal infections should include coverage for anaerobic infections along with Enterobacteriaceae. Coverage of Pseudomonas aeruginosa and Enterococcus faecalis is also a recommendation for hospital-associated intra-abdominal infections. 

Newer drugs: eravacycline, a novel fluorocycline antibiotic, has been evaluated against complicated mixed aerobic/anaerobic intra-abdominal infections. eravacycline had good anaerobic in vitro activity with MICs of 4μg/ml or less against all Bacteroides and Parabacteroides strains tested, except for two B. ovatus strains that had MICs of 8 mcg/ml and one strain that had a MIC of 16 mcg/ml. Eravacycline was four-to-eight fold more active than tigecycline.[28] Another novel antibiotic, tazobactam/ceftolozane: The efficacy and safety of tazobactam/ceftolozane in combination with metronidazole, has been assessed and showed a good response for Bacteroides fragilis 95.2% (20/21) in Japanese patients with complicated intraabdominal infections.[29]

Differential Diagnosis

The clinical significance of identifying Bacteroides fragilis in cultures varies considerably based on the type of specimen collected. For example, if Bacteroides fragilis were identified in a swab from a diabetic foot ulcer or a decubitus ulcer, it would not have any clinical implications as the ulcers are usually colonized with a high bacterial load of mixed aerobic and anaerobic growth. On the other hand, if B. fragilis were identified in an aspirate from an intraabdominal fluid collection, then it signifies intrabdominal infection that should have management with targeted antimicrobial therapy along with source control of the infection. Bacteroides fragilis infections should merit consideration in patients with recent surgical intervention (especially abdominal surgery), trauma, and malignancy.

Pertinent Studies and Ongoing Trials

In an experimental study, B. fragilis exerted protective effects on a Clostridoides difficile infection mouse model through the modulation of gut microbiota and alleviating barrier destruction.[30]

Another study identified that Bacteroides fragilis species have a protective effect against antibiotic-associated diarrhea in rats by altering intestinal defenses and identified the vital role of B. fragilis strain ZY-312 in changing the colonic bacterial community.[31]

Diet could influence the determination of gut microbiota composition and the immune response.[32] Palmitic acid(dietary saturated fatty acid) had a stimulatory effect on the growth of B. fragilis and B. thetaiotaomicron.[33]

Prognosis

In a retrospective analysis by Cheng C.W. et al., the overall crude mortality rate of Bacteroides fragilis bacteremia is 30.7%, and malignancy was the most common comorbidity.[34] There have been suggestions that specific bacterial flora of the colon may play a role in the development of colorectal cancer. The risk of colorectal cancer increased in patients with bacteremia from B. fragilis or Streptococcus gallolyticus in a retrospective analysis in Hong Kong. These bacteria might enter the bloodstream from intestinal dysbiosis and perturbed barrier function.[35] However, a recent review from Denmark showed that overall, neither Fusobacterium nucleatum nor B. fragilis demonstrated a specific association with tumors of colorectal cancer patients. Still, both bacteria had a low presence in adenomas.[36]

Complications

Bacteroides species are found in most anaerobic infections, causing significant morbidity with an associated mortality of more than 19%.[1] Sepsis has occurred secondary to Bacteroides fragilis tubo-ovarian abscess requiring hysterectomy and bilateral salpingo-oophorectomy.[37]

Deterrence and Patient Education

Bacteroides fragilis is a bacteria that is a common component of the human colon bacteria. It has involvement in causing disease in humans under certain conditions. The human colon is lined by a mucosal barrier that protects body tissues from being invaded by the bacteria that inhabits the intestinal cavity. When the mucosal barrier is disrupted by trauma, surgery, or tumor, the bacteria invade the surrounding tissues through the disrupted barrier and start an infectious process. The human body's immune systems begin to combat the infection by an inflammatory process aiming to eradicate the infection. The inflammatory reactions of the body would manifest locally as abscess formation and systemically as fever, chills, and if the infection is severe, it may result in sepsis. The management of Bacteroides fragilis infection is usually by source control either by incision and drainage of the pus or aspiration along with antibiotics targeted toward the causative organism.

Pearls and Other Issues

• Bacteroides species are part of the human colon microbiota.
• Bacteroides fragilis is the most common cause of anaerobic infections in humans.
• Infection due to Bacteroides fragilis is usually polymicrobial and results from a disruption in tissue barriers.
• Source control and targeted antimicrobial therapy are the two keys to control Bacteroides fragilis infection.
• The role of Bacteroides fragilis in the development of colorectal cancer has been controversial among several studies.

Enhancing Healthcare Team Outcomes

The management of Bacteroides fragilis infection requires collaboration among healthcare professionals. It usually starts with the clinical suspicion of anaerobic infection in the setting of underlying trauma, recent surgical intervention, or malignancy. The proper specimen collection usually improves the diagnosis of Bacteroides fragilis infection. Anaerobic cultures obtained from sterile sites have the highest diagnostic yield. For example, cerebrospinal fluid cultures, blood cultures, and pleural fluid cultures growing Bacteroides fragilis are clinically significant and warrant treatment for meningitis, bloodstream infection, and empyema.

On the other hand, wound cultures wound swabs, or stool cultures will have very low diagnostic yield and may represent colonization that would not require any treatment. Anaerobic cultures must be collected in the appropriate containers and transported immediately to the microbiology laboratory. The handling of anaerobic infections in the microbiology lab is costly and requires expertise and proper equipment. The clinical interpretation of Bacteroides fragilis cultures usually requires the skill of Infectious disease physicians and pharmacists to help decide the clinical significance and to direct the targeted antimicrobial therapy. Bacteroides infections are typically severe infections and part of a polymicrobial invasion. The management strategy has two major goals: targeted antimicrobial therapy and adequate source control, and that usually involves coordination between the treating healthcare provider and surgical and interventional radiologist consultations. The interprofessional team, including physicians, nurses, lab technicians, and pharmacists, can improve outcomes. Pharmacists review medication selection, dosage, and drug-drug interactions and inform the prescriber of any concerns. Nurses are often involved in specimen collection and administration of antibiotics, as well as patient counsel, follow-up for compliance, and reporting their findings to the clinical staff. Pathologists and lab technicians must ensure proper specimen processing. All these examples of interprofessional collaboration and communication will contribute to better patient outcomes. [Level 5]