Continuing Education Activity

Anaerobic bacteria are part of the normal flora of human skin and mucosal membranes. The site of anaerobic infection is commonly the site of normal colonization. The spectrum of infections ranges from local abscesses to life-threatening infections. Anaerobic bacteria differ from aerobic bacteria in their oxygen requirement. Oxygen is toxic to anaerobes, which can be explained by the absence of enzymes in the anaerobes of catalase, superoxide dismutase, and peroxidase enzymes. The diagnosis requires clinical suspicion and proper microbiological identification. This activity examines when this condition should be considered on differential diagnosis and how to evaluate for it properly. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Identify the etiology of anaerobic infections.
• Review the various clinical manifestations of anaerobic infections,
• Describe the management options available for anaerobic infections.
• Explain the importance of improving care coordination among the interprofessional team to achieve better clinical outcomes in patients having anaerobic infections.

Introduction

Anaerobic bacteria are part of the normal flora of human skin and mucosal membranes. The site of anaerobic infection is commonly the site of normal colonization. The spectrum of infections ranges from local abscesses to life-threatening infections. Anaerobic bacteria differ from aerobic bacteria in their oxygen requirement. Oxygen is toxic to anaerobes which can be explained by the absence of enzymes in the anaerobes of catalase, superoxide dismutase, and peroxidase enzymes. Anaerobes are fastidious organisms and are difficult to grow if proper collection and culture methods are not used. The diagnosis requires clinical suspicion and proper microbiological identification.[1][2]

Based on oxygen requirement, bacteria can be divided into the following groups:

Obligate aerobes require oxygen as a terminal electron acceptor and do not have any other source of energy, such as fermentation.

Obligate anaerobes obtain energy through fermentation and use organic compounds as a terminal electron acceptor.

Facultative anaerobes can grow in the presence or absence of oxygen.

The obligate anaerobes can further be subdivided into 2 types based on a percentage of oxygen that can prove toxic. Strict obligate anaerobes will not survive if there is more than half a percent oxygen in the environment, while moderate obligate anaerobes can still grow in a 2 to 8% oxygen environment.

Etiology

Common sites of anaerobic infections include oral, abdominal, and pelvic cavities; however, anaerobes can cause infections of other regions such as the head, neck, and skin. Clinically significant anaerobes associated with human infections are as follows:

Gram-Positive

Gram-Positive, Spore-forming Bacilli

Clostridium: These are spore-forming anaerobes responsible for some of the more serious human infections. They account for close to 10% of all anaerobic infections. Significant members of this family are Clostridium difficile, which causes C. difficile infection. Clostridium perfringens, which causes gas gangrene or soft tissue infections. Clostridium septicum also causes gas gangrene.

Gram-positive, Non-spore-forming Bacilli

Actinomyces: These colonize the human gastrointestinal (GI) tract, and infections result from a break in the mucocutaneous barrier. The 3 most common anatomic sites affected by Actinomyces are cervicofacial, thoracic, and abdominal.

Propionibacterium: This species is part of the normal flora of skin and mucosa. The most significant member of this family is Propionibacterium acne which plays a role in the pathogenesis of acne vulgaris.

Bifidobacterium: This is normal flora of intestinal tracts. It is usually non-pathogenic; however, pediatric infections have been documented in the form of chronic otitis media, abdominal abscesses, and peritonitis.

Lactobacillus: These organisms are also normally found in the GI tract and can be recovered from numerous food products. They have low pathogenic potential; however, cases of abdominal abscesses, aspiration pneumonia, and bacteremia, particularly in neonates, have been described.

Peptococcus and Peptostreptococcus: These anaerobes are part of the mouth, GI tract, upper respiratory tract, and urogenital tract, as well as the skin. They can be pathogenic and cause numerous infections such as chronic otitis media, chronic sinusitis, aspiration pneumonia, pelvic inflammatory disease, including tube-ovarian abscesses.

Other members include Eubacterium, Bifidobacterium, Arcanobacterium, and microaerophilic Streptococcus (Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius).

Gram-negative

Bacteroides: These are the most frequently recovered anaerobic pathogens from clinical specimens. They are part of human colonic and normal female genital flora. These organisms are most commonly the cause of intra-abdominal infections, particularly abscesses. The majority of these abscesses are mixed infections. They can also cause extra-abdominal infections such as aspiration pneumonia, brain abscesses, among others.

Fusobacterium: One of the species from this group of anaerobes, Fusobacterium necrophorum, is a common cause of peritonsillar abscesses associated with a complication of internal jugular vein thrombosis, known as Lemierre syndrome.

Campylobacter: This is one of the most common causes of acute bacterial gastroenteritis.

Prevotella: These are normal flora of the human oral cavity and intestinal tract. In children, they are frequently associated with head and neck infections such as peritonsillar abscesses, retropharyngeal abscesses as well as perineal or perianal infections such as pilonidal abscesses.

Veillonella: Occasionally associated with abdominal abscesses and aspiration pneumonia in children.

Epidemiology

Anaerobes are part of the indigenous or native flora, particularly the oral cavity, human bowel, and female genital tract. The colonization with anaerobes varies with age, organ site, and environmental factors. For example, infants exclusively breastfed have gut flora with predominantly Bifidobacterium, with few Bacteroides and Enterococcus species. On the other hand, infants who are fed cow's milk have gut flora similar to that of an adult's, which contain gram-negative anaerobes and facultative bacilli.[3][4][5]

Anaerobes are part of indigenous flora, which resists colonization and invasion from non-indigenous flora. However, infections from anaerobes do occur and usually result from a breakdown of the mucocutaneous barrier or immunosuppression. Anaerobic organ infections include, but are not restricted to, brain abscesses, dental infections, aspiration pneumonia, lung abscesses, bite infections (animal/human), abdominal abscesses, and necrotizing infections of soft tissue.

Pathophysiology

The pathogenesis of anaerobic infections includes disruption of the mucosal surface and entry of the anaerobic bacteria with the invasion of the deep tissue. The mechanisms of entry include local trauma, surgery, viscus perforation (for example, appendicitis), tissue necrosis, and impaired clearance of a sterile site (chronic sinusitis, pneumonia). The site and the extent of infection are based on the virulence factors of the organism and host immunity.

The virulence factors which assist anaerobic infections are adhesions factors (fimbriae and lectin), invasion factors (phospholipase C, lipopolysaccharides, and proteases), factors involved in tissue destruction (fibrinolysis, acetylglucosaminidase, and collagenase production), capsular resistance to phagocytosis, and others. Serious infections are seen in the immunocompromised host.

When implicated in an abscess, anaerobes are usually part of a polymicrobial infection. Experimental rat models with mixed infections have shown that the growth of anaerobes, as well as aerobes, is enhanced in polymicrobial infections.

History and Physical

The majority of anaerobic infections in children are local, and bloodstream infections compromise less than 2% of the cases. The approach to anaerobic infections includes the identification of predisposing factors. They are as follows:

1. An organ site infection contagious to a site with indigenous colonization (oral cavity, bowel)
2. Obstruction: For example, nasal foreign body, appendiceal obstruction, bowel obstruction
3. Perforation: Of hollow viscus such as bowel perforation.
4. Host's inability to clear secretions, for example, children with cerebral palsy, are predisposed to aspiration pneumonia.
5. Animal and human bites resulting in penetrating trauma from oral anaerobes

Other important clues of anaerobic infection include the presence of a condition predisposing an individual to an anaerobic infection, for example, tissue necrosis, a foul-smelling discharge, infection leading to thrombophlebitis, no improvement with antibiotics in suspected anaerobic activity.

The clinicians should obtain an anaerobic culture when suspicion of anaerobic infection is present.

Common Organ Site Infections in Anaerobic and Aerobic Infections

Head and neck infection: Anaerobes are commonly implicated in dental infections such as dental abscesses, gingivitis, and periodontitis. Exam findings of dental caries or poor dentition are usually present. Anaerobes are also implicated along with other aerobes in suppurative infections of retropharyngeal abscess, peritonsillar abscess, cervical lymphadenitis, deep neck abscesses, and parotitis. The anaerobe associated with Fusobacterium is linked with a complication of peritonsillar abscess known as Lemierre syndrome. Lemierre syndrome is caused by jugular vein septic thrombophlebitis and metastatic emboli to the lungs and liver.

Anaerobes are also caused by chronic otitis media and chronic sinusitis, along with other aerobes such as Staphylococcus aureus and Pseudomonas. 

Central nervous system (CNS) infections: Anaerobes are commonly isolated in cultures from brain abscesses which result from a complication of sinusitis, otitis media, dental infections. The 3 anaerobes commonly isolated are Fusobacterium, Prevotella, and Bacteroides. The same organisms are also seen in epidural infections.

Intra-abdominal infections: Damage to the intestinal wall as seen in the perforated appendix gives enteric anaerobes access to the peritoneal cavity. Over days to weeks, it results in the formation of abdominal abscesses. Abdominal abscesses are almost always mixed infections containing both aerobes and anaerobes. The most common anaerobe implicated in abdominal infections is Bacteroides fragilis, followed by Lactobacillus and Clostridium species.

Anaerobes are also a common cause of liver abscesses. The common anaerobes associated are Bacteroides and Fusobacterium species.

Pelvic inflammatory disease: Anaerobes are all are involved in pelvic inflammatory diseases (PID). In a sexually active female with signs and symptoms compatible with pelvic inflammatory disease, empiric antimicrobial therapy against anaerobes and anaerobes is indicated. The common anaerobes involved in PID are Prevotella, Porphyromonas, Clostridium.

Pulmonary infections are seen in children who are unable to control upper airway secretions or lack a normal cough reflex, such as in children with cerebral palsy and tracheoesophageal malformations. Aspiration results in pneumonia which can develop into an abscess if untreated. The predominant pathogens involved in aspiration pneumonia are part of the oropharyngeal flora and include Peptostreptococcus, Prevotella, Bacteroides fragilis, and Fusobacterium.

Skin and soft tissue infections: Anaerobes can cause a perirectal abscess or facial abscess in children. Bacteroides fragilis and Clostridium species are usually involved in perirectal infections, and Prevotella, Porphyromonas, and Fusobacterium are involved in oral infections.

Evaluation

Identification of Serious Anaerobic Infections

Timely identification is important to start empiric therapy. Life-threatening infections such as tetanus, gas gangrene, or infantile botulism are caused by the spore-forming anaerobes, Clostridium tetanus, Clostridium perfringens, or Clostridium botulism, respectively.[6][7]

A history of injury, for example, penetrating nail injury or the presence of a devitalized tissue, should prompt evaluation for tetanus in an immunized child.

Gas gangrene is caused by Clostridium perfringens or Clostridium septicum. It is a medical emergency that requires surgical debridement in addition to antibiotic therapy with penicillin-containing antibiotics in combination with clindamycin.

Botulism manifests as descending paralysis, particularly in infants. History of consumption of damaged canned food, use of honey, or living or traveling to endemic regions (high clostridial spore counts) is frequent. Physical examination findings are of an afebrile infant with acute onset of feeding difficulty and bulbar involvement (absence of a gag reflex). For suspected cases, expert review is provided by the California Department of Health.  Stool should be sent to check for Clostridium botulism spores. The mainstay of management is supportive care with or without botulism immunoglobulin (BabyBIG).

In an adolescent with a sore throat, neck pain, and tachycardia out of proportion to fever, Lemierre syndrome should be considered. A neck Doppler ultrasound should be done to look for thrombophlebitis of internal jugular veins and chest x-ray to look for septic emboli.

Local Infections Including Abscesses

Abscesses can be limited to CNS, head, and neck region. The abdominal region can be diagnosed with appropriate anaerobic culture. The specimen should be collected from a sterile site, preferably bypassing the normal flora and with needle aspiration or surgical exploration. Tissue or fluid aspirate is preferred over a swab. After collection, the sample should be sent in an anaerobic transport medium, and it should be inoculated in an oxygen-free environment.

Treatment / Management

Step 1

Management of anaerobic infection depends on the site of infection, the host, and presence or absence of abscess. As a general rule, an abscess should always be drained, and the culture sent for aerobic and anaerobic culture. Also, surgical debridement of necrotic tissue in clostridium necrotizing fasciitis is crucial in treatment.[8][9][10]

Step 2

After obtaining appropriate cultures, the child should be placed on empiric antibiotics with activity against anaerobes.  The following are the choices:

Metronidazole: Has excellent activity against Gram-negatives such as Bacteroides fragilis. Its activity against Gram positives is good, although less reliable. Metronidazole has excellent bioavailability (100%), and it penetrates well into the tissue, including the central nervous system and abdominal cavity. Metronidazole gives a metallic taste in the mouth, which is frequently cited as the reason for discontinuation.

Clindamycin is active against many anaerobes. The resistance of clindamycin to Bacteroides fragilis is increasing, and it is less reliable as compared to metronidazole, penicillin/beta-lactamase inhibitor, or a carbapenem. Clindamycin, whether administered IV or orally, penetrates well into the tissue, including abscesses, bones, joints. Clindamycin, however, does not enter the central nervous system. 

Penicillin/beta-lactamase inhibitor combination: Penicillin alone is active against anaerobes that do not produce beta-lactamase, such as Clostridium perfringens.  However, most gram-negative anaerobes produce beta-lactamase and combination penicillins such as oral amoxicillin/clavulanate or intravenous (IV)/intramuscular (IM) ampicillin/sulbactam, ticarcillin/clavulanate, and piperacillin/tazobactam.

Second-generation cephalosporin: Regarding cephalosporins, the second-generation cephalosporins of cefoxitin, cefotetan, and cefmetazole are more active against Bacteroides fragilis. However, given increasing resistance, they are not recommended as empiric treatment. It is commonly used in surgical prophylaxis.

Carbapenems: Have excellent activity against anaerobes as well as aerobes involved in intra-abdominal and other sites such as CNS. Meropenem is slightly more active than imipenem against gram-negative bacteria.

Quinolones: Have good oral absorption and tissue penetration. However, resistance is increasing, and they should be reserved for children with beta-lactam allergy. Quinolones with activity against anaerobes include levofloxacin and moxifloxacin.

Differential Diagnosis

• Botulism can be confused with other neurological conditions such as Guillain Barre syndrome and infectious causes of paralysis such as enterovirus infection or West Nile Virus paralysis or paresis.

• Aerobic abscesses from Escherichia coli, Pseudomonas such as brain abscess, head and neck abscesses, lung infections, and intra-abdominal infections.

Pearls and Other Issues

• Consider anaerobic infection if the site of suspected infection is adjacent to a normal indigenous anaerobic flora, such as the mouth, bowel, or female genital tract.

• Identifying a predisposition such as obstruction, perforation, injury, the inability of the host to clear secretions, decreased blood flow to the tissue, such as tissue necrosis.

• Clues to an anaerobic infection include foul-smelling discharge, and infection is not responding to antibiotics without any anaerobic activity.

• An attempt should be made to send anaerobic cultures, which involves the proper collection, expeditious transport, and proper culture methods. Tissue or purulent material is preferred over sending swabs.

• Metronidazole has broad-spectrum anaerobic activity with the least resistance. Other anaerobic antibiotics include clindamycin, penicillin beta-lactamase inhibitor combination, second-generation cephalosporins, carbapenems, and quinolones.

Enhancing Healthcare Team Outcomes

Anaerobic infections are common in both outpatients and inpatients. Because these infections can affect various organs and present in diverse ways, they are best managed by an interprofessional team. Primary care providers, nurse practitioners, and other healthcare workers need to consult with an infectious disease expert when faced with an infection that does not respond to conventional antibiotics or has an odd presentation. General surgeons are often consulted for drainage. The pharmacist should review the choice of medication, drug interactions, and patient compliance and report concerns to the team. Nurses should assist with coordination of care, facilitate communication between the interprofessional team members, and assist with patient and family education. Specialty trained nurses, including medical-surgical and infection control, should be involved, as needed.

Anaerobic infections, when misdiagnosed, carry a high mortality.[11][12][13]

The prognosis depends upon the type of anaerobic infection.

• In this era of tetanus vaccination and the availability of supportive care, tetanus is not seen in the developed part of the world. In any child with clean penetrating, wound tetanus vaccination should ensue, and in cases of the contaminated wound, consideration should be made on the use of tetanus vaccine and tetanus immunoglobulins based on the last tetanus vaccine.
• Any contaminated wound should be cleaned, and the removal of a foreign body should be done.
• Good dental and oral hygiene prevent anaerobic infections.
• For abdominal surgeries requiring entrance of hollow viscus, an antibiotic with anaerobic activity such as cefoxitin should be considered.