Anaerobic Infections: General Concepts

Definition of an Anaerobe

An anaerobe is an organism that requires reduced oxygen for growth and fails to grow on the surface of solid media in 10% carbon dioxide (CO ₂ ) in air. In contrast, facultative organisms can grow in the presence or absence of air, and microaerophilic bacteria can grow in 10% CO ₂ in air or under aerobic or anaerobic conditions. As opposed to several anaerobic species inhabiting human bodily surfaces, which can survive only under strict anaerobic conditions (<0.5% oxygen), anaerobes that commonly cause human infections ( Bacteroides fragilis, Prevotella melaninogenica , and Fusobacterium nucleatum ) are generally aerotolerant (i.e., they tolerate 2%–8% oxygen) and can survive for sustained periods, but cannot replicate, in an oxygenated atmosphere.

Anaerobes in the Normal Human Microbiota

Anaerobic bacteria are the predominant forms of life in the human body. Several hundred species of anaerobic organisms have been identified in the human microbiota ; however, many of them cannot be characterized by cultivation in vitro, which has been the cornerstone of microbiology since the 19th century. In an analysis of 13,555 prokaryotic ribosomal RNA (rRNA) gene sequences from the colon, most bacteria identified were considered uncultivated and novel microorganisms. New technologies based on DNA analyses expanded researchers’ knowledge, and two main projects, the Human Microbiome Project, carried out by the National Institutes of Health, and the European Metahit, aim to characterize the normal microbiota in healthy individuals.

Increasing evidence indicates that human microbiota composition is influenced by diet, geography, and environmental exposure. Anaerobes are dominant in mucosal surfaces, such as the oral cavity and the gastrointestinal (GI) and female genital tracts. These sites account for 99% to 99.9% of the culturable microbiota. The microbial species and concentrations vary at different sites ( Table 242.1 ). It is interesting that anaerobes also inhabit areas of the body that are exposed to air: skin, nose, mouth, and throat. It has been hypothesized that the ability of anaerobes to withstand oxygen at these sites is due in part to the presence of aerobes and facultative organisms that consume oxygen and reduce the oxidation-reduction potential. In addition, anaerobes are believed to reside in the portions of these sites that are relatively well protected from oxygen, such as gingival crevices.

Anaerobes normally abound in the oral microbiota, with concentrations ranging from 10 ² /mL in saliva ( Veillonella parvula being predominant) to 10 ¹² /mL in gingival scrapings. The ratio of anaerobic to aerobic bacteria ranges from 1:1 on teeth to 1000:1 in the gingival crevices. The indigenous oral anaerobic microbiota primarily comprises Prevotella and Porphyromonas spp., with Fusobacterium and Bacteroides (non– B. fragilis group; see later) present in lower numbers. Until recently the lower respiratory tract was considered sterile below the larynx; however, more recent studies using culture-independent techniques have documented the presence of a respiratory tract microbiota that extends from the nasal passages to the alveoli.

Low numbers of anaerobic bacteria are present in the normally acidic conditions of the stomach and upper intestine. In people with decreased gastric acidity, the microbiota of the stomach resembles that of the oral cavity. The upper intestine contains relatively few organisms until the distal ileum, where the microbiota begins to resemble that of the colon. A stagnant proximal, small intestinal segment caused by stricture, obstruction, diverticulum, or blind loop results in colonic concentrations of bacteria with a predominance of anaerobes. In the colon there are up to 10 ¹² organisms per gram of stool, with anaerobes outnumbering aerobes by approximately 1000:1 and accounting for 99.9% of the total bacterial burden. The predominant culturable anaerobes are Bacteroides spp. (principally members of the B. fragilis group, including B. fragilis, B. thetaiotaomicron, B. ovatus, B. vulgatus, B. uniformis, and Parabacteroides distasonis ) and Clostridium, Peptostreptococcus, and Fusobacterium spp. However, many of the bacteria in the human colon cannot be cultivated by current laboratory methods.

The normal female genital tract is colonized by 10 ⁷ to 10 ⁹ bacteria per mL, with an anaerobic-to-aerobic ratio of 1:1 to 10:1. The predominant anaerobic species are Prevotella, Bacteroides, Fusobacterium, Clostridium , and the anaerobic Lactobacillus spp. Bacteroides spp. are found in the genital tract of approximately 50% of women, with B. fragilis making up less than 15% of this microbial population. The skin microbiota contains anaerobes as well, the predominant species being Cutibacterium (formerly Propionibacterium ) acnes and, to a lesser extent, other species of Cutibacterium and Peptostreptococcus.

The Microbiome in Health and Disease

Commensal bacteria in general and commensal anaerobes in particular have been implicated as crucial mediators of several physiologic, metabolic, and immunologic functions in the mammalian host (see also Chapter 2 ). The occupation of distinct ecologic niches within the intestinal environment that would otherwise be filled with potentially pathogenic organisms is among the most important roles that anaerobes serve as components of the normal colonic microbiota. In what is termed colonization resistance, the presence of anaerobes effectively interferes with colonization by potentially pathogenic bacterial species through the depletion of oxygen and nutrients, the production of enzymes and toxic end products, and the modulation of the host's intestinal innate immune response. For example, Bacteroides thetaiotaomicron stimulates Paneth cells to produce RegIIIγ, a bactericidal lectin that can result in killing of gram-positive bacteria. The normal colonic microbiota plays an important role in protection against Clostridioides difficile (formerly Clostridium difficile )–associated diarrhea or colitis, a toxin-mediated, potentially life-threatening disease that results when C. difficile spores in the colon transform to vegetative forms with toxin production because of antibiotic elimination of critical components of the competing colonic microbiota and a consequent decrease in microbiota diversity. Changes in the microbiota are accompanied by changes in the metabolome that support C. difficile germination and growth (see Chapter 243 ).

A large body of evidence, including randomized controlled trials, systematic reviews, and meta-analyses, provides clear evidence that fecal microbiota transplantation is a highly effective treatment against recurrent C. difficile infection. Beyond the treatment of C. difficile infection, fecal microbiota transplantation has been investigated in other disorders associated with alteration of the gut microbiota, in particular, ulcerative colitis and metabolic syndrome, but at present there are no definitive conclusions.

The anaerobic component of the intestinal microbiota is also responsible for the production of secreted products that are helpful in human health. The production of vitamin K by anaerobes in the intestine is beneficial to the host, and the production of bile by these organisms is useful in fat absorption and cholesterol regulation. The gut microbiota is integral to the host's digestion and nutrition. Microbiota components can generate nutrients from substrates that are otherwise indigestible by the host. For example, carbohydrate fermentation by Bacteroides and other intestinal bacteria results in the production of volatile fatty acids that are reabsorbed and used by the host as an energy source. The capacity of gut microbial digestion of xyloglucans, commonly found in dietary vegetables, has been mapped to a single locus in a certain species of Bacteroides .

The microbiota contributes to the development and homeostasis of the immune system. The anaerobic intestinal microbiota influences the development of an intact mucosa and of mucosa-associated lymphoid tissue. Germ-free animals exhibit reductions in vascularity, digestive enzyme activity, and muscle wall thickness as well as undeveloped gut-associated lymphoid tissue. Colonization of these mice with a single species, B. thetaiotaomicron, affects the expression of various host genes that influence nutrient uptake, metabolism, angiogenesis, mucosal barrier function, and development of the enteric nervous system. Through its symbiosis factor polysaccharide A (PSA), B. fragilis influences the development and function of the immune system and protects mice against colitis in a model of inflammatory bowel disease. In addition, PSA can confer protection both prophylactically and therapeutically, restrain inflammatory processes, and ameliorate disease in an extraintestinal site in a mouse model of multiple sclerosis.

Although the gut microbiota confers many benefits (as discussed previously), its dysregulation, termed dysbiosis , may play a role in the pathogenesis of diseases characterized by inflammation and aberrant immune responses, such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, asthma, and type 1 diabetes. Furthermore, the gut microbiota has been associated with obesity, metabolic syndrome, cardiovascular disease, and even mental illness.

Etiology and Microbiology of Anaerobic Clinical Infections

Despite the number of anaerobic species represented in the normal human microbiota, relatively few are involved in human infections. Infections involving anaerobes are often polymicrobial and usually result from the disruption of mucosal surfaces by surgery, trauma, tumors, or ischemia and the subsequent infiltration of resident microbiota. Cecal contents are the source of microorganisms in the case of intraabdominal infections after disruption of intestinal continuity and contamination of the peritoneal cavity. Infections of the head and neck are caused by the commensal microbiota of the mouth. After contamination of previously sterile sites by the mucosal microbiota, the relatively few anaerobic bacteria that survive in the infected site are those that have resisted changes in oxidation-reduction potential and host defense mechanisms.

Table 242.2 shows the gram-negative and gram-positive anaerobes most commonly isolated from clinical specimens.