INTRODUCTION — Anaerobic bacteria are the predominant cultivable forms of life in the human body. While the role of these microbes as pathogens was well established at the turn of the 20th century, they are often neglected in part due to the fact that clinical laboratories show great variation in application of recommended methods for recovery and identification of anaerobes. Important features that may limit detection of some of these organisms are:
●The lack of resources and lack of perceived need for this technology, depending to some extent on the health care institution size and population served. Provider demand is also a factor. Nevertheless, virtually all labs provide Gram stains that frequently show the often unique morphology of these bacteria.
●Fastidious growth requirements that often limit recovery.
●Ubiquity on mucocutaneous surfaces that hampers obtaining meaningful cultures due to difficulty avoiding contamination by normal flora.
●The presence of mixed flora including other known pathogens often requires clinical expertise to differentiate pathogens requiring treatment and commensals or symbiotes that do not.
During the past several decades, there has been renewed interest in anaerobic infections, based upon verification of their role as pathogens by recovery from infected sites, efficacy of antibiotic treatment, elucidation of virulence factors, and reproduction of disease in experimental animals. We now appear to be in an era where therapy is frequently directed at anaerobes based upon an assumption that the organisms are there and that specific antibiotics are effective.
The history of the appreciation of anaerobes as pathogens and the composition of normal flora in humans will be reviewed here. The pathophysiology, clinical clues, recovery, and range of infections caused by these organisms are discussed separately. (See "Pathophysiology, clinical clues, and recovery of organisms in anaerobic infections" and "Anaerobic bacterial infections".)
DEFINITION OF ANAEROBES — Anaerobic bacteria are defined as bacteria that grow in the absence of oxygen and fail to show surface growth in 10 percent carbon dioxide in air. They may be further classified by relative aerotolerance: strict anaerobes cannot tolerate 0.5 percent oxygen; most clinically important anaerobes (Bacteroides fragilis, Prevotella melaninogenica [formerly classified as Bacteroides melaninogenicus], and Fusobacterium nucleatum spp) are moderate anaerobes that tolerate 2 to 8 percent oxygen. Most of these organisms can survive in air for sustained periods, but they cannot replicate in atmospheric oxygen.
HISTORICAL PERSPECTIVE — Louis Pasteur is credited with the discovery of anaerobes with the successful cultivation of Clostridium butyricum in the absence of atmospheric oxygen in 1862 [1]. Veillon and Zuber from the Faculty of Medicine of Paris published a series of important contributions in the 1890s concerning the role of anaerobic bacteria as the cause of putrid discharge from infections at multiple anatomic sites, including pelvic infections, brain abscess, lung gangrene, and appendicitis [2].
Early reports — The classic toxin-mediated clostridial syndromes, gas gangrene, botulism, and tetanus, were also well recognized by the end of the 19th century. In fact, Clostridium tetani was recovered in pure culture by 1890, and studies of tetanus immunization had begun [1].
At the beginning of the 20th century, numerous papers in the French and German literature reviewed the role of anaerobic bacteria in diverse types of infections. Many were described as "fusospirochetal infections," characterized by the appearance of fusiform gram-negative rods (presumably F. nucleatum spp) and anaerobic spirochetes. In retrospect, it seems that these infections were probably analogous to those encountered in current practice, but the organisms identified generated considerable interest owing to their unique morphologic character.
Pathogenesis studies — Among the major contributions was the observation by Schottmueller that anaerobic streptococci, rather than group A beta-hemolytic streptococci, were actually the predominant pathogens in puerperal sepsis [3]. He postulated that the infection was acquired endogenously from the normal genital flora. This was a novel thesis at the time because nearly all infectious diseases were thought to be exogenous and contagious.
Contributions by American investigators in the early 1900s included the hallmark studies of the bacteriology and pathophysiology of lung abscess by David Smith in the late 1920s [4,5]. This investigator noted that the organisms in the abscess walls obtained at autopsy resembled those seen in the gingival crevice, leading to the postulate that aspiration of gingival crevice bacteria was the mechanism of infection. This hypothesis was subsequently supported by the intratracheal inoculation of pyorrhea pus into experimental animals to demonstrate the sequential progression from pneumonitis ("aspiration pneumonia") to lung abscess. (See "Lung abscess in adults".)
In an amazing series of experiments, 17 different organisms were isolated from the inoculum and then each used alone and in combination with intratracheal challenge to various animals. Eventually, he showed that four microbial species were required to reproduce lung abscess: anaerobic streptococci, an anaerobic spirochete, an anaerobic vibrio, and an anaerobic fusiform bacillus. This was one of the first studies of microbial synergy, the demonstration that two or more organisms could produce a pathologic lesion that could not be reproduced with a simpler inoculum.
Two American surgeons, Meleney and Altemeier, made additional important contributions. Meleney noted the role of anaerobic bacteria in soft tissue infections and described the condition subsequently known as "Meleney synergistic gangrene," a rare but characteristic eroding ulcer at the site of retention sutures (see "Necrotizing soft tissue infections"). This lesion harbors Staphylococcus aureus and an anaerobic streptococcus and can be reproduced in animals only with an inoculum of both.
Altemeier examined the bacteriology of appendicitis in the late 1930s and was able to isolate anaerobic bacteria from 96 of 100 patients [6]. He also noted that putrid discharge was found exclusively in the presence of infections involving anaerobic bacteria and that these were also the only organisms to produce the characteristic putrid odor both in vivo and in vitro [7].
Two decades of disinterest — Interest in anaerobic infections largely disappeared in the period from 1940 through 1960. There were relatively few clinical reports, and clinical laboratories made no attempt to recover anaerobes. The organisms seemed to be out of sight and out of mind.
Renewed attention — Renewed interest in anaerobic infections in the middle and late 1960s followed three simultaneous developments:
●The GasPak jar became available and made isolation of anaerobes relatively easy for most microbiology laboratories.
●The taxonomic classification of anaerobic bacteria was finally put in order, primarily by the tedious studies by workers from the Virginia Polytechnic Institute.
●Studies of the activity of antibiotics against anaerobes in vitro and in clinical trials were conducted by Sydney Finegold and others; this work initially highlighted the potential role of lincomycin, and subsequent reports dealt with clindamycin, metronidazole, cefoxitin, and a host of other antibiotics [8].
Studies from 1970 through 1980 showed that anaerobic bacteria accounted for a relatively large number of infections, although the frequency was profoundly influenced by the anatomic site and the mechanism of disease acquisition (exogenous versus endogenous). Detection of anaerobes in the laboratory was also highly variable depending upon the methods used to collect, transport, and process specimens. A review of the experience at the Mayo Clinic in the early 1970s found that B. fragilis was second only to Escherichia coli as a cause of gram-negative bacillary bacteremia [9]. There were multiple additional studies from the 1970s (summarized below) that showed high yields of anaerobes when properly studied. These results have been translated into practice through the widespread use of drugs directed specifically at anaerobic bacteria; two of the most frequent are clindamycin and metronidazole.
The extensive publicity accorded to anaerobic bacteria and anaerobic infections in the 1970s resulted in general acceptance of these organisms as major pathogens in selected types of infections. This recognition was accompanied by large multicenter clinical trials, studies of antibiotic sensitivity testing [10-12], and the widespread use of antimicrobials with coverage against anaerobes.
As a result of this successful education campaign, the incidence of anaerobic infections was reduced. The result was a virtual disappearance of anaerobic bacterial bacteremia to the extent that some authorities proposed a discontinuation of routine anaerobic blood cultures [13-15]. However, a subsequent increase in both anaerobic infections and anaerobes with resistance to commonly used antibiotics has occurred.
Current status — The "anaerobic bandwagon" of the 1970s appeared to be highly effective in achieving recognition of anaerobic bacteria and their role in selected infections. This resulted in increased availability of anaerobic microbiology and appropriate use of antibiotics.
However, there is concern that some anaerobic infections are not being detected due in part to a decline in the quality of microbiology laboratories, reflecting economic realities, outsourcing, and reliance on empiric antibiotics. Possibly most important is the fact that anaerobic cultures require a high level of microbiology expertise to separate and identify the multitude of different microbes at the infected site and the fact that anaerobic cultures usually come back after treatment decisions are made. In most cases, treatment is empiric based on predictable pathogens according to the site of infection, results of therapeutic trials, and possibly the Gram stain results. It is noteworthy that the incidence of anaerobic infections appears to be rising, which is likely the result of an increase in the number of patients with complex underlying illnesses [16]. As an example, one report from the Mayo Clinic found a decline in the incidence of anaerobic bacteremia from 1974 to 1988, followed by an increase to an average of 53 cases per year from 1993 to 1996 and to 94 cases per year from 2001 to 2004 [16]. This issue is increasingly relevant in the context of both recognition and antibiotic selection due to increasing resistance of anaerobes to antibiotics, including moxifloxacin, cefoxitin, carbapenems, and clindamycin. (See "Anaerobic bacterial infections", section on 'Antimicrobial resistance'.)
NORMAL FLORA — Most mucocutaneous surfaces of humans harbor a rich indigenous flora composed of aerobic and anaerobic bacteria, the microbial species and concentrations of which vary at different anatomic sites (table 1). Anaerobic bacteria are the dominant forms, often accounting for 99 to 99.9 percent of the culturable flora [14,17]. The total number of bacterial species in a single individual probably exceeds 500, with the colon alone reported to have 500 to 1000 species per individual.
However, in general, most of the normal flora cannot be grown or characterized by current laboratory methods. This was illustrated in an analysis of 13,555 prokaryotic ribosomal RNA gene sequences from the colon in which most bacteria were considered uncultivated and novel micro-organisms [18]. However, there has been enhanced success with expanded methods to cultivate a wider array of human anaerobic and fastidious bacteria.
Upper airways — The upper airways, including the oral cavity, nasal passages, oropharynx, and nasopharynx, harbor a complex flora that differs at various sites despite anatomic continuity; these are known as ecologic niches [17]. Concentrations of bacteria in saliva are approximately 108/mL with 90 percent anaerobic bacteria; the predominant organism is Veillonella parvula. Dental plaque includes a complicated matrix of bacteria, including Streptococcus mutans, the principal organism implicated in dental caries, but anaerobic bacteria have also been implicated. (See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections".)
The environment in the gingival crevice is similar to that of the colon in that the oxidation-reduction potential is -300 mV, concentrations of bacteria reach 1012/mL (the maximum density of bacterial growth), and anaerobic bacteria account for 99 percent of the culturable flora. In healthy persons, the sinuses, eustachian tubes, and respiratory passages below the level of the larynx are generally sterile.
The most important anaerobic potential pathogens found in the upper airways are Fusobacterium nucleatum, Prevotella melaninogenica, the Prevotella oralis group, the Bacteroides ureolyticus group, and Peptostreptococcus spp, which represent the predominant organisms in anaerobic oral and pleuropulmonary infections [19-21]. Studies have implicated Fusobacterium necrophorum, the agent of Lemierre disease, as a possibly important cause of pharyngitis [22-26]. (See "Evaluation of acute pharyngitis in adults", section on 'Other bacteria'.)
Gastrointestinal tract — The gastrointestinal tract shows marked variations in bacteriologic patterns in concentrations at different levels [27-30].
Stomach — The stomach is protected by the gastric acid barrier and consequently harbors relatively small numbers of bacteria derived from swallowed salivary bacteria that are predominately gram positive. The number and types of bacteria increase with loss of gastric acidity.
Small intestine — The small bowel is the site of rapid motility, so the organisms commonly found are simply passing through. Interruption of this flow, as with a stagnant segment (stricture, obstruction, diverticulum, blind loop), results in colonic concentrations of bacteria with a predominance of anaerobes [27,31]. This bacterial overgrowth pattern may be responsible for malabsorption and is best treated with antibiotics directed against anaerobes. There is speculation that overgrowth may play a role in irritable bowel syndrome [32]. (See "Pathophysiology of irritable bowel syndrome", section on 'Alteration in fecal microflora'.)
Colon — The largest concentrations of anaerobic bacteria are found in the relatively stagnant terminal ileum and colon, where concentrations reach 1011 per gram, and anaerobic bacteria account for approximately 99.9 percent of the cultivable flora [28,29]. The most important and frequent anaerobic bacteria are Bacteroides spp (principally members of the B. fragilis group), Prevotella spp, Clostridium spp, and Peptostreptococcus spp. Use of 16S rRNA gene sequencing that detects bacteria shows substantial individual variation that appears strongly influenced by diet and medications with less impact by host genetic make-up [18,33-35]. The totality is referred to as "the gut microbiome", although additional genomic approaches are needed to detect viruses, fungi, and parasites. Studies in animals suggest a possible role for this microbiome in important conditions, such as obesity, diabetes, and the metabolic syndrome [36]. (See 'The microbiome' below.)
The colon flora becomes established after weaning and is thought to remain relatively stable throughout life (assuming a stable diet and other environmental influences) unless it is disrupted by antibiotic treatment. Its role in maintaining health is believed to be in establishing ecologic balance by preventing colonization with exogenous organisms.
This protection, known as "colonization resistance," is compromised with antibiotic treatment, which enhances the potential for infection with enteric pathogens and colonization by resistant bacteria, such as vancomycin-resistant enterococci, and resistant gram-negative bacilli. These bacteria cause many nosocomial infections, including serious infections in patients with neutropenia or critical illness. (See "Overview of neutropenic fever syndromes" and "Infections and antimicrobial resistance in the intensive care unit: Epidemiology and prevention".)
A logical extension of this thesis is "selective modulation of the fecal flora" by use of antibiotics that are directed against aerobic gram-negative bacilli but preserve the anaerobic component of the flora in an effort to prevent colonization by resistant strains [37]. The goal is to prevent nosocomial pneumonia, bacteremia, and other serious infections in patients who are critically ill. The majority of data comes from studies of selective decontamination of the colonic flora to prevent nosocomial or ventilator-associated pneumonia. These studies generally show a highly significant reduction in rates of nosocomial pneumonia but no reduction in mortality rates. (See "Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Decontamination of the oropharynx and digestive tract'.)
Another important role of colonic bacteria is defense against two forms of antibiotic-associated diarrhea; the most familiar form is Clostridioides difficile-associated diarrhea or colitis, which is a toxin-mediated, potentially life-threatening disease that presumably results when C. difficile spores in the colon transform to vegetative forms with toxin production due to antibiotic elimination of critical components of the competing colonic flora [38]. The second form of antibiotic-associated diarrhea appears to be due to elimination of colonic anaerobes, which are critical for metabolizing carbohydrates to produce short-chain fatty acids that are absorbed in the colon; with elimination of critical anaerobes (especially Clostridia species, Bacteroides, and Bifidobacteria), the colon cannot handle the carbohydrates, and the result is an osmotic diarrhea that promptly resolves when antibiotics are stopped [39].
Genital tract — The flora of the female genital tract is less stable than that of the gastrointestinal tract. Concentrations of bacteria in the vagina or cervix average approximately 108 per mL during reproductive years [40-42], but there is considerable variation (105 to 1011 per mL) in studies that may be related to technique or to real differences. Simultaneous cultures of material from the cervix and vagina show unique bacteriologic patterns, and sequential cultures show considerable shifts at various stages of the menstrual cycle that may be hormonally influenced [40-43]. Approximately 50 percent are anaerobic bacteria, but this can vary. In fact, approximately 20 percent of women have no detectable anaerobes or at least low concentrations.
The dominant organisms are aerobic, microaerobic, and anaerobic lactobacilli; the most common anaerobes are Lactobacillus, Peptostreptococcus, and Bacteroides spp, including Prevotella bivia (formerly Bacteroides bivius). B. fragilis is found in only 2 to 10 percent [44]. Factors that appear to influence the bacteriologic findings in the genital tract include [44-48]:
●Menarche
●Menopause
●Pregnancy
●Antibiotic therapy
●Gynecologic surgery
The role of the genital tract flora in maintaining homeostasis is not well studied, although antibiotic treatment clearly predisposes to vaginal candidiasis. Bacterial vaginosis (BV) appears to reflect dysbiosis of the genital tract flora [41,49]:
●Concentrations of lactobacilli, which presumably maintain homeostasis, are notably reduced.
●The dominant organisms are anaerobic bacteria as indicated by Gram stain and culture.
●Vaginal effluent contains a predominance of the short-chain volatile fatty acids produced by anaerobes.
Current therapeutic recommendations for BV are restricted to drugs directed against anaerobes (metronidazole and clindamycin). (See "Bacterial vaginosis: Clinical manifestations and diagnosis".)
Skin — The skin flora contains large numbers of anaerobic bacteria. The predominant organisms are Cutibacterium (formerly Propionibacterium) acnes and, to a lesser extent, other species of Cutibacterium and Peptostreptococcus [49].
THE MICROBIOME — There have been relatively few new developments in clinical and laboratory studies of anaerobic bacteria with important clinical application in recent years. However, the closely related studies of the microbiome have evolved with extraordinary potential to inform medicine in novel ways. This field of study is relatively young but is moving rapidly based on a multicenter analysis using molecular methods (16S ribosomal analyses) to define the unique microbiomes at 15 different anatomical sites in 300 people [50]. Metagenomics ("shotgun" sequencing), RNA sequencing, proteomics, and evolving computational tools are further expanding our knowledge of the microbiome beyond its bacterial members. Some of this work defies standard teaching. For example, it was commonly taught that the respiratory tract in health is sterile from the larynx down, but some research indicates a microbial continuum from the nares to alveoli [51].
The dominant bacteria in most sites are obligate anaerobes, but their role in health and disease requires a somewhat different approach than the traditional methods of the infectious disease model based on Koch's postulates. It appears that these bacteria communicate in ways that are poorly understood and may have important effects in many conditions not traditionally considered infectious diseases. These include cardiovascular disease, diabetes, psychiatric and neurologic diseases, asthma, obesity, the metabolic syndrome, cancers, inflammatory bowel disease, and even therapeutic responses to medications and vaccines [52-60]. The ultimate goal is to be able to use this information to improve health, as with antibiotics and probiotics. Most of the bacteria detected as part of these studies to date have names that few recognize. This work is in the early stage of development. Nevertheless, the early studies have defined consequences of antibiotic abuse [61], and there is evidence that specific gut bacteria-derived metabolites may impact cardiovascular disease outcomes in humans [62]. Thus, the studies of the normal flora, anaerobes, and synergy may ultimately provide new opportunities to understand pathophysiology and to prevent and treat disease. The only practical application of these data with established merit is the use of fecal microbiota transplantation (FMT) for treatment of recurrent C. difficile colitis. FMT is under evaluation for other conditions, such as inflammatory bowel disease, irritable bowel syndrome, eradication of resistant bacteria, and impact on cancer therapeutics, especially immunotherapy [63]. Of note, there remains concern for negative effects of the transplanted microbiome such as obesity, diabetes, and metabolic syndrome [64]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Trimethylamine-N-oxide' and "Probiotics for gastrointestinal diseases", section on 'Irritable bowel syndrome' and "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)
SUMMARY
●Anaerobic bacteria are the predominant forms of life in the human body. While the role of these microbes as pathogens was well established at the turn of the 20th century, they are often neglected in part due to the fact that few clinical laboratories reliably detect them. (See 'Introduction' above.)
●During the past several decades, there has been renewed interest in anaerobic infections, based upon verification of their role as pathogens by recovery from infected sites, efficacy of antibiotic treatment, and elucidation of virulence factors. We now appear to be in an era where therapy is frequently directed at anaerobes based upon an assumption that the organisms are there and that specific antibiotics are effective. (See 'Introduction' above.)
●Anaerobic bacteria are defined as bacteria that grow in the absence of oxygen and fail to show surface growth in 10 percent carbon dioxide in air. They may be further classified by relative aerotolerance: strict anaerobes cannot tolerate 0.5 percent oxygen; most clinically important anaerobes (Bacteroides fragilis, Prevotella melaninogenica [formerly classified as Bacteroides melaninogenicus], and Fusobacterium nucleatum) are moderate anaerobes that tolerate 2 to 8 percent oxygen. (See 'Definition of anaerobes' above.)
●There is concern that some anaerobic infections are not being detected due in part to a decline in the appropriate testing in microbiology laboratories, reflecting economic realities, outsourcing, and reliance on empiric antibiotics. In addition, the incidence of anaerobic infections appears to be rising, which is likely the result of an increase in the number of patients with complex underlying illnesses. (See 'Current status' above.)
●Most mucocutaneous surfaces of humans harbor a rich indigenous flora composed of aerobic and anaerobic bacteria, the microbial species and concentrations of which vary at different anatomic sites (table 1). Anaerobic bacteria are the dominant forms, often accounting for 99 to 99.9 percent of the culturable flora. (See 'Normal flora' above.)
●The upper airways, including the oral cavity, nasal passages, oropharynx, and nasopharynx, harbor a complex flora that differs at various sites despite anatomic continuity. The most important potential anaerobic pathogens found in the upper airways are F. nucleatum, P. melaninogenica, the Prevotella oralis group, the Bacteroides ureolyticus group, and Peptostreptococcus spp, which represent the predominant organisms in anaerobic oral and pleuropulmonary infections. (See 'Upper airways' above.)
●The gastrointestinal tract shows marked variations in bacteriologic patterns in concentrations at different levels. The stomach is protected by the gastric acid barrier and consequently harbors relatively small numbers of bacteria derived from swallowed salivary bacteria that are predominately gram positive. (See 'Normal flora' above and 'Stomach' above.)
●The small bowel is the site of rapid motility, so the organisms commonly found are simply passing through. Interruption of this flow, as with a stagnant segment (stricture, obstruction, diverticulum, blind loop), results in colonic concentrations of bacteria with a predominance of anaerobes. (See 'Small intestine' above.)
●The largest concentrations of anaerobic bacteria are found in the relatively stagnant terminal ileum and colon, where concentrations reach 1011 per gram, and anaerobic bacteria account for approximately 99.9 percent of culturable flora. The most important and frequent anaerobic bacteria are Bacteroides spp (principally members of the B. fragilis group), Prevotella spp, Clostridium spp, and Peptostreptococcus spp. (See 'Colon' above.)
●The dominant organisms in the female genital tract are aerobic, microaerobic, and anaerobic lactobacilli; the most common anaerobes are Lactobacillus, Peptostreptococcus, and Bacteroides spp, including Prevotella bivia (formerly Bacteroides bivius). (See 'Genital tract' above.)
●The skin flora contains large numbers of anaerobic bacteria. The predominant organisms are Cutibacterium (formerly Propionibacterium) acnes and, to a lesser extent, other species of Cutibacterium and Peptostreptococcus. (See 'Skin' above.)
●There have been relatively few new developments in clinical and laboratory studies of anaerobic bacteria with important clinical application in recent years. However, the closely related studies of the microbiome have evolved with extraordinary potential to inform medicine in novel ways. The only practical application of these data with established merit to date is the use of fecal microbiota transplantation for treatment of recurrent Clostridioides difficile colitis. (See 'The microbiome' above and "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John G Bartlett, MD, who contributed to an earlier version of this topic review.
