mucous membranes of healthy normal persons. It is doubtful whether a normal viral ora exists in humans. The skin and mucous membranes always harbor a variety of microorganisms that can be arranged into two groups: (1) The resident ora consists of relatively xed types of microorganisms regularly found in a given area at a given age; if disturbed, it promptly reestablishes itself. (2) The transient ora consists of nonpathogenic or potentially pathogenic microorganisms that inhabit the skin or mucous membranes for hours, days, or weeks; it is derived from the environment, does not pro- duce disease, and does not establish itself permanently on the surface. Members of the transient ora are gener- ally of little signicance so long as the normal resident ora remains intact. However, if the resident ora is dis- turbed, transient microorganisms may colonize, prolif- erate, and produce disease. Organisms frequently encountered in specimens obtained from various areas of the human bodyand considered normal oraare listed in Table 111. The classication of anaerobic normal bacterial ora is dis- cussed in Chapter 22. ROLE OF THE RESIDENT FLORA The microorganisms that are constantly present on body surfaces are commensals. Their flourishing in a given area depends upon physiologic factors of tempera- ture, moisture, and the presence of certain nutrients and inhibitory substances. Their presence is not essential to life, because germ-free animals can be reared in the complete absence of a normal microbial flora. Yet the resident flora of certain areas plays a definite role in maintaining health and normal function. Members of the resident ora in the intestinal tract synthesize vita- min K and aid in the absorption of nutrients. On mucous membranes and skin, the resident flora may prevent colonization by pathogens and possible disease through bacterial interference. The mechanism of bacterial interference is not clear. It may involve compe- tition for receptors or binding sites on host cells, compe- tition for nutrients, mutual inhibition by metabolic or toxic products, mutual inhibition by antibiotic materi- als or bacteriocins, or other mechanisms. Suppression of the normal ora clearly creates a partial local void that tends to be lled by organisms from the environment or from other parts of the body. Such organisms behave as opportunists and may become pathogens. On the other hand, members of the normal flora may themselves produce disease under certain circum- stances. These organisms are adapted to the noninvasive mode of life dened by the limitations of the environ- ment. If forcefully removed from the restrictions of that environment and introduced into the bloodstream or tissues, these organisms may become pathogenic. For example, streptococci of the viridans group are the most common resident organisms of the upper respiratory tract. If large numbers of them are introduced into the bloodstream (eg, following tooth extraction or tonsillec- tomy), they may settle on deformed or prosthetic heart valves and produce infective endocarditis. Small num- bers occur transiently in the bloodstream with minor trauma (eg, dental scaling or vigorous brushing). Bac- teroides species are the commonest resident bacteria of the large intestine and are quite harmless in that loca- tion. If introduced into the free peritoneal cavity or into pelvic tissues along with other bacteria as a result of trauma, they cause suppuration and bacteremia. There are many other examples, but the important point is that microbes of the normal resident ora are harmless and may be beneficial in their normal location in the host and in the absence of coincident abnormalities. They may produce disease if introduced into foreign locations in large numbers and if predisposing factors are present. NORMAL FLORA OF THE SKIN Because of its constant exposure to and contact with the environment, the skin is particularly apt to contain tran- sient microorganisms. Nevertheless, there is a constant and well-defined resident flora, modified in different 196 Normal Microbial Flora of the Human Body 11 4010_1-16 2/11/04 9:27 AM Page 196 anatomic areas by secretions, habitual wearing of cloth- ing, or proximity to mucous membranes (mouth, nose, and perineal areas). The predominant resident microorganisms of the skin are aerobic and anaerobic diphtheroid bacilli (eg, corynebacterium, propionibacterium); nonhemolytic aerobic and anaerobic staphylococci (Staphylococcus epi- dermidis, occasionally S aureus, and peptostreptococcus species); gram-positive, aerobic, spore-forming bacilli that are ubiquitous in air, water, and soil; alpha- hemolytic streptococci (viridans streptococci) and ente- rococci (enterococcus species); and gram-negative col- iform bacilli and acinetobacter. Fungi and yeasts are often present in skin folds; acid-fast, nonpathogenic mycobacteria occur in areas rich in sebaceous secretions (genitalia, external ear). Among the factors that may be important in elimi- nating nonresident microorganisms from the skin are the low pH, the fatty acids in sebaceous secretions, and the presence of lysozyme. Neither profuse sweating nor washing and bathing can eliminate or signicantly mod- ify the normal resident ora. The number of supercial microorganisms may be diminished by vigorous daily scrubbing with soap containing hexachlorophene or other disinfectants, but the ora is rapidly replenished from sebaceous and sweat glands even when contact with other skin areas or with the environment is com- pletely excluded. Placement of an occlusive dressing on skin tends to result in a large increase in the total micro- bial population and may also produce qualitative alter- ations in the ora. Anaerobes and aerobic bacteria often join to form synergistic infections (gangrene, necrotizing fasciitis, cellulitis) of skin and soft tissues. The bacteria are fre- quently part of the normal microbial ora. It is usually difficult to pinpoint one specific organism as being responsible for the progressive lesion, since mixtures of organisms are usually involved. NORMAL FLORA OF THE MOUTH &UPPER RESPIRATORY TRACT The ora of the nose consists of prominent corynebacte- ria, staphylococci (S epidermidis, S aureus), and strepto- cocci. The mucous membranes of the mouth and pharynx are often sterile at birth but may be contaminated by passage through the birth canal. Within 412 hours after birth, viridans streptococci become established as the most prominent members of the resident ora and remain so for life. They probably originate in the respi- ratory tracts of the mother and attendants. Early in life, aerobic and anaerobic staphylococci, gram-negative diplococci (neisseriae, Moraxella catarrhalis), diph- theroids, and occasional lactobacilli are added. When teeth begin to erupt, the anaerobic spirochetes, pre- votella species (especially P melaninogenica), fusobac- terium species, rothia species, and capnocytophaga species (see below) establish themselves, along with some anaerobic vibrios and lactobacilli. Actinomyces species are normally present in tonsillar tissue and on the gingivae in adults, and various protozoa may also be present. Yeasts (candida species) occur in the mouth. In the pharynx and trachea, a similar ora establishes itself, whereas few bacteria are found in normal bronchi. Small bronchi and alveoli are normally sterile. The pre- dominant organisms in the upper respiratory tract, par- Table 111. Normal bacterial ora. Skin Staphylococcus epidermidis Staphylococcus aureus (in small numbers) Micrococcus species Nonpathogenic neisseria species Alpha-hemolytic and nonhemolytic streptococci Diphtheroids Propionibacteriumspecies Peptostreptococcus species Small numbers of other organisms (candida species, acine- tobacter species, etc) Nasopharynx Any amount of the following: diphtheroids, non- pathogenic neisseria species, -hemolytic streptococci; S epidermidis, nonhemolytic streptococci, anaerobes (too many species to list; varying amounts of prevotella species, anaerobic cocci, fusobacterium species, etc) Lesser amounts of the following when accompanied by organisms listed above: yeasts, haemophilus species, pneumococci, S aureus, gram-negative rods, Neisseria meningitidis Gastrointestinal tract and rectum Various Enterobacteriaceae except salmonella, shigella, yersinia, vibrio, and campylobacter species Non-dextrose-fermenting gram-negative rods Enterococci Alpha-hemolytic and nonhemolytic streptococci Diphtheroids S aureus in small numbers Yeasts in small numbers Anaerobes in large numbers (too many species to list) Genitalia Any amount of the following: corynebacterium species, lactobacillus species, -hemolytic and nonhemolytic streptococci, nonpathogenic neisseria species The following when mixed and not predominant: entero- cocci, Enterobacteriaceae and other gram-negative rods, S epidermidis, Candida albicans, and other yeasts Anaerobes (too many to list); the following may be impor- tant when in pure growth or clearly predominant: pre- votella, clostridium, and peptostreptococcus species NORMAL MICROBIAL FLORA OF THE HUMAN BODY / 197 4010_1-16 2/11/04 9:27 AM Page 197 ticularly the pharynx, are nonhemolytic and alpha- hemolytic streptococci and neisseriae. Staphylococci, diphtheroids, haemophili, pneumococci, mycoplasmas, and prevotellae are also encountered. Infections of the mouth and respiratory tract are usu- ally caused by mixed oronasal flora, including anaer- obes. Periodontal infections, perioral abscesses, sinusitis, and mastoiditis may involve predominantly Prevotella melaninogenica, fusobacteria, and peptostreptococci. Aspiration of saliva (containing up to 10 2 of these organisms and aerobes) may result in necrotizing pneu- monia, lung abscess, and empyema. The Role of the Normal Mouth Flora in Dental Caries Caries is a disintegration of the teeth beginning at the surface and progressing inward. First the surface enamel, which is entirely noncellular, is demineralized. This has been attributed to the effect of acid products of bacterial fermentation. Subsequent decomposition of the dentin and cement involves bacterial digestion of the protein matrix. An essential rst step in caries production appears to be the formation of plaque on the hard, smooth enamel surface. The plaque consists mainly of gelatinous deposits of high-molecular-weight glucans in which acid-producing bacteria adhere to the enamel. The car- bohydrate polymers (glucans) are produced mainly by streptococci (Streptococcus mutans, peptostreptococci), perhaps in association with actinomycetes. There appears to be a strong correlation between the presence of S mutans and caries on specific enamel areas. The essential second step in caries production appears to be the formation of large amounts of acid (pH < 5.0) from carbohydrates by streptococci and lactobacilli in the plaque. High concentrations of acid demineralize the adjoining enamel and initiate caries. In experimental germ-free animals, cariogenic streptococci can induce the formation of plaque and caries. Adherence to smooth surfaces requires both the synthesis of water-insoluble glucan polymers by glucosyl- transferases and the participation of binding sites on the surface of microbial cells. (Perhaps carbohydrate poly- mers also aid the attachment of some streptococci to endocardial surfaces.) Other members of the oral microora, eg, veillonellae, may complex with glucosyl- transferase of Streptococcus salivarius in saliva and then synthesize water-insoluble carbohydrate polymers to adhere to tooth surfaces. Adherence may be initiated by salivary IgA antibody to S mutans. Certain diphtheroids and streptococci that produce levans can induce specic soft tissue damage and bone resorption typical of peri- odontal disease. Proteolytic organisms, including actino- mycetes and bacilli, play a role in the microbial action on dentin that follows damage to the enamel. The develop- ment of caries also depends on genetic, hormonal, nutri- tional, and many other factors. Control of caries involves physical removal of plaque, limitation of sucrose intake, good nutrition with adequate protein intake, and reduc- tion of acid production in the mouth by limitation of available carbohydrates and frequent cleansing. The application of uoride to teeth or its ingestion in water results in enhancement of acid resistance of the enamel. Control of periodontal disease requires removal of calcu- lus (calcied deposit) and good mouth hygiene. Periodontal pockets in the gingiva are particularly rich sources of organisms, including anaerobes, that are rarely encountered elsewhere. While they may participate in periodontal disease and tissue destruction, attention is drawn to them when they are implanted elsewhere, eg, producing infective endocarditis or bacteremia in a gran- ulopenic host. Examples are capnocytophaga species and Rothia dentocariosa. Capnocytophaga species are fusiform, gram-negative, gliding anaerobes; rothia species are pleomorphic, aerobic, gram-positive rods. Both prob- ably participate in the complex microbial ora of peri- odontal disease with prominent bone destruction. In granulopenic immunodecient patients, they can lead to serious opportunistic lesions in other organs. NORMAL FLORA OF THE INTESTINAL TRACT At birth the intestine is sterile, but organisms are soon introduced with food. In breast-fed children, the intes- tine contains large numbers of lactic acid streptococci and lactobacilli. These aerobic and anaerobic, gram- positive, nonmotile organisms (eg, bifidobacterium species) produce acid from carbohydrates and tolerate pH 5.0. In bottle-fed children, a more mixed ora exists in the bowel, and lactobacilli are less prominent. As food habits develop toward the adult pattern, the bowel ora changes. Diet has a marked inuence on the rela- tive composition of the intestinal and fecal ora. Bowels of newborns in intensive care nurseries tend to be colo- nized by Enterobacteriaceae, eg, klebsiella, citrobacter, and enterobacter. In the normal adult, the esophagus contains microor- ganisms arriving with saliva and food. The stomachs acidity keeps the number of microorganisms at a mini- mum (10 3 10 5 /g of contents) unless obstruction at the pylorus favors the proliferation of gram-positive cocci and bacilli. The normal acid pH of the stomach markedly protects against infection with some enteric pathogens, eg, cholera. Administration of cimetidine for peptic ulcer leads to a great increase in microbial ora of the stomach, including many organisms usually preva- lent in feces. As the pH of intestinal contents becomes alkaline, the resident flora gradually increases. In the 198 / CHAPTER 11 4010_1-16 2/11/04 9:27 AM Page 198 adult duodenum, there are 10 3 10 6 bacteria per gram of contents; in the jejunum and ileum, 10 5 10 8 bacteria per gram; and in the cecum and transverse colon, 10 8 10 10 bacteria per gram. In the upper intestine, lac- tobacilli and enterococci predominate, but in the lower ileum and cecum, the ora is fecal. In the sigmoid colon and rectum, there are about 10 11 bacteria per gram of contents, constituting 1030% of the fecal mass. Anaer- obes outnumber facultative organisms by 1000-fold. In diarrhea, the bacterial content may diminish greatly, whereas in intestinal stasis the count rises. In the normal adult colon, 9699% of the resident bacterial ora consists of anaerobes: bacteroides species, especially B fragilis; fusobacterium species; anaerobic lac- tobacilli, eg, bifidobacteria; clostridia (C perfringens, 10 3 10 5 /g); and anaerobic gram-positive cocci (pep- tostreptococcus species). Only 14% are facultative aer- obes (gram-negative coliform bacteria, enterococci, and small numbers of protei, pseudomonads, lactobacilli, candidae, and other organisms). More than 100 distinct types of organisms occur regularly in normal fecal ora. Minor trauma (eg, sigmoidoscopy, barium enema) may induce transient bacteremia in about 10% of procedures. Intestinal bacteria are important in synthesis of vita- min K, conversion of bile pigments and bile acids, absorption of nutrients and breakdown products, and antagonism to microbial pathogens. The intestinal ora produces ammonia and other breakdown products that are absorbed and can contribute to hepatic coma. Among aerobic coliform bacteria, only a few serotypes persist in the colon for prolonged periods, and most serotypes of Escherichia coli are present only over a period of a few days. Antimicrobial drugs taken orally can, in humans, tem- porarily suppress the drug-susceptible components of the fecal ora. This is commonly done by the preoperative oral administration of insoluble drugs. For example, neomycin plus erythromycin can in 12 days suppress part of the bowel ora, especially aerobes. Metronidazole accomplishes that for anaerobes. If lower bowel surgery is performed when the counts are at their lowest, some pro- tection against infection by accidental spill can be achieved. However, soon thereafter the counts of fecal ora rise again to normal or higher than normal levels, principally of organisms selected out because of relative resistance to the drugs employed. The drug-susceptible microorganisms are replaced by drug-resistant ones, par- ticularly staphylococci, enterobacters, enterococci, protei, pseudomonads, Clostridium difcile, and yeasts. The feeding of large quantities of Lactobacillus aci- dophilus may result in the temporary establishment of this organism in the gut and the concomitant partial suppression of other gut microora. The anaerobic ora of the colon, including B fragilis, clostridia, and peptostreptococci, plays a main role in abscess formation originating in perforation of the bowel. Prevotella bivia and P disiens are important in abscesses of the pelvis originating in the female genital organs. Like B fragilis, these species are penicillin-resis- tant; therefore, another agent should be used. NORMAL FLORA OF THE URETHRA The anterior urethra of both sexes contains small num- bers of the same types of organisms found on the skin and perineum. These organisms regularly appear in nor- mal voided urine in numbers of 10 2 10 4 /mL. NORMAL FLORA OF THE VAGINA Soon after birth, aerobic lactobacilli appear in the vagina and persist as long as the pH remains acid (sev- eral weeks). When the pH becomes neutral (remaining so until puberty), a mixed flora of cocci and bacilli is present. At puberty, aerobic and anaerobic lactobacilli reappear in large numbers and contribute to the mainte- nance of acid pH through the production of acid from carbohydrates, particularly glycogen. This appears to be an important mechanism in preventing the establish- ment of other, possibly harmful microorganisms in the vagina. If lactobacilli are suppressed by the administra- tion of antimicrobial drugs, yeasts or various bacteria increase in numbers and cause irritation and inamma- tion. After menopause, lactobacilli again diminish in number and a mixed ora returns. The normal vaginal ora includes group B streptococci in as many as 25% of women of childbearing age. During the birth process, a baby can acquire group B streptococci, which subse- quently may cause neonatal sepsis and meningitis. The normal vaginal ora often includes also alpha hemolytic streptococci, anaerobic streptococci (peptostreptococci), prevotella species, clostridia, Gardnerella vaginalis, Ure- aplasma urealyticum, and sometimes listeria or mobilun- cus species. The cervical mucus has antibacterial activity and contains lysozyme. In some women, the vaginal introitus contains a heavy flora resembling that of the perineum and perianal area. This may be a predisposing factor in recurrent urinary tract infections. Vaginal organisms present at time of delivery may infect the newborn (eg, group B streptococci). NORMAL FLORA OF THE CONJUNCTIVA The predominant organisms of the conjunctiva are diphtheroids (Corynebacterium xerosis), S epidermidis, and nonhemolytic streptococci. Neisseriae and gram- negative bacilli resembling haemophili (moraxella species) are also frequently present. The conjunctival flora is normally held in check by the flow of tears, which contain antibacterial lysozyme. NORMAL MICROBIAL FLORA OF THE HUMAN BODY / 199 4010_1-16 2/11/04 9:27 AM Page 199 REVIEW QUESTIONS 1. A 26-year-old woman visits her physician because of an unusual vaginal discharge. On examination the physician observes a thin, homogeneous, white-gray discharge that adheres to the vaginal wall. The pH of the dis- charge is 5.5 (normal: < 4.3). On Gram stain, many epithelial cells covered with gram-vari- able rods are seen. Bacterial vaginosis is diag- nosed. Which one of the following normal geni- tal flora microorganisms is present in greatly decreased numbers in bacterial vaginosis? (A) Corynebacteriumspecies (B) Staphylococcus epidermidis (C) Prevotella species (D) Candida albicans (E) Lactobacillus species 2. Certain microorganisms are never considered to be members of the normal ora. They are always considered to be pathogens. Which one of the following organisms ts into that category? (A) Streptococcus pneumoniae (B) Escherichia coli (C) Mycobacterium tuberculosis (D) Staphylococcus aureus (E) Neisseria meningitidis 3. A 9-year-old girl develops fever and severe pain on the right side of her throat. On examination, redness and swelling in the right peritonsillar area are seen. A peritonsillar abscess is diag- nosed. The most likely organisms to be cultured from this abscess are (A) Staphylococcus aureus (B) Streptococcus pneumoniae (C) Corynebacterium species and Prevotella melaninogenica (D) Normal oral nasal ora (E) Viridans streptococci and Candida albicans 4. A 70-year-old man with a history of diverticulosis of the sigmoid colon experiences a sudden onset of severe left lower quadrant abdominal pain. Fever develops. The severe pain gradually sub- sides and is replaced by a constant aching pain and marked abdominal tenderness. A diagnosis of probable ruptured diverticulum is made and the patient is taken to the operating room. The diag- nosis of ruptured diverticulum is conrmed and an abscess next to the sigmoid colon is found. The most likely bacteria to be found in the abscess are (A) Mixed normal gastrointestinal ora (B) Bacteroides fragilis alone (C) Escherichia coli alone (D) Clostridium perfringens alone (E) Enterococcus species alone 5. Antimicrobial therapy can decrease the amount of susceptible bowel flora and allow prolifera- tion of relatively resistant colonic bacteria. Which one of the following species can prolifer- ate and produce a toxin that causes diarrhea? (A) Enterococcus species (B) Staphylococcus epidermidis (C) Pseudomonas aeruginosa (D) Clostridium difcile (E) Bacteroides fragilis 6. Which one of the following microorganisms can be part of the normal vaginal flora and cause meningitis in newborns? (A) Candida albicans (B) Corynebacteriumspecies (C) Staphylococcus epidermidis (D) Ureaplasma urealyticum (E) Group B streptococci 7. Most serotypes of Escherichia coli can be expected to remain in the colon for what period of time? (A) A few days (B) A few weeks (C) 6 months (D) 2 years (E) A lifetime 8. Which one of the following microorganisms is closely associated with dental caries? (A) Candida albicans (B) Streptococcus mutans (C) Prevotella melaninogenica (D) Neisseria subava (E) Staphylococcus epidermidis 9. Anaerobic bacteria such as Bacteroides fragilis occur in the sigmoid colon in a concentration of about 10 11 /g of stool. At what concentration do faculta- tive organisms such as Escherichia coli occur? (A) 10 11 /g (B) 10 10 /g (C) 10 9 /g (D) 10 8 /g (E) 10 7 /g 10. Streptococcus pneumoniae can be part of the normal flora of 540% of people. At what anatomic site can it be found? (A) Conjunctiva (B) Nasopharynx (C) Colon (D) Urethra (E) Vagina (continued) 200 / CHAPTER 11 4010_1-16 2/11/04 9:27 AM Page 200 Answers 1. E 6. E 2. C 7. A 3. D 8. D 4. A 9. B 5. D 10. D REFERENCES Hentges DJ: The anaerobic microflora of the human body. Clin Infect Dis 1993;16(Suppl 4):S175. Macowiak PA: The normal microbial flora. N Engl J Med 1982;307:83. The pathogenesis of periodontal diseases. J Periodontol 1999;70:457. Redondo-Lopez V, Cook RL, Sobel JD: Emerging role of lacto- bacilli in the control and maintenance of the vaginal bacterial microora. Rev Infect Dis 1984;6(Suppl 1):S62. NORMAL MICROBIAL FLORA OF THE HUMAN BODY / 201 4010_1-16 2/11/04 9:27 AM Page 201