Chapter 25: Streptococci and Enterococci

Bacteria of the genus Streptococcus are gram-positive cocci typically arranged in chains. The genus includes three of the most important pathogens of humans. The group A streptococcus (S pyogenes) is the cause of “strep throat,” which can lead to scarlet fever, rheumatic fever, and rheumatic heart disease; the ability of some hypervirulent strains to cause catastrophic deep tissue infections led British tabloids to apply the gory label “flesh-eating bacteria.” The group B streptococcus (S agalactiae) is an important but preventable cause of sepsis in newborns and the pneumococcus (S pneumoniae) a leading cause of both pneumonia and meningitis in persons of all ages. Although usually harmless members of the oropharyngeal flora, some viridans group streptococci can cause pyogenic infections and others subacute bacterial endocarditis. Similarly, the normally gut dwelling enterococci are an increasingly problematic cause of health-care associated infections.

Group Characteristics

Streptococci stain readily with common dyes, demonstrating that coccal cells are generally smaller and more ovoid in shape than staphylococci. They are usually arranged in chains with oval cells touching end to end, because they divide in one plane and tend to remain attached (Figure 25–1). Length may vary from a single pair to continuous chains of over 30 cells, depending on the species and growth conditions. Medically important streptococci are not acid-fast, do not form spores, and are nonmotile. Some members form capsules composed of polysaccharide complexes or hyaluronic acid.

Streptococci grow best in enriched media under aerobic or anaerobic conditions (facultative). Sheep blood agar is preferred because it satisfies the growth requirements and also serves as an indicator for patterns of hemolysis. The colonies are small, ranging from pinpoint size to 2 mm in diameter, and they may be surrounded by a zone where the erythrocytes suspended in agar have been hemolyzed. When the zone is clear, this state is called β-hemolysis (Figure 25–2). When the zone is hazy with a green discoloration of the agar, it is called α-hemolysis. Streptococci are metabolically active, attacking a variety of carbohydrates, proteins, and amino acids. Glucose fermentation yields mostly lactic acid. In contrast to staphylococci, streptococci are catalase negative.

CLASSIFICATION

At the turn of the 20th century, a classification based on hemolysis and biochemical tests was sufficient to associate some streptococcal species with infections in humans and animals. Rebecca Lancefield, who demonstrated carbohydrate antigens in cell wall extracts of the β-hemolytic streptococci, put this taxonomy on a sounder basis. Her studies formed a classification by serogroups (eg, A, B, C), each of which is generally correlated with one of the previously established species. Later it was discovered that some nonhemolytic streptococci had the same cell wall antigens. Over the years it has become clear that possession of one of the Lancefield antigens defines a particularly virulent segment of the streptococcal genus regardless of hemolytic patterns. These are called the pyogenic streptococci, and in medical circles they are now better known by their Lancefield letter than the older species name. Pediatricians instantly recognize GBS as an acronym for group B streptococcus, but may be confused by use of the proper name, Streptococcus agalactiae (Table 25–1).

For practical purposes, the type of hemolysis and certain biochemical reactions remain valuable for the initial recognition and presumptive classification of streptococci, and as an indication of what subsequent taxonomic tests to perform. Thus, β-hemolysis indicates that the strain has one of the Lancefield group antigens, but some Lancefield-positive strains or groups may be α-hemolytic or even nonhemolytic. The streptococci are considered here as follows: (1) pyogenic streptococci (Lancefield groups); (2) pneumococci; and (3) viridans and other streptococci (Table 25–1).

Pyogenic Streptococci

Of the many Lancefield groups, the ones most frequently isolated from humans are A, B, C, F, and G. Of these, groups A (S pyogenes) and B (S agalactiae) are the most common causes of serious disease. The group D carbohydrate is found in the genus Enterococcus, which used to be classified among the streptococci.

Pneumococci

This category contains a single species, S pneumoniae, commonly called the pneumococcus. Its distinctive feature is the presence of a capsule composed of polysaccharide polymers that vary in antigenic specificity. More than 90 capsular immunotypes have been defined. Although the pneumococcal cell wall shares some common antigens with other streptococci, it does not possess any of the Lancefield group antigens. Streptococcus pneumoniae is α-hemolytic.

Viridans and Other Streptococci

Viridans streptococci are α-hemolytic and lack both the group carbohydrate antigens of the pyogenic streptococci and the capsular polysaccharides of the pneumococcus. The term encompasses several species, including S salivarius and S mitis. Viridans streptococci are members of the resident oral microbiota of humans. They rarely demonstrate invasive qualities. A variety of other streptococci may be encountered, which lack the features of the pyogenic streptococci or pneumococci; these would be classified with the viridans group, except that they are not α-hemolytic. Such strains are usually assigned descriptive terms such as nonhemolytic streptococci or microaerophilic streptococci. They have been less thoroughly studied, but generally have the same biologic behavior as the viridans streptococci.

Group A Streptococci (Streptococcus Pyogenes)

BACTERIOLOGY

MORPHOLOGY AND GROWTH

Group A streptococci (GAS) typically appear in purulent lesions or broth cultures as spherical or ovoid cells in chains of short to medium length (4-10 cells). On blood agar plates, colonies are usually compact, small, and surrounded by a 2 to 3 mm zone of β-hemolysis (Figure 25–2), which is easily seen and sharply demarcated. β-Hemolysis is caused by either of two hemolysins, streptolysin S and the oxygen-labile streptolysin O, both of which are produced by most group A strains. Strains that lack streptolysin S are β-hemolytic only under anaerobic conditions, because the remaining streptolysin O is not active in the presence of oxygen. This feature is of practical importance, because such strains would be missed in clinical laboratories if cultures were incubated only aerobically.

STRUCTURE

The structure of GAS is illustrated in Figure 25–3. The cell wall is built on a peptidoglycan matrix that provides rigidity, as in other gram-positive bacteria. Within this matrix lies the group carbohydrate antigen, which by definition is present in all GAS. A number of other molecules such as M protein and lipoteichoic acid (LTA) are attached to the cell wall, but extend beyond, often in association with, the hair-like pili. Group A streptococci are divided into more than 100 serotypes based on antigenic differences in the M protein.

M Protein

The M protein itself is a fibrillar coiled-coil molecule (Figure 25–4) with structural homology to myosin. Its carboxy terminus is rooted in the peptidoglycan of the cell wall, and the amino-terminal regions extend out from the surface. The specificity of the multiple serotypes of M protein is determined by variations in the amino acid sequences at the amino-terminal portion of the molecule. Because of its exposed location, this part of the M protein is also the most available to immune surveillance. The middle part of the molecule is less variable, and some carboxy-terminal regions are conserved across many M types. There is increasing evidence that some of the many known biologic functions of M protein can be assigned to specific domains of the molecule. This includes both antigenicity and the capacity to bind other molecules such as fibrinogen, serum factor H, and immunoglobulins. There are more than 100 immunotypes of M protein, which are the basis of a subtyping system for GAS.

Other Surface Molecules

A number of surface proteins have been described on the basis of their similarity with M protein or some unique binding capacity. Of these, a fibronectin-binding protein F and LTA are both exposed on the streptococcal surface (Figure 25–3) and play a role in pathogenesis. An IgG-binding protein has the capacity to bind the Fc portion of antibodies in much the same way as staphylococcal protein A. In principle, this could interfere with opsonization by creating a covering of antibody molecules on the streptococcal surface that are facing the “wrong way.” Many GAS have a nonantigenic hyaluronic acid capsule. Although this capsule has been shown to be antiphagocytic, its role in disease is clouded by the fact that strains which lack it are still fully virulent.

EXTRACELLULAR PRODUCTS

Streptolysin O

Streptolysin O is a pore-forming cytotoxin, lysing leukocytes, tissue cells, and platelets. The toxin inserts directly into the cell membrane of host cells, forming transmembrane pores in a manner similar to complement and staphylococcal α-toxin. Streptolysin O is antigenic, and the quantitation of antibodies against it is the basis of a standard serologic test called antistreptolysin O (ASO).

Streptococcal Superantigen Toxins

Just as with Staphylococcus aureus, approximately 10% of GAS produce one of a family of exotoxins whose major biologic effect is through the superantigen (SAg) mechanism (Figure 22–7). Over many decades, these toxins have been assigned a number of names linked to their association with scarlet fever (erythrogenic toxin) and with streptococcal toxic shock (streptococcal pyrogenic exotoxins [Spe]). As with S aureus, there are several antigenically distinct proteins (SpeA, SpeB, and so on). Because the staphylococcal and streptococcal SAgs have similar amino acid structure and biologic activity, in this book they are called StaphSAgs and StrepSAgs. StrepSAgs have multiple effects, including fever, rash (scarlet fever), T-cell proliferation, B-lymphocyte suppression, and heightened sensitivity to endotoxin. Most of these actions are due to cytokine release through the superantigen mechanism. At least one StrepSAg (SpeB) also has direct enzymatic activity digesting tissue and extracellular matrix proteins.

Other Extracellular Products

Most strains of GAS produce a number of other extracellular products including streptokinase, hyaluronidase, nucleases, and a C5a peptidase. The C5a peptidase is an enzyme that degrades complement component C5a, the main factor that attracts phagocytes to sites of complement deposition. The enzymatic actions of the others likely play some role in tissue injury or spread, but no specific roles have been defined. Some are antigenic and have been the basis of serologic tests. Streptokinase causes lysis of fibrin clots through conversion of plasminogen in normal plasma to the protease plasmin.

GROUP A STREPTOCOCCAL DISEASE

EPIDEMIOLOGY

Pharyngitis

Group A streptococci are the most common bacterial cause of pharyngitis in school-age children 5 to 15 years of age. Transmission is person-to-person from the large droplets produced by infected persons during coughing, sneezing, or even conversation (Figure 25–5). This droplet transmission is most efficient at the short distances (2-5 feet) at which social interactions commonly take place in families and schools, particularly in fall and winter months. Asymptomatic carriers (less than 1%) may also be the source of GAS, particularly if colonized in the nose as well as the throat. Although GAS survive for some time in dried secretions, environmental sources and fomites are not important means of spread. Unless the condition is treated, the organisms persist for 1 to 4 weeks after symptoms have disappeared.

Impetigo

Impetigo occurs when transient skin colonization with GAS is combined with minor trauma such as insect bites. The tiny skin pustules are spread locally by scratching and to others by direct contact or shared fomites such as towels. Impetigo is most common in summer months when insects bite and when the general level of hygiene is low. The M protein types of GAS most commonly associated with impetigo are different from those causing respiratory infection.

Wound and Puerperal Infections

Group A streptococci, once a leading cause of postoperative wound and puerperal infections, retain this potential, but the conditions favoring these diseases are now less common in developed countries. As with staphylococci, transmission from patient-to-patient is by the hands of physicians or other medical attendants who fail to follow recommended handwashing practices. Organisms may be transferred from another patient or may come from the health-care workers themselves.

Streptococcal Toxic Shock Syndrome

Since the late 1980s, a severe invasive form of GAS soft tissue infection appeared with increased frequency worldwide. Rapid progression to death in only a few days has occurred in previously healthy persons. The outstanding features of these infections are their multiorgan involvement, suggesting a toxin and rapid invasiveness with spread to the bloodstream and distant organs. Soft-tissue necrosis and streptococcal gangrenous myositis can rapidly ensue without the trauma associated with clostridial gas gangrene (see Chapter 29). The toxic features together with the discovery that almost all the isolates produce StrepSAgs have caused this syndrome to be labeled streptococcal toxic shock syndrome (STSS).

Poststreptococcal Sequelae

The association between GAS and the inflammatory disease acute rheumatic fever (ARF) is based on epidemiologic studies linking GAS pharyngitis, the clinical features of rheumatic fever, and heightened immune responses to streptococcal products. ARF does not follow skin or other nonrespiratory infection with GAS. Although some M types are more “rheumatogenic,” it is not practical to define risk in advance. The general approach is that recurrences of ARF can be triggered by infection with any GAS. Injury to the heart caused by recurrences of ARF leads to rheumatic heart disease, a major cause of heart disease worldwide. Although ARF has declined in developed countries, resurgence in the form of small regional outbreaks began in the late 1980s. These outbreaks involved children of a higher socioeconomic status than that previously associated with ARF and a shift in prevalent M types. The underlying basis of the resurgence is unknown. In contrast, ARF is rampant in many developing countries, particularly in Africa, the Middle East, India, and South America.

Poststreptococcal glomerulonephritis may follow either respiratory or cutaneous GAS infection and involves only certain “nephritogenic” strains. It is more common in temperate climates where insect bites lead to impetigo. The average latent period between infection and glomerulonephritis is 10 days from a respiratory infection, but generally about 3 weeks from a skin infection. Nephritogenic strains are limited to a few M types and seem to have declined in recent years.

PATHOGENESIS

Acute Infections

As with other pathogens, adherence to mucosal surfaces is a crucial step in initiating disease (Figure 25–6). Along with pili, a dozen specific adhesins have been described that facilitate the ability of the GAS to adhere to epithelial cells of the nasopharynx and/or skin. Of these, the most important are M protein, LTA, and protein F. In the nasopharynx, all three appear to be involved in mediating attachment to the fatty acid binding sites in the glycoprotein fibronectin covering the epithelial cell surface. The role of M protein in the pharynx is not direct, but it appears to function as an anchor for LTA, which is essential for it to reach its binding site (Figure 25–3).

However, M protein appears to be direct and dominant in binding to the skin through its ability to interact with subcorneal keratinocytes, the most numerous cell type in cutaneous tissue. This adherence takes place at domains of the M protein that bind to receptors on the keratinocyte surface. Protein F is also involved primarily in adherence to antigen-presenting Langerhans cells. Expression of M protein and protein F is regulated in response to environmental conditions (O₂, CO₂), which could play a role in establishing the microbe or in relation to the immune response.

Clinical evidence makes it clear that GAS have the capacity to be highly invasive. The events following attachment that trigger invasion are only starting to be understood. It appears that M protein, protein F, and other fibronectin-binding proteins are required for the invasion of nonprofessional phagocytes. There is also evidence that StrepSAg genes are linked to invasiveness. The invasion itself involves integrin receptors and is accompanied by cytoskeleton rearrangements, but the molecular events do not yet make a coherent story.

After the initial events of attachment and invasion, the concerted activity of the M protein, immunoglobulin-binding proteins, and the C5a peptidase play the key roles in allowing the streptococcal infection to continue (Figure 25–7). M protein plays an essential role in GAS resistance to phagocytosis because of the ability of domains of the molecule to bind serum factor H. This leads to a diminished availability of alternative pathway-generated complement component C3b for deposition on the streptococcal surface in the same manner as polysaccharide capsules (Figure 22–4). In the presence of M type-specific antibody, classical pathway opsonophagocytosis proceeds, and the streptococci are rapidly killed. As a second antiphagocytic mechanism, the C5a peptidase inactivates C5a and thus blocks chemotaxis of polymorphonuclear neutrophils (PMNs) and other phagocytes to the site of infection.

The precise role of other bacterial factors in the pathogenesis of acute infection is uncertain, but the combined effect of streptokinase, DNAase, and hyaluronidase may prevent effective localization of the infection, whereas the streptolysins produce tissue injury and are toxic to phagocytic cells. Antibodies against these components are formed in the course of streptococcal infection but are not known to be protective.

In STSS, as with staphylococcal toxic shock syndrome, the findings of shock, renal impairment, coagulopathy, and rash seem to be explained by the massive cytokine release stimulated by the superantigenicity of the StrepSAgs. Exotoxin production, however, does not explain the enhanced invasiveness of GAS, which is an added feature of STSS compared to its staphylococcal counterpart. Although the enzymatic activity of some StrepSAgs has been linked to invasiveness, the underlying mechanisms are unclear. One theory is that STSS may be due to the horizontal transfer of StrepSAg genes to GAS clones with enhanced invasive potential, a deadly combination.

Poststreptococcal Sequelae

Of the many theories advanced to explain the role of GAS in ARF, an autoimmune mechanism related to antigenic similarities between streptococci antigens and human tissues has the most experimental support. Streptococcal pharyngitis patients who develop ARF have higher levels of antistreptococcal and autoreactive antibodies than those who do not. Some of these antibodies have been shown to react with both heart tissue and streptococcal antigens.

The antigen stimulating these antibodies is most probably M protein, but the group A carbohydrate is also a possibility. There is similarity between the structure of regions of the M protein and myosin, and M protein fragments have been shown to stimulate antibodies that bind to human heart sarcolemma membranes, cardiac myosin, synovium, and articular cartilage. Acute rheumatic fever is a prime example of the molecular mimicry mechanism of Type II autoimmune hypersensitivity (see Chapter 2). Immunochemical studies of M protein are now directed at locating the epitopes in the large M protein molecule, which stimulate protective antibody (anti-factor H binding sites) and those that stimulate anti-self antibodies. There is evidence these domains are in different locations in the M protein coiled coil (Figure 25–4). If they can be separated, there is hope for an M protein-based vaccine that does not cause the very disease (ARF) it is designed to prevent. A further complication with this approach is establishing the consistency of these relationships among the many M types.

Patients with ARF also show enhanced T_H1 responses to streptococcal antigens. Cytotoxic T lymphocytes may be stimulated by M protein, and cytotoxic lymphocytes have been observed in the blood of patients with ARF. A cellular reaction pattern consisting of lymphocytes and macrophages aggregated around fibrinoid deposits is found in human hearts. This lesion, called the Aschoff body (Figure 25–8), is considered characteristic of rheumatic carditis.

Genetic factors are probably also important in ARF because only a small percentage of individuals infected with GAS develop the disease. Attack rates have been highest among those of lower socioeconomic status and vary among those of different racial origins. The gene for an alloantigen found on the surface of B lymphocytes occurs four to five times more frequently in patients with rheumatic fever than in the general population. This further suggests a genetic predisposition to hyperreactivity to streptococcal products.

The renal injury of acute glomerulonephritis is caused by deposition in the glomerulus of antigen–antibody complexes with complement activation and consequent inflammation. This is a type III hypersensitivity (see Chapter 2). The M proteins of some nephritogenic strains have been shown to share antigenic determinants with glomeruli, which suggests an autoimmune mechanism similar to rheumatic fever. Streptokinase has also been implicated both through molecular mimicry and through its plasminogen activation capacity.

IMMUNITY

It has long been known that an antibody directed against M protein is protective for subsequent GAS infections. This protection, however, is only for subsequent infection with strains of the same M type. This is called type-specific immunity. This protective IgG is directed against factor H-binding epitopes in the amino-terminal regions of the molecule and reverses the antiphagocytic effect of M protein. Streptococci opsonized with type-specific antibody bind complement C3b by the classical pathway, facilitating phagocyte recognition. There is evidence that mucosal IgA is also important in blocking adherence, whereas the IgG is able to protect against invasion. Unfortunately, because there are over 100 M types, repeated infections with new M types occur. Eventually, immunity to the common M types is acquired and infections become less common in adults. In ARF patients, it is the hyperreaction seen in each episode that produces the lesions associated with rheumatic heart disease.

GROUP A STREPTOCOCCAL INFECTIONS: CLINICAL ASPECTS

MANIFESTATIONS

Streptococcal Pharyngitis

Although it may occur at any age, streptococcal pharyngitis occurs most frequently between the ages of 5 and 15 years. The illness is characterized by acute sore throat, malaise, fever, and headache. Infection typically involves the tonsillar pillars, uvula, and soft palate, which become red, swollen, and covered with a yellow-white exudate. The cervical lymph nodes that drain this area may also become swollen and tender. This clinical syndrome overlaps with viral pharyngitis taking place at the same age.

GAS pharyngitis is usually self-limiting. Typically, the fever is gone by the third to fifth day, and other manifestations subside within 1 week. Antimicrobial therapy hastens resolution only if begun within a day, but can avert sequelae. Occasionally, the infection spreads locally to produce peritonsillar or retropharyngeal abscesses, otitis media, suppurative cervical adenitis, and acute sinusitis. Rarely, more extensive spread occurs, producing meningitis, pneumonia, or bacteremia with metastatic infection in distant organs. In the preantibiotic era, these suppurative complications were responsible for a mortality rate of 1% to 3% after acute streptococcal pharyngitis. Such complications are much less common now, and fatal infections are rare.

Impetigo

The primary lesion of streptococcal impetigo is a small (up to 1 cm) vesicle surrounded by an area of erythema. The vesicle enlarges over a period of days, becomes pustular, and eventually breaks to form a yellow crust. The lesions usually appear in 2- to 5-year-old children on exposed body surfaces, typically the face and lower extremities. Multiple lesions may coalesce to form deeper ulcerated areas. Although S aureus produces a clinically distinct bullous form of impetigo, it can also cause vesicular lesions resembling streptococcal impetigo. Both pathogens are isolated from some cases.

Erysipelas

Erysipelas is a distinct form of streptococcal infection of the skin and subcutaneous tissues, primarily affecting the dermis. It is characterized by a spreading area of erythema and edema with rapidly advancing, well-demarcated edges, pain, and systemic manifestations, including fever and lymphadenopathy. Infection usually occurs on the face (Figure 25–9), and a previous history of streptococcal sore throat is common.

Puerperal Infection

Infection of the endometrium at or near delivery is a life-threatening form of GAS infection. Now rare in developed countries, sepsis with GAS was a common cause of death in women after childbirth before effective infection control measures (hand sanitation and surgical gloves) were implemented (see Chapter 3). Other organisms can cause puerperal fever, but this form is the most likely to produce a rapidly progressive infection.

Disease Associated With Streptococcal Superantigen Toxins

Infection with strains that elaborate any of the StrepSAgs may superimpose the signs of scarlet fever on a patient with streptococcal pharyngitis. In scarlet fever, the buccal mucosa, temples, and cheeks are deep red, except for a pale area around the mouth and nose (circumoral pallor). Punctate hemorrhages appear on the hard and soft palates, and the tongue becomes covered with a yellow-white exudate through which the red papillae are prominent (strawberry tongue). A diffuse red “sandpaper” rash appears on the second day of illness, spreading from the upper chest to the trunk and extremities. Circulating antibody to the toxin neutralizes these effects. For unknown reasons, scarlet fever is both less frequent and less severe than early in the 20th century.

STSS may begin at the site of any GAS infection even at the site of seemingly minor trauma. The systemic illness starts with vague myalgia, chills, and severe pain at the infected site. Most commonly, this is in the skin and soft tissues and leads to necrotizing fasciitis and myonecrosis. The striking nature of this progression when it involves the extremities is the basis of the label “flesh-eating bacteria.” STSS continues with nausea, vomiting, and diarrhea followed by hypotension, shock, and organ failure. The outstanding laboratory findings are a lymphocytosis; impaired renal function (azotemia); and, in over half the cases, bacteremia. Some patients are in irreversible shock by the time they reach a medical facility. Many survivors have been left as multiple amputees as the result of metastatic spread of the streptococci.

Poststreptococcal Sequelae

Acute rheumatic fever is a nonsuppurative inflammatory disease characterized by fever, carditis, subcutaneous nodules, chorea, and migratory polyarthritis. The diagnosis is based on a set of primarily clinical findings (Jones Criteria) recommended by the American Heart Association. Evidence of a previous GAS infection is included in these criteria, but there is no test which is diagnostic of ARF. Cardiac enlargement, valvular murmurs, and effusions are seen clinically and reflect myocardial, endocardial, and epicardial damage, which can lead to heart failure. Attacks typically begin 3 weeks (range 1-5 weeks) after an attack of GAS pharyngitis and, in the absence of anti-inflammatory therapy, last 2 to 3 months.

ARF also has a predilection for recurrence with subsequent streptococcal infections as new M types are encountered. The first attack usually occurs between the ages of 5 and 15 years. The risk of recurrent attacks after subsequent GAS infection continues into adult life and then decreases. Repeated attacks lead to progressive damage to the endocardium and heart valves, with scarring and valvular stenosis or incompetence (rheumatic heart disease).

Poststreptococcal glomerulonephritis is primarily a disease of childhood that begins 1 to 4 weeks after streptococcal pharyngitis and 3 to 6 weeks after skin infection. It is characterized clinically by edema, hypertension, hematuria, proteinuria, and decreased serum complement levels. Pathologically, there are diffuse proliferative lesions of the glomeruli. The clinical course is usually benign, with spontaneous healing over weeks to months. Occasionally, a progressive course leads to renal failure and death.

DIAGNOSIS

Although the clinical features of streptococcal pharyngitis are fairly typical, there is enough overlap with viral pharyngitis that a culture of the posterior pharynx and tonsils is required for diagnosis. A direct Gram-stained smear of the throat is not helpful because of the other streptococci in the pharyngeal flora. However, smears from normally sterile sites usually demonstrate streptococci. Sheep blood agar plates incubated anaerobically give the best yield, because they favor the demonstration of β-hemolysis (see streptolysins earlier in chapter). β-Hemolytic colonies are identified by Lancefield grouping using immunofluorescence, agglutination methods, or PCR. In smaller laboratories, a surrogate method based on the exquisite susceptibility of GAS to bacitracin and the relative resistance of strains of other groups may be used for presumptive separation of group A strains from the others (Table 25–2).

Detection of group A antigen extracted directly from throat swabs is now available in a wide variety of kits marketed for use in physicians’ offices. These methods are rapid and specific, but are at best only 90% sensitive compared with culture. Given the importance of the detection of group A streptococci in the prevention of ARF (it is the reason physicians culture sore throats), missing 10% or more of cases is not tolerable. Patients with a positive direct antigen test may be treated without culture, but the American Academy of Pediatrics recommends that negative results must be confirmed by culture before withholding treatment.

Several serologic tests have been developed to aid in the diagnosis of poststreptococcal sequelae by providing evidence of a previous GAS infection. They include the ASO, anti-DNAase B, and some tests that combine multiple antigens. High titers of ASO are usually found in sera of patients with rheumatic fever, so that test is used most widely.

TREATMENT

Group A streptococci are highly susceptible to penicillin G, the antimicrobial of choice. Concentrations as low as 0.01 μg/mL have a bactericidal effect, and penicillin resistance is so far unknown. Numerous other antimicrobials are also active, including other β-lactams and macrolides, but not aminoglycosides. Patients allergic to penicillin are usually treated with clindamycin or azithromycin, and impetigo is often treated with clindamycin to cover the prospect of S aureus involvement. Adequate treatment of streptococcal pharyngitis within 10 days of onset prevents rheumatic fever by removing the antigenic stimulus; its effect on the duration of the pharyngitis is not dramatic because of the short course of the natural infection. Treatment of the acute infection may not prevent the development of acute glomerulonephritis.

PREVENTION

Penicillin prophylaxis with long-acting preparations is used to prevent recurrences of ARF during the most susceptible ages (5-15 years). Patients with a history of rheumatic fever or known rheumatic heart disease receive antimicrobial prophylaxis while undergoing procedures known to cause transient bacteremia, such as dental extraction. Multivalent vaccines using M protein epitopes that are not cross-reactive to self are in clinical trials with encouraging results.

BACTERIOLOGY

Group B streptococci (GBS) produce short chains and diplococcal pairs of spherical or ovoid gram-positive cells. Colonies are larger and β-hemolysis due to a pore-forming cytolysin (β-hemolysin) is less distinct than with GAS and may even be absent. In addition to the Lancefield B antigen, GBS produce polysaccharide capsules of nine antigenic types (Ia, Ib, II–VIII), all of which contain sialic acid in the form of terminal side chain residues. Pili and surface proteins are also present.

GROUP B STREPTOCOCCAL DISEASE

EPIDEMIOLOGY

Group B streptococci are the leading cause of sepsis and meningitis in the first few days of life. The organism is resident in the gastrointestinal tract, with secondary spread to other sites, the most important of which is the vagina. Group B streptococci can be found in the lower gastrointestinal and vaginal flora of 10% to 40% of women. During pregnancy and childbirth, these organisms may gain access to the amniotic fluid or colonize the newborn as it passes through the birth canal (Figure 25–10). Group B streptococci produce disease in approximately 2% of these encounters. The risk is much higher when factors are present that decrease the infant’s innate resistance (prematurity) or increase the chances of transmission such as rupture of the amniotic membranes for 18 hours or more before delivery. Some infants are healthy at birth but develop sepsis 1 to 3 months later. It is not known whether the organism in these “late-onset” cases was acquired from the mother, in the nursery, or in the community after leaving the hospital.

PATHOGENESIS

Group B streptococci disease requires the proper combination of organism and host factors. The GBS capsule is the major organism factor. For the initial stages of infection, pili and a number of surface exposed proteins that attach to fibronectin and extracellular matrix proteins have been identified. The sialic acid moiety of the capsule has been shown to bind serum factor H, which in turn accelerates degradation of C3b before it can be effectively deposited on the surface of the organism. This makes alternative pathway-mediated mechanisms of opsonophagocytosis relatively ineffective (Figure 22–4). Thus, complement-mediated phagocyte recognition requires specific antibody and the classical pathway. Newborns have this antibody only if they receive it from their mother as transplacental IgG. Those who lack the protective “cover” of antibody specific to the type of GBS they encounter must rely on alternative pathway mechanisms, a situation in which the GBS has an advantage over less virulent organisms. Group B streptococci have also been shown to produce a peptidase that inactivates C5a, the major chemoattractant of PMNs (polymorphonuclear leukocytes). This may correlate with the observation that serious neonatal infections often show a paucity of infiltrating PMNs. The pore-forming cytolysin may contribute to tissue-destructive elements of invasive disease.

IMMUNITY

Antibody is protective against GBS disease, but as with group A streptococcal M protein, the antibody must be specific to the infecting type of GBS. Fortunately, there are only nine types, and type III produces the majority of early and late-onset cases. Antibody is acquired by GBS infection, and specific IgG may be transmitted transplacentally to the fetus, providing protection in the perinatal period. In the presence of type-specific antibody, classical pathway C3b deposition, phagocyte recognition, and killing proceed normally.

GROUP B STREPTOCOCCI: CLINICAL ASPECTS

MANIFESTATIONS

The clinical findings of poor feeding, irritability, lethargy, jaundice, respiratory distress, and hypotension are nonspecific and similar to those found in other serious infections in the neonatal period. Fever is sometimes absent, and infants may even be hypothermic. Pneumonia is common, and meningitis is present in 5% to 10% of cases. Most infections have GBS circulating in the bloodstream without localizing findings. The disease onset is typically in the first few days of life, and signs of infection are present at birth in almost 50% of cases. The late-onset (1-3 month) cases have similar findings, but are more likely to have meningitis and focal infections in the bones and joints. Even with increased awareness and improved supportive therapy, the mortality rate for early-onset GBS infection still approaches 10%.

Group B streptococci infections in adults are uncommon and fall into two groups. The first group comprises peripartum chorioamnionitis and bacteremia, the mother’s side of the neonatal syndrome. Other infections include pneumonia and a variety of skin and soft tissue infections similar to those produced by other pyogenic streptococci. Although adult GBS infections may be serious, they are usually not fatal unless patients are immunocompromised. Group B streptococci infections are not associated with rheumatic fever or acute glomerulonephritis.

DIAGNOSIS

The laboratory diagnosis of GBS infection is by culture of blood, cerebrospinal fluid, or other appropriate specimen. Definitive identification involves serologic determination of the Lancefield group by the same methods used for GAS. Maximal detection of vaginal colonization in pregnant women requires obtaining specimens from the rectum as well as vagina. Recovery of GBS by culture necessitates selective media and enrichment broth, whereas PCR is a sensitive test for direct detection.

TREATMENT

Group B streptococci are susceptible to the same antimicrobials as group A organisms. Penicillin is the treatment of choice and there is no known resistance to β-lactam agents. However, in the initial stage, neonatal infections are often initially treated with combinations of penicillin (or ampicillin) and an aminoglycoside because of known synergism and the possibility of other bacterial agents. Once GBS is confirmed, therapy can be completed with penicillin alone.

PREVENTION

Strategies for the prevention of neonatal GBS disease are focused on reducing contact of the newborn with the organism. In colonized women, attempts to eradicate the carrier state have not been successful since GBS reside in the gastrointestinal tract, but intrapartum (during labor) antimicrobial prophylaxis with intravenous penicillin has been shown to reduce transmission and disease. It is now recommended by expert obstetric and perinatology groups that all newborns at risk receive such prophylaxis. Risk is defined by the presence of vaginal or rectal GBS in a culture taken during the third trimester (35-37 weeks). Thus, all expectant mothers must be screened by selective culture or PCR (see Diagnosis) and intrapartum prophylaxis with penicillin (or clindamycin for allergic patients) administered to all found culture positive or PCR positive.

An alternative risk-based approach (eg, prematurity, prolonged membrane rupture, and fever) is easier for obstetricians to apply, but has now been discarded as much less effective in preventing GBS disease. Implementation of these screening and prophylaxis procedures was followed by a dramatic decrease (more than 70%) in neonatal early-onset GBS disease. For women who present in labor without culture results, a risk-based assessment is all that can be used to decide whether to administer prophylaxis. Prevention by immunization with purified GBS capsular polysaccharide has been shown to be feasible, and considerable effort is now being directed at the development of a vaccine.

Other Pyogenic Streptococci

The other pyogenic streptococci occasionally produce various respiratory, skin, wound, soft tissue, and genital infections, which may resemble those caused by group A and B streptococci. Although a few foodborne outbreaks of pharyngitis have been linked to groups C and G streptococci, their role as a cause of everyday sore throats is not established. These streptococci are susceptible to penicillin, and infections are managed in a manner similar to that with deep tissue infections caused by group A and B strains. None of the non-group A pyogenic streptococci have been associated with poststreptococcal sequelae.

Streptococcus pneumoniae

BACTERIOLOGY

Streptococcus pneumoniae (pneumococci) are gram-positive, oval cocci typically arranged end to end in pairs (diplococcus), giving the cells a bullet shape (Figure 25–11). On blood agar, pneumococci produce round, glistening 0.5 to 2.0 mm colonies surrounded by a zone of α-hemolysis. Both colonies and broth cultures have a tendency to undergo autolysis because of their susceptibility to peroxides produced during growth and the action of autolysins, a family of pneumococcal enzymes that degrade peptidoglycan. Accelerating the autolytic process with bile salts is the basis of the bile solubility test that separates pneumococci from other α-hemolytic streptococci.

The distinguishing structural feature of the pneumococcus is its capsule (Figure 25–12). All virulent strains have surface capsules, composed of high-molecular-weight polysaccharide polymers that are complex mixtures of monosaccharides, oligosaccharides, and sometimes other components. The exact makeup of the polymer is unique and distinctly antigenic for each of more than 90 serotypes. Pneumococcal cell wall structure is similar to that of other streptococci, and a variety of surface proteins are rooted in the peptidoglycan extending outward into the capsule. One group of these, the choline-binding proteins, is able to bind to both pneumococcal cell wall cholines and carbohydrates that are present on the surface of epithelial cells.

EXTRACELLULAR PRODUCTS

All pneumococci produce pneumolysin, which is a member of the family of transmembrane pore-forming toxins that includes staphylococcal α toxin, S pyogenes streptolysin O, and others. The pneumococcus does not secrete pneumolysin, but it is released on lysis of the organisms augmented by autolysins. Pneumolysin has a number of other effects, including its ability to stimulate cytokines and disrupt the cilia of human respiratory epithelial cells. Pneumococci also produce a neuraminidase, which cleaves sialic acid that is present in host mucin, glycolipids, and glycoproteins.

PNEUMOCOCCAL DISEASE

EPIDEMIOLOGY

Streptococcus pneumoniae is a leading cause of pneumonia, acute purulent meningitis, bacteremia, and other invasive infections. In the United States, it is responsible for an estimated 3000 cases of meningitis, 50 000 cases of bacteremia, and 500 000 cases of pneumonia each year. Worldwide, more than 5 million children die every year from pneumococcal disease. S pneumoniae is also the most common cause of otitis media, a virtually universal disease of childhood with millions of cases every year. Pneumococcal infections occur throughout life, but are most common in the very young (less than 2 years) and in the elderly (more than 60 years). Alcoholism, diabetes mellitus, chronic renal disease, asplenia, and some malignancies are associated with more frequent and serious pneumococcal infection.

Infections are derived from colonization of the nasopharynx, where pneumococci can be found in 5% to 40% of healthy persons depending on age, season, and other factors. The highest rates are among children in the winter. Respiratory secretions containing pneumococci may be transmitted from person-to-person by direct contact or from the microaerosols created by coughing and sneezing in close quarters. Such conditions are favored by crowded living conditions, particularly when colonized persons are mixed with susceptible ones, as in child care centers, recruitment barracks, and prisons. As with other bacterial pneumonias, viral respiratory infection and underlying chronic disease are important predisposing factors.

Surveillance data show that just over 20 of the 90 pneumococcal serotypes produce disease more often than the others. There is also a variation among types in the age and geographic distribution of cases. These differences are presumably due to enhanced virulence factors in these types, but the specific reasons are not known. These features do not influence the medical management of individual cases but are important in devising prevention strategies such as immunization (see following text).

PATHOGENESIS

Pneumococcal adherence to nasopharyngeal cells involves multiple factors. The primary relationship is the bridging effect of the choline-binding proteins’ attachment to cell wall cholines and carbohydrates covering or exposed on the surface of host epithelial cells. This binding may be aided by the exposure of additional receptors by neuraminidase digestion, viral infection, or pneumolysin-stimulated cytokine activation of host cells. Aspiration of respiratory secretions containing these pneumococci is the initial step leading to pneumonia (Figure 25–13). This must be a common event. Normally, aspirated organisms are cleared rapidly by the defense mechanisms of the lower respiratory tract, including the cough and epiglottic reflexes; the mucociliary “blanket”; and phagocytosis by alveolar macrophages. Host factors that impair the combined efficiency of these defenses allow pneumococci to reach the alveoli and multiply there. These include chronic pulmonary diseases; damage to bronchial epithelium from smoking or air pollution; and respiratory dysfunction from alcoholic intoxication, narcotics, anesthesia, and trauma.

When organisms reach the alveolus, pneumococcal virulence factors operate in two stages. The first stage is early in infection, when the capsule and some surface proteins of intact organisms act to block phagocytosis. This allows the organisms to multiply and spread despite an acute inflammatory response. The second stage occurs when organisms begin to disintegrate and release a number of factors either synthesized by the pneumococcus or part of its structure, thus causing injury. These include pneumolysin, autolysin, and components of the cell wall.

Capsule

The polysaccharide capsule of S pneumoniae is the major determinant of virulence. Unencapsulated mutants do not produce disease in humans or laboratory animals. Like the GBS capsule, pneumococcal polysaccharide interferes with effective deposition of complement on the organism’s surface and thus phagocyte recognition and engulfment. This property is particularly important in the absence of specific antibody, when alternative pathway is the primary means for C3b-mediated opsonization. In addition to the capsule, some of the surface choline-binding proteins may participate in this antiphagocytic effect by binding the serum factor H. When antibody specific to the capsular polysaccharide appears, classical pathway opsonophagocytosis proceeds efficiently.

Pneumolysin

Some of the clinical features seen in the course of pneumococcal infections are not explainable by the capsule alone. These include the dramatic abrupt onset, toxicity, fulminant course, and disseminated intravascular coagulation seen in some cases. Pneumolysin’s toxicity for pulmonary endothelial cells and direct effect on cilia contributes to the disruption of the endothelial barrier and facilitates the access of pneumococci to the alveoli and eventually their spread beyond into the bloodstream. Pneumolysin also has direct effects on phagocytes and suppresses host inflammatory and immune functions. Because pneumolysin is not actively secreted outside the bacterial cell, the action of the autolysins is required to release it.

The combined effects of pneumococcal and host factors produce a pneumonia, which progresses through a series of stages. Initial alveolar multiplication produces a profuse out-pouring of serous edema fluid, which is then followed by an influx of PMNs and erythrocytes (Figure 25–13). By the second or third day of illness, the lung segment has increased three- to fourfold in weight through accumulation of this cellular, hemorrhagic fluid typically in a single lobe of the lung. In the consolidated alveoli, neutrophils predominate initially, but once actively growing, pneumococci are no longer present, macrophages replace the granulocytes, and resolution of the lesion ensues. A remarkable feature of pneumococcal pneumonia is the lack of structural damage to the lung, which usually leads to complete resolution on recovery.

IMMUNITY

Immunity to S pneumoniae infection is provided by antibody directed against the specific pneumococcal capsular type. When antibody binds to the capsular surface, C3b is deposited by classical pathway mechanisms, and phagocytosis can proceed. Because the number of serotypes is large, complete immunity through natural experience is not realistic, which is why pneumococcal infections occur throughout life. Infections are most often seen in the very young, when immunologic experience is minimal, and in the elderly, when immunity begins to wane and risk factors are more common. Recently, experience with pneumococcal vaccines has unmasked a phenomenon called capsule switching in which the antigenic makeup of the capsule changes. This is felt to be due to in vivo transformation and recombination with external DNA. We should not be too surprised at this since the discovery of DNA as the keeper of the genetic code was through experiments transforming pneumococci.

PNEUMOCOCCAL DISEASE: CLINICAL ASPECTS

MANIFESTATIONS

Pneumococcal Pneumonia

Pneumococcal pneumonia begins abruptly with a shaking chill and high fever. Cough with production of sputum pink to rusty in color (indicating the presence of red blood cells), and pleuritic chest pain are common. Physical findings usually indicate pulmonary consolidation. Children and young adults typically demonstrate a lobular or lobar consolidation on chest radiography, whereas older patients may show a less localized bronchial distribution of the infiltrates. Without therapy, sustained fever, pleuritic pain, and productive cough continue until a “crisis” occurs 5 to 10 days after onset of the disease. The crisis involves a sudden decrease in temperature and improvement in the patient’s condition. It is associated with effective levels of opsonizing antibody reaching the lesion. Although infection may occur at any age, the incidence and mortality of pneumococcal pneumonia increase sharply after 50 years.

Pneumococcal Meningitis

Streptococcus pneumoniae is one of the three leading causes of acute bacterial meningitis. The signs and symptoms are similar to those produced by other bacteria. Acute purulent meningitis may follow pneumococcal pneumonia or infection at another site or may appear with no apparent antecedent infection. It may also develop after trauma involving the skull. The mortality and frequency of sequelae are slightly higher with pneumococcal meningitis than with other forms of pyogenic meningitis.

Other Infections

Pneumococci are common causes of sinusitis and otitis media. The latter frequently occurs in children in association with viral infection. Chronic infection of the mastoid or respiratory sinus sometimes extends to the subarachnoid space to cause meningitis. Pneumococci may also cause endocarditis, arthritis, and peritonitis, usually in association with bacteremia. Patients with ascites caused by diseases such as cirrhosis and nephritis may develop spontaneous pneumococcal peritonitis. Pneumococci do not cause pharyngitis or tonsillitis.

DIAGNOSIS

Gram smears of material from sputum and other sites of pneumococcal infection typically show gram-positive, lancet-shaped diplococci (Figure 25–11). Sputum collection may be difficult, however, and specimens contaminated with respiratory flora are useless for diagnosis. Other types of lower respiratory specimens may be needed for diagnosis. S pneumoniae grows well overnight on blood agar medium and is usually distinguished from viridans streptococci by susceptibility to the synthetic chemical ethylhydrocupreine (optochin) or by a bile solubility (Table 25–2). Bacteremia is common in pneumococcal pneumonia and meningitis, and blood cultures are valuable supplements to cultures of local fluids or exudates. Detection of pneumococcal capsular antigen in body fluids is possible but valuable primarily when cultures are negative.

TREATMENT

For decades pneumococci were uniformly susceptible to penicillin at concentrations of 0.06 μg/mL or less. In the late 1960s, this began to change, and strains with decreased susceptibility to all β-lactams began to emerge that resulted in treatment failures in cases of pneumonia and meningitis. The resistance is not absolute and can be overcome with increased dosage, depending on the minimum inhibitory concentration (MIC) and the site of infection. The mechanism involves alterations in the β-lactam target, the transpeptidase penicillin-binding proteins (PBPs) that cross-link peptidoglycan in cell wall synthesis. Resistant strains have mutations in one or more of these transpeptidases, which cause decreased affinity for penicillin and other β-lactams. Penicillinase is not produced. Resistance rates now exceed 10% in most locales and may be greater than 40% in some areas. Resistance to erythromycin is increasing and is more likely with penicillin-resistant strains.

Antibiotic selection differs with the site of the infection and whether it is to be carried out in an inpatient or outpatient setting. Penicillin is still effective for susceptible strains, but the uncertainty has caused a shift toward third-generation cephalosporins (ceftriaxone, cefotaxime) for primary treatment. Even though penicillin-resistant strains also have decreased susceptibility to cephalosporins, the pharmacologic features of these agents make it easier to achieve blood levels higher than the MIC. Penicillin-resistant strains (MIC > 2.0 μg/mL) for patients without meningitis are treated with fluoroquinolones, clindamycin, or an active third-generation cephalosporin. Patients with meningitis caused by pneumococci with a penicillin MIC more than 0.06 μg/mL require high doses of an active third-generation cephalosporin plus vancomycin unless the cephalosporin MIC is less than or equal to 0.5 μg/mL. The therapeutic response to treatment of pneumococcal pneumonia is often dramatic. Reduction in fever, respiratory rate, and cough can occur in 12 to 24 hours but may occur gradually over several days. Chest radiography may yield normal results only after several weeks.

PREVENTION

Two pneumococcal vaccines prepared from capsular polysaccharide are now available. The first pneumococcal polysaccharide vaccine (PPV), available since 1977, contains purified polysaccharide extracted from the 23 serotypes of S pneumoniae most commonly isolated from invasive disease. It shares the T-cell-independent characteristics of other polysaccharide immunogens and is recommended for use only in those older than 2 years. In 2000, a pneumococcal conjugate vaccine (PCV) was introduced in which polysaccharide was conjugated with protein. This vaccine stimulates T-dependent T_H2 responses and is effective beginning at 2 months of age. In 2010 the original 7-valent vaccine was replaced by a 13-valent (PCV13) conjugate vaccine and is the standard for childhood immunization. Because of its broader coverage, the 23-valent PPV is recommended after age 2 except for immunocompromised children under 5, who should still receive PCV. The phenomenon of capsule switching (see Immunity above) is of concern as a mechanism for evading these vaccines. That is, a significant antigenic change in any of the serotypes covered by either vaccine could be the basis of failure to protect.

Viridans and Nonhemolytic Streptococci

The viridans group comprises all α-hemolytic streptococci that remain after the criteria for defining pyogenic streptococci and pneumococci have been applied. Characteristically members of the resident flora of the oral and nasopharyngeal cavities, they have the basic bacteriologic features of streptococci but lack the specific antigens, toxins, and virulence of the other groups. Although the viridans group includes many species (Table 25–2), they are usually not completely identified in practice because there is little clinical difference among them. The exception is for isolates from blood in patients with bacterial endocarditis.

Although their virulence is very low, viridans strains can cause disease when they are protected from host defenses. The prime example is subacute bacterial endocarditis. In this disease, viridans streptococci reach previously damaged heart valves as a result of transient bacteremia associated with manipulations, such as tooth extraction, which disturb their usual habitat. Protected by fibrin and platelets, they multiply on the valve, causing local and systemic disease that is fatal if untreated. Extracellular production of glucans, complex polysaccharide polymers, may enhance their attachment to cardiac valves in a manner similar to the pathogenesis of dental caries by S mutans (see Chapter 41). The clinical course of viridans streptococcal endocarditis is subacute, with slow progression over weeks or months. It is effectively treated with penicillin, but uniformly fatal if untreated. The disease is particularly associated with valves damaged by recurrent rheumatic fever. The decline in the occurrence of rheumatic heart disease has reduced the incidence of this particular type of endocarditis.

BACTERIOLOGY

Until genomic studies dictated their separation into the genus Enterococcus, the enterococci were classified as streptococci. Indeed, the most common enterococcal species share the bacteriologic characteristics previously described for pyogenic streptococci, including presence of the Lancefield group D antigen. The term “enterococcus” derives from their presence in the intestinal tract and the many biochemical and cultural features that reflect that habitat. These include the ability to grow in the presence of high concentrations of bile salts and sodium chloride. Most enterococci produce nonhemolytic or α-hemolytic colonies that are larger than those of most streptococci. A dozen species are recognized based on biochemical and cultural reactions (Table 25–2) of which Enterococcus faecalis and Enterococcus faecium are the most common.

ENTEROCOCCAL DISEASE

EPIDEMIOLOGY

Enterococci are part of the resident intestinal flora. Although they are capable of producing disease in many settings, the hospital environment is where a substantial increase has occurred in the last two decades. Patients with extensive abdominal surgery, transplantation, or indwelling devices or those who are undergoing procedures such as peritoneal dialysis are at greatest risk. Prolonged hospital stays and prior antimicrobial therapy, particularly with flouro quinolones, cephalosporins, or aminoglycosides, are also risk factors. Most infections are acquired from the endogenous flora but spread between patients has been documented. A substantial number of nosocomial urinary tract, intra-abdominal, and bloodstream infections are due to enterococci.

PATHOGENESIS

Enterococci are a significant cause of disease in hospitals and extended-care facilities, but they are not highly virulent. On their own, they do not produce fulminant disease and in wound and soft tissue infections are usually mixed with other members of the intestinal flora. Some have even doubted their significance when isolated together with more virulent members of the Enterobacteriaceae or Bacteroides fragilis. Enterococcus faecalis has been shown to form biofilms sticking to medical devices and possess surface proteins adherent to urinary epithelium and is an important cause of bacterial endocarditis. More than anything, enterococci, especially E faecium, seem to be very effective at withstanding environmental and antimicrobial agent stresses.

ENTEROCOCCAL DISEASE: CLINICAL ASPECTS

MANIFESTATIONS

Enterococci cause opportunistic urinary tract infections (UTIs) and occasionally wound and soft tissue infections, in much the same fashion as members of the Enterobacteriaceae. Infections are often associated with urinary tract manipulations, malignancies, biliary tract disease, and gastrointestinal disorders. Vascular or peritoneal catheters are often points of entry. Respiratory tract infections are rare. There is sometimes an associated bacteremia, which can result in the development of endocarditis on previously damaged cardiac valves.

TREATMENT

The outstanding feature of the enterococci is their high and increasing levels of resistance to antimicrobial agents. Their inherent relative resistance to most β-lactams, complete resistance to all cephalosporins, and high-level resistance to aminoglycosides can be viewed as a kind of virulence factor in the hospital environment where these agents are widely used. Enterococci also have particularly efficient means of acquiring plasmid and transposon resistance genes from themselves and other species. All enterococci require 4 to 16 μg/mL of penicillin for inhibition owing to decreased affinity of their PBPs for all β-lactams. Higher levels of resistance have been increasing, especially in E faecium, owing to altered PBPs. Ampicillin remains the most consistently active agent against E faecalis.

Enterococci share with streptococci a resistance to aminoglycosides based on failure of the antibiotic to be actively transported into the cell. Despite this, many strains of enterococci are inhibited and rapidly killed by low concentrations of penicillin when combined with an aminoglycoside. Under these conditions, the action of penicillin on the cell wall allows the aminoglycoside to enter the cell, where it can then act at its ribosomal site. Some strains show high-level resistance to aminoglycosides based on mutations at the ribosomal binding site or the presence of aminoglycoside-inactivating enzymes. These strains do not demonstrate synergistic effects with penicillin.

Recently, resistance to vancomycin, the antibiotic most used for ampicillin-resistant strains of enterococci has emerged. Vancomycin resistance is due to a subtle change in peptidoglycan precursors, which are generated by ligases that modify the terminal amino acids of cross-linking side chains at the point where β-lactams bind. The modifications decrease the binding affinity for penicillins 1000-fold without a detectable loss in peptidoglycan strength. Although hospitals vary, the average rate of resistance in enterococci isolated from intensive care units is around 20%. Enterococci are intrinsically resistant to sulfonamides and often resistant to tetracyclines and erythromycin.

Ampicillin remains the agent of choice for most UTIs and minor soft tissue infections. More severe infections, particularly endocarditis, are usually treated with combinations of a penicillin and aminoglycoside. Vancomycin is used for ampicillin-resistant strains in combination with other agents, as guided by susceptibility testing. If the strain is vancomycin resistant, linezolid is an alternative.