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Streptococcal and Enterococcal Infections

Streptococcal and Enterococcal Infections

Michael R. Wessels

Many varieties of streptococci are found as part of the normal human flora colonizing the respiratory, gastrointestinal, and genitourinary tracts. Several species are important causes of human disease. Group A Streptococcus, or S. pyogenes, is responsible for streptococcal pharyngitis, one of the most common bacterial infections of school-age children, and for the postinfectious syndromes of acute rheumatic fever and poststreptococcal glomerulonephritis. Group B Streptococcus, or S. agalactiae, is the leading cause of bacterial sepsis and meningitis in newborns and a major cause of endometritis and fever in parturient women. Enterococci are important causes of urinary tract infection, nosocomial bacteremia, and endocarditis. Viridans streptococci are the most common cause of bacterial endocarditis.

Streptococci are gram-positive bacteria of spherical to ovoid shape that characteristically form chains when grown in liquid media. Most streptococci that cause human infections are facultative anaerobes, although some are strict anaerobes. Streptococci are relatively fastidious organisms, requiring enriched media for growth in the laboratory. No single scheme for classification of streptococci is entirely satisfactory. Consequently, clinicians and clinical microbiologists often identify streptococci by any of several classification systems, including hemolytic pattern, Lancefield group, species name, and common or trivial name. Many of the streptococci associated with human infection produce a zone of complete hemolysis around the bacterial colony when cultured on blood agar, a pattern known as β hemolysis. The β-hemolytic streptococci can be classified by the Lancefield system, a serologic grouping based on the reaction of specific antisera with cell-wall carbohydrate antigens of the bacteria. With rare exceptions, organisms belonging to Lancefield groups A, B, C, and G are all β-hemolytic streptococci, and each is associated with characteristic patterns of human infection. Other streptococci produce a zone of partial (α) hemolysis, often imparting a greenish appearance to the agar. These α-hemolytic streptococci are further identified by biochemical testing and include S. pneumoniae, an important cause of pneumonia, meningitis, and other infections, and several species of streptococci referred to collectively as the viridans streptococci, which are part of the normal oral flora and are important as agents of subacute bacterial endocarditis. Finally, some streptococci are nonhemolytic, a pattern sometimes called γ hemolysis. The classification of the major groups of streptococci responsible for human infections is outlined in Table1 . Among the organisms classified serologically as group D streptococci, the enterococci are now considered to constitute a separate genus on the basis of DNA homology studies. Thus species previously designated as S. faecalis and S. faecium have been renamed Enterococcus faecalis and E. faecium, respectively.

GROUP A STREPTOCOCCI

Lancefield's group A consists of a single species, S. pyogenes. As its species name implies, this organism is associated with a variety of suppurative infections. In addition, group A streptococci can trigger the postinfectious syndromes of acute rheumatic fever (which is uniquely associated with S. pyogenes infection; and poststreptococcal glomerulonephritis.

PATHOGENESIS

Group A streptococci elaborate a number of cell-surface components and extracellular products important both in the pathogenesis of infection and in the immune response of the human host. The cell wall contains a carbohydrate antigen that may be released by treatment with acid. The reaction of such acid extracts with group A–specific antiserum is the basis for the definitive identification of a streptococcal strain as S. pyogenes. The major surface protein of group A streptococci is M protein, which occurs in more than 100 antigenically distinct types and is the basis for the serotyping of strains with specific antisera. The M protein molecules are fibrillar structures anchored in the cell wall of the organism that extend as hairlike projections away from the cell surface. The amino acid sequence of the distal or amino-terminal portion of the M protein molecule is quite variable, accounting for the antigenic variation of the different M types, while more proximal regions of the protein are relatively conserved. A newer technique for assignment of M type to group A streptococcal isolates uses the polymerase chain reaction to amplify the variable region of the M protein gene. DNA sequence analysis of the amplified gene segment can be compared with an extensive database [developed at the Centers for Disease Control and Prevention (CDC)] for assignment of M type. This method eliminates the need for typing sera, which are available in only a few reference laboratories. The presence of M protein on a group A streptococcal isolate correlates with its capacity to resist phagocytic killing in fresh human blood; this phenomenon appears to be due, at least in part, to the binding of plasma fibrinogen to M protein molecules on the streptococcal surface, which interferes with complement activation and deposition of opsonic complement fragments on the bacterial cell. This resistance to phagocytosis may be overcome by M protein–specific antibodies; thus individuals with antibodies to a given M type acquired as a result of prior infection are protected against subsequent infection with organisms of the same M type but not against that with different M types.

Group A streptococci also elaborate, to varying degrees, a polysaccharide capsule composed of hyaluronic acid. The production of large amounts of hyaluronic acid capsule by certain strains lends a characteristic mucoid appearance to the bacterial colonies. The capsular polysaccharide also plays an important role in protecting the organisms from ingestion and killing by phagocytes. In contrast to M protein, the hyaluronic acid capsule is a weak immunogen, and antibodies to hyaluronate have not been shown to be important in protective immunity; the presumed explanation is the apparent structural identity between streptococcal hyaluronic acid and the hyaluronic acid of mammalian connective tissues. The capsular polysaccharide may also play a role in group A streptococcal colonization of the pharynx by binding to CD44, a hyaluronic acid–binding protein expressed on human pharyngeal epithelial cells.

Group A streptococci produce a large number of extracellular products that may be important in local and systemic toxicity and in the spread of infection through tissues. These products include streptolysins S and O, toxins that damage cell membranes and account for the hemolysis produced by the organisms; streptokinase; DNases; protease; and pyrogenic exotoxins A, B, and C. The pyrogenic exotoxins, previously known as erythrogenic toxins, cause the rash of scarlet fever. Since the mid-1980s, pyrogenic exotoxin–producing strains of group A Streptococcus have been linked to unusually severe invasive infections, including necrotizing fasciitis and a systemic syndrome termed the streptococcal toxic shock syndrome. Several extracellular products stimulate specific antibody responses useful in the serodiagnosis of recent streptococcal infection. Tests for these antibodies are used primarily for the detection of preceding streptococcal infection in cases of suspected acute rheumatic fever or poststreptococcal glomerulonephritis.

CLINICAL MANIFESTATIONS

Pharyngitis

Although seen in patients of all ages, group A streptococcal pharyngitis is one of the most common bacterial infections of childhood, accounting for 20 to 40% of all cases of exudative pharyngitis in children; it is rare among those under the age of 3. Younger children may manifest streptococcal infection with a syndrome of fever, malaise, and lymphadenopathy without exudative pharyngitis. Infection is acquired through contact with another individual carrying the organism. Respiratory droplets are the usual mechanism of spread, although other routes, including food-borne outbreaks, have been well described.

The incubation period is 1 to 4 days. Symptoms include sore throat, fever and chills, malaise, and sometimes abdominal complaints and vomiting, particularly in children. Both symptoms and signs are quite variable, ranging from mild throat discomfort with minimal physical findings to high fever and severe sore throat associated with intense erythema and swelling of the pharyngeal mucosa and the presence of purulent exudate over the posterior pharyngeal wall and tonsillar pillars. Enlarged, tender anterior cervical lymph nodes commonly accompany exudative pharyngitis.

The differential diagnosis of streptococcal pharyngitis includes the many other bacterial and viral causes of pharyngitis (Table 2). Streptococcal infection is unlikely to be the cause of pharyngitis when symptoms and signs suggestive of viral infection are prominent (conjunctivitis, coryza, cough, hoarseness, or discrete ulcerative lesions of the buccal or pharyngeal mucosa). Other infections commonly producing exudative pharyngitis include infectious mononucleosis and adenovirus infection. Now rare in the United States, the pseudomembrane of diphtheria may give a similar appearance. The coryneform organism Arcanobacterium haemolyticum may cause pharyngitis, often in association with a scarlet fever–like rash. Other causes of pharyngitis, usually without a purulent exudate, include coxsackievirus, influenza virus, mycoplasmas, and Neisseria gonorrhoeae and acute infection with HIV. Because of the range of clinical presentations of streptococcal pharyngitis and the large number of other agents that can produce the same clinical picture, diagnosis of streptococcal pharyngitis on clinical grounds alone is not reliable.

The throat culture remains the diagnostic “gold standard.” Culture of a throat specimen that is properly collected (i.e., by vigorous rubbing of a sterile swab over both tonsillar pillars) and properly processed is the most sensitive and specific means available to make a definitive diagnosis. A rapid diagnostic kit for latex agglutination or enzyme immunoassay of swab specimens can serve as a useful adjunct to the throat culture. While precise figures on sensitivity and specificity vary among studies, the rapid diagnostic kits generally are >95% specific. Thus a positive result can be relied upon for definitive diagnosis and eliminates the need for a throat culture. However, because the rapid diagnostic tests are less sensitive than throat culture (with a relative sensitivity ranging from 55 to 90% in comparative studies), a negative result should be confirmed with a throat culture.

TREATMENT

In the usual course of uncomplicated streptococcal pharyngitis, symptoms resolve after 3 to 5 days. The course is shortened little by treatment, which is given primarily to prevent suppurative complications and rheumatic fever. Prevention of rheumatic fever depends on eradication of the organism from the pharynx, not simply on resolution of symptoms, and requires 10 days of penicillin treatment—either a single intramuscular dose of benzathine penicillin G or a 10-day course of oral penicillin (Table 3). Erythromycin may be substituted for penicillin in the treatment of individuals allergic to penicillin. Once-daily azithromycin is a more convenient but expensive alternative. Although azithromycin is approved for a 5-day course of treatment, only limited data support equivalent efficacy to a standard 10-day treatment course. Resistance to erythromycin and other macrolides is common in isolates from several countries, including Spain, Italy, Finland, Japan, and Korea. Macrolide resistance may be becoming more prevalent elsewhere with the increasing use of this class of antibiotics. In areas in which resistance rates exceed 5 to 10%, macrolides should be avoided unless results of susceptibility testing are known. Follow-up culture after treatment is no longer routinely recommended but may be warranted in selected cases, such as those involving patients or families with frequent streptococcal infections or those occurring in situations in which the risk of rheumatic fever is thought to be high (e.g., when cases of rheumatic fever have recently been reported in the community).

COMPLICATIONS

Suppurative complications of streptococcal pharyngitis have become uncommon with the widespread use of antibiotics for most cases of symptomatic streptococcal infection. The complications result from the spread of infection from the pharyngeal mucosa to deeper tissues by direct extension or by the hematogenous or lymphatic route and may include cervical lymphadenitis, peritonsillar or retropharyngeal abscess, sinusitis, otitis media, meningitis, bacteremia, endocarditis, and pneumonia. Local complications, such as abscess formation in the peritonsillar or parapharyngeal space, should be considered in a patient with unusually severe or prolonged symptoms or localized pain associated with high fever and a toxic appearance. Nonsuppurative complications include acute rheumatic fever and poststreptococcal glomerulonephritis, both of which are thought to result from immune responses to streptococcal infection. Penicillin treatment of streptococcal pharyngitis has been shown to reduce the likelihood of acute rheumatic fever but not that of poststreptococcal glomerulonephritis.

Bacteriologic Treatment Failure and the Asymptomatic CarrierState

Surveillance cultures have shown that up to 20% of individuals in certain populations may have asymptomatic pharyngeal colonization with group A streptococci. There are no definitive guidelines for management of these asymptomatic carriers or of asymptomatic individuals who still have a positive throat culture after a full course of treatment for symptomatic pharyngitis. A reasonable course of action is to give a single 10-day course of penicillin for symptomatic pharyngitis and, if positive cultures persist, not to re-treat unless symptoms recur. Studies of the natural history of streptococcal carriage and infection have shown that the risk both of developing rheumatic fever and of transmitting infection to others is substantially lower among asymptomatic carriers than among individuals with symptomatic pharyngitis. Therefore, overly aggressive attempts to eradicate carriage are probably not justified under most circumstances. An exception is the situation in which an asymptomatic carrier is a potential source of infection to others. Outbreaks of food-borne infection and nosocomial puerperal infection have been traced to asymptomatic carriers who may harbor the organisms in the throat, on the skin, or in the vagina or anus.

TREATMENT

In cases in which a carrier is transmitting infection to others, attempts to eradicate carriage are warranted, although data are limited on the best regimen to use to clear the organism after penicillin alone has failed. The combination of penicillin V (500 mg four times daily for 10 days) and rifampin (600 mg twice daily for the last 4 days) has been used to eliminate pharyngeal carriage. A 10-day course of oral vancomycin (250 mg four times daily) and rifampin (600 mg twice daily) has eradicated rectal colonization. However, experience is not extensive with any regimen.

Scarlet Fever

Scarlet fever consists of streptococcal infection, usually pharyngitis, accompanied by a characteristic rash. The rash arises from the effects of one of three toxins, currently designated streptococcal pyrogenic exotoxins A, B, and C, and previously known as erythrogenic or scarlet fever toxins. In the past, scarlet fever was thought to reflect infection of an individual lacking toxin-specific immunity with a toxin-producing strain of group A Streptococcus. Susceptibility to scarlet fever was correlated with results of the Dick test, in which a small amount of erythrogenic toxin injected intradermally produced local erythema in susceptible individuals but elicited no reaction in those with specific immunity. Subsequent studies have suggested that development of the scarlet fever rash may reflect a hypersensitivity reaction requiring prior exposure to the toxin. For reasons that are not clear, scarlet fever has become less common in recent years, although strains of group A streptococci that produce pyrogenic exotoxins continue to be prevalent in the population.

The symptoms of scarlet fever are the same as those of pharyngitis alone. The rash typically begins on the first or second day of illness over the upper trunk, spreading to involve the extremities but sparing the palms and soles. The rash is made up of minute papules, giving a characteristic “sandpaper” feel to the skin. Associated findings include circumoral pallor, “strawberry tongue” (enlarged papillae on a coated tongue, which later may become denuded), and accentuation of the rash in the skin folds (Pastia's lines). Subsidence of the rash in 6 to 9 days is followed after several days by desquamation of the palms and soles. The differential diagnosis of scarlet fever includes other causes of fever and generalized rash, such as measles and other viral exanthems, Kawasaki disease, toxic shock syndrome, and systemic allergic reactions (e.g., drug eruptions).

Skin and Soft Tissue Infections

Group A streptococci—and occasionally other streptococcal species—cause a variety of infections involving the skin, subcutaneous tissues, muscles, and fascia. While several clinical syndromes, recognized according to the tissues involved, offer a useful means for classification of skin and soft tissue infections, not all cases fit exactly into a single category. The classic syndromes should be considered as general guides to predicting the level of tissue involvement in a particular patient, the probable clinical course, and the likelihood that surgical intervention or aggressive life-support will be required.

IMPETIGO (PYODERMA)

Impetigo is a superficial infection of the skin caused primarily by group A streptococci and occasionally by other streptococci or by Staphylococcus aureus. Impetigo is seen most often in young children, tends to occur during the warmer months, and is more common in semitropical or tropical climates than in cooler regions. Infection is more common among children living under conditions of poor hygiene. Prospective studies have shown that colonization of unbroken skin with group A streptococci precedes the development of clinical infection. Minor trauma, such as a scratch or an insect bite, may then serve to inoculate organisms into the skin. Impetigo is best prevented, therefore, by attention to adequate hygiene. The usual sites of involvement are the face (particularly around the nose and mouth) and the legs, although lesions may occur at other locations. Individual lesions begin as red papules, which evolve quickly into vesicular and then pustular lesions that break down and coalesce to form characteristic honeycomb-like crusts. Lesions are generally not painful, and patients do not appear ill. Fever is not a feature of impetigo and, if present, suggests either infection extending to deeper tissues or another diagnosis.

The classic presentation of impetigo usually poses little diagnostic difficulty. Cultures of impetiginous lesions often yield S. aureus as well as group A streptococci, but longitudinal studies have shown that, in almost all cases, streptococci can be isolated initially, with staphylococci appearing later, presumably as secondary colonizing flora. In the past, penicillin was nearly always effective against these infections; in recent years, however, penicillin treatment failures have become more common, an observation suggesting that S. aureus infection may have become more prominent as a cause of impetigo. Bullous impetigo due to S. aureus is distinguished from typical streptococcal infection by the presence of more extensive, bullous lesions that break down and leave thin paper-like crusts instead of the thick amber crusts of streptococcal impetigo. Other skin lesions that may be confused with impetigo include herpetic lesions—either those of orolabial herpes simplex or those of chickenpox or zoster. Herpetic lesions can generally be distinguished by their appearance as more discrete, grouped vesicles and by a positive Tzanck test. In difficult cases, cultures of vesicular fluid should yield group A streptococci in impetigo and the responsible virus in Herpesvirus infections.

TREATMENT

Treatment of streptococcal impetigo is the same as that for streptococcal pharyngitis. In view of evidence that S. aureus has become a relatively frequent cause of impetigo, empirical regimens should cover both streptococci and S. aureus. For example, either dicloxacillin or cephalexin can be given at a dose of 250 mg four times daily for 10 days. Topical mupirocin ointment is also effective. Rheumatic fever is not a sequela to streptococcal skin infections, although poststreptococcal glomerulonephritis may follow either skin or throat infection. The reason for this difference is not known. One hypothesis is that the immune response necessary for development of rheumatic fever occurs only after infection of the pharyngeal mucosa. In addition, the strains of group A streptococci that cause pharyngitis are generally of different M protein types than those associated with skin infections; thus the strains that cause pharyngitis may have rheumatogenic potential, while the skin-infecting strains may not.

CELLULITIS

Inoculation of organisms into the skin may lead to infection involving the skin and subcutaneous tissues, or cellulitis. The portal of entry may be a traumatic or surgical wound, an insect bite, or any other break in skin integrity. Often, no entry site is apparent.

One form of streptococcal cellulitis, erysipelas, is characterized by a bright red appearance of the involved skin, which forms a plateau sharply demarcated from surrounding normal skin. The lesion is warm to the touch, may be tender, and appears shiny and swollen. The skin often has a peau d'orange texture, which is thought to reflect involvement of superficial lymphatics; superficial blebs or bullae may form, usually 2 or 3 days after onset. The lesion typically develops over a few hours and is associated with fever and chills. Erysipelas tends to occur in certain characteristic locations: the malar area of the face (often with extension over the bridge of the nose to the contralateral malar region) and the lower extremities. After one episode, recurrence at the same site—sometimes years later—is not uncommon.

Classic cases of erysipelas, with the typical features described above, are almost always due to β-hemolytic streptococci, usually those of group A and occasionally those of group C or G. Often, however, the appearance of streptococcal cellulitis is not sufficiently distinctive to permit a specific diagnosis on clinical grounds. The area of involvement may not be one of the typical sites for erysipelas, the lesion may be less intensely red than usual and may fade into surrounding skin, and/or the patient may appear only mildly ill. In such cases, it is prudent to broaden the spectrum of empiric antimicrobial therapy to include other pathogens, particularly S. aureus, that can produce cellulitis with the same appearance. Staphylococcal infection should be suspected if cellulitis develops around a wound or an ulcer.

Streptococcal cellulitis tends to develop at anatomic sites in which normal lymphatic drainage has been disrupted, such as sites of prior episodes of cellulitis, the arm ipsilateral to a mastectomy and axillary lymph node dissection, a lower extremity previously involved in deep venous thrombosis or chronic lymphedema, or the leg from which a saphenous vein has been harvested for coronary artery bypass grafting. The organism may enter via a breach in the dermal barrier at a location some distance from the eventual site of clinical cellulitis. For example, some patients with recurrent episodes of leg cellulitis following saphenous vein removal stop having recurrent episodes only after treatment of tinea pedis on the affected extremity. Fissures in the skin presumably serve as a portal of entry for streptococci, which then produce infection more proximally in the leg at the site of previous injury. Streptococcal cellulitis may also involve recent surgical wounds. Group A streptococci are among the few bacterial pathogens that typically produce signs of wound infection and surrounding cellulitis within the first 24 h after surgery. These wound infections are usually associated with a thin exudate and may spread rapidly, either as cellulitis in the skin and subcutaneous tissue or as a deeper tissue infection (see below). Streptococcal wound infection or localized cellulitis may also be associated with lymphangitis, manifested by red streaks extending proximally along superficial lymphatics from the site of infection.

TREATMENT

Deep Soft-Tissue Infections

Necrotizing fasciitis, also referred to as hemolytic streptococcal gangrene, is an infection involving the superficial and/or deep fascia investing the muscles of an extremity or the trunk. The source of the infection is either the skin, with organisms introduced into the tissue as a result of trauma (sometimes trivial), or the bowel flora, with organisms released during abdominal surgery or from an occult enteric source, such as a diverticular or appendiceal abscess. The site of inoculation in both forms of necrotizing fasciitis may be inapparent and is often some distance from the site of clinical involvement; e.g., the introduction of organisms via minor trauma to the hand may be associated with clinical infection of the tissues overlying the shoulder or chest. In cases associated with the bowel flora, the infection is usually polymicrobial, involving a mixture of anaerobic bacteria (such as Bacteroides fragilis or anaerobic streptococci) and facultative organisms (usually gram-negative bacilli). Cases unrelated to contamination from bowel organisms are most commonly caused by group A streptococci, either alone or in combination with other organisms (most often S. aureus). Overall, group A streptococci are implicated in about 60% of cases of necrotizing fasciitis. The onset of symptoms is usually quite acute and is marked by severe pain at the site of involvement, malaise, fever, chills, and a toxic appearance. The physical findings, particularly early in the illness, may not be striking, with only minimal erythema of the overlying skin. Pain and tenderness are usually severe; in contrast, in more superficial cellulitis, the skin appearance is more abnormal, but pain and tenderness are only mild or moderate. As the infection progresses (often in a matter of several hours), the severity and extent of symptoms worsen, and skin changes become more evident, with the appearance of dusky or mottled erythema and edema. The marked tenderness of the involved area may evolve into anesthesia as the spreading inflammatory process produces infarction of cutaneous nerves.

Although myositis is more commonly due to S. aureus infection, group A streptococci occasionally produce abscesses in skeletal muscles (streptococcal myositis), with little or no involvement of the surrounding fascia or overlying skin. The presentation is usually subacute, but a fulminant form has been described in association with severe systemic toxicity, bacteremia, and a high mortality rate. The fulminant form may reflect the same basic disease process as that seen in necrotizing fasciitis, but with the necrotizing inflammatory process extending into the muscles themselves rather than remaining limited to the fascial layers.

 Once necrotizing fasciitis is suspected, early surgical exploration is both diagnostically and therapeutically indicated. Surgery reveals necrosis and inflammatory fluid tracking along the fascial planes above and between muscle groups, without involvement of the muscles themselves. The process usually extends beyond the area of clinical involvement, and extensive debridement is required. Drainage and debridement are central to the management of necrotizing fasciitis; antibiotic treatment is a useful adjunct, but surgery is life-saving.

Treatment for streptococcal myositis consists of surgical drainage—usually by an open procedure that permits evaluation of the extent of the infection and ensures adequate debridement of involved tissues—and high-dose penicillin.

Pneumonia and Empyema

Group A streptococci are an occasional cause of pneumonia, generally in previously healthy individuals. The onset of symptoms may be abrupt or gradual. Pleuritic chest pain, fever, chills, and dyspnea are the characteristic symptoms. Cough is usually present but may not be prominent. Approximately one-half of patients with group A streptococcal pneumonia have an accompanying pleural effusion. In contrast to the sterile parapneumonic effusions typical of pneumococcal pneumonia, those complicating streptococcal pneumonia are almost always infected. The empyema fluid is usually visible by chest radiography on initial presentation and may enlarge rapidly. These pleural collections should be drained early, as they tend to become loculated rapidly, resulting in a chronic fibrotic reaction that may require thoracotomy for removal.

Bacteremia, Puerperal Sepsis, and Streptococcal Toxic Shock Syndrome

Group A streptococcal bacteremia is usually associated with an identifiable local infection. Bacteremia occurs rarely with otherwise uncomplicated pharyngitis, occasionally with cellulitis or pneumonia, and relatively frequently with necrotizing fasciitis. Bacteremia without an identified source raises the possibility of endocarditis, an occult abscess, or osteomyelitis. A variety of focal infections may arise secondarily from streptococcal bacteremia, including endocarditis, meningitis, septic arthritis, osteomyelitis, peritonitis, and visceral abscesses.

Group A streptococci are occasionally implicated in infectious complications of childbirth, usually endometritis and associated bacteremia. In the preantibiotic era, puerperal sepsis was commonly caused by group A streptococci, but currently it is more often caused by group B streptococci. Several nosocomial outbreaks of puerperal infection due to group A streptococci have been traced to an asymptomatic carrier, usually an individual present at the delivery of the infant. The site of carriage may be the skin, throat, anus, or vagina.

Beginning in the late 1980s, several reports described patients who had group A streptococcal infections associated with shock and multisystem organ failure. This syndrome has been called the streptococcal toxic shock syndrome (TSS) because it shares certain features with staphylococcal TSS. In 1993, a case definition for group A streptococcal TSS was formulated by a group of clinicians, microbiologists, and epidemiologists in conjunction with the CDC (Table 4). The general features of the illness include fever, hypotension, renal impairment, and respiratory distress syndrome. Various types of rash have been described, but rash usually does not develop. Laboratory abnormalities include a marked shift to the left in the white blood cell differential, with many immature granulocytes; hypocalcemia; hypoalbuminemia; and thrombocytopenia, which usually becomes more pronounced on the second or third day of illness. In contrast to those with staphylococcal TSS, the majority of patients with streptococcal TSS are bacteremic. The most common associated infection is a soft tissue infection—necrotizing fasciitis, myositis, or cellulitis—although a variety of other associated local infections have been described, including pneumonia, peritonitis, osteomyelitis, and myometritis. Streptococcal TSS is associated with a mortality rate of 30%, with most deaths secondary to shock and respiratory failure. Because of its rapidly progressive and lethal course, early recognition of the syndrome is essential. Patients should be given aggressive supportive care in the form of fluid resuscitation, pressors, and mechanical ventilation in addition to antimicrobial therapy and, in cases associated with necrotizing fasciitis, surgical debridement. Exactly why certain patients develop this fulminant syndrome is not known. Early studies of the streptococcal strains isolated from these patients demonstrated a strong association with the production of pyrogenic exotoxin A. This association has been inconsistent in subsequent cases series. Pyrogenic exotoxin A and several other streptococcal exotoxins act as superantigens to trigger release of inflammatory cytokines from T lymphocytes. Fever, shock, and organ dysfunction in streptococcal TSS may reflect, in part, the systemic effects of superantigen-mediated cytokine release.

TREATMENT

In light of the possible role of pyrogenic exotoxins or other streptococcal toxins in streptococcal TSS, treatment of the affected patients with clindamycin has been advocated by some authorities, who argue that, through its direct action on protein synthesis, clindamycin is more effective in rapidly terminating toxin production than penicillin—a cell-wall agent (Table 3). Support for this view comes from studies of an experimental model of streptococcal myositis, in which mice treated with clindamycin had a higher rate of survival than those given penicillin. Comparable data on the treatment of human infections are not available. Although clindamycin resistance in group A streptococci is uncommon (<2% among U.S. isolates), it has been documented. Thus, if clindamycin is used for initial treatment of a critically ill patient, penicillin should be given as well until the antibiotic susceptibility of the streptococcal isolate is known.

Intravenous immunoglobulin has been used as adjunctive therapy for streptococcal TSS; pooled immunoglobulin preparations contain antibodies capable of neutralizing the effects of streptococcal toxins (Table 3). Anecdotal reports and case series have suggested favorable clinical responses to intravenous immunoglobulin, but no prospective controlled trials of this modality of therapy have yet been reported.

STREPTOCOCCI OF GROUPS C AND G

Group C and group G streptococci are β-hemolytic bacteria that occasionally cause human infections similar to those caused by group A streptococci, including pharyngitis, cellulitis and soft-tissue infections, pneumonia, bacteremia, endocarditis, and septic arthritis. Puerperal sepsis, meningitis, epidural abscess, intraabdominal abscess, urinary tract infection, and neonatal sepsis have also been reported. Group C streptococci are a common cause of infection in domesticated animals, especially horses and cattle, and some human infections have been acquired through contact with animals or through consumption of unpasteurized milk. Bacteremia and septic arthritis more frequently involve group G than group C streptococci. Group C or G streptococcal bacteremia occurs most often in patients who are elderly or chronically ill and, in the absence of an obvious local infection, is likely to reflect endocarditis. Septic arthritis, sometimes involving multiple joints, may complicate endocarditis or develop in its absence.

TREATMENT

Penicillin is the drug of choice for treatment of infections due to group C or G streptococci. Antibiotic treatment is the same as for patients with similar syndromes due to group A Streptococcus (Table 3). Patients with bacteremia or septic arthritis should receive intravenous penicillin (2 to 4 mU every 4 h). All group C and G streptococci are sensitive to penicillin; nearly all are inhibited in vitro by concentrations of ≤0.03 µg/mL. Occasional isolates exhibit tolerance: although inhibited by low concentrations of penicillin, they are killed only by significantly higher concentrations. The clinical significance of tolerance is unknown. Because of the poor clinical response of some patients to penicillin alone, the addition of gentamicin (1 mg/kg every 8 h for patients with normal renal function) is recommended by some authorities for treatment of endocarditis or septic arthritis due to group C or G streptococci; however, combination therapy has not been shown to be superior to treatment with penicillin alone. Patients with joint infections often require repeated aspiration or open drainage and debridement for cure; the response to treatment may be slow, particularly in debilitated patients and those with involvement of more than one joint. Infection of prosthetic joints almost always requires removal of the prosthesis in addition to antibiotic therapy.

GROUP B STREPTOCOCCI

Identified first as a cause of mastitis in cows, streptococci belonging to Lancefield's group B have since been recognized as a major cause of sepsis and meningitis in human neonates. Group B streptococci are also a frequent cause of peripartum fever in women and an occasional cause of serious infection in nonpregnant adults. Lancefield group B consists of a single species, S. agalactiae, which is definitively identified with specific antiserum to the group B cell wall–associated carbohydrate antigen. A streptococcal isolate can be classified presumptively as belonging to group B on the basis of biochemical tests, including hydrolysis of sodium hippurate (in which 99% of isolates are positive), hydrolysis of bile esculin agar (in which 99 to 100% are negative), bacitracin susceptibility (in which 92% are resistant), and production of CAMP factor (in which 98 to 100% are positive). CAMP factor is a phospholipase produced by group B streptococci that results in synergistic hemolysis with β lysin produced by certain strains of S. aureus. Its presence can be demonstrated by cross-streaking of the test isolate and an appropriate staphylococcal strain on a blood agar plate. Group B streptococci causing human infections are encapsulated by one of nine antigenically distinct polysaccharides. The capsular polysaccharide has been shown experimentally to be important in the virulence of the organism. Antibodies to the capsular polysaccharide afford protection against group B streptococci of the same (but not of a different) capsular type.

INFECTION IN NEONATES

Two general types of group B streptococcal infection in infants are defined by the age of the patient at presentation. Early-onset infections occur within the first week of life, with a median age of 20 h at the onset of illness. Approximately half of these infants have signs of group B streptococcal disease at birth. The infection is acquired during or shortly before birth from organisms colonizing the maternal genital tract. Surveillance studies have shown that 5 to 40% of women are vaginal or rectal carriers of group B streptococci. Approximately 50% of infants delivered vaginally by carrier mothers become colonized, although only 1 to 2% of those colonized develop clinically evident infection. Prematurity and maternal risk factors (prolonged labor, obstetric complications, and maternal fever) are often involved. The presentation of early-onset infection is the same as that of other forms of neonatal sepsis. Typical findings include respiratory distress, lethargy, and hypotension. Essentially all infants with early-onset disease are bacteremic, one-third to one-half have pneumonia and/or respiratory distress syndrome, and one-third have meningitis.

Late-onset infections occur in infants between 1 week and 3 months of age, with a mean age at onset of 3 to 4 weeks. The infecting organism may be acquired during delivery (as in early-onset cases) or during later contact with a colonized mother, nursery personnel, or another source. Meningitis is the most common manifestation of late-onset infection and in most cases is associated with a strain of capsular type III of the organism. Infants present with fever, lethargy or irritability, poor feeding, and seizures. The various other types of late-onset infection include bacteremia without an identified source, osteomyelitis, septic arthritis, and facial cellulitis associated with submandibular or preauricular adenitis.

TREATMENT

Penicillin is the treatment of choice for all group B streptococcal infections. Empiric broad-spectrum therapy for suspected bacterial sepsis, consisting of ampicillin and gentamicin, is generally administered until culture results become available. If cultures yield group B streptococci, many pediatricians continue to administer gentamicin, along with ampicillin or penicillin, for a few days until clinical improvement becomes evident. Infants with bacteremia or soft-tissue infection should receive penicillin at a dosage of 200,000 units/kg per day in divided doses; those with meningitis should receive 400,000 units/kg per day. Meningitis should be treated for at least 14 days because of the risk of relapse with shorter courses.

Prevention

The incidence of group B streptococcal infection is unusually high among infants of women with risk factors: preterm delivery, early rupture of membranes (>24 h before delivery), prolonged labor, fever, or chorioamnionitis. Because the usual source of the organisms infecting a neonate is the mother's birth canal, efforts have been made to prevent group B streptococcal infections by the identification of high-risk carrier mothers and their treatment with various forms of antibiotic or immunoprophylaxis. Prophylactic administration of ampicillin or penicillin to such patients during delivery has been shown to reduce the risk of infection in the newborn. This approach has been hampered by the logistical difficulties of identifying colonized women before delivery, since the results of vaginal cultures early in pregnancy are poor predictors of carrier status at delivery. The CDC has recommended that women be screened for anogenital colonization at 35 to 37 weeks of pregnancy by means of a swab culture of the lower vagina and anorectum; intrapartum chemoprophylaxis is recommended for women who are culture-positive and to all women, regardless of culture status, who have previously given birth to an infant with group B streptococcal infection or who have a history of group B streptococcal bacteriuria during pregnancy. Women whose culture status is unknown and who develop premature labor (<37 weeks), prolonged rupture of membranes (>18 h), or intrapartum fever should also receive intrapartum chemoprophylaxis. The recommended regimen for chemoprophylaxis is 5 million units of penicillin G followed by 2.5 million units every 4 h until delivery. Cefazolin is an alternative for women with a history of penicillin allergy who are thought not to be at high risk for anaphylaxis. For women with a history of an immediate hypersensitivity reaction, clindamycin or erythromycin may be substituted, but only if the colonizing isolate has been demonstrated to be susceptible. If susceptibility testing results are not available or indicate resistance, vancomycin should be used in this situation.

Treatment of all pregnant women who are colonized or who have risk factors for neonatal infection will result in exposure of 15 to 25% of pregnant women and newborns to antibiotics, with the attendant risks of allergic reactions and selection for resistant organisms. Although still in the developmental stages, a group B streptococcal vaccine may ultimately offer a better solution to prevention. Because transplacental passage of maternal antibodies produces protective antibody levels in the newborn, efforts are under way to develop a vaccine against group B streptococci that can be given to childbearing women before or during pregnancy. Results of phase 1 clinical trials of group B streptococcal capsular polysaccharide–protein conjugate vaccines suggest that a multivalent conjugate vaccine would be safe and highly immunogenic.

INFECTION IN ADULTS

The majority of group B streptococcal infections in adults are related to pregnancy and parturition. Peripartum fever, the most common manifestation, is sometimes accompanied by symptoms and signs of endometritis or chorioamnionitis (abdominal distention and uterine or adnexal tenderness). Blood cultures are often positive, as are cultures of vaginal swabs. Bacteremia is usually transitory but occasionally results in meningitis or endocarditis. Infections in adults that are not associated with the peripartum period generally involve individuals who are elderly or have some underlying chronic illness, such as diabetes mellitus or a malignancy. Among the infections that develop with some frequency in adults are cellulitis and soft tissue infection (including infected diabetic skin ulcers), urinary tract infection, pneumonia, endocarditis, and septic arthritis. Other reported infections include meningitis, osteomyelitis, and intraabdominal or pelvic abscesses.

TREATMENT

Group B streptococci are less sensitive to penicillin than group A organisms, requiring somewhat higher doses. Adults with serious localized infections (pneumonia, pyelonephritis, abscess) should receive doses in the range of 12 million units of penicillin G daily, while patients with endocarditis or meningitis should receive 18 to 24 million units per day in divided doses. Vancomycin is an acceptable alternative for patients allergic to penicillin.

ENTEROCOCCI AND NONENTEROCOCCAL GROUP D STREPTOCOCCI

ENTEROCOCCI

Lancefield group D includes the enterococci, organisms now classified in a separate genus from other streptococci, and nonenterococcal group D streptococci. Enterococci are distinguished from nonenterococcal group D streptococci by their ability to grow in the presence of 6.5% sodium chloride and by the results of other biochemical tests. The enterococcal species that are significant pathogens for humans are E. faecalis and E. faecium. These organisms tend to produce infection in patients who are elderly or debilitated or in whom mucosal or epithelial barriers have been disrupted or the balance of the normal flora altered by antibiotic treatment. Urinary tract infections due to enterococci are quite common, particularly among patients who have received antibiotic treatment or undergone instrumentation of the urinary tract. Enterococci are a frequent cause of nosocomial bacteremia in patients with intravascular catheters. These organisms account for 10 to 20% of cases of bacterial endocarditis on both native and prosthetic valves. The presentation of enterococcal endocarditis is usually subacute but may be acute, with rapidly progressive valve destruction. Enterococci are frequently cultured from bile and are involved in infectious complications of biliary surgery and in liver abscesses. Moreover, enterococci are often isolated from polymicrobial infections arising from the bowel flora (e.g., intraabdominal abscesses), from abdominal surgical wounds, and from diabetic foot ulcers. While such mixed infections are frequently cured by antimicrobials not active against enterococci, specific therapy directed against enterococci is warranted when these organisms are the predominant species or are isolated from blood cultures.

TREATMENT

Unlike streptococci, enterococci are not reliably killed by penicillin or ampicillin alone at concentrations achieved clinically in the blood or tissues. Ampicillin reaches sufficiently high urinary concentrations to constitute adequate monotherapy for uncomplicated urinary tract infections. Because in vitro testing has shown evidence of synergistic killing of most enterococcal strains by the combination of penicillin or ampicillin with an aminoglycoside, combined therapy is recommended for enterococcal endocarditis and meningitis; the regimen is penicillin (3 to 4 million units every 4 h) or ampicillin (2 g every 4 h) plus moderate-dose gentamicin (1 mg/kg every 8 h for patients with normal renal function). Enterococcal endocarditis should be treated for a minimum of 4 weeks and for 6 weeks if symptoms have been present for ≥3 months or if the infection involves a prosthetic heart valve. For nonendocarditis bacteremia and other serious enterococcal infections, it is not known whether the efficacy of single-agent β-lactam therapy is improved by the addition of gentamicin, but many infectious disease specialists use combination therapy for such infections, especially in critically ill patients. Vancomycin, in combination with gentamicin, may be substituted for penicillin in allergic patients. Enterococci are resistant to all cephalosporins; therefore, this class of antibiotics should not be used for treatment of enterococcal infections.

Antimicrobial susceptibility testing should be performed routinely on enterococcal isolates from patients with serious infections, and therapy should be adjusted according to the results (Table 5). Most enterococci are resistant to streptomycin, and this drug should not be used for treatment of enterococcal infection unless in vitro testing of the strain indicates susceptibility. Though less widespread than streptomycin resistance, high-level resistance to gentamicin—with a minimum inhibitory concentration (MIC) of >2000 µg/mL—has become common. Gentamicin-resistant enterococci should be tested for susceptibility to streptomycin; occasional gentamicin-resistant enterococci are sensitive to streptomycin. If the isolate is resistant to all aminoglycosides, treatment with penicillin or ampicillin alone may be successful. The prolonged administration (i.e., for at least 6 weeks) of high-dose ampicillin (e.g., 12 g/d) is recommended for endocarditis due to these highly resistant enterococci.

Enterococci may be resistant to penicillins via two distinct mechanisms. The first is the production of β-lactamase (mediating resistance to penicillin and ampicillin), which has been reported for E. faecalis isolates from several locations in the United States and other countries. Because the amount of β-lactamase produced by enterococci may be insufficient for detection by routine antibiotic susceptibility testing, isolates from serious infections should be screened specifically for β-lactamase production with use of a chromogenic cephalosporin or by another method. For the treatment of β-lactamase-producing strains, vancomycin, ampicillin/sulbactam, amoxicillin/clavulanate, or imipenem may be used in combination with gentamicin.

The second mechanism of penicillin resistance is not mediated by β-lactamase and may be due to altered penicillin-binding proteins. This intrinsic penicillin resistance is common among E. faecium isolates, which routinely are more resistant to β-lactam antibiotics than are isolates of E. faecalis. Moderately resistant enterococci (MICs of penicillin and ampicillin, 16 to 64 µg/mL) may be susceptible to high-dose penicillin or ampicillin plus gentamicin, but strains with MICs of ≥200 µg/mL must be considered resistant to clinically achievable levels of β-lactam antibiotics, including imipenem. Vancomycin plus gentamicin is the recommended regimen for infections due to enterococci with high-level intrinsic resistance to β-lactams.

Vancomycin-resistant enterococci, first reported from clinical sources in the late 1980s, have become common in many hospitals.

Three major vancomycin resistance phenotypes have been described: VanA, VanB, and VanC. The VanA phenotype is associated with high-level resistance to vancomycin and to teicoplanin, a related glycopeptide antibiotic not currently available in the United States. VanB and VanC strains are resistant to vancomycin but susceptible to teicoplanin, although teicoplanin resistance may develop during treatment in VanB strains. For enterococci resistant to both vancomycin and β-lactams, there are no established therapies that provide uniformly bactericidal activity. Regimens that have been tried with some success in individual cases or experimentally include ciprofloxacin plus rifampin plus gentamicin; ampicillin plus vancomycin (particularly if in vitro testing shows synergistic bacteriostatic activity); and chloramphenicol or tetracycline (if the strain is susceptible in vitro). Two newer agents with activity against vancomycin-resistant enterococci are quinupristin/dalfopristin and linezolid, which were approved for use in the United States in 1999 and 2000, respectively. Quinupristin/dalfopristin is a streptogramin combination with in vitro bacteriostatic activity against E. faecium, including vancomycin-resistant isolates, but not against E. faecalis or other enterococcal species. Favorable clinical responses have been obtained in approximately three-quarters of patients treated with this agent. Linezolid is an oxazolidinone antibiotic with good bacteriostatic activity against nearly all enterococci, including vancomycin-resistant enterococci. Limited clinical experience suggests that linezolid is at least as efficacious as quinupristin/dalfopristin.

OTHER GROUP D STREPTOCOCCI

The main nonenterococcal group D streptococcal species that causes human infections is S. bovis. S. bovis endocarditis is often associated with neoplasms of the gastrointestinal tract—most frequently a colon carcinoma or polyp—but is also reported in association with other bowel lesions. When occult gastrointestinal lesions are carefully sought, abnormalities are found in ≥60% of patients with S. bovis endocarditis. In contrast to the enterococci, nonenterococcal group D streptococci like S. bovis are reliably killed by penicillin as a single agent, and penicillin is the treatment of choice for S. bovis infections.

VIRIDANS AND OTHER STREPTOCOCCI

VIRIDANS STREPTOCOCCI

Consisting of multiple species of α-hemolytic streptococci, the viridans streptococci are a heterogeneous group of organisms that are important as agents of bacterial endocarditis. Several species of viridans streptococci, including S. salivarius, S. mitis, S. sanguis, and S. mutans, are part of the normal flora of the mouth, where they live in close association with the teeth and gingiva. Some species contribute to the development of dental caries. The transient viridans streptococcal bacteremia induced by eating, tooth-brushing, flossing, and other sources of minor trauma, together with adherence to biologic surfaces, is thought to account for the predilection of these organisms to cause endocarditis. Viridans streptococci are also isolated, often as part of a mixed flora, from sites of sinusitis, brain abscess, and liver abscess.

Viridans streptococcal bacteremia occurs relatively frequently in neutropenic patients, particularly after bone marrow transplantation or high-dose chemotherapy for cancer. Some of these patients develop a sepsis syndrome with high fever and shock. Risk factors for viridans streptococcal bacteremia include chemotherapy with high-dose cytosine arabinoside, prior treatment with trimethoprim-sulfamethoxazole or a fluoroquinolone, treatment with antacids or histamine antagonists, mucositis, and profound neutropenia.

The S. milleri group (also referred to as the S. intermedius or S. anginosus group) includes three species that cause human disease: S. intermedius, S. anginosus, and S. constellatus. These organisms are often considered viridans streptococci, although they differ somewhat from other viridans streptococci in both their hemolytic pattern (they may be α-, β-, or nonhemolytic) and the disease syndromes they cause. This group commonly produces suppurative infections, particularly abscesses of brain and abdominal viscera, and infections related to the oral cavity or respiratory tract, such as peritonsillar abscess, lung abscess, and empyema.

TREATMENT

Isolates from neutropenic patients with bacteremia are often resistant to penicillin; thus these patients should be treated presumptively with vancomycin until the results of susceptibility testing become available. Viridans streptococci isolated in other clinical settings usually are sensitive to penicillin.

ABIOTROPHIA SPECIES (NUTRITIONALLY VARIANT STREPTOCOCCI)

Occasional isolates cultured from the blood of patients with endocarditis fail to grow when subcultured on solid media. These nutritionally variant streptococci require supplemental thiol compounds or active forms of vitamin B₆ (pyridoxal or pyridoxamine) for growth in the laboratory. The nutritionally variant streptococci are generally grouped with the viridans streptococci because they cause similar types of infections. However, they have been reclassified on the basis of 16S ribosomal RNA sequence comparisons into a separate genus, Abiotrophia, with two species: A. defectivus and A. adjacens.

TREATMENT

Treatment failure and relapse appear to be more common in cases of endocarditis due to nutritionally variant streptococci than in those due to the usual viridans streptococci. Thus the addition of gentamicin (1 mg/kg every 8 h for patients with normal renal function) to the penicillin regimen is recommended in therapy for endocarditis due to the nutritionally variant organisms.

OTHER STREPTOCOCCI

S. suis is an important pathogen in swine and has been reported to cause meningitis in humans, usually in individuals with occupational exposure to pigs. Strains of S. suis associated with human infections have generally reacted with Lancefield group R typing serum and sometimes with group D typing serum as well. Isolates may be α- or β-hemolytic and are sensitive to penicillin. S. iniae, a pathogen of fish, has been associated with infections in humans who have handled live or freshly killed fish. Cellulitis of the hand is the most common form of human infection, although bacteremia and endocarditis have been reported. Anaerobic streptococci, or peptostreptococci, are part of the normal flora of the oral cavity, bowel, and vagina. Infections caused by the anaerobic streptococci are discussed in

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