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, GAS can trigger the postinfectious syndromes of ARF (which is uniquely associated with S. pyogenes infection; Chap. 46) and PSGN.
Worldwide, GAS infections and their postinfectious sequelae (primarily ARF and rheumatic heart disease) account for an estimated 500,000 deaths per year. Although data are incomplete, the incidence of all forms of GAS infection and that of rheumatic heart disease are thought to be tenfold higher in resource-limited countries than in developed countries (Fig. 44-1).
Prevalence of rheumatic heart disease in children 5–14 years old. The circles within Australia and New Zealand represent indigenous populations (and also Pacific Islanders in New Zealand). (From JR Carapetis et al: Lancet Infect Dis 5:685, 2005, with permission.)
GAS elaborates a number of cell-surface components and extracellular products important in both the pathogenesis of infection and the human immune response. The cell wall contains a carbohydrate antigen that may be released by acid treatment. The reaction of such acid extracts with group A–specific antiserum is the basis for definitive identification of a streptococcal strain as S. pyogenes. The major surface protein of GAS 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 GAS isolates uses the polymerase chain reaction to amplify the variable region of the emm gene, which encodes M protein. 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 emm 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 GAS 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.
GAS also elaborates, to varying degrees, a polysaccharide capsule composed of hyaluronic acid. The production of large amounts of capsule by certain strains imparts a characteristic mucoid appearance to the colonies. The capsular polysaccharide plays an important role in protecting GAS 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 GAS colonization of the pharynx by binding to CD44, a hyaluronic acid–binding protein expressed on human pharyngeal epithelial cells.
GAS produces 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; SpyCEP, a serine protease that cleaves and inactivates the chemoattractant cytokine interleukin 8, thereby inhibiting neutrophil recruitment to the site of infection; and several pyrogenic exotoxins. Previously known as erythrogenic toxins, the pyrogenic exotoxins cause the rash of scarlet fever. Since the mid-1980s, pyrogenic exotoxin–producing strains of GAS have been linked to unusually severe invasive infections, including necrotizing fasciitis and the streptococcal toxic shock syndrome (TSS). Several extracellular products stimulate specific antibody responses useful for serodiagnosis of recent streptococcal infection. Tests for these antibodies are used primarily for detection of preceding streptococcal infection in cases of suspected ARF or PSGN.
Although seen in patients of all ages, GAS pharyngitis is one of the most common bacterial infections of childhood, accounting for 20–40% 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 1–4 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 etiologies (Table 44-2). Streptococcal infection is an unlikely cause when symptoms and signs suggestive of viral infection are prominent (conjunctivitis, coryza, cough, hoarseness, or discrete ulcerative lesions of the buccal or pharyngeal mucosa). 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 of definitive diagnosis. A rapid diagnostic kit for latex agglutination or enzyme immunoassay of swab specimens is a useful adjunct to throat culture. While precise figures on sensitivity and specificity vary, rapid diagnostic kits generally are >95% specific. Thus a positive result can be relied upon for definitive diagnosis and eliminates the need for throat culture. However, because rapid diagnostic tests are less sensitive than throat culture (relative sensitivity in comparative studies, 55–90%), a negative result should be confirmed by throat culture.
TABLE 44-2INFECTIOUS ETIOLOGIES OF ACUTE PHARYNGITIS ||Download (.pdf) TABLE 44-2 INFECTIOUS ETIOLOGIES OF ACUTE PHARYNGITIS
|ORGANISM ||ASSOCIATED CLINICAL SYNDROME(S) |
|Rhinovirus ||Common cold |
|Coronavirus ||Common cold |
|Adenovirus ||Pharyngoconjunctival fever |
|Influenza virus ||Influenza |
|Parainfluenza virus ||Cold, croup |
|Coxsackievirus ||Herpangina, hand-foot-and-mouth disease |
|Herpes simplex virus ||Gingivostomatitis (primary infection) |
|Epstein-Barr virus ||Infectious mononucleosis |
|Cytomegalovirus ||Mononucleosis-like syndrome |
|HIV ||Acute (primary) infection syndrome |
|Group A streptococci ||Pharyngitis, scarlet fever |
|Group C or G streptococci ||Pharyngitis |
|Mixed anaerobes ||Vincent’s angina |
|Arcanobacterium haemolyticum ||Pharyngitis, scarlatiniform rash |
|Neisseria gonorrhoeae ||Pharyngitis |
|Treponema pallidum ||Secondary syphilis |
|Francisella tularensis ||Pharyngeal tularemia |
|Corynebacterium diphtheriae ||Diphtheria |
|Yersinia enterocolitica ||Pharyngitis, enterocolitis |
|Yersinia pestis ||Plague |
|Chlamydiae || |
| Chlamydia pneumoniae ||Bronchitis, pneumonia |
| Chlamydia psittaci ||Psittacosis |
|Mycoplasmas || |
| Mycoplasma pneumoniae ||Bronchitis, pneumonia |
TREATMENT Gas Pharyngitis
In the usual course of uncomplicated streptococcal pharyngitis, symptoms resolve after 3–5 days. The course is shortened little by treatment, which is given primarily to prevent suppurative complications and ARF. Prevention of ARF depends on eradication of the organism from the pharynx, not simply on resolution of symptoms, and requires 10 days of penicillin treatment (Table 44-3). A first-generation cephalosporin, such as cephalexin or cefadroxil, may be substituted for penicillin in cases of penicillin allergy if the nature of the allergy is not an immediate hypersensitivity reaction (anaphylaxis or urticaria) or another potentially life-threatening manifestation (e.g., severe rash and fever).
Alternative agents are erythromycin and azithromycin. Azithromycin is more expensive but offers the advantages of better gastrointestinal tolerability, once-daily dosing, and a 5-day treatment course. Resistance to erythromycin and other macrolides is common among 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 with resistance rates exceeding 5–10%, 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 ARF is thought to be high (e.g., when cases of ARF have recently been reported in the community).
TABLE 44-3TREATMENT OF GROUP A STREPTOCOCCAL INFECTIONS ||Download (.pdf) TABLE 44-3 TREATMENT OF GROUP A STREPTOCOCCAL INFECTIONS
|INFECTION ||TREATMENTa |
|Pharyngitis ||Benzathine penicillin G (1.2 mU IM) or penicillin V (250 mg PO tid or 500 mg PO bid) × 10 days |
| ||(Children <27 kg: Benzathine penicillin G [600,000 units IM] or penicillin V [250 mg PO bid or tid] × 10 days) |
|Impetigo ||Same as pharyngitis |
|Erysipelas/cellulitis ||Severe: Penicillin G (1–2 mU IV q4h) |
| ||Mild to moderate: Procaine penicillin (1.2 mU IM bid) |
|Necrotizing fasciitis/myositis ||Surgical debridement plus penicillin G (2–4 mU IV q4h) plus clindamycinb (600–900 mg IV q8h) |
|Pneumonia/empyema ||Penicillin G (2–4 mU IV q4h) plus drainage of empyema |
|Streptococcal toxic shock syndrome ||Penicillin G (2–4 mU IV q4h) plus clindamycinb (600–900 mg IV q8h) plus IV immunoglobulinb (2 g/kg as a single dose) |
Suppurative complications of streptococcal pharyngitis have become uncommon with the widespread use of antibiotics for most symptomatic cases. These 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 peritonsillar or parapharyngeal abscess formation, 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 ARF (Chap. 46) and PSGN, 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 ARF but not that of PSGN.
Bacteriologic treatment failure and the asymptomatic carrier state
Surveillance cultures have shown that up to 20% of individuals in certain populations may have asymptomatic pharyngeal colonization with GAS. There are no definitive guidelines for management of these asymptomatic carriers or of asymptomatic patients 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 ARF 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 probably are 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, vagina, or anus or on the skin.
TREATMENT Asymptomatic Pharyngeal Colonization with GAS
When a carrier is transmitting infection to others, attempts to eradicate carriage are warranted. Data are limited on the best regimen to clear GAS after penicillin alone has failed. Regimens reported to have efficacy superior to that of penicillin alone for eradication of carriage include (1) oral clindamycin (7 mg/kg; 300 mg maximum) three times daily for 10 days or (2) penicillin (as recommended for treatment of pharyngitis in Table 44-3) plus oral rifampin (10 mg/kg; 300 mg maximum) twice daily for the first 4 days of treatment. A 10-day course of oral vancomycin (250 mg four times daily) and rifampin (600 mg twice daily) has eradicated rectal colonization.
Scarlet fever consists of streptococcal infection, usually pharyngitis, accompanied by a characteristic rash (Fig. 44-2). The rash arises from the effects of one of several toxins, currently designated streptococcal pyrogenic exotoxins 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 GAS. 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 GAS 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 skinfolds (Pastia’s lines). Subsidence of the rash in 6–9 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, TSS, and systemic allergic reactions (e.g., drug eruptions).
Scarlet fever exanthem. Finely punctate erythema has become confluent (scarlatiniform); petechiae can occur and have a linear configuration within the exanthem in body folds (Pastia’s lines). (From Fitzpatrick, Johnson, Wolff: Color Atlas and Synopsis of Clinical Dermatology, 4th ed, New York, McGraw-Hill, 2001, with permission.)
Skin and soft tissue infections
GAS—and occasionally other streptococcal species—can cause a variety of infections involving the skin, subcutaneous tissues, muscles, and fascia. While several clinical syndromes offer a useful means for classification of these infections, not all cases fit exactly into one category. The classic syndromes are 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, a superficial infection of the skin, is caused primarily by GAS and occasionally by other streptococci or Staphylococcus aureus. Impetigo is seen most often in young children, tends to occur during 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 GAS precedes 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 (Fig. 44-3). Lesions generally are 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 GAS. In almost all cases, streptococci are isolated initially and staphylococci appear later, presumably as secondary colonizing flora. In the past, penicillin was nearly always effective against these infections. However, an increasing frequency of penicillin treatment failure suggests that S. aureus may have become more prominent as a cause of impetigo. Bullous impetigo due to S. aureus is distinguished from typical streptococcal infection by 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 GAS in impetigo and the responsible virus in herpesvirus infections.
Impetigo contagiosa is a superficial streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. Occasionally, bullous lesions may be seen. (Courtesy of Mary Spraker, MD; with permission.)
TREATMENT Streptococcal Impetigo
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. Culture may be indicated to rule out methicillin-resistant S. aureus, especially if the response to empirical treatment is unsatisfactory. ARF is not a sequela to streptococcal skin infections, although PSGN 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 ARF occurs only after infection of the pharyngeal mucosa. In addition, the strains of GAS 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.
Inoculation of organisms into the skin may lead to cellulitis: infection involving the skin and subcutaneous tissues. 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 (Fig. 44-4). 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 2–3 days after onset. The lesion typically develops over a few hours and is associated with fever and chills. Erysipelas tends to occur on 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 typical features, are almost always due to β-hemolytic streptococci, usually GAS and occasionally 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 involved may not be typical 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 empirical 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.
Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques.
Streptococcal cellulitis tends to develop at anatomic sites in which normal lymphatic drainage has been disrupted, such as sites of prior 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 dermal breach some distance from the eventual site of clinical cellulitis. For example, some patients with recurrent 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. GAS is 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 infection site.
TREATMENT Streptococcal Cellulitis
See Table 44-3 and Chap. 26.
Deep soft-tissue infections
Necrotizing fasciitis (hemolytic streptococcal gangrene) involves 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 tissue through 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 inoculation site 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. Cases associated with the bowel flora are 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 GAS alone or in combination with other organisms (most often S. aureus). Overall, GAS is implicated in ~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 on, 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 over 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, GAS occasionally produces 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 seen in necrotizing fasciitis, but with the necrotizing inflammatory process extending into the muscles themselves rather than remaining limited to the fascial layers.
TREATMENT Deep Soft-Tissue Infections
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 (Table 44-3), 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 infection and ensures adequate debridement of involved tissues—and high-dose penicillin (Table 44-3).
GAS is 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 manifestations. Cough is usually present but may not be prominent. Approximately one-half of patients with GAS 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 its volume may increase 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
GAS 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. GAS is occasionally implicated in infectious complications of childbirth, usually endometritis and associated bacteremia. In the preantibiotic era, puerperal sepsis was commonly caused by GAS; currently, it is more often caused by GBS. Several nosocomial outbreaks of puerperal GAS infection have been traced to an asymptomatic carrier, usually someone present at delivery. The site of carriage may be the skin, throat, anus, or vagina.
Beginning in the late 1980s, several reports described patients with GAS infections associated with shock and multisystem organ failure. This syndrome was called streptococcal TSS because it shares certain features with staphylococcal TSS. In 1993, a case definition for streptococcal TSS was formulated (Table 44-4). 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 patients with staphylococcal TSS, the majority 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 receive aggressive supportive care (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 case 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.
TABLE 44-4PROPOSED CASE DEFINITION FOR THE STREPTOCOCCAL TOXIC SHOCK SYNDROMEa ||Download (.pdf) TABLE 44-4 PROPOSED CASE DEFINITION FOR THE STREPTOCOCCAL TOXIC SHOCK SYNDROMEa
Isolation of group A streptococci (Streptococcus pyogenes)
From a normally sterile site
From a nonsterile site
Clinical signs of severity
≥2 of the following signs
Liver function impairment
Adult respiratory distress syndrome
A generalized erythematous macular rash that may desquamate
Soft tissue necrosis, including necrotizing fasciitis or myositis; or gangrene
TREATMENT Streptococcal Toxic Shock Syndrome
In light of the possible role of pyrogenic exotoxins or other streptococcal toxins in streptococcal TSS, treatment with clindamycin has been advocated by some authorities (Table 44-3), who argue that, through its direct action on protein synthesis, clindamycin is more effective in rapidly terminating toxin production than is penicillin—a cell-wall agent. Support for this view comes from studies of an experimental model of streptococcal myositis, in which mice given clindamycin had a higher rate of survival than those given penicillin. Comparable data on the treatment of human infections are not available, although retrospective analysis has suggested a better outcome when patients with invasive soft-tissue infection are treated with clindamycin rather than with cell wall-active antibiotics. Although clindamycin resistance in GAS 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. IV immunoglobulin has been used as adjunctive therapy for streptococcal TSS (Table 44-3). Pooled immunoglobulin preparations contain antibodies capable of neutralizing the effects of streptococcal toxins. Anecdotal reports and case series have suggested favorable clinical responses to IV immunoglobulin, but no adequately powered, prospective, controlled trials have been reported.
No vaccine against GAS is commercially available. A formulation that consists of recombinant peptides containing epitopes of 26 M-protein types has undergone phase 1 and 2 testing in volunteers. Early results indicate that the vaccine is well tolerated and elicits type-specific antibody responses. Vaccines based on a conserved region of M protein or on a mixture of other conserved GAS protein antigens are in earlier stages of development.
Household contacts of individuals with invasive GAS infection (e.g., bacteremia, necrotizing fasciitis, or streptococcal TSS) are at greater risk of invasive infection than the general population. Asymptomatic pharyngeal colonization with GAS has been detected in up to 25% of persons with >4 h/d of same-room exposure to an index case. However, antibiotic prophylaxis is not routinely recommended for contacts of patients with invasive disease because such an approach (if effective) would require treatment of hundreds of contacts to prevent a single case.