INTRODUCTION — Group A streptococcus (GAS; eg, Streptococcus pyogenes) is an aerobic gram-positive coccus that is a common cause of acute bacterial pharyngitis and other cutaneous and invasive infections in children [1]. Invasive GAS infections are defined as bacteremia, pneumonia, osteomyelitis, septic arthritis, or any other infection associated with the isolation of GAS from a normally sterile body site [1]. Invasive infections also include necrotizing fasciitis and spontaneous gangrenous myositis.

The epidemiology, clinical manifestations, treatment, and prognosis of GAS bacteremia and/or invasive GAS infection in children will be reviewed here. GAS bacteremia in adults and issues related to specific manifestations of invasive GAS infections (toxic shock syndrome and necrotizing fasciitis) are discussed separately:

●(See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention".)

●(See "Necrotizing soft tissue infections".)

●(See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

●(See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

EPIDEMIOLOGY — GAS bacteremia usually occurs secondary to a primary site of infection, most commonly in the skin and soft tissues [2-4]. The estimated incidence of GAS bacteremia and/or invasive infection in children is 1 to 3 cases per 100,000 per year [5-9]. The incidence is greatest in children <1 year (4 to 9 cases per 100,000) [6,7,10,11].

The frequency with which GAS bacteremia and/or invasive GAS infection occurs in children has been evaluated in two single-institution case series [2,12]. In one study, which reviewed blood cultures over a 10-year period (1993 to 2002), GAS accounted for 3.3 percent of all positive blood cultures in children and GAS bacteremia was noted in 13 per 1000 pediatric hospital admissions [2]. In another study, which evaluated invasive GAS infections in hospitalized children during a similar time period (1993 to 2001), the reported incidence ranged from 1 to 2.5 cases per 1000 hospital admissions per year [12].

Invasive GAS attack rates have been relatively stable in the United States since the mid-1990s. Approximately 100 to 200 pediatric cases were reported to the Active Bacterial Core (ABC) surveillance at the Centers for Disease Control and Prevention (CDC) each year from 2012 through 2017 [6,8-10,13,14]. While incidence rates at the national level have been stable, there may be regional variation. As an example, in population-based surveillance in Utah (which is not part of the ABC network), the incidence of invasive GAS in children <18 years increased between 2002 and 2010 (from 3 to 14 cases per 100,000), in part due to an increase in cases of pneumonia [15].

The incidence of severe GAS infection increased between 1985 and 1994, predominantly in North America and Europe [16-19]. The reason for the marked increase is not well defined. Interest focused on changes in the strains of GAS-causing invasive infections [3,4,18-20]. It has been suggested that alterations in the distribution of M-types causing infection and an increasing prevalence of toxin-producing strains could be responsible [18-20]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

In favor of this theory is the observation that a finite number of M-types of GAS (1, 3, 4, 6, and 28) cause approximately 50 percent of invasive infections; the remaining 50 percent are caused by a variety of different strains, including nontypeable strains [1,3,4,16,18,20,21]. In addition, all GAS strains isolated from invasive cases produce a toxin called NADase [21]. The M-1 strains, which have been the most common isolate from bacteremic cases, also produce this toxin, whereas strains of M-1 isolated prior to 1985, before the increase in prevalence of invasive GAS infections, did not [21].

Predisposing factors — The following predisposing factors are associated with invasive GAS infection [1-3,11,22-24]:

●Varicella-zoster virus (VZV) – Prior to widespread use of the VZV vaccine, approximately 15 to 30 percent of cases of GAS bacteremia and/or invasive GAS infection were associated with VZV infection [11,12,22-30]. Fever on or beyond the fourth day of the exanthem in children with VZV should prompt consideration of GAS bacteremia [31]. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

VZV vaccination appears to prevent VZV-associated GAS infection; however, whether this has had an impact on the overall rate of invasive GAS disease is uncertain. One report from a tertiary center in the United States found that while the percentage of VZV-related GAS hospitalizations declined from 27 to 2 percent before and after widespread use of the varicella vaccine, the overall annual hospitalization rate for invasive GAS infection did not change [12]. Another study from Israel found that the overall annual rate of pediatric invasive GAS infections fell by nearly 50 percent (from 2.4 to 1.3 cases per 100,000) after introduction of the varicella vaccine [32]. (See "Vaccination for the prevention of chickenpox (primary varicella infection)".)

●Influenza infection – GAS is a common cause of secondary bacterial infection in children with influenza and contributes to influenza-related morbidity and mortality [33,34]. (See "Seasonal influenza in children: Clinical features and diagnosis".)

●Trauma, burns, and surgery – Approximately 30 to 40 percent of invasive GAS infections are associated with recent skin disruption from minor trauma (eg, cuts, abrasions, body piercing), burns, eczema, and/or recent surgery [3,11,12,22].

●Immunosuppression or immunodeficiency – Invasive GAS infections commonly occur in children with underlying immunocompromised conditions including HIV, nephrotic syndrome, solid organ transplant, primary immune disorders, autoimmune disorders, and chronic immunosuppressive medication use [2,35].

●Malignant neoplasm – Underlying malignancy has been noted in 5 to 10 percent of patients with invasive GAS infection [11,12,22,23].

●Age <1 year – The risk of invasive GAS infection is highest in infants under the age of one year [10,11,22]. In neonates, GAS infection can occur as a result of vertical transmission from the mother or from nosocomial acquisition from medical personnel [36].

●Intravenous drug use – Intravenous drug use is a risk factor for invasive GAS infection in adolescents and adults [20,37-42]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

SOURCES OF BACTEREMIA — GAS bacteremia may arise in patients with infections of the skin, soft tissues, pharynx, and lungs.

Skin infection — The most frequent source of GAS bacteremia in children is the skin [31]. Cellulitis, minor trauma, burns, and varicella-zoster virus (VZV) infection are the most commonly associated predisposing conditions. Affected patients may have other signs of invasive GAS infection, such as osteomyelitis, septic arthritis, necrotizing fasciitis, or myonecrosis [20]. (See "Necrotizing soft tissue infections".)

Pharyngitis and respiratory tract — Bacteremia associated with GAS pharyngitis is an uncommon occurrence; even with scarlet fever, it occurs in only 0.3 percent of febrile patients [1]. Nevertheless, among patients with scarlet fever, the pharynx is the most common source of bloodstream GAS. Bacteremic children infrequently have additional complications such as extension of infection into the sinuses, peritonsillar tissue, or mastoids (septic scarlet fever or scarlet fever anginosa).

The least common source of bacteremia in children has been the lower respiratory tract. When bacteremic GAS pneumonia occurs, it usually is associated with prior viral infections, particularly influenza [43,44]. In 2009, studies in Utah showed a marked increase in invasive GAS infections following influenza [43]. Similarly, during the 2010 seasonal influenza epidemic in Great Britain, there was a marked increase in the prevalence of GAS pneumonia and bacteremia; this phenomenon was associated with a greater than 50 percent mortality [44].

CLINICAL MANIFESTATIONS — The clinical manifestations of GAS bacteremia include those of the primary site of infection and of the bacteremia. High fever (>39°C [102.2°F]), elevated white blood cell count, and elevated erythrocyte sedimentation rate (ESR) are typical but nonspecific findings [2,29,45]. A scarlatiniform rash followed by desquamation is often noted.

A focal source of infection is present in 60 to 90 percent of cases and may include the following [2,5,11,12,22,23,46,47]:

●Cellulitis (15 to 35 percent)

●Lymphadenitis (5 to 17 percent)

●Abscess (5 to 15 percent)

●Septic arthritis (7 to 14 percent)

●Myositis (12 percent)

●Osteomyelitis (5 to 8 percent)

●Pneumonia/empyema (5 to 10 percent)

●Necrotizing fasciitis (1 to 9 percent)

●Peritonitis (1 to 5 percent)

●Thrombophlebitis (0.5 to 5 percent)

●Meningitis (1 to 3 percent)

●Pericarditis (1 to 3 percent)

Patients without a focal source of infection tend to have a less severe disease course [23].

The clinical course may be fulminant, and severe organ dysfunction can occur, including [2,5,22,23,46]:

●Disseminated intravascular coagulation (10 to 20 percent)

●Hepatic dysfunction (17 percent)

●Toxic shock syndrome (5 to 15 percent)

●Hypotension (10 to 15 percent)

●Respiratory failure (10 to 15 percent)

●Renal failure (5 percent)

Bacteremia associated with the early onset of shock and organ failure is characteristic of the case definition of streptococcal toxic shock syndrome. Affected patients typically develop renal failure, acute respiratory distress syndrome, hepatic dysfunction, and a diffuse capillary leak syndrome. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Patients with GAS bacteremia also can develop secondary infections. Musculoskeletal infections are the most common focal infections resulting from the bacteremia. In one case series, 12 of 29 patients with acute hematogenous osteomyelitis caused by GAS had a positive blood culture [47].

TREATMENT

Overview of management — Management of patients with GAS bacteremia, particularly those with toxic shock syndrome and/or necrotizing fasciitis, includes [48]:

●Prompt administration of parenteral antibiotics, which typically consist of penicillin G and clindamycin. (See 'Choice of antibiotic therapy' below.)

●Fluid management to maintain adequate perfusion and prevent end-organ damage. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)".)

●Surgical evaluation and, if warranted, surgical exploration and resection of necrotic tissue. (See "Necrotizing soft tissue infections", section on 'Surgical debridement'.)

●Intravenous immune globulin (IVIG) is not routinely warranted for treatment of GAS bacteremia but may be reasonable for select patients with severe and refractory shock [48]. Data supporting this practice are limited and are discussed separately. (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention", section on 'Intravenous immune globulin'.)

Optimal management of a patient with GAS bacteremia most commonly requires a team of clinicians including surgeons and infectious disease and critical care specialists.

Choice of antibiotic therapy — For treatment of GAS bacteremia in children, particularly those with toxic shock syndrome and necrotizing fasciitis, we suggest combination therapy with:

●Penicillin G 200,000 to 400,000 units/kg per day intravenously, divided every 4 to 6 hours in patients with normal renal function; maximum daily dose of 24 million units, and

●Clindamycin 25 to 40 mg/kg per day intravenously, divided every 6 to 8 hours; maximum daily dose of 2.7 grams

Although GAS is exquisitely susceptible to beta-lactam antibiotics, clinical failures can occur with penicillin therapy alone, particularly in patients with invasive GAS infections in which a larger number of organisms may be present [49]. Clindamycin may be more effective in these settings in part because its efficacy is not affected by inoculum size or stage of growth. However, clindamycin should not be used as a single agent, because it is not bactericidal and because GAS resistance to clindamycin is increasing in some geographic regions [50,51]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention", section on 'Antibiotic therapy'.)

Although clinical trials are lacking, evidence from observational studies suggests that for treatment of invasive GAS infection, therapy with a beta-lactam plus clindamycin is superior to beta-lactam alone [49,52,53]. This is illustrated by the following:

●In a retrospective review of 56 children with invasive GAS infection, treatment failure occurred in 68 percent of children who received only a cell wall-inhibiting antibiotic (eg, beta-lactams) [49]. Among children who also received a protein synthesis-inhibiting antibiotic (eg, clindamycin), 84 percent showed clinical improvement in the initial 24 hours, whereas only 14 percent of patients who received only a cell wall-inhibiting antibiotic (eg, beta-lactams) had clinical improvement within 24 hours.

●In a retrospective study of 84 adult patients with severe invasive GAS infection (eg, streptococcal toxic shock syndrome, necrotizing fasciitis, septic shock, cellulitis with hypotension), addition of clindamycin to beta-lactam therapy was associated with decreased mortality (15 versus 39 percent) [53].

Antibiotic therapy ultimately should be tailored to antibiotic susceptibilities. An increasing number of GAS isolates with constitutive or inducible resistance to macrolide-lincosamide-streptogramin B (MLS) antibiotics, including clindamycin, have been identified in Europe and the United States [50,54,55].

Duration of therapy — Patients with GAS bacteremia are treated for a minimum of 14 days. However, in patients with serious soft tissue infection (eg, necrotizing fasciitis), length of therapy depends upon the clinical response of the soft tissue infection to antibiotic treatment. Therapy is usually continued for 14 days from the last positive culture obtained during surgical debridement. There are no clinical studies addressing the optimal duration of antibiotic therapy in GAS bacteremia, and duration of antibiotic therapy should be individualized.

How long combination agents should be used is unknown. For children without necrotizing fasciitis who are initially treated with combination penicillin and clindamycin, we suggest that clindamycin can be discontinued once the child is afebrile, clinically well, and without evidence of shock or other manifestations of toxic shock syndrome.

PROGNOSIS — GAS bacteremia remains a serious infection. The estimated mortality rate associated with invasive GAS infections in children ranges from 2 to 8 percent [2,5,7,22,23,28,45,46]. Long-term disability occurs in an additional 3 to 8 percent of children following invasive GAS infection [2,23].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Sepsis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Group A streptococcal (GAS) bacteremia usually occurs secondary to a primary site of infection, most commonly in the skin and soft tissues. The estimated incidence of GAS bacteremia and/or invasive infection in children is 2 to 3 cases per 100,000 per year. GAS bacteremia occurs in 1 to 13 per 1000 pediatric hospital admissions. (See 'Epidemiology' above.)

●Preceding varicella-zoster virus (VZV) infection has been associated with invasive GAS infection, although widespread use of the VZV vaccine appears to prevent VZV-associated invasive GAS infection. Fever on or beyond the fourth day of the exanthem in children with VZV should prompt consideration of GAS bacteremia. Other predisposing factors for invasive GAS infection include influenza infection; preceding skin disruption from minor trauma, burns, eczema, and/or recent surgery; underlying immunocompromise; malignancy; and age less than one year. (See 'Predisposing factors' above.)

●The clinical manifestations of GAS bacteremia include those of the primary site of infection and of the bacteremia. High fever, elevated white blood cell count, and elevated erythrocyte sedimentation rate (ESR) are common but nonspecific. The clinical course may be fulminant, and severe organ dysfunction can occur. The majority of patients have a focal site of infection, most commonly involving the soft tissues. Patients without a focal source of infection tend to have less severe disease. (See 'Clinical manifestations' above.)

●Optimal management of a patient with GAS bacteremia includes prompt treatment with antibiotics, management of the complications of shock and organ dysfunction, and aggressive surgical debridement when appropriate. Intravenous immune globulin (IVIG) is not routinely warranted for treatment of GAS bacteremia but may be reasonable for select patients with severe and refractory shock. (See 'Overview of management' above and "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention", section on 'Intravenous immune globulin'.)

●We suggest that GAS bacteremia in children be initiated with penicillin and clindamycin rather than penicillin or clindamycin alone (Grade 2C). This is particularly important for the treatment of toxic shock syndrome and necrotizing fasciitis. (See 'Choice of antibiotic therapy' above.)

•Penicillin G 200,000 to 400,000 units/kg per day intravenously, divided every 4 to 6 hours; maximum daily dose of 24 million units

•Clindamycin 25 to 40 mg/kg per day intravenously, divided every 6 to 8 hours; maximum daily dose of 2.7 grams

●Patients with GAS bacteremia are treated for a minimum of 14 days. However, in patients with serious soft tissue infection (eg, necrotizing fasciitis), length of therapy depends upon the clinical response of the soft tissue infection to antibiotic treatment. (See 'Duration of therapy' above.)

●GAS bacteremia remains a serious infection. The mortality rate in children with GAS bacteremia and/or invasive infection is approximately 2 to 8 percent, and long-term disability occurs in an additional 3 to 8 percent. (See 'Prognosis' above.)