Version May 2024
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".)
INCIDENCE — 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 [5-8]. The incidence is greatest in children <1 year (3 to 5 cases per 100,000) [6,7].
Among hospitalized patients, invasive GAS infection accounts for approximately 0.3 to 0.9 percent of pediatric hospital admissions [9,10].
●United States – 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 2015 through 2019 [7,8,11-14]. There were only 74 cases reported in 2020, likely due to the impact of social distancing and other infection control measures during the height of the COVID-19 pandemic [8]. Similarly, in a report from Texas Children's Hospital, there were considerably fewer hospital admissions for invasive GAS infections in 2020 compared with previous years, though the rate increased again by 2022 [10]. In December of 2022, the CDC issued a health advisory regarding an increase in the number of cases of pediatric invasive GAS infection reported to the ABC surveillance program in November through early December [15]. The CDC is investigating these reports. Based on preliminary data, the increase likely reflects that rates of invasive GAS infection appear to have returned to levels similar to those seen in pre-pandemic years [16].
●Europe – Several European countries have reported an increase in the number of invasive GAS infections among children <10 years old during the fall and winter of 2022 compared with prior years [17,18]. For example, in the United Kingdom (UK), there were 107 cases of invasive GAS infection in children <10 years reported from mid-September to early December 2022 (average of 11 cases per week) [18]. This rate is markedly higher than during and immediately following the height of the COVID-19 pandemic and it is also considerably higher than in pre-pandemic years. From mid-September to early December 2022, there were 13 deaths attributable to invasive GAS infection reported in children <15 years old in the UK, which is considerably more than reported in prior years [18].
Other European countries, including France, Ireland, the Netherlands, and Sweden have reported similar increases in rates of invasive GAS infection, particularly among children <10 years old [17]. The rise in invasive GAS infection parallels a >3-fold increase in reported cases of scarlet fever. The increase may reflect an early GAS season coinciding with an increase in circulating respiratory viruses. There have been no observed increases in antibiotic resistance among isolated GAS strains. Enhanced surveillance activities have been implemented in the affected areas and public health organizations are emphasizing the importance of early recognition of GAS infections, including scarlet fever, and prompt treatment. (See "Complications of streptococcal tonsillopharyngitis", section on 'Scarlet fever' and "Treatment and prevention of streptococcal pharyngitis in adults and children".)
MICROBIOLOGY — Certain strains of GAS may be more likely to cause invasive infection [3,4,19-21]. A small number of M-types of GAS (1, 3, 4, 6, and 28) are responsible for approximately 50 percent of invasive infections; the remaining 50 percent are caused by a variety of different strains, including nontypeable strains [1,3,4,19,21-23]. In addition, all GAS strains isolated from invasive cases produce a toxin called NADase [23].
PREDISPOSING FACTORS — The following predisposing factors are associated with invasive GAS infection [1-3,24-27]:
●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 [24-34]. Fever on or beyond the fourth day of the exanthem in children with VZV should prompt consideration of GAS bacteremia [35]. (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 [28]. 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 [36]. (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 [37,38]. (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 [3,24,25,28]. (See "Burn wound infection and sepsis".)
●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 [2,39].
●Malignant neoplasm – Underlying malignancy has been noted in 5 to 10 percent of patients with invasive GAS infection [24-26,28].
●Age <1 year – The risk of invasive GAS infection is highest in infants under the age of one year [24,25,40]. In neonates, GAS infection can occur as a result of vertical transmission from the mother or from nosocomial acquisition from medical personnel [41].
●Intravenous drug use – Intravenous drug use is a risk factor for invasive GAS infection in adolescents and adults [21,42-47]. (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 [35]. 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 [21]. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Burn wound infection and sepsis" and "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. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis".)
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, which is associated with increased mortality risk [48,49].
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 [2,33,50]. A scarlatiniform rash (picture 1 and picture 2) 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 [2,5,24-26,28,51,52]:
●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 [26].
The clinical course may be fulminant, and severe organ dysfunction can occur, including [2,5,25,26,51]:
●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 [52].
TREATMENT
Overview of management — Optimal management of a patient with GAS bacteremia most commonly requires a team of clinicians including infectious disease specialists, surgeons, and critical care providers.
Management of patients with GAS bacteremia, particularly those with toxic shock syndrome and/or necrotizing fasciitis, includes [53]:
●Prompt administration of parenteral antibiotics, which typically consist of penicillin G and clindamycin. (See 'Antibiotic therapy' below.)
●Fluid management and hemodynamic support to maintain adequate perfusion and prevent end-organ damage. (See "Septic shock in children in resource-abundant settings: 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 [53]. 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'.)
Antibiotic therapy
Preferred regimen — 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
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 [54-56].
GAS is exquisitely susceptible to beta-lactam antibiotics; however, 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 [57]. 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 [54,58]. (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 [57,59,60]. 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) [57]. 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) [60].
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 [2,5,6,25,26,32,50,51]. Long-term disability occurs in an additional 3 to 8 percent of children following invasive GAS infection [2,26].
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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
●Incidence – 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 invasive GAS infection in children is 2 to 3 cases per 100,000 per year. Invasive GAS infection accounts for approximately 0.3 to 0.9 percent of pediatric hospital admissions. (See 'Incidence' above.)
●Predisposing factors – Predisposing factors that increase the risk of invasive GAS infection include (see 'Predisposing factors' above):
•Influenza infection
•Varicella-zoster infection
•Preceding skin disruption from minor trauma, burns, eczema, or recent surgery
•Age <1 year
•Underlying immunocompromise
•Malignancy
•Intravenous drug use
●Clinical manifestations – The clinical manifestations of GAS bacteremia include those of the primary site of infection and signs and symptoms attributable to 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. Among patients with focal infections, skin and soft tissue infections are the most common sites. Patients without a focal source of infection tend to have less severe disease. (See 'Clinical manifestations' above.)
●Management – Optimal management of a patient with invasive GAS infections includes prompt treatment with antibiotics, management of the complications of shock and organ dysfunction, and aggressive surgical debridement when appropriate. (See 'Overview of management' above.)
•Antibiotic therapy – Antibiotic therapy should be tailored to antibiotic susceptibilities. In most cases, we suggest treatment with penicillin plus clindamycin rather than either agent alone (Grade 2C). This is particularly important for the treatment of toxic shock syndrome and necrotizing fasciitis. (See '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
The minimum duration of treatment is at least 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.)
•Intravenous immune globulin (IVIG) – IVIG is not routinely necessary for treatment of invasive GAS infections but may be reasonable for select patients with severe and refractory shock. This is discussed separately. (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention", section on 'Intravenous immune globulin'.)
●Prognosis – GAS bacteremia is a serious infection. The mortality rate in children with invasive GAS infection is approximately 2 to 8 percent, and long-term disability occurs in an additional 3 to 8 percent. (See 'Prognosis' above.)
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