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Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention

Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention
Author:
Dennis L Stevens, MD, PhD
Section Editors:
Morven S Edwards, MD
Michael R Wessels, MD
Deputy Editor:
Elinor L Baron, MD, DTMH
Literature review current through: Aug 2021. | This topic last updated: Feb 03, 2021.

INTRODUCTION — Group A Streptococcus (GAS; Streptococcus pyogenes) is an aerobic gram-positive coccus that causes a broad array of infections. GAS is most commonly associated with pharyngitis or skin and soft tissue infection; these are not typically associated with invasive infection.

Less commonly, GAS causes invasive disease; invasive GAS infection refers to infection in the setting of culture isolation of GAS from a normally sterile site (most commonly blood; less commonly pleural, pericardial, joint, or cerebrospinal fluid) [1,2].

Forms of invasive GAS infection include [1,3,4]:

Necrotizing soft tissue infection (see "Necrotizing soft tissue infections")

Pregnancy-associated infection (see "Pregnancy-related group A streptococcal infection" and "Postpartum endometritis")

Bacteremia (may occur in association with or in the absence of another infection)

Toxic shock syndrome (TSS) occurs as a complication of invasive GAS disease in approximately one-third of cases [5].

The treatment and prevention of invasive GAS infection will be reviewed here. Issues related to the epidemiology, clinical manifestations, and diagnosis of invasive GAS infection are discussed separately. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Issues related to GAS bacteremia in children are discussed separately. (See "Group A streptococcal (Streptococcus pyogenes) bacteremia in children".)

TREATMENT

Streptococcal toxic shock syndrome — Management of streptococcal TSS includes treatment of septic shock and associated complications, surgical debridement of infection (if warranted), antimicrobial therapy, and administration of intravenous immune globulin. Such cases frequently require coordinated care from a team including individuals with clinical expertise in critical care, surgery, and infectious disease.

Management of septic physiology — Streptococcal sepsis leads to diffuse capillary leak and intractable hypotension. Therefore, large quantities of intravenous (IV) fluids may be necessary to maintain perfusion (up to 10 to 20 L/day); vasopressors may also be required. The approach to management of septic shock is discussed separately. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Surgical debridement — Streptococcal TSS may occur in the setting of necrotizing soft tissue infection. In such cases, early aggressive surgical intervention is critical. Issues related to surgical management of necrotizing soft tissue infection are discussed separately. (See "Surgical management of necrotizing soft tissue infections".)

Antibiotic therapy — Empiric antimicrobial therapy should be initiated pending culture results; thereafter, antimicrobial therapy should be tailored accordingly. Regimens for empiric and tailored therapy are summarized below. (See 'Empiric therapy' below and 'Tailored therapy' below.)

General principles — In general, antimicrobial treatment of streptococcal TSS consists of a beta-lactam agent (which inhibits cell wall synthesis) in combination with clindamycin (which inhibits protein synthesis).

S. pyogenes is exquisitely susceptible to beta-lactam antibiotics, which are bactericidal; however, penicillin monotherapy has been associated with high morbidity and mortality in the setting of GAS infections associated with toxin production (eg, TSS and necrotizing soft tissue infection) [2,5-10].

Studies of experimental infection have noted an association between penicillin monotherapy and treatment failure in the setting of high inoculum [11-15]. In general, beta-lactam antibiotics are believed to be most effective against rapidly growing bacteria. Therefore, the efficacy is likely greatest in the early stages of infection when organisms are multiplying quickly and may be diminished as organism concentrations increase and the rate of bacterial growth slows. In the setting of deep-seated infection, the concentration of organisms may be sufficiently high to reduce the effectiveness of beta-lactam antibiotics [11]. In addition, diminished efficacy of penicillin monotherapy in the setting of high inoculum has been attributed to the available numbers of penicillin-binding proteins (PBPs) on the organism surface that are available at various points during the phases of bacterial growth. In one in vitro study, fewer PBPs were observed during stationary-phase growth [14].

For these reasons, clindamycin should be used together with a beta-lactam antibiotic for treatment of streptococcal TSS; the beta-lactam antibiotic is included in case the infection is caused by an isolate that is resistant to clindamycin. Other potential advantages of clindamycin for treatment of streptococcal TSS include: (1) clindamycin efficacy is not affected by inoculum size or stage of growth, (2) clindamycin suppresses bacterial toxin production, (3) clindamycin is associated with a longer postantibiotic effect than beta-lactam agents, and (4) clindamycin suppresses synthesis of PBPs, which are involved in cell wall synthesis and degradation (in addition to serving as binding targets for penicillin) [14,16-19]. There are no additive, synergistic, or antagonistic effects of clindamycin and penicillin in vitro.

The above approach to use of clindamycin is supported by observational studies [20-23]. As an example, in a retrospective study including 1079 patients with invasive GAS infection treated with beta-lactam antibiotics (of whom 343 received adjunctive clindamycin), use of adjunctive clindamycin was associated with lower mortality (6.5 versus 11 percent; adjusted odds ratio 0.44 [95% CI 0.23-0.81]); this survival benefit was maintained even among the 661 patients without shock or necrotizing fasciitis (2.6 versus 6.1 percent; aOR 0.40 [95% CI 0.15-0.91]) [23].

Targeted antibiotic therapy should be guided by antibiotic susceptibility testing. There have been reports of increasing frequency of GAS isolates with inducible or constitutive resistance to clindamycin (15 percent in one study) and other macrolide-lincosamide-streptogramin B (MLS) antibiotics [24-26]. In the United States in the early 2000s, clindamycin resistance occurred in less than 1 percent of isolates overall [24], but this increased to 15 percent between 2011 and 2015 [27]. An increasing number of GAS isolates with constitutive or inducible resistance to MLS antibiotics, including clindamycin, have been identified in Europe [25]. In China, clindamycin resistance has been observed in as many as 94 percent of isolates [28].

Antibiotic regimens — Empiric antimicrobial therapy should be initiated pending culture results; thereafter, antimicrobial therapy should be tailored accordingly.

Empiric therapy — At initial presentation, streptococcal TSS cannot be distinguished immediately from sepsis syndromes due to other pathogens. Therefore, empiric therapy should consist of broad-spectrum antibiotic treatment to cover not only GAS, but also Staphylococcus aureus (including methicillin-resistant S. aureus) as well as gram-negative bacilli.

For empiric treatment of suspected streptococcal TSS, we favor the following regimen (pending culture results):

Clindamycin (adults: 900 mg IV every eight hours; children: 30 to 40 mg/kg per day IV, divided every 6 to 8 hours; maximum daily dose 2.7 g)

PLUS

Vancomycin (adults: dosing summarized in table (table 1); children: 15 mg/kg/dose IV every 6 to 8 hours, usual maximum 4 g per day)

PLUS one of the following:

A carbapenem (adults: imipenem 500 mg IV every 6 hours; higher dosing of 1 g every 6 to 8 hours may be used for patients with obesity, recent broad-spectrum antibiotic treatment, or recent colonization with resistant organisms OR meropenem 1 g IV every 8 hours; children: imipenem 15 to 25 mg/kg/dose every 6 hours [maximum 4 g per day] or meropenem 25 mg/kg/dose every 8 hours [maximum 1 g per dose])

A combination drug containing a penicillin plus beta-lactamase inhibitor (adults: piperacillin-tazobactam 4.5 g every 6 hours; children: 80 mg/kg piperacillin/kg/dose IV every 6 hours or 100 mg/kg piperacillin/kg/dose IV every 8 hours [maximum 16 g piperacillin per day])

Patients with known hypersensitivity to penicillin may be treated with clindamycin plus vancomycin plus a carbapenem. If carbapenems are not tolerated, clindamycin plus vancomycin plus a fluoroquinolone may be used.

Tailored therapy — Once a diagnosis of streptococcal TSS is established, treatment consists of:

Clindamycin (adults: 900 mg IV every eight hours; children: 30 to 40 mg/kg IV per day, divided every six to eight hours; maximum daily dose 2.7 g)

PLUS

Penicillin G (adults: 4 million units IV every four hours; children: 200,000 to 400,000 units/kg IV per day, divided every four to six hours in patients with normal renal function; maximum pediatric daily dose 24 million units).

For patients with beta-lactam hypersensitivity (in the absence of anaphylaxis), alternatives to penicillin include ceftriaxone (adults: 1 to 2 g IV every 12 hours; children: 50 mg/kg IV every 12 to 24 hours [maximum dose 2 g every 12 hours]), cefazolin (adults: 2 g IV every 8 hours; children: 50 to 100 mg/kg/day IV divided every 8 hours [maximum daily dose 12 g/day]).

For patients with history of anaphylaxis to beta-lactams, alternatives to penicillin include vancomycin (adults: dosing summarized in table (table 1); children: 45 mg/kg/day IV in three divided doses) or daptomycin (adults: 6 mg/kg IV every 24 hours; children: 10 mg/kg IV once daily [<6 years of age], 7 mg/kg IV once daily [7 to 11 years of age], 4 to 6 mg/kg IV once daily [>12 years of age]).

Once antibiotic susceptibility data are available, the approach is as follows:

For patients with streptococcal TSS due to GAS isolates susceptible to clindamycin – Combination therapy with penicillin and clindamycin should be continued until patients are clinically and hemodynamically stable for at least 48 to 72 hours; thereafter, penicillin monotherapy may be administered.

For patients with streptococcal TSS due to GAS isolates resistant to clindamycin – Combination therapy with penicillin and linezolid (adults and children ≥12 years: 600 mg IV every 12 hours; children <12 years of age: 10 mg/kg IV every 8 hours [maximum 600 mg/dose]) or tedizolid (adults: 200 mg IV every 24 hours; not US Food and Drug Administration approved for use in children) should be continued until patients are clinically and hemodynamically stable for at least 48 to 72 hours; thereafter, penicillin monotherapy may be administered. Like clindamycin, linezolid and tedizolid also suppress toxin production [29,30].

The above approach is based on retrospective and animal data.

Duration of therapy — There are no clinical studies addressing the optimal duration of antibiotic therapy in streptococcal TSS. The duration of antibiotic therapy should be tailored to individual patient circumstances, including the source of infection and clinical response to treatment.

Patients with bacteremia should be treated for at least 14 days. In patients with complicating deep-seated infection (such as necrotizing fasciitis), length of therapy depends on the clinical course and the adequacy of surgical debridement; therapy is usually continued for 14 days from the last positive culture obtained during surgical debridement. (See "Necrotizing soft tissue infections", section on 'Treatment'.)

Adjunctive therapy — Adjunctive therapies evaluated for treatment of invasive GAS infection include intravenous immune globulin (IVIG), hyperbaric oxygen, and anti-tumor necrosis factor (TNF) antibody.

Intravenous immune globulin — We favor administration of IVIG for treatment of patients with streptococcal TSS. Dosing (for adults and children) consists of 1 g/kg on day 1, followed by 0.5 g/kg on days 2 and 3.

This approach is supported by a 2018 meta-analysis including five studies of patients with streptococcal TSS treated with clindamycin (one randomized and four nonrandomized), in which use of IVIG was associated with 30-day reduction in mortality (33.7 to 15.7 percent) [31]. Prior data from retrospective studies and statistically underpowered prospective trials have been inconclusive on the efficacy of IVIG for streptococcal TSS [22,32-34].

The proposed rationale for use of IVIG in streptococcal TSS is to boost antibody levels via passive immunity in the setting of overwhelming infection. Several mechanisms have been suggested, including opsonization of GAS for phagocytic killing, neutralization of streptococcal toxins, inhibition of T cell proliferation, and inhibition of inflammatory cytokines such as TNF-alpha and interleukin 6 [35-40]. Some IVIG preparations contain neutralizing antibodies against several streptococcal toxins such as the pyrogenic exotoxins (streptococcal pyrogenic exotoxin [SPE]A, SPEB, SPEC, and mitogenic factor), streptolysin O, and DNase B; specific antibody preparations are not commercially available [41]. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Differences between neutralizing activities have been observed in different batches of IVIG from different manufacturers. In one study, Vigam-S (obtained from plasma collected from donors in the United States) had consistently high inhibition against all GAS superantigens, while European IVIG preparations had the lowest activity; an Australian preparation had intermediate activity [42].

Other therapies — The use of hyperbaric oxygen has been reported in a small number of patients with streptococcal TSS [43]. There are no controlled trials, and the efficacy of this treatment is not known. (See "Hyperbaric oxygen therapy".)

Use of anti-TNF antibody has been studied in an animal model of streptococcal TSS with promising results [44]; further study is needed.

Invasive GAS infection (in absence of toxic shock)

Bacteremia — The approach to treatment of bacteremia that occurs in association with other clinical manifestation(s) should be guided by the primary presentation:

Issues related to treatment of necrotizing soft tissue infections are discussed separately. (See "Necrotizing soft tissue infections", section on 'Antibiotic therapy'.)

Issues related to treatment of pregnancy-associated GAS infection are discussed separately. (See "Pregnancy-related group A streptococcal infection".)

Issues related to treatment of streptococcal toxic shock syndrome are discussed above. (See 'Streptococcal toxic shock syndrome' above.)

General principles related to antimicrobial treatment of streptococcal TSS are summarized above. (See 'General principles' above.)

For initial treatment of GAS bacteremia (in the absence of shock, organ failure, or necrotizing infection), we favor combination therapy with penicillin G and clindamycin; penicillin G monotherapy is a reasonable alternative. Clindamycin suppresses toxin production and reduces the risk of treatment failure. This approach is based on retrospective and animal data [12,13,21].

Issues related to drug dosing, beta-lactam hypersensitivity, and clindamycin are summarized above. (See 'Tailored therapy' above.)

The optimal duration of antibiotic therapy for GAS bacteremia is uncertain; data are limited. For patients initially treated with combination therapy who do not have shock, organ failure, or necrotizing infection, discontinuation of clindamycin within 48 hours is reasonable. Thereafter, penicillin monotherapy should be continued to complete at least 14 days of treatment. The duration of antibiotic therapy should be tailored to individual patient circumstances, including the source of infection and clinical response to treatment.

It is uncertain whether intravenous therapy is required for the entire duration of antibiotic therapy. For patients with GAS bacteremia (in the absence of shock, organ failure, or necrotizing infection), it may be reasonable to complete the course of antibiotic therapy with an oral agent following completion of surgical debridement (if needed), clearance of bacteremia, and resolution of systemic signs of infection. Oral regimens are summarized in the table (table 2).

Respiratory tract infection — The approach to treatment of respiratory tract infection due to GAS is the same as the approach to treatment of GAS bacteremia. (See 'Bacteremia' above.)

Pleural effusion associated with GAS pneumonia often represents an empyema. Patients with pleural effusion should undergo thoracentesis; if purulent fluid is encountered, it should be drained promptly to control infection and to prevent complications from pleural adhesions. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

PROGNOSIS — The mortality rate for invasive GAS infection ranges from 25 to 48 percent [1,5,7,45-47]. In one series including 67 cases of GAS bacteremia, shock was the most important predictor of mortality (79 versus 16 percent) [45].

The mortality rate for streptococcal TSS ranges from 30 to 79 percent [4,5,48-51]. Mortality rates are lower in children than adults. One series including 144 children noted a mortality rate of 18 percent [52]; another series including 192 children noted a mortality of 4 percent [34].

In one retrospective study including 66 patients with streptococcal TSS comparing physical and laboratory findings of patients who survived with patients who died, patients who died had lower mean systolic blood pressure (99 versus 120 mmHg), lower mean body temperature (37.0 versus 38.3ºC), higher mean serum creatinine (3.0 versus 2.0 mg/dL), lower mean white blood cell count (1000 versus 16,000 cells per microL), and lower platelet count (120,000 versus 170,000 cells per microL) [51].

Mortality due to streptococcal TSS is substantially higher than mortality due to staphylococcal TSS. Streptococcal TSS is frequently associated with deep soft tissue infection, so source control can be difficult. In addition, streptococcal TSS occurs more frequently among patients with underlying medical conditions than staphylococcal TSS. (See "Staphylococcal toxic shock syndrome".)

PREVENTION

Prophylaxis for contacts — GAS is a highly contagious organism; close contacts of a case of invasive GAS infection have a high likelihood of becoming colonized with a virulent strain [53]. The risk of subsequent invasive GAS disease among household contacts of persons with invasive GAS infections is higher (200- to 2000-fold) than the risk among the general population [54], but subsequent invasive GAS infections are rare [55].

The optimal approach to postexposure prophylaxis for prevention of invasive GAS infection is uncertain. The goal is clearance of asymptomatic colonization to reduce the likelihood of a secondary infection.

Decisions regarding administration of prophylaxis depend on the degree of exposure and the immune status of the contact. Significant exposures include close family members, patients who are kissing or sleeping in the same bed, and caretakers who spend many hours daily with an infected individual. Prophylaxis is warranted for contacts who are immunosuppressed, pregnant, have had recent surgery, or have any type of open wound.

The regimen for prophylaxis consists of penicillin (adults: 250 mg orally four times daily for 10 days; children: 25 mg/kg/dose [maximum 250 mg per dose] orally four times daily for 10 days). Alternative regimens for individuals with beta-lactam hypersensitivity are listed below. Before choosing an alternative antibiotic, susceptibility of the index patient isolate to the selected drug should be confirmed.

Clindamycin (adults: 20 mg/kg/day orally [maximum daily dose 900 mg] in three divided doses for 10 days; children: 25 to 30 mg/kg/day orally [maximum daily dose 900 mg])

or

Azithromycin (adults and children: 12 mg/kg/day [maximum daily dose 500 mg] as a single daily dose for five days).

Infection control — In addition to standard precautions, patients with invasive GAS infection associated with soft tissue involvement warrant droplet precautions as well as contact precautions; patients with streptococcal toxic shock or streptococcal pneumonia warrant droplet precautions [56]. Droplet and contact precautions may be discontinued after the first 24 hours of antimicrobial therapy.

Strategies for management of GAS outbreaks in health care facilities include adherence to infection control practices (particularly hand washing), and attentive wound care [57]. If more than one case of invasive GAS infection occurs in a six-month period, an epidemiologic work-up is indicated (including cultures of specimens from epidemiologically linked health care workers) [55].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

SUMMARY AND RECOMMENDATIONS

Forms of invasive group A streptococcal (GAS) infection include necrotizing soft tissue infection, pregnancy-associated infection, bacteremia, and respiratory tract infection. Toxic shock syndrome (TSS) occurs as a complication of invasive GAS disease in approximately one-third of cases. (See 'Introduction' above.)

Issues related to treatment of necrotizing soft tissue infections and pregnancy-related GAS infection are discussed separately. (See "Necrotizing soft tissue infections" and "Surgical management of necrotizing soft tissue infections" and "Pregnancy-related group A streptococcal infection".)

Management of streptococcal TSS includes treatment of septic shock and associated complications, surgical debridement of infection (if warranted), and antimicrobial therapy. (See "Evaluation and management of suspected sepsis and septic shock in adults" and "Surgical management of necrotizing soft tissue infections".)

We typically use the following antibiotic regimens; dosing is summarized above (see 'Antibiotic regimens' above):

For patients with suspected streptococcal TSS, we favor treatment with vancomycin, clindamycin, and either a combination drug containing a penicillin plus beta-lactamase inhibitor or a carbapenem.

For patients with an established diagnosis of streptococcal TSS, we suggest treatment with combination antibiotic therapy including penicillin G and an antibiotic that suppresses protein synthesis such as clindamycin (rather than penicillin G alone) (Grade 2C), given the importance of toxin production in the pathogenesis of streptococcal TSS.

Antibiotic therapy should be adjusted based on antibiotic susceptibility once available. The duration of antibiotic therapy should be tailored to individual patient circumstances, including the source of infection and clinical response to treatment. (See 'Tailored therapy' above and 'Duration of therapy' above.)

For patients with streptococcal TSS, we suggest administering intravenous immune globulin (Grade 2C). (See 'Intravenous immune globulin' above.)

For initial treatment of GAS bacteremia (in the absence of shock, organ failure, or necrotizing infection), we suggest combination therapy with penicillin G and an antibiotic that suppresses protein synthesis such as clindamycin (Grade 2C); penicillin G monotherapy is a reasonable alternative. (See 'Bacteremia' above.)

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Topic 3169 Version 36.0

References

1 : Management of invasive group A streptococcal infections.

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