Invasive group A streptococcal disease: Management and chemoprophylaxis

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Since the resurgence of invasive group A streptococcal disease (IGAS) in the 1980s, attention has been directed toward chemoprophylaxis of contacts of IGAS and optimizing clinical management of individuals with this disease. In 2006, Canadian guidelines were developed to address the prevention and control of IGAS ^[1]. This document updates and highlights evidence-based management of contacts of IGAS cases and clinical management of the disease in accordance with these guidelines.

Epidemiology

The most common clinical presentations of IGAS infections are toxic shock syndrome (TSS), with or without a focus of infection, necrotizing fasciitis (NF) or myositis, bacteremia with no septic focus, and pneumonia. The incidence of IGAS disease in Canada, based on reported cases, has increased over the past decade. In 2015, the reported incidence was 5.3 per 100,000 population with 1893 cases reported – a significant increase from a rate of 2.8 per 100,000 and 863 cases reported in 2000 ^[2][3]. In Canada and the United States, rates are highest in infants, young children and the elderly.

Risk factors for IGAS among adults include human immunodeficiency virus infection, cancer, heart disease, diabetes, lung disease, alcohol abuse, injection drug use and the postpartum period. Among children, recent pharyngitis ^[4] and varicella are risk factors ^[5], although varicella vaccine programs have reduced varicella-associated IGAS ^[6][7]. For both adults and children, recent soft tissue trauma and non-steroidal anti-inflammatory drug (NSAID) use are additional risk factors.

Two studies ^[5][8] assessing secondary cases in household contacts reported rates of 0.66 and 2.94 per 1000, respectively, which were 20 to 100 times the rates in the overall populations studied. Most secondary cases occurred within 7 days of the index case. There is little information on transmission risk in other settings, such as child care centres and schools, but secondary cases appear to be rare. A secondary case associated with varicella has been reported in a child care centre ^[9]. Nosocomial transmission is well documented, including transmission to health care workers ^[10][11].

Case definitions for reporting invasive group A streptococcal infection

Currently, IGAS is reportable in all provinces and territories in Canada. Within each province or territory, rapid notification of medical health officers ensures timely reporting to the appropriate provincial/territorial public health official. Confirmed cases are reported to the Public Health Agency of Canada (PHAC).

The PHAC Guidelines for the prevention and control of invasive group A streptococcal disease ^[1] are based on consensus definitions and summarized below:

Confirmed case of IGAS

• Laboratory confirmation: Isolation of group A streptococcus (GAS) from a normally sterile site, with or without clinical evidence of severe invasive disease).

Severe IGAS: In the above context, clinical evidence of severe invasive disease includes the following:

a. Streptococcal TSS, characterized by hypotension (systolic blood pressure of 90 mmHg or less in adults, or less than the fifth percentile for age in children) AND at least two of the following signs:

• Renal impairment (creatinine level of at least 2X the upper limit normal for age or 2X the patient’s baseline)
• Coagulopathy (platelet count of 100×10⁹/L or lower, or disseminated intravascular coagulation)
• Liver function abnormality (levels of aspartate aminotransferase, alanine aminotransferase or total bilirubin >2X the upper limit normal for age)
• Acute respiratory distress syndrome
• Generalized erythematous macular rash that may later desquamate;

b. Soft-tissue necrosis (including NF, myositis or gangrene);

c. Meningitis

d. Pneumonia (with isolation of GAS from a sterile site such as pleural fluid). Note that bronchoalveolar lavage (BAL) is not considered to be from a sterile site.

e. A combination of the above.

f. Any other life-threatening condition or infection resulting in death

Non-severe IGAS: Includes bacteremia, cellulitis, wound infections, soft tissue abscesses, lymphadenitis, septic arthritis, osteomyelitis, without evidence of streptococcal TSS or soft tissue necrosis.

Probable case of IGAS

• Invasive disease in the absence of another identified etiology and with isolation of GAS from a non-sterile site (e.g., BAL). Pneumonia with isolation of GAS from BAL and with no other cause identified may be considered IGAS for purposes of patient management, but would not be nationally notifiable.

Clinical presentation of severe invasive group A streptococcal disease

While the criteria above are useful for clinical and reporting purposes, clinicians should be aware that TSS has a wide spectrum of clinical presentation, from patients with evolving TSS who do not yet meet full criteria, to severe life-threatening disease with multi-system involvement. Patients with suspected or evolving TSS should receive urgent empiric therapy. Streptococcal TSS is clinically indistinguishable from staphylococcal TSS.

Similarly, NF patients who present early may pose diagnostic challenges. Clinical features associated with NF include: severe pain or tenderness (often out of proportion to clinical appearance), toxic appearance, hemodynamic instability, rapid rate of progression, and ‘woody’ induration. Nerve involvement may cause anesthesia or hyperesthesia of the overlying skin. Crepitus is more strongly associated with polymicrobial or clostridial NF. GAS-related NF cases are more likely to be associated with a generalized rash, pharyngitis, conjunctivitis, and/or strawberry tongue ^[4]. As with TSS, early and aggressive intervention is critical. Combined medical and surgical therapy is fundamental to optimize outcome ^[12][13].

GAS pneumonia may be clinically indistinguishable from other causes of pneumonia but often exhibits a rapidly progressive course with large pleural effusions.

Management of severe invasive group A streptococcal disease

Management of severe IGAS disease involves supportive treatment using fluids and electrolytes; specific therapy with antimicrobials; and measures to minimize or neutralize the effects of toxin production, when indicated. An infectious diseases physician should be consulted for management of suspected IGAS.

Empiric antimicrobial therapy of TSS or suspected TSS should include coverage of Staphylococcus aureus and GAS with a beta-lactamase stable beta-lactam (i.e., cloxacillin) in combination with clindamycin. Because TSS has been associated with methicillin-resistant Staphylococcus aureus (MRSA), addition of empiric vancomycin, pending culture results, may be prudent for areas or populations with significant rates of MRSA colonization.

Empiric antibiotic therapy for necrotizing fasciitis depends on clinical presentation and risk factors for IGAS, MRSA colonization risk, exposure to potential water-borne pathogens (aeromonas and vibrio) and risk factors for clostridial or polymicrobial myonecrosis (associated with chemotherapy, recent GI surgery, penetrating trauma, intra-abdominal or pelvic focus of infection, or pregnancy complications). Initial therapy generally provides broad coverage for gram-positive, gram-negative, and anaerobic organisms with special consideration for GAS and clostridia. Definitive diagnosis of NF is based on emergent surgical exploration, which also facilitates early debridement and expedites microbiological identification of pathogens. Empiric regimens may include either a beta-lactam-beta-lactamase inhibitor (i.e., piperacillin-tazobactam) or a carbapenem, in combination with clindamycin, with consideration of adding vancomycin for MRSA coverage depending on local prevalence and risk factors ^[13][14]. In otherwise healthy children with none of the above risk factors for organisms other than GAS, some experts may choose penicillin plus clindamycin as initial therapy. Antibiotic therapy should be tailored to gram-stain, culture and sensitivity results, when available.

Penicillin remains the treatment of choice for confirmed GAS cases ^[14]. Adding clindamycin, which is a potent inhibitor of toxin production with antimicrobial activity that is unaffected by inoculum size, is strongly recommended for all empiric and confirmed severe IGAS cases. This combination has been associated with improved outcomes in severe IGAS cases ^[15]. Consideration may be given to discontinuing clindamycin after 48 h to 72 h of treatment if the patient is hemodynamically stable, blood is sterile and there is no further progression of necrosis. Clindamycin is not recommended for monotherapy of IGAS because GAS resistance rates to clindamycin have increased ^[14], whereas, to date, there is no GAS resistance to penicillin.

Intravenous immune globulin (IVIG) should be considered on the day of clinical presentation in the treatment of streptococcal TSS or other severe invasive (toxin-mediated) disease, especially when the patient is severely ill or the condition is refractory to initial aggressive therapy with fluids. The proposed mechanism of action of IVIG in IGAS is multifactorial and includes toxin neutralization, opsonization and improved phagocytic killing, and suppression of the massive inflammatory response through Fc-receptor interactions. Suggested regimens include 150 mg/kg to 500 mg/kg per day for 5 to 6 days or a single dose of 1 g/kg to 2 g/kg ^[14]-[18].

Other specific treatments may be required depending on the clinical situation (e.g., surgical debridement of necrotic tissue, surgical drainage of empyema).

Although it is unclear whether or not NSAIDs contribute to the development of severe IGAS, physicians managing patients with suspected IGAS should prescribe NSAIDs cautiously ^[4].

Infection control for invasive group A streptococcal disease in health care settings

Readers are encouraged to consult the PHAC Guidelines for the prevention and control of invasive group A streptococcal disease ^[1] and related infection control guidelines ^[19]-[21]. These documents also address preventing noninvasive group A streptococcal disease in health care institutions. Local provincial/territorial guidelines should be consulted, when available.

Definition of close contacts

• Household contacts who, within the previous 7 days, have spent at least 4 h per day on average or a total of 20 h with the IGAS case (index case).
• Non-household persons who have shared a bed with the case or had sexual relations with the index case.
• Persons who have had direct contact with the mucous membranes or oral or nasal secretions of the index case (e.g., by mouth-to-mouth resuscitation or open mouthed kissing) or unprotected direct contact with an open skin lesion of the index case.
• Injection drug users who have shared a needle with the index case.
• Contacts in child care settings (see below).
• Selected hospital contacts (See PHAC Guideline: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/06vol32/32s2/index-eng.php).
• Selected contacts in long-term care facilities (See PHAC Guideline: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/06vol32/32s2/index-eng.php).

Management of close contacts

• Close contacts of all confirmed IGAS cases (i.e., whether severe or non-severe) should be alerted to signs and symptoms of IGAS, and advised to seek immediate medical attention should they develop febrile illness or any other clinical manifestation of GAS infection within 30 days of diagnosis in the index case.
• Chemoprophylaxis: Target group and prophylaxis window
  • Chemoprophylaxis should only be offered to close contacts of a confirmed case of severe IGAS who have been exposed during the period from 7 days before the onset of symptoms in the index case to 24 h after initiating antimicrobial therapy in the case.
  • Chemoprophylaxis should be started as soon as possible, preferably within 24 h of identifying the case, but is still recommended up to 7 days after the last contact with the case. Provincial/territorial protocols for prophylaxis may vary; clinicians should become familiar with local policies. Variations in approach to chemoprophylaxis exist across jurisdictions ^[22][23]. The level of risk may vary for different groups of individuals, and there may also be circumstances for which different decisions regarding chemoprophylaxis are made.
  • Chemoprophylaxis is not routinely recommended for contacts of non-severe IGAS cases (e.g., bacteremia without toxic shock; septic arthritis). These cases tend to have milder disease and so do their contacts ^[1].
• Child care centres
• Chemoprophylaxis is recommended for all children and staff in family or home child care settings, when any the above criteria are met.
• Chemoprophylaxis is generally not recommended in group or institutional child care centres and preschools. However, this step may be considered in specific situations, such as when more than one case of IGAS disease occurs among children or staff in a child care centre within one month, or during a concurrent varicella outbreak in a child care centre.
• Choice of chemoprophylaxis agents
  • First-generation cephalosporins (e.g., cephalexin) are the preferred agents (Table 1). Alternative agents include second- and third-generation cephalosporins (e.g., cefuroxime axetil and cefixime). Penicillin is less effective in eradicating GAS colonization than cephalosporins ^[24][25]. Macrolides (e.g., erythromycin, clarithromycin and azithromycin) may be used for chemoprophylaxis in individuals with a beta-lactam allergy. Macrolide prophylaxis should be accompanied by periodic reassessment based on local rates of macrolide-resistant GAS. Clindamycin may also be used for chemoprophylaxis in patients who are unable to tolerate beta-lactams.
• Cultures from contacts
  • Cultures have no role in the identification of asymptomatic close contacts of sporadic IGAS cases occurring in the community. Routine cultures are not required for follow-up of contacts receiving antibiotic chemoprophylaxis.

Summary

• IGAS incidence has increased in the past decade, with infants, young children and the elderly at greatest risk.
• Treatment of confirmed IGAS includes penicillin plus clindamycin.
• IVIG should be considered in the management of severe IGAS.
• NF diagnosis requires early surgical exploration and debridement of necrotic tissue if possible. Outcome of NF is enhanced by surgical debridement combined with antimicrobial therapy. Chemoprophylaxis for close contacts of severe IGAS cases should follow the definitions above and detailed in the PHAC Guideline.

TABLE 1: Recommended chemoprophylaxis regimens for close contacts of invasive group A streptococcal disease
Drug	Dosage	Comments
First-generation cephalosporins:	First-line treatment in children and adults:	Recommended drugs for pregnant and lactating women. Should be used with caution in patients allergic to penicillin
cephalexin	25 mg/kg to 50 mg/kg daily, to a maximum of 1 g/day, in two to four divided doses for 10 days
cefadroxil	25 mg/kg to 50 mg/kg daily, to a maximum of 1 g/day, in two divided doses (children) or once daily (adults). No liquid preparation available.
clarithromycin	Second-line treatment: Children: 15 mg/kg daily, in divided doses every 12 h, to a maximum of 250 mg orally twice daily for 10 days Adults: 250 mg orally twice daily for 10 days	Contraindicated in pregnancy. Sensitivity testing is recommended in areas where macrolide resistance is unknown or known to be 10% or greater
clindamycin	Second-line treatment: Children: 8 to 16 mg/kg  daily, divided into three or four equal doses, to a maximum of 600 mg daily  for 10 days Adults: 150 mg every 6 h for 10 days	Alternative for persons who are unable to tolerate beta-lactam antibiotics
Adapted from reference [1]

Acknowledgements

This practice point was reviewed by the Acute Care Committee of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE

Members: Michelle Barton-Forbes MD; Sean Bitnun MD; Natalie A. Bridger MD (past member); Shalini Desai MD (past member); Michael Forrester MD; Ruth Grimes MD (Board Representative); Nicole Le Saux MD (Chair); Karina Top MD
Liaisons: Upton D. Allen MBBS, Canadian Pediatric AIDS Research Group; Tobey Audcent MD, Committee to Advise on Tropical Medicine and Travel (CATMAT), Public Health Agency of Canada; Carrie Byington MD, Committee on Infectious Diseases, American Academy of Pediatrics; Marc Lebel MD, IMPACT (Immunization Monitoring Program, ACTIVE); Jane McDonald MD, Association of Medical Microbiology and Infectious Disease Canada; Dorothy L. Moore MD, National Advisory Committee on Immunization (NACI); Howard Njoo MD, Public Health Agency of Canada
Consultant: Noni E. MacDonald MD
Principal authors: Dorothy L. Moore MD, Upton D. Allen MBBS, Timothy Mailman MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.