Journal of Infection (2014) xx, 1e7

www.elsevierhealth.com/journals/jinf

Management of invasive group A streptococcal infections Claire S. Waddington a,b,*, Thomas L. Snelling a,b,1, Jonathan R. Carapetis a,b a

Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, PO Box West Perth, WA 6872, Australia b Princess Margaret Hospital, 100 Roberts Road, Subiaco, Perth 6008, Western Australia, Australia Accepted 20 August 2014 Available online - - -

KEYWORDS Group A streptococcus; Invasive disease; Paediatric; Streptococcal toxic shock syndrome; Necrotising fasciitis

Summary Invasive group A streptococcal (GAS) disease in children includes deep soft tissue infection, bacteraemia, bacteraemic pneumonia, meningitis and osteomyelitis. The expression of toxins and super antigens by GAS can complicate infection by triggering an overwhelming systemic inflammatory response, referred to as streptococcal toxic shock syndrome (STSS). The onset and progression of GAS disease can be rapid, and the associated mortality high. Prompt antibiotics therapy and early surgical debridement of infected tissue are essential. Adjunctive therapy with intravenous immunoglobulin and hyperbaric therapy may improve outcomes in severe disease. Nosocomial outbreaks and secondary cases in close personal contacts are not uncommon; infection control measures and consideration of prophylactic antibiotics to those at high risk are important aspects of disease control. To reduce a substantial part of the global burden of GAS disease, an affordable GAS vaccine with efficacy against a broad number of strains is needed. Crown Copyright ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. All rights reserved.

Introduction The invasion of group A streptococci (GAS; Streptococcus pyogenes) into normally sterile parts of the body results

in a range of severe disease, including bacteraemia, sepsis syndrome, bacteraemic pneumonia, meningitis, puerperal sepsis and deep soft tissue infection including necrotising fasciitis. Disease onset can be rapid, and can progress at

* Corresponding author. Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, PO Box WestPerth, WA 6872, Australia. Tel.: þ61 8 94897777. E-mail addresses: [email protected] (C.S. Waddington), [email protected] (T.L. Snelling), [email protected] (J.R. Carapetis). 1 Tel.: þ61 8 94897777. http://dx.doi.org/10.1016/j.jinf.2014.08.005 0163-4453/Crown Copyright ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. All rights reserved. Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

2 an alarming rate.1,2 Expression of bacterial toxins can lead to an overwhelming systemic inflammatory response causing streptococcal toxic shock syndrome (STSS).3e5 The mainstay of treatment for invasive GAS disease is prompt administration of antibiotics, surgical debridement of infected tissue, and supportive care.6 Despite this, the associated mortality for invasive GAS disease is high.7e9 To try to improve outcomes, a number of adjunctive therapies including intravenous immunoglobulin (IVIG) administration have been used, but definitive data supporting their use is lacking particularly in the paediatric context.10e13 Prevention of disease currently is limited to reduction in secondary transmission through prompt outbreak investigation and implementation of infection control measures.14 The role of antimicrobial prophylaxis for the prevention of disease in close contacts of those with invasive GAS is uncertain.10,14 Ultimately, it is hoped that the successful development of a vaccine against GAS will provide protection both for those at risk of invasive disease as well as for those in whom the sequelae of GAS disease, particularly acute rheumatic fever (ARF) and rheumatic heart disease (RHD), remain a significant burden.15e17

Epidemiology The global burden of GAS disease is significant, and is one of the leading causes of death attributable to a specific pathogen.7 GAS infection results in a remarkable range of disease of varying severity, from superficial skin infection and pharyngitis, through to life threatening invasive disease.7,18 Superficial infections account for the greatest number of paediatric cases of GAS disease and are for the most part benign and self-limiting.7 In contrast invasive infection is relatively rare but is often complicated by multi-organ failure and shock, and is associated with high mortality.7 GAS infection can also lead to the development of immune-mediated sequelae, including ARF, RHD and post-streptococcal glomerulonephritis (PSGN), the chronic nature of which means that these conditions account for a significant proportion of the global burden of disease attributable to GAS.7 Overcrowding and poor access to health care facilitate disease progression and spread leading to a disproportionately high overall disease burden in resource-limited settings.7 The incidence of invasive GAS disease in resource-rich settings ranges between 1.5 and 3.5 cases per 100,000 people.8,18e20 Data from resource-poor settings are more limited; recent studies suggest that rates in developing countries as well as in indigenous populations living in highresource settings are several-fold higher than that observed in affluent settings.7,21e24 The highest incidence of invasive disease is seen in the elderly, followed by young children, particularly those under one years of age.18e20 In the United States for example, the incidence of invasive GAS disease per 100,000 people was 5.3 in those aged under one year, 3.6 in those aged 1e2 years, and 2.6 in those aged 2e4 years.18 Despite the availability of effective antibiotics against GAS, the mortality rate from invasive GAS disease is estimated to be between approximately 7% and 30%.8,10,18,19,25,26 Furthermore, data from Europe, North America and

C.S. Waddington et al. Australia suggest that the incidence and severity of invasive GAS has increased over recent decades,4,7,27e30 possibly due to changes in the predominant circulating GAS strains.31

Clinical features Overall, skin and soft tissue infections are the most frequently encountered primary focus of invasive GAS disease, accounting for approximately one third of cases.18,19,25 Respiratory tract infections, followed by septic arthritis, necrotising fasciitis, puerperal sepsis and meningitis account for most of the remaining cases.19 In as many of a third of bacteraemic cases no identifiable focus of infection can be found.18,19 The frequency of different sites of infection varies by age; osteomyelitis, epiglottitis and meningitis are more frequent in children less than 10 years old, compared to older patients.19 The most severe manifestations of invasive GAS disease are necrotising fasciitis and STSS, characterised by fever, rash, hypotension, shock and multi-organ failure. Necrotising fasciitis and STSS may occur together; fortunately, both are relatively rare in children.32 In a cohort of 572 patients under the age of 10 years in the United States, 4.6% had STSS and 0.9% had necrotising fasciitis.18 Pre-existing skin lesions, serving as a portal for GAS invasion, are the most frequently identified risk factor for invasive GAS disease.19 In children, primary varicella is an important predisposing condition.19,20,33 Injecting drug use, alcoholism, immunosuppression, diabetes, malignancy, and recent childbirth are additional risk factors. The ability of GAS to cause severe disease in otherwise fit and healthy individuals is notable, with between a fifth and a third of cases occurring in individuals with no predisposing risk factors.18,19 This is especially true in children; in the United States, only 22% of children aged less than 10 years with invasive GAS disease had an underlying risk factor compared to 72% of patients over 10 years of age.18

Pathology Group A streptococci possess a large number of virulence mechanisms, with a high degree of variability in virulence determinants exhibited between different GAS serotypes.34 The cell wall associated M protein, encoded for by the emm gene, is a major antigenic epitope and virulence factor of GAS,35,36 and forms the basis of the serotyping of GAS isolates.37 The M protein acts as an epithelial adhesion factor,38 inhibits phagocytosis and allows the organism to overcome innate immune responses.39e41 There are at least 180 different emm types of GAS, and new types are still being identified. Temporal, geographical and seasonal variations in the dominant strains are well described, and can result in variable disease epidemiology.31,42e44 Strain diversity appears to be greater in resource poor settings compared to resource rich settings.42,44 GAS strains also vary in terms of their tropism for different tissues such as skin and throat.45,46 GAS serotypes isolated in invasive disease correspond with prevalent community carriage and pharyngitis-associated serotypes.44 An exception to this is

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

Invasive GAS disease serotypes associated with necrotising fasciitis which are frequently of emm type 1.47 Group A streptococci can secrete a range of toxins which can trigger a systemic inflammatory response to GAS infection, including STSS.9,13 The underlying pathology in STSS is the secretion of ‘superantigens’ which are able to bypass the normal antigen presenting processes of the immune system and instead bind directly to T cell antigen receptors, resulting in polyclonal T-cell stimulation and massive cytokine release.5 STSS complicates approximate 10e15% cases of invasive GAS and has an associated mortality of up to 50%.5 The frequency of STSS appears to depend partly on the focus of infection; in necrotising fasciitis, STSS is reported to affect around half of patients.19 Despite advances in understanding the pathology of STSS, effective interventions to modify disease severity have not been forthcoming. Consequently the mortality from invasive GAS disease complicated by STSS remains high. In one large European study the mortality rate was 15% in patients without STSS to 44% in those with STSS.19

Treatment Prior to the antibiotic era, GAS disease was a leading cause of death throughout the world. During the post-antibiotic era a decrease in the GAS attributable mortality has occurred in countries where effective and appropriate antibiotic therapy for GAS infection is widely available.48,49 Remarkably GAS remains universally sensitive to penicillin despite its widespread use therefore penicillin remains the mainstay of therapy for all GAS infection, including invasive disease.6 Surgical drainage of pus and/or debridement of infected tissue is an important adjunct to antimicrobial therapy in invasive disease and has been shown to improve outcome in children.50 In the treatment of invasive GAS disease, the addition of clindamycin to penicillin therapy is beneficial. The mechanistic rationale for this is twofold. Firstly, despite exquisite sensitivity of GAS to penicillin in vitro, the in vivo efficacy is limited by the “inoculum effect” whereby antibiotic susceptibility is reduced by large bacterial loads.51 In contrast, clindamycin is unaffected by inoculum size. Secondly, clindamycin acts to inhibit bacterial protein synthesis, including toxin production, a process which contributes substantially to the pathogenesis of GAS most notably in the context of STSS.6,52e54 Clinical data have confirmed that the addition of clindamycin to penicillin therapy is beneficial with a recent study reporting an odds ratio of survival of 8.6 when clindamycin was added to penicillin compared with penicillin monotherapy.13 Similarly, a prospective study of 84 cases of invasive GAS in Australia showed that despite a having more severe disease, clindamycin treated patients had a lower risk of death than those who did not receive clindamycin (15% vs. 39% respectively).10 This association remained after adjustment for age and the presence of STSS.6 In children, a retrospective review of 56 patients with invasive GAS reported a 68% failure rate when cell wall-inhibiting antibiotics such as penicillin were used alone; inclusion of an antibiotic that inhibited protein synthesis improved rates of arrested disease progression by at least 35%.50

3

The role of intravenous immunoglobulin STSS substantially increases the risk of death from invasive GAS disease.26 IVIG has been suggested as an adjunctive therapy in the setting of STSS in an attempt to reduce the high mortality rate. IVIG has been reported to enhance the bactericidal activity of serum by facilitating bacterial opsonisation, neutralising super antigens and toxins, stimulating leukocytes and by exerting a generalised antiinflammatory effect through its effects on Fc receptor expression, complement, cytokines and B and T cells.55e59 Generating robust clinical data to support the use of IVIG has been difficult.11,59 An observational cohort study of 21 patients treated with IVIG suggested that IVIG increased the 30-day survival rates to 67% compared to 34% in historical controls.12 An attempt to quantify the benefit of IVIG thorough a double-blind, placebo-controlled trial unfortunately had to be terminated early due to slow patient recruitment; available data did however suggest a trend towards improved survival with 4 of 11 placebo recipients compared to the 1 of 10 IVIG recipients dying by 28 days.11 These data have been supported by a recent prospective observational study of 67 patients which showed 28-day survival rates of 87% in the IVIG group compared to 50% in the untreated group.13 Similarly a prospective observational study of patients with invasive GAS disease in Australia reported a reduction in mortality rate from 18% to 7% when IVIG was added to antimicrobial therapy, although statistical significance could not be demonstrated with the small numbers.10 Paediatric data are even more limited. A multicentre, retrospective cohort study however failed to show a difference in mortality rate between IVIG recipients (5 of 84; 6.0%) and non-recipients (3 of 108; 2.8%) although mortality was low overall.60 Difference in other endpoints including total cost of hospital care, and length of intensive care unit were also not shown60; the appropriateness and relevance of these endpoints has been questioned however.32 In the absence of randomised controlled clinical trials of IVIG, particularly in specific patient cohorts such as children, it is difficult to reliably quantify the benefit of IVIG therapy. Given the severity of disease that can result from STSS and the relatively good safety profile of IVIG, coupled with the evidence suggesting potential benefit of IVIG, it should however be considered as adjunctive therapy in cases of STSS. The appropriate dose of IVIG in invasive GAS disease remains unknown, although in practice a single infusion of 2 g per kilogram, extrapolated from the dose used in the treatment of Kawasaki disease, is often used.6

Hyperbaric oxygen therapy Hyperbaric oxygen therapy involves administering oxygen at two to three times the atmospheric pressure of oxygen at sea level.61 Infected tissue, particularly in the context of necrotising fasciitis, presents a hypoxic environment relative to that of healthy tissue. In this setting bacterial killing mediated by neutrophil free radical production and phagocytosis is reduced; hyperbaric oxygen therapy might counteract this by increasing the amount of oxygen dissolved in blood, thereby reducing the hypoxic tissue environment.61

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

4 Data supporting hyperbaric-oxygen therapy in the treatment of necrotising fasciitis are limited to case reports and series, principally based on adult cases of severe disease where surgical and antimicrobial therapy has failed.62,63 In this context, hyperbaric therapy has been suggested to improve mortality rates. In 29 adults with necrotising fasciitis, the mortality rate of those receiving hyperbaric therapy was 23% compared to 66% in those who did not, despite more severe disease in the intervention group.62 Hyperbaric therapy also appeared to reduce the need for repeated surgical debridement. A case series of 14 children with GAS necrotising fasciitis complicating primary varicella disease reported a subjective benefit in 6 of the 12 cases where hyperbaric therapy was used.64 Given the rarity of GAS necrotising fasciitis in the paediatric population it is unlikely that more definitive data supporting a role for hyperbaric therapy will be available in the near term. Extrapolation of the limited adult data may however warrant a trial of hyperbaric therapy in cases of necrotising fasciitis where more conventional therapy has failed.

Prevention of disease transmission The potential for puerperal sepsis to result from healthcare interventions and settings, and the preventive role of hand washing has been recognised for over a century.65 In contemporary case series between 6% and 12% of cases of invasive GAS disease are reported to be nosocomially acquired.14,18,20,66 Most nosocomially acquired cases manifest as surgical site infections or puerperal sepsis.8,14 Outbreaks of invasive GAS disease, particularly in surgical, obstetrics and gynaecology, and burns units are well described, and should be suspected when two or more cases of invasive GAS occur with a temporal or spatial link.8,14 Both symptomatic and asymptomatically colonised healthcare workers (HCWs) can act as a source of infection. In Canada, symptomatic workers were shown to account for 8% of outbreaks and colonised, asymptomatic HCWs for as many as 34% of outbreaks.1 The environment can also be a source of GAS66 highlighting the need for policies around the decontamination of the environmental and equipment.14 To prevent secondary transmission, patients should be isolated for at least 24 h after antibiotic therapy is commenced.14 Mother to baby transmission of GAS is recognised.67 To prevent this it has been suggested that antibiotics should be administered to mother and baby if either develops suspected or confirmed invasive GAS disease in the 28 days following parturition.14 Interruption of breast feeding and separation of mothers and babies is not recommended. Clustering of invasive GAS disease in families is also reported.8,14,68,69 Invasive GAS has been associated with an increase in risk of disease in close contacts of 200e2000 times above baseline.8,10,70 The role of prophylactic antibiotics for close contacts of those with invasive GAS disease is debated, with their use recommended by some6 but not all public health authorities.14 The variations in estimates of the relative risk increase in contacts compared to baseline translate into predictions of the numbers need to treat to prevent one secondary case of between approximately 220 and 2000 contacts, considerably altering the risk-benefit analysis for chemoprophylaxis.10,14 Proof that antibiotic

C.S. Waddington et al. administration to contacts modifies risk is also lacking, and is unlikely to be forthcoming due to the small numbers of cases. Despite the uncertainties, antibiotic prophylaxis should be considered following identification of an index case,10 with consideration given to the number of associated cases, severity of cases, vulnerability of patients, and likely source of the outbreak.14 Where prophylaxis is used, cephalosporins may be preferred over penicillins as they are associated with increased rates of GAS clearance from colonised sites.71 Alternative regimens include macrolides and clindamycin.6 The choice of antimicrobial should be agreed locally based on the clinical circumstances, whether the source has been identified and eliminated, the susceptibility of the patients, and the likely site of infection if it occurred.14

Prospects for the future Despite the availability of effective antibiotics against GAS, the global burden of disease remains significant and the mortality, particularly from invasive disease, unacceptably high. An effective GAS vaccine could substantially decrease the burden of disease, and in an ideal world, would prevent pharyngeal colonisation, carriage, symptomatic and asymptomatic infection and post infectious sequelae.15 Despite the obvious need, progress has been hampered for many decades due to the large number of antigenically distinct emm types of GAS and concerns about the risk of inadvertently inducing a cross reacting immune response capable of causing immune-mediated manifestations. Despite this, progress and support for a GAS vaccine is gaining momentum, and two candidate vaccines have reached phase 1 trials.17

Conclusions Invasive GAS disease is frequently severe, and is associated with high mortality.1,2 Prompt antibiotic therapy is critical to reduce mortality, with penicillin and clindamycin in combination the optimal antimicrobial choice in both adult and paediatric cases. Both STSS and necrotising fasciitis are associated with particularly poor outcomes.3e5 Although evidence for IVIG and hyperbaric therapy in these settings is limited, they may confer some advantage.10e13 Due consideration should be given to the prevention of secondary cases of invasive GAS disease.14 Infection control measures are important to try to prevent nosocomial transmission, and antimicrobial prophylaxis should be considered in close contacts of those with invasive disease.10,14 It is hoped that progress towards an effective GAS vaccine will translate into a significant reduction in the global burden of GAS disease in the future.15e17

Conflict of interest None.

References

1. Daneman N, McGeer A, Low DE, Tyrrell G, Simor AE, McArthur M, et al. Hospital-acquired invasive Group A

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

Invasive GAS disease

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

streptococcal infections in Ontario, Canada, 1992e2000. Clin Infect Dis 2005 Aug 1;41(3):334e42. PubMed PMID: 16007530. Steer AC, Danchin MH, Carapetis JR. Group A streptococcal infections in children. J Paediatr Child Health 2007 Apr;43(4): 203e13. PubMed PMID: 17444820. Epub 2007/04/21. eng. Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. The working group on severe streptococcal infections. Jama 1993 Jan 20;269(3): 390e1. PubMed PMID: 8418347. Epub 1993/01/20. eng. Hribalova V. Streptococcus pyogenes and the toxic shock syndrome. Ann Intern Med 1988 May;108(5):772. PubMed PMID: 3282471. McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Annu Rev Microbiol 2001;55:77e104. PubMed PMID: 11544350. Allen U, Moore D. Invasive Group A streptococcal disease: management and chemoprophylaxis. Paediatr Child Health 2010 May;15(5):295e302. PubMed PMID: 21532795. Pubmed Central PMCID: 2912623. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of Group A streptococcal diseases. Lancet Infect Dis 2005 Nov;5(11):685e94. PubMed PMID: 16253886. Epub 2005/10/29. eng. Davies HD, McGeer A, Schwartz B, Green K, Cann D, Simor AE, et al. Invasive Group A streptococcal infections in Ontario, Canada. Ontario Group A streptococcal study group. N Engl J Med 1996 Aug 22;335(8):547e54. PubMed PMID: 8684408. Low DE. Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin 2013 Jul;29(3): 651e75. PubMed PMID: 23830657. Carapetis JR, Jacoby P, Carville K, Ang SJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive Group A streptococcal infections. Clin Infect Dis 2014 Aug; 59(3):358e65. PubMed PMID: 24785239. Darenberg J, Ihendyane N, Sjolin J, Aufwerber E, Haidl S, Follin P, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003 Aug 1;37(3):333e40. PubMed PMID: 12884156. Kaul R, McGeer A, Norrby-Teglund A, Kotb M, Schwartz B, O’Rourke K, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndromeea comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999 Apr;28(4):800e7. PubMed PMID: 10825042. Linner A, Darenberg J, Sjolin J, Henriques-Normark B, NorrbyTeglund A. Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome e a comparative observational study. Clin Infect Dis 2014 Sep 15;59(6):851e7. PubMed PMID: 24928291. Steer JA, Lamagni T, Healy B, Morgan M, Dryden M, Rao B, et al. Guidelines for prevention and control of Group A streptococcal infection in acute healthcare and maternity settings in the UK. J Infect 2012 Jan;64(1):1e18. PubMed PMID: 22120112. Dale JB, Fischetti VA, Carapetis JR, Steer AC, Sow S, Kumar R, et al. Group A streptococcal vaccines: paving a path for accelerated development. Vaccine 2013 Apr 18;31(Suppl 2): B216e22. PubMed PMID: 23598485. Epub 2013/04/26. eng. Steer AC, Batzloff M, Mulholland EK, Carapetis JR. Group A streptococcal vaccines: facts versus fantasy. Curr Opin Infect Dis 2009;22:544e52. Moreland NJ, Waddington CS, Williamson DA, Sriskandan S, Smeesters PR, Proft T, et al. Working towards a Group A streptococcal vaccine: report of a collaborative Trans-Tasman workshop. Vaccine 2014 Jun 24;32(30):3713e20. PubMed PMID: 24837510. O’Loughlin RE, Roberson A, Cieslak PR, Lynfield R, Gershman K, Craig A, et al. The epidemiology of invasive Group A

5

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

streptococcal infection and potential vaccine implications: United States, 2000e2004. Clin Infect Dis 2007 Oct 1;45(7): 853e62. PubMed PMID: 17806049. Epub 2007/09/07. eng. Lamagni TL, Darenberg J, Luca-Harari B, Siljander T, Efstratiou A, Henriques-Normark B, et al. Epidemiology of severe Streptococcus pyogenes disease in Europe. J Clin Microbiol 2008 Jul;46(7):2359e67. PubMed PMID: 18463210. Pubmed Central PMCID: 2446932. O’Grady K-A, Kelpie L, Andrews RA, Curtis N, Nolan TM, Selvaraj G, et al. The epidemiology of invasive Group A streptococcal disease in Victoria,. Aust Med J Aust 2007;186: 565e9. Brent AJ, Ahmed I, Ndiritu M, Lewa P, Ngetsa C, Lowe B, et al. Incidence of clinically significant bacteraemia in children who present to hospital in Kenya: community-based observational study. Lancet 2006 Feb 11;367(9509):482e8. PubMed PMID: 16473125. Epub 2006/02/14. eng. Steer AC, Jenney A, Kado J, Good MF, Batzloff M, Waqatakirewa L, et al. Prospective surveillance of invasive Group A streptococcal disease, Fiji, 2005-2007. Emerg Infect Dis 2009 Feb;15(2):216e22. PubMed PMID: 19193265. Pubmed Central PMCID: 2657613. Norton R, Smith HV, Wood N, Siegbrecht E, Ross A, Ketheesan N. Invasive Group A streptococcal disease in North Queensland (1996e2001). Indian J Med Res 2004 May; 119(Suppl):148e51. PubMed PMID: 15232182. Carapetis JR, Walker AM, Hibble M, Sriprakash KS, Currie BJ. Clinical and epidemiological features of Group A streptococcal bacteraemia in a region with hyperendemic superficial streptococcal infection. Epidemiol Infect 1999 Feb;122(1): 59e65. PubMed PMID: 10098786. Pubmed Central PMCID: 2809588. Epub 1999/03/31. eng. Public Health England. Group A streptococcal infections [24/06/2014]. Available from: http://www.hpa.org.uk/ Topics/InfectiousDiseases/InfectionsAZ/StreptococciGroupA. Stevens DL. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment. Emerg Infect Dis 1995 Jul-Sep;1(3):69e78. PubMed PMID: 8903167. Pubmed Central PMCID: 2626872. Cone LA, Woodard DR, Schlievert PM, Tomory GS. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 1987 Jul 16;317(3): 146e9. PubMed PMID: 3299086. Gaworzewska E, Colman G. Changes in the pattern of infection caused by Streptococcus pyogenes. Epidemiol Infect 1988 Apr;100(2):257e69. PubMed PMID: 3128449. Pubmed Central PMCID: 2249231. Stevens DL, Tanner MH, Winship J, Swarts R, Ries KM, Schlievert PM, et al. Severe Group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 1989 Jul 6;321(1):1e7. PubMed PMID: 2659990. O’Brien KL, Beall B, Barrett NL, Cieslak PR, Reingold A, Farley MM, et al. Epidemiology of invasive Group A Streptococcus disease in the United States, 1995e1999. Clin Infect Dis 2002 Aug 1;35(3):268e76. PubMed PMID: 12115092. Epub 2002/07/13. eng. Carapetis J, Robins-Browne R, Martin D, Shelby-James T, Hogg G. Increasing severity of invasive Group A streptococcal disease in Australia: clinical and molecular epidemiological features and identification of a new virulent M-nontypeable clone. Clin Infect Dis 1995 Nov;21(5):1220e7. PubMed PMID: 8589146. Epub 1995/11/01. eng. Valiquette L, Low DE, McGeer AJ. Assessing the impact of intravenous immunoglobulin in the management of streptococcal toxic shock syndrome: a noble but difficult quest. Clin Infect Dis 2009 Nov 1;49(9):1377e9. PubMed PMID: 19788361.

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

6 33. Tyrrell GJ, Lovgren M, Kress B, Grimsrud K. Varicella-associated invasive Group A streptococcal disease in Alberta, Canadae2000e2002. Clin Infect Dis 2005 Apr 1;40(7):1055e7. PubMed PMID: 15825001. 34. Cunningham MW. Pathogenesis of Group A streptococcal infections. Clin Microbiol Rev 2000 Jul;13(3):470e511. PubMed PMID: 10885988. Pubmed Central PMCID: 88944. Epub 2000/07/25. eng. 35. Lancefield RC. The antigenic complex of Streptococcus haemolyticus : I. Demonstration of a type-specific substance in extracts of streptococcus haemolyticus. J Exp Med 1928 Jan 1;47(1):91e103. PubMed PMID: 19869404. Pubmed Central PMCID: 2131344. Epub 1928/01/01. eng. 36. McMillan DJ, Dreze PA, Vu T, Bessen DE, Guglielmini J, Steer AC, et al. Updated model of Group A streptococcus M proteins based on a comprehensive worldwide study. Clin Microbiol Infect 2013 May;19(5):E222e9. PubMed PMID: 23464795. Epub 2013/03/08. eng. 37. Lancefield RC. Current knowledge of type-specific M antigens of Group A streptococci. J Immunol 1962 Sep;89:307e13. PubMed PMID: 14461914. Epub 1962/09/01. eng. 38. Courtney HS, Hasty DL, Dale JB. Molecular mechanisms of adhesion, colonization, and invasion of Group A streptococci. Ann Med 2002;34(2):77e87. PubMed PMID: 12108578. Epub 2002/07/11. eng. 39. Smeesters PR, McMillan DJ, Sriprakash KS. The streptococcal M protein: a highly versatile molecule. Trends Microbiol 2010 Jun;18(6):275e82. PubMed PMID: 20347595. Epub 2010/03/30. eng. 40. Fischetti VA. Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev 1989 Jul;2(3): 285e314. PubMed PMID: 2670192. Pubmed Central PMCID: 358122. Epub 1989/07/01. eng. 41. Bisno AL, Brito MO, Collins CM. Molecular basis of Group A streptococcal virulence. Lancet Infect Dis 2003 Apr;3(4): 191e200. PubMed PMID: 12679262. Epub 2003/04/08. eng. 42. Steer AC, Law I, Matatolu L, Beall BW, Carapetis JR. Global emm type distribution of Group A streptococci: systematic review and implications for vaccine development. Lancet Infect Dis 2009 Oct;9(10):611e6. PubMed PMID: 19778763. Epub 2009/09/26. eng. 43. Kaplan EL, Wotton JT, Johnson DR. Dynamic epidemiology of Group A streptococcal serotypes associated with pharyngitis. Lancet 2001 Oct 20;358(9290):1334e7. PubMed PMID: 11684215. Epub 2001/10/31. eng. 44. Bessen DE, Carapetis JR, Beall B, Katz R, Hibble M, Currie BJ, et al. Contrasting molecular epidemiology of Group A streptococci causing tropical and nontropical infections of the skin and throat. J Infect Dis 2000 Oct;182(4):1109e16. PubMed PMID: 10979907. Epub 2000/09/09. eng. 45. Bessen DE, Sotir CM, Readdy TL, Hollingshead SK. Genetic correlates of throat and skin isolates of Group A streptococci. J Infect Dis 1996 Apr;173(4):896e900. PubMed PMID: 8603968. Epub 1996/04/01. eng. 46. Smeesters PR, Dramaix M, Van Melderen L. The emm-type diversity does not always reflect the M protein genetic diversityeis there a case for designer vaccine against GAS. Vaccine 2010 Jan 22;28(4):883e5. PubMed PMID: 19963033. Epub 2009/12/08. eng. 47. Wajima T, Murayama SY, Sunaoshi K, Nakayama E, Sunakawa K, Ubukata K. Distribution of emm type and antibiotic susceptibility of Group A streptococci causing invasive and noninvasive disease. J Med Microbiol 2008 Nov;57(Pt 11):1383e8. PubMed PMID: 18927416. 48. Katz AR, Morens DM. Severe streptococcal infections in historical perspective. Clin Infect Dis 1992 Jan;14(1):298e307. PubMed PMID: 1571445.

C.S. Waddington et al. 49. Ellis H. The last year before the dawn of antibiotics. Br J Hosp Med 2009 Aug;70(8):475. PubMed PMID: 19684540. 50. Zimbelman J, Palmer A, Todd J. Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J 1999 Dec;18(12):1096e100. PubMed PMID: 10608632. 51. Sakata H. Susceptibility and emm type of Streptococcus pyogenes isolated from children with severe infection. Journal of infection and chemotherapy. Off J Jpn Soc Chemother 2013 Dec;19(6):1042e6. PubMed PMID: 23703641. Pubmed Central PMCID: 3855535. 52. Mascini EM, Jansze M, Schouls LM, Verhoef J, Van Dijk H. Penicillin and clindamycin differentially inhibit the production of pyrogenic exotoxins A and B by Group A streptococci. Int J Antimicrob Agents 2001 Oct;18(4):395e8. PubMed PMID: 11691576. 53. Sriskandan S, McKee A, Hall L, Cohen J. Comparative effects of clindamycin and ampicillin on superantigenic activity of Streptococcus pyogenes. J Antimicrob Chemother 1997 Aug; 40(2):275e7. PubMed PMID: 9301995. 54. Goscinski G, Tano E, Thulin P, Norrby-Teglund A, Sjolin J. Release of SpeA from Streptococcus pyogenes after exposure to penicillin: dependency on dose and inhibition by clindamycin. Scand J Infect Dis 2006;38(11e12):983e7. PubMed PMID: 17148065. 55. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens [see comment]. J Clin Invest 1993 Feb;91(2):602e7. PubMed PMID: 8432865. Pubmed Central PMCID: 287991. 56. Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc C, Desai R, et al. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clinical and experimental immunology 1996 May; 1996 May;104(Suppl 1): 3e9. PubMed PMID: 8625540. 57. Negi VS, Elluru S, Siberil S, Graff-Dubois S, Mouthon L, Kazatchkine MD, et al. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol 2007 May;27(3):233e45. PubMed PMID: 17351760. 58. Norrby-Teglund A, Low DE, McGeer A, Kotb M. Superantigenic activity produced by Group A streptococcal isolates is neutralized by plasma from IVIG-treated streptococcal toxic shock syndrome patients. Adv Exp Med Biol 1997;418:563e6. PubMed PMID: 9331714. 59. Alejandria MM, Lansang MA, Dans LF, Mantaring 3rd JB. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev 2013;9:CD001090. PubMed PMID: 24043371. 60. Shah SS, Hall M, Srivastava R, Subramony A, Levin JE. Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clin Infect Dis 2009 Nov 1;49(9):1369e76. PubMed PMID: 19788359. Pubmed Central PMCID: 2761980. 61. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. N Engl J Med 1996 Jun 20;334(25):1642e8. PubMed PMID: 8628361. 62. Riseman JA, Zamboni WA, Curtis A, Graham DR, Konrad HR, Ross DS. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery 1990 Nov;108(5):847e50. PubMed PMID: 2237764. 63. Brown DR, Davis NL, Lepawsky M, Cunningham J, Kortbeek J. A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy. Am J Surg 1994 May;167(5):485e9. PubMed PMID: 8185032. 64. Brogan TV, Nizet V, Waldhausen JH, Rubens CE, Clarke WR. Group A streptococcal necrotizing fasciitis complicating primary varicella: a series of fourteen patients. Pediatr Infect Dis J 1995 Jul;14(7):588e94. PubMed PMID: 7567287.

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005

Invasive GAS disease 65. Lancaster HO. Semmelweis: a rereading of Die aetiologie... Part I: puerperal sepsis before 1845; Die aetiologie. J Med Biogr 1994 Feb;2(1):12e21. PubMed PMID: 11615264. 66. Daneman N, Green KA, Low DE, Simor AE, Willey B, Schwartz B, et al. Surveillance for hospital outbreaks of invasive Group A streptococcal infections in Ontario, Canada, 1992 to 2000. Ann Intern Med 2007 Aug 21;147(4):234e41. PubMed PMID: 17709757. 67. Panaro NR, Lutwick LI, Chapnick EK. Intrapartum transmission of Group A streptococcus. Clin Infect Dis 1993 Jul;17(1): 79e81. PubMed PMID: 8353251. 68. Schwartz B, Elliott JA, Butler JC, Simon PA, Jameson BL, Welch GE, et al. Clusters of invasive Group A streptococcal infections in family, hospital, and nursing home settings. Clin Infect Dis 1992 Aug;15(2):277e84. PubMed PMID: 1520763.

7 69. Roy S, Kaplan EL, Rodriguez B, Schreiber JR, Salata RA, Palavecino E, et al. A family cluster of five cases of Group A streptococcal pneumonia. Pediatrics 2003 Jul;112(1 Pt 1): e61e5. PubMed PMID: 12837907. 70. Prevention of Invasive Group ASIWP. Prevention of invasive Group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the centers for disease control and prevention. Clin Infect Dis 2002 Oct 15;35(8):950e9. PubMed PMID: 12355382. 71. Casey JR, Pichichero ME. Meta-analysis of cephalosporins versus penicillin for treatment of Group A streptococcal tonsillopharyngitis in adults. Clin Infect Dis 2004 Jun 1;38(11): 1526e34. PubMed PMID: 15156437.

Please cite this article in press as: Waddington CS, et al., Management of invasive group A streptococcal infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.005