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The treatment of severe group a streptococcal infections

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Abstract

Group A streptococci can cause a variety of diseases ranging from uncomplicated superficial infections to severe systemic infections associated with high morbidity and mortality. Since the late 1980s a drastic resurgence of highly aggressive invasive streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have been noted worldwide. This has prompted intense research in the field and important new information has been gained regarding the pathogenesis and treatment of life-threatening invasive group A streptococcal infections. Exotoxins with superantigenic activities have been identified as central mediators of the systemic effects seen in streptococcal toxic shock syndrome. Novel therapeutic strategies include agents that can inhibit these superantigens, and one promising candidate is intravenous polyspecific immunoglobulin that contains neutralizing antibodies against a wide spectrum of streptococcal superantigens. Intravenous immunoglobulin adjunctive therapy was shown in a case-control study to reduce mortality in patients with streptococcal toxic shock syndrome.

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References and Recommended Reading

  1. Cone LA, Woodard DR, Schlievert PM, Tomory GS: Clinical and bacteriological observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 1987, 317:146–149.

    Article  PubMed  CAS  Google Scholar 

  2. Stevens DL: Invasive group A streptococcus infections. Clin Infect Dis 1992, 14:2–13.

    PubMed  CAS  Google Scholar 

  3. The Working Group on Severe Streptococcal Infections: Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. JAMA 1993, 269:390–391.

    Article  Google Scholar 

  4. Davies DH, McGeer A, Schwartz B, et al., and The Ontario group A streptococcal study group: Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med 1996, 135:547–554.

    Article  Google Scholar 

  5. Efstratiou A: Group A streptococci in the 1990s. J Antimicrob Chemother 2000, 45:3–12.

    Article  PubMed  CAS  Google Scholar 

  6. Chatellier S, Ihendyane N, Kansal RG, et al.: Genetic relatedness and superantigen expression of M type 1 group A streptococci isolates from severe and nonsevere invasive disease. Infect Immun 2000, 68:3523–3534. The study describes clonality and superantigen expression in group A streptococcal M1T1 isolates from patients with severe or nonsevere invasive disease. The results show that highly related, some indistinguishable, strains can cause disease of starkly varying severity in different individuals. The report underscores the contribution of host factors in determining the outcome of infection.

    Article  PubMed  CAS  Google Scholar 

  7. Glauser MP: Pathophysiologic basis for sepsis: considerations for future strategies of intervention. Crit Care Med 2000, 28(Suppl 1):S4-S8.

    Article  PubMed  CAS  Google Scholar 

  8. Bone RC: The pathogenesis of sepsis. Ann Intern Med 1991, 115:457–469.

    PubMed  CAS  Google Scholar 

  9. Okusawa S, Gelfand JA, Ikejima T, et al.: Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 1988, 81:1162–1172.

    Article  PubMed  CAS  Google Scholar 

  10. Tracey KJ, Beutler B, Lowry SF, et al.: Shock and tissue injury induced by recombinant human cachectin. Science 1986, 234:470–474.

    Article  PubMed  CAS  Google Scholar 

  11. Wang H, Bloom O, Zhang M, et al.: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285:248–251. This study identifies HMG-1 protein as a late mediator of endotoxin lethality in mice. Anti-HMG-1 was found to attenuate this lethality, even when given 2 hours postendotoxin infusion. Fatal septic patients showed elevated serum HMG-1 levels. The authors propose that HMG-1 may be a novel target for therapeutic intervention.

    Article  PubMed  CAS  Google Scholar 

  12. Calandra T, Echtenacher B, Roy DL, et al.: Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000, 6:164–170. This report demonstrates that macrophage MIF is a critical mediator of septic shock. MIF was found at elevated levels in mice with bacterial peritonitis, and in patients with severe sepsis or septic shock. Anti-MIF protected against lethal peritonitis even when the treatment was delayed up to 8 hours after cecal puncture and ligation. The authors propose that MIF is a potential target for therapeutic intervention.

    Article  PubMed  CAS  Google Scholar 

  13. Levi M, Ten Cate H: Disseminated intravascular coagulation. N Engl J Med 1999, 341:586–592.

    Article  PubMed  CAS  Google Scholar 

  14. Fisher CJJ, Yan SB: Protein C levels as a prognostic indicator of outcome in sepsis and related diseases. Crit Care Med 2000, 28 (Suppl):S49-S56.

    Article  PubMed  Google Scholar 

  15. Colman RW, Schmaier AH: Contact system: a vascular biology modulatory with anti-coagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997, 90:3819–3843.

    PubMed  CAS  Google Scholar 

  16. Herwald H, Mörgelin M, Olsén, et al.: Activation of the contactphase system on bacterial surfaces - a clue to serious complications in infectious diseases. Nat Med 1998, 4:298–302.

    Article  PubMed  CAS  Google Scholar 

  17. Rasmussen M, Bjorck L: Proteolysis and its regulation at the surface of Streptococcus pyogenes. Mol Microbiol 2002, 43:537–544. This is a comprehensive review of the streptococcal proteinases, their action, and how they can contribute to the pathogenesis of group A streptocccal infections. The review describes novel models for the involvement of proteolysis in the pathogenesis.

    Article  PubMed  CAS  Google Scholar 

  18. Fischetti VA: Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev 1989, 2:285–314.

    PubMed  CAS  Google Scholar 

  19. Boyle MD: Variation of multifunctional surface binding proteins-a virulence strategy for group A streptococci? J Theor Biol 1995, 21:415–426.

    Article  Google Scholar 

  20. Sriskandan S, Cohen J: Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis. Infect Dis Clin North Am 1999, 13:397–412.

    Article  PubMed  CAS  Google Scholar 

  21. Beutler B: Toll-like receptors: how they work and what they do. Curr Opin Hematol 2002, 9:2–10.

    Article  PubMed  Google Scholar 

  22. Kotb M: Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev 1995, 8:411–426.

    PubMed  CAS  Google Scholar 

  23. Llewelyn M, Cohen J: Superantigens: microbial agents that corrupt immunity. Lancet Infect Dis 2002, 2:156–162.

    Article  PubMed  CAS  Google Scholar 

  24. Norrby-Teglund A, Kotb M: Host-microbe interactions in the pathogenesis of invasive group A streptococcal infections. J Med Microbiol 2000, 49:849–852.

    PubMed  CAS  Google Scholar 

  25. Kotb M: Superantigens of gram-positive bacteria: structurefunction analyses and their implications for biological activity. Curr Opin Microbiol 1998, 1:56–65.

    Article  PubMed  CAS  Google Scholar 

  26. Hemmi H, Takeuchi O, Kawai T, et al.: A Toll-like receptor recognizes bacterial DNA. Nature 2000, 408:740–745.

    Article  PubMed  CAS  Google Scholar 

  27. Heeg K, Sparwasser T, Lipford GB, et al.: Bacterial DNA as an evolutionary conserved ligand signalling danger of infection to immune cells. Eur J Clin Microbiol Infect Dis 1998, 17:464–469.

    PubMed  CAS  Google Scholar 

  28. Chatellier S, Kotb M: Preferential stimulation of human lymphocytes by oligodeoxynucleotides that copy DNA CpG motifs present in virulent genes of group A streptococci. Eur J Immunol 2000, 30:993–1001.

    Article  PubMed  CAS  Google Scholar 

  29. Hytönen J, Haataja S, Gerlach D, et al.: The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity. Mol Microbiol 2001, 39:512–519.

    Article  PubMed  Google Scholar 

  30. Hackett SP, Stevens DL: Streptococcal toxic shock syndrome: synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O. J Infect Dis 1992, 165:879–885.

    PubMed  CAS  Google Scholar 

  31. Shanley TP, Schrier D, Kapur V, et al.: Streptococcal cysteine protease augments lung injury induced by products of group A streptococci. Infect Immun 1996, 64:870–877.

    PubMed  CAS  Google Scholar 

  32. Muller MP, McGeer A, Low DE, and Ontario Group A Streptococcal Study: Successful outcome in six patients treated conservatively for suspected necrotizing fasciitis (NF) due to group A streptococccus (GAS) [abstract]. Paper presented at 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16–19, 2001. Chicago.

  33. Norrby SR: Side effects of cephalosporins. Drugs 1987, 34:105–120.

    PubMed  Google Scholar 

  34. Stevens DL, Gibbons AE, Bergstrom R, Winn V: The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988, 158:23–28.

    PubMed  CAS  Google Scholar 

  35. Eagle H: Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952, 13:389–399.

    Article  PubMed  CAS  Google Scholar 

  36. Stevens DL, Yan S, Bryant AE: Penicillin-binding protein expression at different growth stages determines penicillin efficacy in vitro and in vivo: an explanation for the inoculum effect. J Infect Dis 1993, 167:1401–1405.

    PubMed  CAS  Google Scholar 

  37. Mascini EM, Jansze M, Schouls LM, et al.: Penicillin and clindamycin differentially inhibit the production of pyrogenic exotoxins A and B by group A streptococci. Int J Antimicrob Agents 2001, 18:395–398.

    Article  PubMed  CAS  Google Scholar 

  38. De Azavedo JC, Yeung RH, Bast DJ, et al.: Prevalence and mechanisms of macrolide resistance in clinical isolates of group A streptococci from Ontario, Canada. Antimicrob Agents Chemother 1999, 43:2144–2147.

    PubMed  Google Scholar 

  39. Descheemaeker P, Chapelle S, Lammens C, et al.: Macrolide resistance and erythromycin resistance determinants among Belgian Streptococcus pyogenes and Streptococcus pneumoniae isolates. J Antimicrob Chemother 2000, 45:167–173.

    Article  PubMed  CAS  Google Scholar 

  40. Savoia D, Avanmzini C, Bosio K, et al.: Macrolide resistance in group A Streptococci. J Antimicrob Chemother 2000, 45:41–47.

    Article  PubMed  CAS  Google Scholar 

  41. Aracil B, Minambres M, Oteo J, et al.: High prevalence of erythromycin-resistant and clindamycin-susceptible (M phenotype) viridans group streptococci from pharyngeal samples: a reservoir of mef genes in commensal bacteria. J Antimicrob Chemother 2001, 48:592–594.

    Article  PubMed  CAS  Google Scholar 

  42. Facinelli B, Spinaci C, Magi G, et al.: Association between erythromycin resistance and ability to enter human respiratory cells in group A streptococci. Lancet 2001, 358:30–33. The authors demonstrate an association between erythromycin resistance and cell invasiveness in group A streptococci. Strains combining erythromycin resistance and ability to enter human respiratory tract cells may be able to escape β-lactams by virtue of intracellular location and macrolides by virtue of resistance.

    Article  PubMed  CAS  Google Scholar 

  43. Abraham E: Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med 1999, 25:556–566.

    Article  PubMed  CAS  Google Scholar 

  44. Schneider J, Voerman HJ: Abrupt hemodynamic improvement in late septic shock with physiological doses of glucocorticoids. Intensive Care Med 1991, 17:436–437.

    Article  PubMed  CAS  Google Scholar 

  45. Bollaert P, Charpentier C, Levy B, et al.: Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998, 26:645–650.

    Article  PubMed  CAS  Google Scholar 

  46. Briegel J, Kellermann W, Forst H, et al.: Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group. Clin Invest 1994, 72:782–787.

    Article  CAS  Google Scholar 

  47. Bernard GR, Vincent JL, Laterre PF, et al.: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344:699–709. The efficacy and safety of recombinant human APC for severe sepsis was tested in a randomized, double-blind, placebo-controlled phase III clinical trial. The results of 1690 randomized patients revealed a significant reduction in mortality rate in the group receiving active drug (P = 0.005).

    Article  PubMed  CAS  Google Scholar 

  48. Norrby-Teglund A, Stevens DL: Novel therapies in streptococcal toxic shock syndrome: attenuation of virulence factor expression and modulation of the host response. Curr Opin Infect Dis 1998, 11:285–291.

    PubMed  CAS  Google Scholar 

  49. Ballow M: Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. Allergy Clin Immunol 1997, 100:151–157.

    Article  CAS  Google Scholar 

  50. Basma H, Norrby-Teglund A, McGeer A, et al.: Opsonic antibodies to the surface M protein, present in pooled normal immunoglobulins (IVIG), may contribute to its clinical efficacy in severe invasive group A streptococcal infections. Infect Immun 1998, 66:2279–2283.

    PubMed  CAS  Google Scholar 

  51. Patel R, Rouse MS, Florez MV, et al.: Lack of benefit of intravenous immune globulin in a murine model of group A streptococcal necrotizing fasciitis. J Infect Dis 2000, 181:230–234.

    Article  PubMed  CAS  Google Scholar 

  52. Norrby-Teglund A, Kaul R, Low DE, et al.: Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigen-induced T cell proliferation and cytokine production. J Immunol 1996, 156:3057–3064.

    PubMed  CAS  Google Scholar 

  53. Norrby-Teglund A, Kaul R, Low DE, et al.: Evidence for the presence of streptococcal superantigen neutralizing antibodies in normal polyspecific IgG (IVIG). Infect Immun 1996, 64:5395–5398.

    PubMed  CAS  Google Scholar 

  54. Lissner R, Struff WG, Autenrieth IB, et al.: Efficacy and potential clinical applications of Pentaglobin, an IgM-enriched immunoglobulin concentrate suitable for intravenous infusion. Eur J Surg 1999, 584(Suppl):17–25.

    Google Scholar 

  55. Stegmayr B, Bjorck S, Holm S, et al.: Septic shock induced by group A streptococcal infection: clinical and therapeutic aspects. Scand J Infect Dis 1992, 24:589–597.

    PubMed  CAS  Google Scholar 

  56. Andersson U, Björck L, Skansén-Saphir U, Andersson J: Pooled human IgG modulates cytokine production in lymphocytes and monocytes. Immunol Rev 1994, 139:21–43.

    Article  PubMed  CAS  Google Scholar 

  57. Kaul R, McGeer A, Norrby-Teglund A, et al., and The Canadian Streptococcal Study Group: Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome - a comparative observational study. Clin Infect Dis 1999, 28:800–807. In this study the efficacy of IVIG as adjunctive therapy for STSS was assessed. Twenty-one patients with STSS between 1994 and 1995 were treated with high-dose IVIG and were compared with 32 STSS patients between 1992 and 1995 who did not receive any IVIG. The proportion of cases with 30-day survival was significantly higher than that of controls (67% vs 34%, respectively, P = 0.02).

    PubMed  CAS  Google Scholar 

  58. Arad G, Levy R, Hillman D, Kaempfer R: Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation. Nat Med 2000, 6:414–421.

    Article  PubMed  CAS  Google Scholar 

  59. Visvanathan K, Charles A, Bannan J, et al.: Inhibition of bacterial superantigens by peptides and antibodies. Infect Immun 2001, 69:875–884.

    Article  PubMed  CAS  Google Scholar 

  60. Ulrich RG, Olson MA, Bavari S: Development of engineered vaccines effective against structurally related bacterial superantigens. Vaccine 1998, 16:1857–1864.

    Article  PubMed  CAS  Google Scholar 

  61. Haywood CT, McGeer, Low DE: Clinical experience with 20 cases of group A streptococcus necrotizing fasciitis and myonecrosis: 1995 to 1997. Plast Reconstr Surg 1999, 103:1567–1573. In this study a total of seven (35%) patients were diagnosed as having a cause for their signs and symptoms other than necrotizing fasciitis when they intially presented to a physician; one patient died.

    Article  PubMed  CAS  Google Scholar 

  62. Kaul R, McGeer A, Low DE, et al., and the Ontario Group A Streptococcal Study Group: Population-based surveillance for group A streptococcal necrotizing fasciitis: clinical features, prognostic indicators, and microbiologic analysis of seventyseven cases. Am J Med 1997, 103:18–24.

    Article  PubMed  CAS  Google Scholar 

  63. Lamothe F, D’Amico P, Ghosn P, et al.: Clinical usefulness of intravenous human immunoglobulins in invasive group A streptococcal disease: case report and review. J Clin Infect Dis 1995, 21:1469–1470.

    CAS  Google Scholar 

  64. Perez CM, Kubak BM, Cryer HG, et al.: Adjunctive treatment of streptococcal toxic shock syndrome with intravenous immunoglobulin: case report and review. Am J Med 1997, 102:111–113.

    Article  PubMed  CAS  Google Scholar 

  65. Cawley MJ, Briggs M, Haith LRJ, et al.: Intravenous immunoglobulin as adjunctive treatment for streptococcal toxic shock syndrome associated with necrotizing fasciitis: case report and review. Pharmacotherapy 1999, 19:1094–1098.

    Article  PubMed  CAS  Google Scholar 

  66. Yong JM: Necrotising fasciitis. Lancet 1994, 343:1427.

    Article  PubMed  CAS  Google Scholar 

  67. Mahieu LM, Holm SE, Goossens HJ, Van Acker KJ: Congenital streptococcal toxic shock syndrome with absence of antibodies against streptococcal pyrogenic exotoxins. J Pediatr 1995, 127:987–989.

    Article  PubMed  CAS  Google Scholar 

  68. Barry W, Hudgins L, Donta ST, Pesanti EL: Intravenous immunoglobulin therapy for toxic shock syndrome. JAMA 1992, 267:3315–3316.

    Article  PubMed  CAS  Google Scholar 

  69. Nadal D, Lauener RP, Braegger CP, et al.: T cell activation and cytokine release in streptococcal toxic shock-like syndrome. J Pediatr 1993, 122:727–729.

    Article  PubMed  CAS  Google Scholar 

  70. Chiu CH, Ou JT, Chang KS, Lin TY: Successful treatment of severe streptococcal toxic shock syndrome with a combination of intravenous immunoglobulin, dexamethasone and antibiotics. Infection 1997, 25:47–48.

    Article  PubMed  CAS  Google Scholar 

  71. Norrby-Teglund A, Norrby SR: Streptococcal toxic shock syndrome: modern therapy. In Infección 2002. Edited by Picazo JJ, Bouza E. Bilbao:Servisitem; 2002:221–242.

    Google Scholar 

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Norrby-Teglund, A., Norrby, S.R. & Low, D.E. The treatment of severe group a streptococcal infections. Curr Infect Dis Rep 5, 28–37 (2003). https://doi.org/10.1007/s11908-003-0062-2

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