Research Original Investigation
New Drug for Necrotizing Soft-Tissue Infection
necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32(7):1535-1541. 15. Anaya DA, Bulger EM, Kwon YS, Kao LS, Evans H, Nathens AB. Predicting death in necrotizing soft tissue infections: a clinical score. Surg Infect (Larchmt). 2009;10(6):517-522. 16. Hackett SP, Stevens DL. Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor-beta synthesis. J Infect Dis. 1993;168 (1):232-235. 17. Marrack P, Blackman M, Kushnir E, Kappler J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J Exp Med. 1990;171(2):455464.
18. Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990;248 (4956):705-711.
immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. 1999;28(4):800-807.
19. Opal SM, Palardy JE, Parejo NA, Creasey AA. The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis. Crit Care Med. 2001;29(1):13-17.
22. Johansson L, Thulin P, Low DE, Norrby-Teglund A. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin Infect Dis. 2010;51(1):58-65.
20. Ramachandran G, Tulapurkar ME, Harris KM, et al. A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes. J Infect Dis. 2013;207(12):1869-1877.
23. Davies HD, McGeer A, Schwartz B, et al; Ontario Group A Streptococcal Study Group. Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med. 1996;335(8):547554.
21. Kaul R, McGeer A, Norrby-Teglund A, et al; The Canadian Streptococcal Study Group. Intravenous
Invited Commentary
Treatment for Necrotizing Soft-Tissue Infections More Skin in the Game Robert G. Sawyer, MD
The article by Bulger et al1 represents an advance in the world of surgical infections as the first interventional trial using an immunomodulatory agent to treat necrotizing soft-tissue infections. Any prospective interventional study is difficult to execute, and one in such a complicated disease state with such severe morbid effects is even more laudable. Although the study was small, there were signs of possible improvements during treatment with the novel agent AB103, because the Sequential Organ Failure Assessment scores improved in the active treatment arms compared with the placebo arm at 14 days. There was no significant difference Related article page 528 in mortality rates, although this would not be expected given the size of the cohorts. Although the clinical data are impressive, the cytokine data are less convincing. For example, levels of tumor necrosis factor were highest in the group re-
536
ceiving 0.25 mg/kg of AB103 but lowest in the group receiving 0.50 mg/kg. This paradoxical dose-response relationship is not easily explained. It seems either that the baseline characteristics were imbalanced between groups in a way not captured by severity of illness scoring or that cytokines in fact play a minimal role in the pathophysiologic mechanism of this disease. Given the recent publication by Seok et al2 describing poor correlation between murine models and human inflammatory diseases, the latter explanation may be more likely. All in all, we can be cautiously optimistic about the use of AB103 as an immunomodulator in necrotizing soft-tissue infection. Obviously, larger studies are required to demonstrate its true efficacy. However, if in this situation the baby is AB103, the bath water is further cytokine analysis, and more research in this direction is not warranted; changing the focus toward either proteomics or metabolomics may be more worthwhile.
ARTICLE INFORMATION
Conflict of Interest Disclosures: None reported.
Author Affiliation: Department of Surgery, University of Virginia Medical School, Charlottesville.
REFERENCES
Corresponding Author: Robert G. Sawyer, MD, Department of Surgery, University of Virginia Medical School, PO Box 800709, Charlottesville, VA 22908-0709 ([email protected]).
1. Bulger EM, Maier RV, Sperry J, et al. A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial [published online April 16, 2014]. JAMA Surg. doi:10.1001/jamasurg.2013 .4841.
Published Online: April 16, 2014. doi:10.1001/jamasurg.2013.4870.
2. Seok J, Warren HS, Cuenca AG, et al; Inflammation and Host Response to Injury, Large
Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507-3512.
JAMA Surgery June 2014 Volume 149, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/21/2015
jamasurgery.com
New Drug for Necrotizing Soft-Tissue Infection
necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32(7):1535-1541. 15. Anaya DA, Bulger EM, Kwon YS, Kao LS, Evans H, Nathens AB. Predicting death in necrotizing soft tissue infections: a clinical score. Surg Infect (Larchmt). 2009;10(6):517-522. 16. Hackett SP, Stevens DL. Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor-beta synthesis. J Infect Dis. 1993;168 (1):232-235. 17. Marrack P, Blackman M, Kushnir E, Kappler J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J Exp Med. 1990;171(2):455464.
18. Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990;248 (4956):705-711.
immunoglobulin therapy for streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. 1999;28(4):800-807.
19. Opal SM, Palardy JE, Parejo NA, Creasey AA. The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis. Crit Care Med. 2001;29(1):13-17.
22. Johansson L, Thulin P, Low DE, Norrby-Teglund A. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin Infect Dis. 2010;51(1):58-65.
20. Ramachandran G, Tulapurkar ME, Harris KM, et al. A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes. J Infect Dis. 2013;207(12):1869-1877.
23. Davies HD, McGeer A, Schwartz B, et al; Ontario Group A Streptococcal Study Group. Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med. 1996;335(8):547554.
21. Kaul R, McGeer A, Norrby-Teglund A, et al; The Canadian Streptococcal Study Group. Intravenous
Invited Commentary
Treatment for Necrotizing Soft-Tissue Infections More Skin in the Game Robert G. Sawyer, MD
The article by Bulger et al1 represents an advance in the world of surgical infections as the first interventional trial using an immunomodulatory agent to treat necrotizing soft-tissue infections. Any prospective interventional study is difficult to execute, and one in such a complicated disease state with such severe morbid effects is even more laudable. Although the study was small, there were signs of possible improvements during treatment with the novel agent AB103, because the Sequential Organ Failure Assessment scores improved in the active treatment arms compared with the placebo arm at 14 days. There was no significant difference Related article page 528 in mortality rates, although this would not be expected given the size of the cohorts. Although the clinical data are impressive, the cytokine data are less convincing. For example, levels of tumor necrosis factor were highest in the group re-
536
ceiving 0.25 mg/kg of AB103 but lowest in the group receiving 0.50 mg/kg. This paradoxical dose-response relationship is not easily explained. It seems either that the baseline characteristics were imbalanced between groups in a way not captured by severity of illness scoring or that cytokines in fact play a minimal role in the pathophysiologic mechanism of this disease. Given the recent publication by Seok et al2 describing poor correlation between murine models and human inflammatory diseases, the latter explanation may be more likely. All in all, we can be cautiously optimistic about the use of AB103 as an immunomodulator in necrotizing soft-tissue infection. Obviously, larger studies are required to demonstrate its true efficacy. However, if in this situation the baby is AB103, the bath water is further cytokine analysis, and more research in this direction is not warranted; changing the focus toward either proteomics or metabolomics may be more worthwhile.
ARTICLE INFORMATION
Conflict of Interest Disclosures: None reported.
Author Affiliation: Department of Surgery, University of Virginia Medical School, Charlottesville.
REFERENCES
Corresponding Author: Robert G. Sawyer, MD, Department of Surgery, University of Virginia Medical School, PO Box 800709, Charlottesville, VA 22908-0709 ([email protected]).
1. Bulger EM, Maier RV, Sperry J, et al. A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial [published online April 16, 2014]. JAMA Surg. doi:10.1001/jamasurg.2013 .4841.
Published Online: April 16, 2014. doi:10.1001/jamasurg.2013.4870.
2. Seok J, Warren HS, Cuenca AG, et al; Inflammation and Host Response to Injury, Large
Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507-3512.
JAMA Surgery June 2014 Volume 149, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/21/2015
jamasurgery.com
