930
Views
20
CrossRef citations to date
0
Altmetric
Reviews

Emerging drugs for the treatment of sepsis

, , &
Pages 27-37 | Received 24 Sep 2015, Accepted 14 Dec 2015, Published online: 11 Jan 2016

References

  • Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(21):2063.
  • Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.
  • Moss M Epidemiology of sepsis: race, sex, and chronic alcohol abuse. Clin Infect Dis. 2005;41:S490–7.
  • Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–1310.
  • Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–1554.
  • Lagu T, Rothberg MB, Shieh M-S, et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40(3):754–761.
  • Vincent J-L, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–2329.
  • Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787–1794.
  • Annane D, Sharshar T Cognitive decline after sepsis. Lancet Respir Med. 2015;3(1):61–69.
  • Zimmerman JE, Kramer AA, Knaus WA. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit Care. 2013;17(2):R81.
  • Angus DC. The search for effective therapy for sepsis: back to the drawing board? JAMA. 2011;306(23):2614–2615.
  • Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195–203.
  • Marshall JC, Maier RV, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32(11):S513–26.
  • Surviving Sepsis Campaign | Bundles [Internet]. [ cited 2015 Aug 27]. Available from : http://www.survivingsepsis.org/Bundles/Pages/default.aspx.
  • Annane D, Bellissant E, Bollaert P-E, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22):2362–2375.
  • Kumar G, Kumar N, Taneja A, et al. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest. 2011;140(5):1223–1231.
  • Fleischmann C, Scherag A, Adhikari NK, et al. Global burden of sepsis: a systematic review. Crit Care. 2015;19(Suppl 1):P21.
  • Pfuntner A, Wier LM, Steiner C. Costs for hospital stays in the United States, 2010: statistical brief #146. In: Healthcare Cost and Utilization Project (HCUP) statistical briefs [Internet]. Rockville (MD): Agency for Health Care Policy and Research (US); 2006 [ cited 2015 Aug 27]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK121966/.
  • Marks L The birth pangs of monoclonal antibody therapeutics: the failure and legacy of Centoxin. Mabs. 2012;4(3):403–412.
  • 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(10):699–709.
  • Abraham E, Laterre P-F, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353(13):1332–1341.
  • Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–843.
  • Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–2064.
  • Lilly. Lilly Announces Withdrawal of Xigris® Following Recent Clinical Trial Results [Internet]. 2011. [ cited 2015 Sep 7]. Available from : https://investor.lilly.com/releasedetail.cfm?releaseid=617602.
  • Cohen J The immunopathogenesis of sepsis. Nature. 2002;420(6917):885–891.
  • Hotchkiss RS, Monneret G, Payen D Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–874.
  • Esmon CT Protein C anticoagulant system: anti-inflammatory effects. Semin Immunopathol. 2012;34(1):127–132.
  • Toh CH, Hoots WK. SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost. 2007;5(3):604–606.
  • Moresco EMY, LaVine D, Beutler B. Toll-like receptors. Curr Biol. 2011;21(13):R488–93.
  • Opal SM, Scannon PJ, Vincent JL, et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis. 1999;180(5):1584–1589.
  • Zavascki AP, Goldani LZ, et al. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother. 2007;60(6):1206–1215.
  • Nakanowatari Y, Nemoto K, Hara S, et al. Effects of direct haemoperfusion through fibres immobilizing polymyxin B and nafamostat mesilate on endotoxaemia in conscious Guinea-pigs. Clin Exp Pharmacol Physiol. 2008;35(1):17–22.
  • Aoki H, Kodama M, Tani T, et al. Treatment of sepsis by extracorporeal elimination of endotoxin using polymyxin B-immobilized fiber. Am J Surg. 1994;167(4):412–417.
  • Uriu K, Osajima A, Hiroshige K, et al. Endotoxin removal by direct hemoperfusion with an adsorbent column using polymyxin B-immobilized fiber ameliorates systemic circulatory disturbance in patients with septic shock. Am J Kidney Dis. 2002;39(5):937–947.
  • Bengsch S, Boos K-S, Nagel D, et al. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock. 2005;23(6):494–500.
  • Vincent J-L, Laterre P-F, Cohen J, et al. A pilot-controlled study of a polymyxin B-immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-abdominal infection. Shock. 2005;23(5):400–405.
  • Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–2452.
  • Payen DM, Guilhot J, Launey Y, et al. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 2015;41(6):975–984.
  • Klein DJ, Foster D, Schorr CA, et al. The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial. Trials. 2014;15:218.
  • Marshall JC, Foster D, Vincent J-L, et al. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004;190(3):527–534.
  • Flohé S, Börgermann J, Domínguez FE, et al. Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis. Shock. 1999;12(1):17–24.
  • Nierhaus A, Montag B, Timmler N, et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003;29(4):646–651.
  • Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180(7):640–648.
  • Leentjens J, Kox M, Koch RM, et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186(9):838–845.
  • Anaya DA, McMahon K, Nathens AB, et al. Predictors of mortality and limb loss in necrotizing soft tissue infections. Arch Surg. 2005;140(2):151–157.
  • Herman A, Kappler JW, Marrack P, et al. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772.
  • Sharpe AH, Freeman GJ The B7-CD28 superfamily. Nat Rev Immunol. 2002;2(2):116–126.
  • Arad G, Levy R, Nasie I, et al. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biol. 2011;9(9):e1001149.
  • Bulger EM, Maier RV, Sperry J, et al. A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial. JAMA Surg. 2014;149(6):528–536.
  • Schwab I, Nimmerjahn F Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013;13(3):176–189.
  • Shankar-Hari M, Spencer J, Sewell WA, et al. Bench-to-bedside review: Immunoglobulin therapy for sepsis – biological plausibility from a critical care perspective. Crit Care. 2011;16(2):206.
  • Almansa R, Tamayo E, Andaluz-Ojeda D, et al. The original sins of clinical trials with intravenous immunoglobulins in sepsis. Crit Care. 2015;19:90.
  • Alejandria MM, Lansang MAD, Dans LF, et al. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;9:CD001090.
  • Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, et al. Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care. 2013;17(5):R247.
  • Trautmann M, Held TK, Susa M, et al. Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clin Exp Immunol. 1998;111(1):81–90.
  • Welte T, Dellinger RP, Ebelt H, et al. Concept for a study design in patients with severe community-acquired pneumonia: a randomised controlled trial with a novel IGM-enriched immunoglobulin preparation - The CIGMA study. Respir Med. 2015;109(6):758–767.
  • Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003;167(4):512–520.
  • Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385(9977):1511–1518.
  • Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(7):519–528.
  • Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–3843.
  • Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101(9):3722–3729.
  • Németh K, Leelahavanichkul A, Yuen PST, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15(1):42–49.
  • Mei SHJ, Haitsma JJ, Dos Santos CC, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182(8):1047–1057.
  • TiGenix. Cx611 [Internet]. [ cited 2015 Sep 6]. Available from : http://www.tigenix.com/en/page/15/cx611.
  • Kolev M, Le Friec G, Kemper C Complement–tapping into new sites and effector systems. Nat Rev Immunol. 2014;14(12):811–820.
  • Solomkin JS, Jenkins MK, Nelson RD, et al. Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation. Surgery. 1981;90(2):319–327.
  • Huber-Lang MS, Younkin EM, Sarma JV, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol. 2002;169(6):3223–3231.
  • Czermak BJ, Sarma V, Pierson CL, et al. Protective effects of C5a blockade in sepsis. Nat Med. 1999;5(7):788–792.
  • Rittirsch D, Flierl MA, Nadeau BA, et al. Functional roles for C5a receptors in sepsis. Nat Med. 2008;14(5):551–557.
  • InflaRx Announces Successful Conduct of Its Clinical Phase I Trial with IFX-1, a New Monoclonal Antibody Inhibiting Complement Driven Inflammation | Business Wire [Internet]. 2012. [ cited 2015 Sep 20]. Available from: http://www.businesswire.com/news/home/20120118006072/en#%3CAnker%20werden%20gesucht…%3E.
  • Afshari A, Wetterslev J, Brok J, et al. Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2008;(3):CD005370. doi:10.1002/14651858.CD005370
  • Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238–247.
  • Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005;115(5):1267–1274.
  • Shi C-S, Shi G-Y, Hsiao H-M, et al. Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood. 2008;112(9):3661–3670.
  • Moll S, Lindley C, Pescatore S, et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost. 2004;2(10):1745–1751.
  • Vincent J-L, Ramesh MK, Ernest D, et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41(9):2069–2079.
  • Ackland GL, Yao ST, Rudiger A, et al. Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats. Crit Care Med. 2010;38(2):388–394.
  • Aboab J, Sebille V, Jourdain M, et al. Effects of esmolol on systemic and pulmonary hemodynamics and on oxygenation in pigs with hypodynamic endotoxin shock. Intensive Care Med. 2011;37(8):1344–1351.
  • Suzuki T, Morisaki H, Serita R, et al. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med. 2005;33(10):2294–2301.
  • Mori K, Morisaki H, Yajima S, et al. Beta-1 blocker improves survival of septic rats through preservation of gut barrier function. Intensive Care Med. 2011;37(11):1849–1856.
  • Ibrahim-Zada I, Rhee P, Gomez CT, et al. Inhibition of sepsis-induced inflammatory response by β1-adrenergic antagonists. J Trauma Acute Care Surg. 2014;76(2):320–327.
  • Balik M, Rulisek J, Leden P, et al. Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Wien Klin Wochenschr. 2012;124(15–16):552–556.
  • Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310(16):1683–1691.
  • Pulido JN, Afessa B, Masaki M, et al. Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock. Mayo Clin Proc. 2012;87(7):620–628.
  • Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilator agent. Anesthesiology. 2006;104(3):556–569.
  • Lilleberg J, Ylönen V, Lehtonen L, et al. The calcium sensitizer levosimendan and cardiac arrhythmias: an analysis of the safety database of heart failure treatment studies. Scand Cardiovasc J. 2004;38(2):80–84.
  • Delaney A, Bradford C, McCaffrey J, et al. Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials. Int J Cardiol. 2010;138(3):281–289.
  • Rehberg S, Ertmer C, Vincent J-L, et al. Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock. Crit Care Med. 2010;38(10):2016–2023.
  • Zager RA, Johnson AC, Lund S, et al. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Renal Physiol. 2006;290(6):F1453–62.
  • Fries M, Ince C, Rossaint R, et al. Levosimendan but not norepinephrine improves microvascular oxygenation during experimental septic shock. Crit Care Med. 2008;36(6):1886–1891.
  • Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31(5):638–644.
  • Morelli A, Donati A, Ertmer C, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Car. 2010;14(6):R232
  • Morelli A, Teboul J-L, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med. 2006;34(9):2287–2293.
  • Orme RML, Perkins GD, McAuley DF, et al. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial. Trials. 2014;15:199.
  • Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887.
  • Gordon AC, Mason AJ, Perkins GD, et al. Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH). BMJ Open. 2014;4(7):e005866.
  • Boucheix OB, Milano SP, Henriksson M, et al. Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs. Shock. 2013;39(6):533–538.
  • Poelstra K, Bakker WW, Klok PA, et al. A physiologic function for alkaline phosphatase: endotoxin detoxification. Lab Investig. 1997;76(3):319–327.
  • Su F, Brands R, Wang Z, et al. Beneficial effects of alkaline phosphatase in septic shock. Crit Care Med. 2006;34(8):2182–2187.
  • Beumer C, Wulferink M, Raaben W, et al. Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets. J Pharmacol Exp Ther. 2003;307(2):737–744.
  • Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med. 2009;37(2):417–423.
  • Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care. 2012;16(1):R14.
  • Vanneman M, Dranoff G Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–251.
  • Lafont E, Urien S, Salem J-E, et al. Modeling for critically ill patients: an introduction for beginners. J Crit Care. 2015;30(6):1287–1294.
  • Unsinger J, McGlynn M, Kasten KR, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184(7):3768–3779.
  • Venet F, Foray A-P, Villars-Méchin A, et al. IL-7 restores lymphocyte functions in septic patients. J Immunol. 2012;189(10):5073–5081.
  • Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.
  • Huang X, Venet F, Wang YL, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA. 2009;106(15):6303–6308.
  • Weber GF, Chousterman BG, He S, et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science. 2015;347(6227):1260–1265.
  • Dinubile MJ. Plasma gelsolin: in search of its raison d’etre. Focus on “Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin”. Am J Physiol Cell Physiol. 2007;292(4):C1240–2.
  • Lee P-S, Waxman AB, Cotich KL, et al. Plasma gelsolin is a marker and therapeutic agent in animal sepsis. Crit Care Med. 2007;35(3):849–855.
  • Dinubile M Adjunctive treatment of severe sepsis. Lancet Infect Dis. 2013;13(11):917–918.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.