Main Article Content

Abstract

Sepsis is a fast progressing disease, triggered by the host response to infection. If untreated, sepsis can rapidly evolve to multi-organ dysfunction and septic shock. Despite numerous advances in palliative intensive care and antibiotic treatment, sepsis remains a major cause of morbidity and mortality. The vascular endothelium is a major target of sepsis-induced events. Upon entry to the bloodstream, bacteria attach to the endothelium within 15s. Attachment triggers dysregulated signals that result in endothelial cell (EC) death and loss of barrier integrity, which give rise to increased capillary permeability clinically associated with hypotension, subcutaneous and body-cavity edema and impaired tissue oxygenation. Early and adequate antimicrobial therapy is the cornerstone of the therapy in sepsis. Broad empirical antimicrobial therapy should be administered as soon as possible after at least two sets of blood cultures have been obtained. This has lead to high load of antimicrobial use and in turn resulted to an emergent problem that is antimicrobial resistance. Cilengitide, the most advanced integrin inhibitor in clinical development, is a cyclized pentapeptidepeptidomimetic designed to compete for the arginine–glycine–aspartic acid (RGD) peptide sequence that regulates integrin-ligand binding. Specifically, cilengitide selectively and potently blocks the ligation of the αvβ3 and αvβ5 integrins to provisional matrix proteins such as vitronectin, fibronectin, fibrinogen, von Willebrand factor. Cilengitide is capable of competitively antagonizing bacterial binding to ECs and as a result removes the signal that perpetuates vascular EC involvement in sepsis and thus presents as a potential as new complementary strategy for the treatment of established sepsis and as prophylaxis in high risk patients. This indeed can result in lowering of the antimicrobials used and will reduce resistance.

Keywords

Septic shock Vascular endothelium Cilengitide, Integrins Antimicrobial resistance

Article Details

How to Cite
Juzer Sabuwala, & Farheen Sultana. (2021). Cilengitide- A novel therapy in sepsis to prevent antimicrobial resistance. International Journal of Research in Pharmacology & Pharmacotherapeutics, 8(3), 366-372. https://doi.org/10.61096/ijrpp.v8.iss3.2019.366-372

References

  1. [1]. Angus D, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine. 369(9), 2013, 840-851.
  2. [2]. Goldenberg N, Steinberg B, Slutsky A, Lee W. Broken Barriers: A New Take on Sepsis Pathogenesis. Science Translational Medicine. 3(88), 2011, 88ps25-88ps25.
  3. [3]. Levy S, Bergman M. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers, 2nd Edition:The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers, 2nd Edition. Clinical Infectious Diseases. 36(2), 2003, 238-238.
  4. [4]. Levy S. The Challenge of Antibiotic Resistance. Scientific American. 278(3), 1998, 46-53.
  5. [5]. Holmes A, Moore L, Sundsfjord A, Steinbakk M, Regmi S, Karkey A et al. Understanding the mechanisms and drivers of antimicrobial resistance. The Lancet. 387(10014), 2016, 176-187.
  6. [6]. Goldenberg N, Steinberg B, Slutsky A, Lee W. Broken Barriers: A New Take on Sepsis Pathogenesis. Science Translational Medicine. 3(88), 2011, 88ps25-88ps25.
  7. [7]. Fleischmann C, Scherag A, Adhikari N, Hartog C, Tsaganos T, Schlattmann P et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. American Journal of Respiratory and Critical Care Medicine. 193(3), 2016, 259-272.
  8. [8]. McDonnell C, Garciarena C, Watkin R, McHale T, McLoughlin A, Claes J et al. Inhibition of major integrin αVβ3reducesStaphylococcus aureusattachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 14(12), 2016, 2536-2547.
  9. [9]. Piccinno A, Pagliarulo A. Cefotaxime for the treatment of gram-positive urinary tract infection. Infection. 13(S1), 1985, S100-S102.
  10. [10]. Angus D, van der Poll T. Severe Sepsis and Septic Shock. New England Journal of Medicine. 369(9), 2013, 840-851
  11. [11]. DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L et al. Book Review: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition. Annals of Pharmacotherapy. 43(2), 2009, 395-395.
  12. [12]. Hynes R. Integrins. Cell. 110(6), 2002, 673-687.
  13. [13]. Humphries J. Integrin ligands at a glance. Journal of Cell Science. 119(19), 2006, 3901-3903.
  14. [14]. McDonnell C, Garciarena C, Watkin R, McHale T, McLoughlin A, Claes J et al. Inhibition of major integrin αVβ3reducesStaphylococcus aureusattachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 14(12), 2016, 2536-2547.
  15. [15]. McDonnell C, Garciarena C, Watkin R, McHale T, McLoughlin A, Claes J et al. Inhibition of major integrin αVβ3reducesStaphylococcus aureusattachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 14(12), 2016, 2536-2547.
  16. [16]. Hynes, R. Integrins. Cell, 110(6), 2002, 673-687.
  17. [17]. Cox, D., Brennan, M. and Moran, N. Integrins as therapeutic targets: lessons and opportunities. Nature Reviews Drug Discovery, 9(10), 2010, 804-820.
  18. [18]. BONE, R., FISHER, C., CLEMMER, T., SLOTMAN, G., METZ, C. and BALK, R. Sepsis syndrome. Critical Care Medicine, 17(5), 1989, 389-393.
  19. [19]. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Critical Care Medicine, 20(6), 1992, 864-874.
  20. [20]. Tracey, K., Beutler, B., Lowry, S., Merryweather, J., Wolpe, S., Milsark, I., Hariri, R., Fahey, T., Zentella, A., Albert, J. and et, a. Shock and tissue injury induced by recombinant human cachectin. Science, 234(4775), 1986, 470-474.
  21. [21]. Ferrer, R., Artigas, A., Suarez, D., Palencia, E., Levy, M., Arenzana, A., Pérez, X. and Sirvent, J. Effectiveness of Treatments for Severe Sepsis. American Journal of Respiratory and Critical Care Medicine, 180(9). 2009, 861-866.
  22. [22]. Bloos, F., Rüddel, H., Thomas-Rüddel, D., Schwarzkopf, D., Pausch, C., Harbarth, S., Schreiber, T., Gründling, M., Marshall, J., Simon, P., Levy, M., Weiss, M., Weyland, A., Gerlach, H., Schürholz, T., Engel, C., Matthäus-Krämer, C., Scheer, C., Bach, F., Riessen, R., Poidinger, B., Dey, K., Weiler, N., Meier-Hellmann, A., Häberle, H., Wöbker, G., Kaisers, U. and Reinhart, K.. Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Medicine, 43(11), 2017, 1602-1612.
  23. [23]. Kumar, A., Ellis, P., Arabi, Y., Roberts, D., Light, B., Parrillo, J., Dodek, P., Wood, G., Kumar, A., Simon, D., Peters, C., Ahsan, M. and Chateau, D. Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock. Chest, 136(5), 2009, 1237-1248.
  24. [24]. Surviving Sepsis Campaign. Critical Care Medicine, 42(1), 2014, 88.
  25. [25]. Kumar, A., Safdar, N., Kethireddy, S. and Chateau, D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study. Critical Care Medicine, 38(8), 2010, 1651-1664.
  26. [26]. Jacobs, F. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis. Critical Care Medicine, 39(3), 2011, 608.
  27. [27]. Guo, Y., Gao, W., Yang, H., Ma, C. and Sui, S. De-escalation of empiric antibiotics in patients with severe sepsis or septic shock: A meta-analysis. Heart & Lung, 45(5), 2016, 454-459.
  28. [28]. Gutiérrez-Pizarraya, A., Leone, M., Garnacho-Montero, J., Martin, C. and Martin-Loeches, I. Collaborative approach of individual participant data of prospective studies of de-escalation in non-immunosuppressed critically ill patients with sepsis. Expert Review of Clinical Pharmacology, 10(4), 2017, 457-465.
  29. [29]. Ferri, M., Ranucci, E., Romagnoli, P. and Giaccone, V. Antimicrobial resistance: A global emerging threat to public health systems. Critical Reviews in Food Science and Nutrition, 57(13), 2015, 2857-2876.
  30. [30]. Tanwar J, Das S, Fatima Z, Hameed S. Multidrug Resistance: An Emerging Crisis. Interdisciplinary Perspectives on Infectious Diseases. 2014, 2014, 1-7.
  31. [31]. Michael C, Dominey-Howes D, Labbate M. The Antimicrobial Resistance Crisis: Causes, Consequences, and Management. Frontiers in Public Health. 2014, 2.
  32. [32]. Shindo Y, Ito R, Kobayashi D, Ando M, Ichikawa M, Shiraki A et al. Risk Factors for Drug-Resistant Pathogens in Community-acquired and Healthcare-associated Pneumonia. American Journal of Respiratory and Critical Care Medicine. 188(8), 2013, 985-995.
  33. [33]. TUMBARELLO M, REPETTO E, TRECARICHI E, BERNARDINI C, DE PASCALE G, PARISINI A et al. Multidrug-resistant Pseudomonas aeruginosa bloodstream infections: risk factors and mortality. Epidemiology and Infection. 139(11), 2011, 1740-1749.
  34. [34]. Self W, Wunderink R, Williams D, Barrett T, Baughman A, Grijalva C. Comparison of Clinical Prediction Models for Resistant Bacteria in Community-onset Pneumonia. Academic Emergency Medicine. 22(6), 2015, 730-740.
  35. [35]. Bochud P, Glauser M, Calandra T. Antibiotics in sepsis. Intensive Care Medicine. 27(14), 2001, S33-S48.
  36. [36]. DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L et al. Book Review: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition. Annals of Pharmacotherapy. 43(2), 2009, 395-395.
  37. [37]. Orsini. Microbiological Profile of Organisms Causing Bloodstream Infection in Critically Ill Patients. Journal of Clinical Medicine Research. 2012.
  38. [38]. DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L et al. Book Review: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition. Annals of Pharmacotherapy. 43(2), 2009, 395-395.
  39. [39]. Tulloch L, Chan J, Carlbom D, Kelly M, Dellit T, Lynch J. Epidemiology and Microbiology of Sepsis Syndromes in a University-Affiliated Urban Teaching Hospital and Level-1 Trauma and Burn Center. Journal of Intensive Care Medicine. 32(4), 2015, 264-272.
  40. [40]. Heffner AC, Horton JM, Marchick MR, Jones AE. Etiology of illness in patients with severe sepsis admitted to the hospital from the emergency department. Clin Infect Dis. 50, 2010, 814–820.
  41. [41]. Kanoksil M, Jatapai A, Peacock SJ, Limmathurotsakul D. Epidemiology, microbiology and mortality associated with community-acquired bacteremia in northeast Thailand: a multicenter surveillance study. PLoS One. 8(1), 2013, 54714.
  42. [42]. Khety Z, Mohanta G, Jain S, Dawoodi S. Changing antimicrobial resistance pattern of isolates from an ICU over a 3 year period. J Assoc Physicians India. 65(2), 2017, 13-6.
  43. [43]. Cai B, Echols R, Magee G, Arjona Ferreira JC, Morgan G, Ariyasu M, et al. Prevalence of carbapenem-resistant gram-negative infections in the United States predominated by Acinetobacterbaumannii and Pseudomonas aeruginosa. Open Forum Infect Dis. 4(3), 2017, 176.
  44. [44]. Dechantsreiter M, Planker E, Mathä B, Lohof E, Hölzemann G, Jonczyk A et al. N-Methylated Cyclic RGD Peptides as Highly Active and Selective αVβ3Integrin Antagonists. Journal of Medicinal Chemistry. 42(16), 1999, 3033-3040.
  45. [45]. Goodman SL, Holzemann G, Sulyok GA, et al. Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins. Journal of Medicinal Chemistry 45, 2002, 1045-51
  46. [46]. Cheresh D. Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. Proceedings of the National Academy of Sciences. 84(18), 1987, 6471-6475.
  47. [47]. Fleischmann C, Scherag A, Adhikari N, Hartog C, Tsaganos T, Schlattmann P et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. American Journal of Respiratory and Critical Care Medicine. 193(3), 2016, 259-272.
  48. [48]. McDonnell C, Garciarena C, Watkin R, McHale T, McLoughlin A, Claes J et al. Inhibition of major integrin αVβ3reducesStaphylococcus aureusattachment to sheared human endothelial cells. Journal of Thrombosis and Haemostasis. 14(12), 2016, 2536-2547.