Neue Erkenntnisse zur Sepsis durch bakterielle Translokation

Zusammenfassung

Bakterielle Translokation als Ursache einer Sepsis ohne fassbaren Fokus ist ein lange bekanntes Konzept, das bisher beim Menschen schwer beweisbar war. Störungen der intestinalen Barriere als komplexes Zusammenspiel physikalischer, biochemischer und immunologischer Faktoren sind hierfür die pathophysiologische Voraussetzung. Neue Befunde legen nahe, dass dieses Konzept um die Möglichkeit der Translokation von Bestandteilen von Bakterien (pathogen associated molecular patterns, PAMPs) erweitert werden muss. Dies schließt nicht aus, dass beide Mechanismen der Stimulation proinflammatorischer Kaskaden mit nachfolgender septischer Reaktion auftreten können. Molekulare Nachweismethoden für Bakterien und deren Bestandteile versuchen diesem erweiterten Konzept in der Diagnostik Rechnung zu tragen, haben aber noch keinen Einzug in die Routine erlangt. Eine spezifische therapeutische Intervention an den Sepsis-triggernden Signalwegen des angeborenen und des spezifischen Immunsystems in der Darmmukosa hat sich bisher nicht ergeben. Selective oral decontamination (SOD) und selective digestive tract decontamination (SDD) sind wirksame prophylaktische Maßnahmen gegen nosokomiale septische Komplikationen. Ein kausaler Zusammenhang mit der Zunahme resistenter Erreger ist hierunter bisher nicht beobachtet worden. Der Einsatz von Probiotika als Prophylaxe gegen septische Komplikationen ist kontrovers und hat in einzelnen Studien zu einer Verschlechterung der Prognose geführt.

Abstract

Bacterial translocation has been put forward as a concept to explain sepsis without an infectious focus, but it has been difficult to prove in humans. Dysfunction of the intestinal barrier, which is composed of physical, biochemical and immunological factors, is the pathophysiological prerequisite for bacterial translocation. Recent findings indicate that not only viable bacteria but also pathogen associated molecular patterns may translocate and cause sepsis. Molecular detection methods for bacteria or their components have been developed to address these new concepts, but they have not yet become widely available. Specific therapeutic interventions within the sepsis cascades and signaling pathways of the innate and specific immune system so far have not been successful. Selective oral decontamination (SOD) und selective digestive tract decontamination (SDD) are efficacious prophylactic measures against nosocomial septic complications. An increased incidence of resistant pathogens has not been encountered. The use of probiotics as prophylaxis against septic complications is controversial and has led in some studies to a worse prognosis.

Schlüsselwörter

Sepsis - bakterielle Translokation - intestinale Barriere - pathogen associated molecular patterns

Key words

sepsis - bacterial translocation - intestinal barrier - pathogen associated molecular patterns

• Literatur

• 1 Reade MC, Angus DC. Epidemiology of sepsis and non-infectious SIRS. In: Cavaillon J-M, Adrie C. Sepsis and non-infectious systemic inflammation. Weinheim: Wiley-VHC Verlag; 2009: 13-39
• 2 Utzolino S, Hopt UT, Kaffarnik M. Postoperative sepsis: diagnosis, special features, management. Zentralbl Chir 2010; 135: 240-248
• 3 Berg RD, Garlington AW. Translocation of Certain Indigenous Bacteria from the Gastrointestinal Tract to the Mesenteric Lymph Nodes and Other Organs in a Gnotobiotic Mouse Model. Infect Immun 1979; 23: 403-411
• 4 Besselink MG, van Santvoort HC, Renooij W et al. Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis. Ann Surg 2009; 250: 712-719
• 5 Swank GM, Deitch EA. Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J Surg 1996; 20: 411-417
• 6 Blikslager AT, Moeser AJ, Gookin JL et al. Restoration of barrier function in injured intestinal mucosa. Physiol Rev 2007; 87: 545-564
• 7 Shen L, Su L, Turner JR. Mechanisms and functional implications of intestinal barrier defects. Dig Dis 2009; 27: 443-449
• 8 Qin X, Sheth SU, Sharpe SM et al. The mucus layer is critical in protecting against ischemia-reperfusion-mediated gut injury and in the restitution of gut barrier function. Shock 2011; 35: 275-281
• 9 Wells JM, Rossi O, Meijerink M et al. Epithelial crosstalk at the microbiota-mucosal interface. PNAS 2011; 108: 4607-4614
• 10 Gatt M, Reddy BS, MacFie J. Review article: bacterial translocation in the critically ill – evidence and methods of prevention. Aliment Pharmacol Ther 2007; 25: 741-757
• 11 Vincent JL, Sakr Y, Sprung CL et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006; 34: 344-353
• 12 Tsujimoto H, Ono S, Mochizuki H. Role of translocation of pathogen-associated molecular patterns in sepsis. Dig Surg 2009; 26: 100-109
• 13 Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol 2009; 24: 943-954
• 14 Tsujimoto H, Ono S, Efron PA et al. Role of Toll-like receptors in the development of sepsis. Shock 2008; 29: 315-321
• 15 Tsolis RM, Young GM, Solnick JV et al. From bench to bedside: stealth of enteroinvasive pathogens. Nat Rev Microbiol 2008; 6: 883-892
• 16 Weiss DS, Raupach B, Takeda K et al. Toll-Like Receptors Are Temporally Involved in Host Defense. J Immunol 2004; 172: 4463-4469
• 17 Roger T, Froidevaux C, Le Roy D et al. Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4. PNAS 2009; 106: 2348-2352
• 18 Kumpf O, Giamarellos-Bourboulis EJ, Koch A et al. Influence of genetic variations in TLR4 and TIRAP / Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Crit Care 2010; 14: R103
• 19 Corr SC, ONeill LA. Genetic Variation in Toll-Like Receptor Signalling and the Risk of Inflammatory and Immune Diseases. Journal of Innate Immunity 2009; 1: 350-357
• 20 Buchholz BM, Bauer AJ. Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis. Neurogastroenterol Motil 2010; 22: 232-245
• 21 Lodes U, Bohmeier B, Lippert H et al. PCR-based rapid sepsis diagnosis effectively guides clinical treatment in patients with new onset of SIRS. Langenbecks Arch Surg 2012; 397: 447-455
• 22 Bauer M, Reinhart K. Molecular diagnostics of sepsis – where are we today?. Int J Med Microbiol 2010; 300: 411-413
• 23 Doring G, Unertl K, Heininger A. Validation criteria for nucleic acid amplification techniques for bacterial infections. Clin Chem Lab Med 2008; 46: 909-918
• 24 Leggieri N, Rida A, Francois P et al. Molecular diagnosis of bloodstream infections: planning to (physically) reach the bedside. Curr Opin Infect Dis 2010; 23: 311-319
• 25 Mizuno T, Yokoyama Y, Nishio H et al. Intraoperative bacterial translocation detected by bacterium-specific ribosomal RNA-targeted reverse-transcriptase polymerase chain reaction for the mesenteric lymph node strongly predicts postoperative infectious complications after major hepatectomy for biliary malignancies. Ann Surg 2010; 252: 1013-1019
• 26 Gerritsen J, Timmerman HM, Fuentes S et al. Correlation between protection against sepsis by probiotic therapy and stimulation of a novel bacterial phylotype. Appl Environ Microbiol 2011; 77: 7749-7756
• 27 Wang Y, Devkota S, Musch MW et al. Regional mucosa-associated microbiota determine physiological expression of TLR2 and TLR4 in murine colon. PLoS One 2010; 5: e13607
• 28 Larsson E, Tremaroli V, Lee YS et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 2011; [Epub ahead of print]
• 29 Buttenschoen K, Radermacher P, Bracht H. Endotoxin elimination in sepsis: physiology and therapeutic application. Langenbecks Arch Surg 2010; 395: 597-605
• 30 Tidswell M, Tillis W, Larosa SP et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med 2010; 38: 72-83
• 31 Phase III Study for Eritoran Does Not Meet Primary Endpoint. http://www.eisai.com/news/news201108.html [Accessed 25-1-2011]
• 32 Selective Decontamination of the Digestive Tract Trialists’ Collaborative Group. Meta-analysis of randomised controlled trials of selective decontamination of the digestive tract. BMJ 1993; 307: 525-532
• 33 Krueger WA, Lenhart FP, Neeser G et al. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically ill surgical patients: a prospective, stratified, randomized, double-blind, placebo-controlled clinical trial. Am J Respir Crit Care Med 2002; 166: 1029-1037
• 34 de Smet AMGA, Kluytmans JAJW, Cooper BS et al. Decontamination of the Digestive Tract and Oropharynx in ICU Patients. N Engl J Med 2009; 360: 20-31
• 35 de Smet AMG, Kluytmans JA, Blok HE et al. Selective digestive tract decontamination and selective oropharyngeal decontamination and antibiotic resistance in patients in intensive-care units: an open-label, clustered group-randomised, crossover study. Lancet Infect Dis 2011; 11: 372-380
• 36 Oostdijk EA, de Smet AM, Kesecioglu J et al. The role of intestinal colonization with gram-negative bacteria as a source for intensive care unit-acquired bacteremia. Crit Care Med 2011; 39: 961-966
• 37 Heininger A, Meyer E, Schwab F et al. Effects of long-term routine use of selective digestive decontamination on antimicrobial resistance. Intensive Care Med 2006; 32: 1569-1576
• 38 Meyer E, Schwab F, Schroeren-Boersch B et al. Dramatic increase of third-generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance, 2001 to 2008. Crit Care 2010; 14: R113
• 39 Ohland CL, MacNaughton WK. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol – Gastrointest Liver Physiol 2010; 298: G807-G819
• 40 Morrow LE. Probiotics in the intensive care unit. Curr Opin Crit Care 2009; 15: 144-148
• 41 Besselink MG, van Santvoort HC, Buskens E et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 651-659
• 42 Kotzampassi K, Giamarellos-Bourboulis EJ, Voudouris A et al. Benefits of a synbiotic formula (Synbiotic 2000Forte) in critically Ill trauma patients: early results of a randomized controlled trial. World J Surg 2006; 30: 1848-1855
• 43 Giamarellos-Bourboulis EJ, Bengmark S, Kanellakopoulou K et al. Pro- and synbiotics to control inflammation and infection in patients with multiple injuries. J Trauma 2009; 67: 815-821
• 44 Rayes N, Seehofer D, Theruvath T et al. Effect of enteral nutrition and synbiotics on bacterial infection rates after pylorus-preserving pancreatoduodenectomy: a randomized, double-blind trial. Ann Surg 2007; 246: 36-41
• 45 Rayes N, Seehofer D, Theruvath T et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant 2005; 5: 125-130
• 46 Watkinson PJ, Barber VS, Dark P et al. The use of pre- pro- and synbiotics in adult intensive care unit patients: systematic review. Clin Nutr 2007; 26: 182-192
• 47 Sanders ME, Akkermans LM, Haller D et al. Safety assessment of probiotics for human use. Gut Microbes 2010; 1: 164-185