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Open Access 01-08-2006 | Research

Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis

Authors: Jose Garnacho-Montero, Teresa Aldabo-Pallas, Carmen Garnacho-Montero, Aurelio Cayuela, Rocio Jiménez, Sonia Barroso, Carlos Ortiz-Leyba

Published in: Critical Care | Issue 4/2006

Abstract

Introduction

Genetic variations may influence clinical outcomes in patients with sepsis. The present study was conducted to evaluate the impact on mortality of three polymorphisms after adjusting for confounding variables, and to assess the factors involved in progression of the inflammatory response in septic patients.

Method

The inception cohort study included all Caucasian adults admitted to the hospital with sepsis. Sepsis severity, microbiological information and clinical variables were recorded. Three polymorphisms were identified in all patients by PCR: the tumour necrosis factor (TNF)-α 308 promoter polymorphism; the polymorphism in the first intron of the TNF-β gene; and the IL-10-1082 promoter polymorphism. Patients included in the study were followed up for 90 days after hospital admission.

Results

A group of 224 patients was enrolled in the present study. We did not find a significant association among any of the three polymorphisms and mortality or worsening inflammatory response. By multivariate logistic regression analysis, only two factors were independently associated with mortality, namely Acute Physiology and Chronic Health Evaluation (APACHE) II score and delayed initiation of adequate antibiotic therapy. In septic shock patients (n = 114), the delay in initiation of adequate antibiotic therapy was the only independent predictor of mortality. Risk factors for impairment in inflammatory response were APACHE II score, positive blood culture and delayed initiation of adequate antibiotic therapy.

Conclusion

This study emphasizes that prompt and adequate antibiotic therapy is the cornerstone of therapy in sepsis. The three polymorphisms evaluated in the present study appear not to influence the outcome of patients admitted to the hospital with sepsis.

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Angus DC, Linde-Zwirble WT, Lidicker L, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002CrossRefPubMed

Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, CUB-Rea Network: Current epidemiology of septic shock. Am J Respir Crit Care Med 2003, 168: 165-172. 10.1164/rccm.2201087CrossRefPubMed

Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C: Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003, 31: 2742-2751. 10.1097/01.CCM.0000098031.24329.10CrossRefPubMed

Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA: Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003, 123: 1615-1624. 10.1378/chest.123.5.1615CrossRefPubMed

Yu DT, Black E, Sands KE, Schwartz JS, Hibberd PL, Graman PS, Lanken PN, Kahn KL, Snydman DR, Parsonnet J, et al.: Severe sepsis: variation in resource and therapeutic modality use among academic centers. Crit Care 2003, 7: R24-R34. 10.1186/cc2171PubMedCentralCrossRefPubMed

Wax RS, Angus DC: The molecular genetics of sepsis: Clinical epidemiology considerations. In 2000 Yearbook of Intensive Care and Emergency Medicine. Edited by: Vincent JL. Springer: Berlin; 2000:3-17.CrossRef

Tabrizi AR, Zehnbauer BA, Freeman BD, Buchman TG: Genetic markers in sepsis. J Am Coll Surg 2001, 192: 106-117. 10.1016/S1072-7515(00)00748-1CrossRefPubMed

American College of Chest Physicians/Society of Critical Care Medicine Consensus Committee: Definition for sepsis and organ failures and guidelines for the use of innovative therapies in sepsis. Chest 1992, 101: 1644-1655.CrossRef

Van Dissel JT, Van Langevelde P, Westendorp RGJ, Kwappenberg K, Frölich M: Anti-inflamatory cytokine profile and mortality in febrile patients. Lancet 1998, 351: 950-953.CrossRefPubMed

10.

Mira JP, Cariou A, Grall P, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riche F, et al.: Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999, 281: 1919-1926. 10.1001/jama.281.20.1919CrossRef

11.

Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA: -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of human promoter. J Inflamm 1996, 46(1): 42-50.

12.

Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV: An investigation of polumorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997, 24: 1-8.CrossRefPubMed

13.

Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al.: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002, 288: 862-871. 10.1001/jama.288.7.862CrossRefPubMed

14.

van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in critically ill patients. N Engl J Med 2001, 345: 1359-1367. 10.1056/NEJMoa011300CrossRefPubMed

15.

The Acute Respiratory Distress Network: Ventilation with lower tidal volumes as compared with traditional volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000, 342: 1301-1308. 10.1056/NEJM200005043421801CrossRef

16.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II, a severity of disease classification system. Crit Care Med 1985, 13: 818-829.CrossRefPubMed

17.

Pittet D, Thiévent B, Wenzel RP, Li N, Gurman G, Suter P: Importance of pre-existing co-morbidities for prognosis of septicemia in critically ill patients. Intensive Care Med 1993, 19: 265-272. 10.1007/BF01690546CrossRefPubMed

18.

Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996, 22: 707-710.CrossRefPubMed

19.

Ferreira FL, Bota DP, Bross A, Mélot C, Vincent JL: Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001, 286: 1754-1758. 10.1001/jama.286.14.1754CrossRefPubMed

20.

Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar A, Garnacho-Montero MC, Moyano-Del-Estad MR: Critical illness polyneuropathy: Risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 2001, 27: 1288-1296. 10.1007/s001340101009CrossRefPubMed

21.

Hosmer DW, Lemeshow SA: Applied Logistic Regression. New York: John Wiley; 1989.

22.

Houch PM, Bratzler DW, Nsa W, Na A, Barlett JG: Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med 2004, 164: 637-644. 10.1001/archinte.164.6.637CrossRef

23.

Aronin SI, Peduzzi P, Quagliarello VJ: Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998, 129: 862-869.CrossRefPubMed

24.

Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, et al.: Epidemiology of sepsis and infection in ICU patients from an international multicentre cohot study. Intensive Care Med 2002, 28: 108-121. 10.1007/s00134-001-1143-zCrossRefPubMed

25.

Legras A, Malvy D, Quinioux AI, Villers D, Bouachour G, Robert R, Thomas R: Nosocomial infections: prospective survey of incidence in five French intensive care units. Intensive Care Med 1998, 24: 1040-1046. 10.1007/s001340050713CrossRefPubMed

26.

Rangel-Frausto M, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The natural history of systemic inflammatory response syndrome (SIRS). JAMA 1995, 273: 117-123. 10.1001/jama.273.2.117CrossRefPubMed

27.

Alberti C, Brun-Buisson C, Chevret S, Antonelli M, Goodman SV, Martin C, Moreno R, Ochagavia AR, Palazzo M, Werdan K, et al.: Systemic inflammatory response and progression to severe sepsis in critically ill infected patients. Am J Resp Crit Care Med 2005, 171: 461-468. 10.1164/rccm.200403-324OCCrossRefPubMed

28.

Tang GJ, Huang SL, Yien HW, Chen WS, Chi CW, Wu CW, Lui WY, Chiu JH, Lee TY: Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med 2000, 28: 2733-2736. 10.1097/00003246-200008000-00008CrossRefPubMed

29.

Stuber F, Petersen M, Bokelmann F, Schade U: A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996, 24: 381-384. 10.1097/00003246-199603000-00004CrossRefPubMed

30.

Schroeder S, Reck M, Hoeft A, Stuber S: Analysis of two human leukocyte antigen-linked polymorphic heat shock protein 70 genes in patients with severe sepsis. Crit Care Med 1999, 27: 1265-1270. 10.1097/00003246-199907000-00006CrossRefPubMed

31.

Rauchschwalbe SK, Maseizik T, Mittelkotter U, Schluter B, Patzig C, Thiede A, Reith HB: Effect of the LT-alpha (+250 G/A) polymorphism on markers of inflammation and clinical outcome in critically ill patients. J Trauma 2004, 56: 815-822.CrossRefPubMed

32.

Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA, et al.: TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immunity 2004, 5: 631-640. 10.1038/sj.gene.6364136CrossRefPubMed

33.

Heesen M, Kunz D, Bachmann-Mannenga B, Merk HF, Bloemeke B: Linkage disequilibrium between tumor necrosis factor (TNF)-α-308 G/A promoter and TNF β Ncol polymorphisms: association with TNF-α response of granulocytes to endotoxin stimulation. Crit Care Med 2003, 31: 211-214. 10.1097/00003246-200301000-00032CrossRefPubMed

34.

Waterer GW, Quasney MW, Cantor RM, Wunderink RG: Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Resp Crit Care Med 2001, 163: 1599-1604.CrossRefPubMed

35.

Gallagher PM, Lowe G, Fitzgerald T, Bella A, Greene CM, McElvaney NG, O'Neill SJ: Association of Il-10 polymorphism with severity of illness in community acquired pneumonia. Thorax 2003, 58: 154-156. 10.1136/thorax.58.2.154PubMedCentralCrossRefPubMed

36.

Schaff BM, Boehmke F, Esnaashari H, Seitzer U, Kothe H, Maass M, Zabel P, Dalhoff K: Pneumococcal septic shock is associated with the interleukin-10-1082 gene promoter polymorphism. Am J Resp Crit Care Med 2003, 168: 476-480. 10.1164/rccm.200210-1164OCCrossRef

37.

Bayley JP, Ottenhoff THM, Verweij CL: Is there a future for TNF promoter polymnorphism. Genes Immunity 2004, 5: 315-329. 10.1038/sj.gene.6364055CrossRefPubMed

38.

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345: 1368-1377. 10.1056/NEJMoa010307CrossRefPubMed

39.

Carlet J: Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med 2006, 34: 525-529. 10.1097/01.CCM.0000198329.85851.8ECrossRefPubMed

40.

Sutherland AM, Walley KR, Manocha S, Russell JA: The association of interleukin 6 haplotype with mortality in critically ill adults. Arch Intern Med 2005, 165: 75-82. 10.1001/archinte.165.1.75CrossRefPubMed

41.

Colhoun HM, Mckeigue PM, Smith GD: Problems of reporting genetic associations with complex outcomes. Lancet 2003, 361: 865-872. 10.1016/S0140-6736(03)12715-8CrossRefPubMed

42.

Polderman KH, Girbes ARJ: Drug intervention trials in sepsis: divergent results. Lancet 2004, 363: 1721-1723. 10.1016/S0140-6736(04)16259-4CrossRefPubMed

Title: Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis
Authors: Jose Garnacho-Montero
Teresa Aldabo-Pallas
Carmen Garnacho-Montero
Aurelio Cayuela
Rocio Jiménez
Sonia Barroso
Carlos Ortiz-Leyba
Publication date: 01-08-2006
Publisher: BioMed Central
Published in: Critical Care / Issue 4/2006
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc4995

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis

Abstract

Introduction

Method

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Method

Results

Conclusion

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