Advertisement

Current Infectious Disease Reports

, Volume 12, Issue 5, pp 336–344 | Cite as

Early Antimicrobial Therapy in Severe Sepsis and Septic Shock

  • Anand KumarEmail author
Article

Abstract

The advent of modern antimicrobial therapy following the discovery of penicillin during the 1940s yielded remarkable improvements in the case fatality rates of serious infections, including septic shock. Since then, pathogens have continuously evolved under selective antimicrobial pressure, resulting in a lack of additional significant improvement in clinical effectiveness of antimicrobial therapy of septic shock despite ever more broad-spectrum and potent drugs. In addition, although substantial effort and money were expended on the development of novel nonantimicrobial therapies of sepsis in the past 30 years, clinical progress in this regard has been limited. This article explores the possibility that the key to significant improvement in the outcome of septic shock may lie, in great part, with improvements in delivery of existing antimicrobials. Recognizing the role of delays in administration of antimicrobial therapy in the poor outcomes of septic shock is central to this effort.

Keywords

Antibiotic Antimicrobial Antifungal Sepsis Septic shock Infection ICU Critical care Treatment Therapy Delay 

Notes

Disclosure

No potential conflict of interest relevant to this article was reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Finland M, Jones WF, Barnes MW: Occurrence of serious bacterial infections since the introduction of antibacterial agents. JAMA 1959, 84:2188–2197.Google Scholar
  2. 2.
    Hemminki E, Paakkulainen A: Effect of antibiotics on mortality from infectious diseases in Sweden and Finland. Am J Public Health 1976, 66:1180–1184.CrossRefPubMedGoogle Scholar
  3. 3.
    Kreger BE, Craven DE, McCabe WR: Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med 1980, 68:344–355.CrossRefPubMedGoogle Scholar
  4. 4.
    Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348:1546–1554.CrossRefPubMedGoogle Scholar
  5. 5.
    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, 29:1303–1310.CrossRefPubMedGoogle Scholar
  6. 6.
    Sands KE, Bates DW, Lanken PN, et al.: Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 1997, 278:234–240.CrossRefPubMedGoogle Scholar
  7. 7.
    Brun-Buisson C, Doyon F, Carlet J, et al.: Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995, 274:968–974.CrossRefPubMedGoogle Scholar
  8. 8.
    Annane D, Aegerter P, Jars-Guincestre MC, et al.: Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 2003, 168:165–172.CrossRefPubMedGoogle Scholar
  9. 9.
    Pakhale S, Roberts D, Light B, et al.: A geographically and temporally comprehensive analysis of septic shock: impact of age, sex and socioeconomic status [abstract]. Crit Care Med 2005, 33:103-M.CrossRefGoogle Scholar
  10. 10.
    Eichacker PQ, Natanson C: Increasing evidence that the risks of rhAPC may outweigh its benefits. Intensive Care Med 2007, 33:396–399.CrossRefPubMedGoogle Scholar
  11. 11.
    Gardlund B, Gardlund B: Activated protein C (Xigris) treatment in sepsis: a drug in trouble. Acta Anaesthesiol Scand 2006, 50:907–910.CrossRefPubMedGoogle Scholar
  12. 12.
    Bone RC, Balk R, Cerra FB, et al.: ACCP/SCCM Consensus Conference: definitions for sepsis and organ failure and guidelines for use of innovative therapies in sepsis. Chest 1992, 101:1644–1655.CrossRefPubMedGoogle Scholar
  13. 13.
    Levy MM, Fink MP, Marshall JC, et al.: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31:1250–1256.CrossRefPubMedGoogle Scholar
  14. 14.
    van der Poll T, van Deventer SJ: Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999, 13:413–426.CrossRefPubMedGoogle Scholar
  15. 15.
    van der Poll T: Coagulation and inflammation. J Endotoxin Res 2001, 7:301–304.CrossRefPubMedGoogle Scholar
  16. 16.
    Freeman BD, Natanson C: Anti-inflammatory therapies in sepsis and septic shock. Expert Opin Investig Drugs 2000, 9:1651–1663.CrossRefPubMedGoogle Scholar
  17. 17.
    Wiggers CJ: Experimental hemorrhage shock. In Physiology of Shock: Cambridge. MA: Harvard University Press; 1950:121–143.Google Scholar
  18. 18.
    De Luca G, Suryapranata H, Ottervanger JP, Antman EM: Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004, 109:1223–1225.CrossRefPubMedGoogle Scholar
  19. 19.
    Simoons ML, Serruys PW, vd Brand M, et al.: Improved survival after early thrombolysis in acute myocardial infarction. A randomised trial by the Interuniversity Cardiology Institute in The Netherlands. Lancet 1985, 2:578–582.CrossRefPubMedGoogle Scholar
  20. 20.
    Wood KE: The presence of shock defines the threshold to initiate thrombolytic therapy in patients with pulmonary embolism. Intensive Care Med 2002, 28:1537–1546.CrossRefPubMedGoogle Scholar
  21. 21.
    Sampalis JS, Lavoie A, Williams JI, et al.: Impact of on-site care, prehospital time, and level of in-hospital care on survival in severely injured patients. J Trauma 1993, 34:252–261.CrossRefPubMedGoogle Scholar
  22. 22.
    Valles J, Rello J, Ochagavia A, et al.: Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003, 123:1615–1624.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang H, Czura CJ, Tracey KJ: Lipid unites disparate syndromes of sepsis. Nat Med 2004, 10:124–125.CrossRefPubMedGoogle Scholar
  24. 24.
    Kumar A, Haery C, Paladugu B, et al.: The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. J Infect Dis 2006, 193:251–258.CrossRefPubMedGoogle Scholar
  25. 25.
    Ovstebo R, Brandtzaeg P, Brusletto B, et al.: Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease. J Clin Microlbiol 2004, 42:2980–2987.CrossRefGoogle Scholar
  26. 26.
    Lala HM, Mills GD, Barratt K, et al.: Meningococcal disease deaths and the frequency of antibiotic administration delays. J Infect 2007, 54:551–557.CrossRefPubMedGoogle Scholar
  27. 27.
    Yagupsky P, Nolte FS: Quantitative aspects of septicemia. Clin Micro Rev 1990, 3:269–279.PubMedGoogle Scholar
  28. 28.
    • Rello J, Lisboa T, Lujan M, et al.: Severity of pneumococcal pneumonia associated with genomic bacterial load. Chest 2009, 136:832–840. This article provides a straightforward demonstration that severity of illness and risk of death is associated with the total bacterial load in serious infections. CrossRefPubMedGoogle Scholar
  29. 29.
    Marra AR, Edmond MB, Forbes BA, et al.: Time to blood culture positivity as a predictor of clinical outcome of staphylococcus aureus bloodstream infection. J Clin Microbiol 2006, 44:1342–1346.CrossRefPubMedGoogle Scholar
  30. 30.
    Kollef MH, Sherman G, Ward S, Fraser VJ: Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999, 115:462–474.CrossRefPubMedGoogle Scholar
  31. 31.
    • Kumar A, Ellis P, Arabi Y, et al.: Initiation of inappropriate antimicrobial therapy results in a five-fold reduction of survival in human septic shock. Chest 2009, 136:1237–1248. This study shows that the adverse impact of inappropriate initial antimicrobial therapy on mortality is substantially greater in septic shock than in other serious infections. CrossRefPubMedGoogle Scholar
  32. 32.
    Ibrahim EH, Sherman G, Ward S, et al.: The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000, 118:146–155.CrossRefPubMedGoogle Scholar
  33. 33.
    Young LS, Martin WJ, Meyer RD, et al.: Gram-negative rod bacteremia: Microbiologic, immunologic, and therapeutic considerations. Ann Intern Med 1977, 86:456–471.PubMedGoogle Scholar
  34. 34.
    Romero-Vivas J, Rubio M, Fernandez C, Picazo JJ: Mortality associated with nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 1995, 21:1417–1423.PubMedGoogle Scholar
  35. 35.
    Nguyen MH, Peacock JE Jr, Tanner DC, et al.: Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med 1995, 155:2429–2435.CrossRefPubMedGoogle Scholar
  36. 36.
    Vergis EN, Hayden MK, Chow JW, et al.: Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study. Ann Intern Med 2001, 135:484–492.PubMedGoogle Scholar
  37. 37.
    McGregor JC, Rich SE, Harris AD, et al.: A systematic review of the methods used to assess the association between appropriate antibiotic therapy and mortality in bacteremic patients. Clin Infect Dis 2007, 45:329–337.CrossRefPubMedGoogle Scholar
  38. 38.
    Kollef MH: Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting it right up front. Clin Infect Dis 2008, 47:S3–S13.CrossRefPubMedGoogle Scholar
  39. 39.
    Byl B, Clevenbergh P, Jacobs F, et al.: Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis 1999, 29:60–66.CrossRefPubMedGoogle Scholar
  40. 40.
    • Raineri E, Pan A, Mondello P, et al.: Role of the infectious diseases specialist consultant on the appropriateness of antimicrobial therapy prescription in an intensive care unit. Am J Infect Control 2008, 36:283–290. This study demonstrates that appropriateness of antimicrobial therapy in the ICU is improved by consultation with an infectious diseases specialist. CrossRefPubMedGoogle Scholar
  41. 41.
    Kollef MH, Morrow LE, Niederman MS, et al.: Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest 2006, 129:1210–1218.CrossRefPubMedGoogle Scholar
  42. 42.
    Singh N, Rogers P, Atwood CW, et al.: Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000, 162:505–511.PubMedGoogle Scholar
  43. 43.
    Jamieson WG, Pliagus G, Marchuk S, et al.: Effect of antibiotic and fluid resuscitation upon survival time in experimental intestinal ischemia. Surg Gynecol Obstet 1988, 167:103–108.PubMedGoogle Scholar
  44. 44.
    Greisman SE, DuBuy JB, Woodward CL: Experimental gram-negative bacterial sepsis: prevention of mortality not preventable by antibiotics alone. Infect Immun 1979, 25:538–557.PubMedGoogle Scholar
  45. 45.
    Bodey GP, Jadeja L, Elting L: Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med 1985, 145:1621–1629.CrossRefPubMedGoogle Scholar
  46. 46.
    Meehan TP, Fine MJ, Krumholz HM, et al.: Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997, 278:2080–2084.CrossRefPubMedGoogle Scholar
  47. 47.
    Houck PM, Bratzler DW, Nsa W, et al.: Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med 2004, 164:637–644.CrossRefPubMedGoogle Scholar
  48. 48.
    •• Kumar A, Roberts D, Wood KE, et al.: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006, 34:1589–1596. This study was the first and most definitive study to date to directly support recommendations that appropriate antimicrobial therapy must be initiated within 1 hour of documentation of septic shock. CrossRefPubMedGoogle Scholar
  49. 49.
    Natsch S, Kullberg BJ, Van der Meer JW, Meis JF: Delay in administering the first dose of antibiotics in patients admitted to hospital with serious infections. Eur J Clin Microbiol Infect Dis 1998, 17:681–684.CrossRefPubMedGoogle Scholar
  50. 50.
    Proulx N, Frechette D, Toye B, et al.: Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005, 98:291–298.CrossRefPubMedGoogle Scholar
  51. 51.
    Lodise J, Patel N, Kwa A, et al.: Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: Impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother 2007, 51:3510–3515.CrossRefPubMedGoogle Scholar
  52. 52.
    Whitelaw DA, Rayner BL, Willcox PA: Community-acquired bacteremia in the elderly: a prospective study of 121 cases. J Am Geriatr Soc 1992, 40:996–1000.PubMedGoogle Scholar
  53. 53.
    • Garnacho-Montero J, Garcia-Cabrera E, Diaz-Martin A, et al.: Determinants of outcome in patients with bacteraemic pneumococcal pneumonia: Importance of early adequate treatment. Scand J Infect Dis 2010, 42:185–192. This study shows that delayed therapy results in increased mortality in patients with bacteremic pneumococcal pneumonia. CrossRefPubMedGoogle Scholar
  54. 54.
    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.PubMedGoogle Scholar
  55. 55.
    Miner JR, Heegaard W, Mapes A, Biros M: Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center. J Emerg Med 2001, 21:387–392.CrossRefPubMedGoogle Scholar
  56. 56.
    Garey KW, Rege M, Pai MP, et al.: Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006, 43:25–31.CrossRefPubMedGoogle Scholar
  57. 57.
    Morrell M, Fraser VJ, Kollef MH, et al.: Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005, 49:3640–3645.CrossRefPubMedGoogle Scholar
  58. 58.
    • Patel GP, Simon D, Scheetz M, et al.: The effect of time to antifungal therapy on mortality in candidemia associated septic shock. Am J Ther 2009, 16:508–511. This study shows that delays of antifungal therapy greater than 15 hours after the first positive blood culture are associated with increased mortality. CrossRefPubMedGoogle Scholar
  59. 59.
    Larche J, Azoulay E, Fieux F, et al.: Improved survival of critically ill cancer patients with septic shock. Intensive Care Med 2003, 29:1688–1695.CrossRefPubMedGoogle Scholar
  60. 60.
    Gacouin A, Le Tulzo Y, Lavoue S, et al.: Severe pneumonia due to Legionella pneumophila: prognostic factors, impact of delayed appropriate antimicrobial therapy. Intensive Care Med 2002, 28:686–691.CrossRefPubMedGoogle Scholar
  61. 61.
    Lodise TP, McKinnon PS, Swiderski L, Rybak MJ: Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003, 36:1418–1423.CrossRefPubMedGoogle Scholar
  62. 62.
    Kang CI, Kim SH, Kim HB, et al.: Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis 2003, 37:745–751.CrossRefPubMedGoogle Scholar
  63. 63.
    Iregui M, Ward S, Sherman G, et al.: Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002, 122:262–268.CrossRefPubMedGoogle Scholar
  64. 64.
    •• Gaieski DF, Pines JM, Band RA, et al.: Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010, 38:1045–1053. This study demonstrates that time to appropriate antimicrobial therapy impacts outcome even in patients receiving early goal-directed resuscitation. CrossRefPubMedGoogle Scholar
  65. 65.
    •• Ferrer R, Artigas A, Suarez D, et al.: Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 2009, 180:861–866. This study shows that time to antimicrobial therapy remains critical when assessed in logistic regression analysis along with other elements of the sepsis resucitation “bundle.” CrossRefPubMedGoogle Scholar
  66. 66.
    Dellinger RP, Levy MM, Carlet JM, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 [erratum appears in Crit Care Med 2008, 36:1394–1396]. Crit Care Med 2008, 36:296–327.CrossRefPubMedGoogle Scholar
  67. 67.
    Varpula M, Karlsson S, Parviainen I, et al. and the Finnsepsis Study Group: Community-acquired septic shock: early management and outcome in a nationwide study in Finland. Acta Anaesthesiol Scand 2007, 51:1320–1326.CrossRefPubMedGoogle Scholar
  68. 68.
    de Sousa AG, Junior CJF, Santos GPD, et al.: The impact of each action in the Surviving Sepsis Campaign measures on hospital mortality of patients with severe sepsis/septic shock. Einstein 2008, 6:323–327.Google Scholar
  69. 69.
    Subramanian S, Yilmaz M, Rehman A, et al.: Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: An observational study. Intensive Care Med 2008, 34:157–162.CrossRefPubMedGoogle Scholar
  70. 70.
    Iscimen R, Cartin-Ceba R, Yilmaz M, et al.: Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med 2008, 36:1518–1522.CrossRefPubMedGoogle Scholar
  71. 71.
    Bagshaw SM, Lapinsky S, Dial S, et al.: Acute kidney injury in septic shock: Clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med 2009, 35:871–881.CrossRefPubMedGoogle Scholar
  72. 72.
    Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, et al.: Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis. Crit Care 2006, 10:R111.CrossRefPubMedGoogle Scholar
  73. 73.
    Calbo E, Alsina M, Rodriguez-Carballeira M, et al.: The impact of time on the systemic inflammatory response in pneumococcal pneumonia. Eur Respir J 2010, 35:614–618.CrossRefPubMedGoogle Scholar
  74. 74.
    Thiel SW, Asghar MF, Micek ST, et al.: Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis. Crit Care Med 2009, 3:819–824.CrossRefGoogle Scholar
  75. 75.
    Nguyen HB, Corbett SW, Steele R, et al.: Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med 2007, 35:1105–1112.CrossRefPubMedGoogle Scholar
  76. 76.
    Sebat F, Musthafa AA, Johnson D, et al.: Effect of a rapid response system for patients in shock on time to treatment and mortality during 5 years. Crit Care Med 2007, 35:2568–2575.CrossRefPubMedGoogle Scholar
  77. 77.
    Barochia AV, Cui X, Vitberg D, et al.: Bundled care for septic shock: an analysis of clinical trials. Crit Care Med 2010, 38:668–678.CrossRefPubMedGoogle Scholar
  78. 78.
    Weinstein MP, Towns ML, Quartey SM, et al.: The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis 1997, 24:584–602.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Section of Critical Care Medicine, Section of Infectious Diseases, JJ399d, Health Sciences CentreWinnipegCanada

Personalised recommendations