Intensive Care Medicine

, Volume 40, Issue 10, pp 1399–1408 | Cite as

De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial

  • Marc Leone
  • Carole Bechis
  • Karine Baumstarck
  • Jean-Yves Lefrant
  • Jacques Albanèse
  • Samir Jaber
  • Alain Lepape
  • Jean-Michel Constantin
  • Laurent Papazian
  • Nicolas Bruder
  • Bernard Allaouchiche
  • Karine Bézulier
  • François Antonini
  • Julien Textoris
  • Claude Martin
  • For the AZUREA Network Investigators
Seven-Day Profile Publication



In patients with severe sepsis, no randomized clinical trial has tested the concept of de-escalation of empirical antimicrobial therapy. This study aimed to compare the de-escalation strategy with the continuation of an appropriate empirical treatment in those patients.


This was a multicenter non-blinded randomized noninferiority trial of patients with severe sepsis who were randomly assigned to de-escalation or continuation of empirical antimicrobial treatment. Recruitment began in February 2012 and ended in April 2013 in nine intensive care units (ICUs) in France. Patients with severe sepsis were assigned to de-escalation (n = 59) or continuation of empirical antimicrobial treatment (n = 57). The primary outcome was to measure the duration of ICU stay. We defined a noninferiority margin of 2 days. If the lower boundary of the 95 % confidence interval (CI) for the difference in patients assigned to the de-escalation group was less than 2 days, as compared with that of patients assigned to the continuation group, de-escalation was considered to be noninferior to the continuation strategy. Secondary outcomes included mortality at 90 days, occurrence of organ failure, number of superinfections, and number of days with antibiotics during the ICU stay.


The median duration of ICU stay was 9 [interquartile range (IQR) 5–22] days in the de-escalation group and 8 [IQR 4–15] days in the continuation group, respectively (P = 0.71). The mean difference was 3.4 (95 % CI −1.7 to 8.5). A superinfection occurred in 16 (27 %) patients in the de-escalation group and six (11 %) patients in the continuation group (P = 0.03). The numbers of antibiotic days were 9 [7–15] and 7.5 [6–13] in the de-escalation group and continuation group, respectively (P = 0.03). Mortality was similar in both groups.


As compared to the continuation of the empirical antimicrobial treatment, a strategy based on de-escalation of antibiotics resulted in prolonged duration of ICU stay. However, it did not affect the mortality rate.


Sepsis Antibiotics De-escalation Empirical Stewardship 



We thank Jean-Charles Reynier, Loundoun Anderson, and Pascal Auquier. We also thank Charlotte Kelway for her attentive reading of our manuscript.

Conflicts of interest

The authors have completed and submitted the International Committee of Medical Journal Editors (ICMJE) Form for Disclosure of Potential conflicts of interest. Dr Leone reported serving as consultant for LFB. Dr. Constantin reported receiving payment for lectures from Baxter, Drager, Fresenius-Kabi, LFB, Convatec, MSD, Maquet, and Hospal. No other disclosures were reported.

Supplementary material

134_2014_3411_MOESM1_ESM.docx (107 kb)
Supplementary material 1 (DOCX 107 kb)


  1. 1.
    Maragakis LL (2010) Recognition and prevention of multidrug-resistant Gram-negative bacteria in the intensive care unit. Crit Care Med 38(8 Suppl):S345–S351PubMedCrossRefGoogle Scholar
  2. 2.
    Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM (2007) Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44:159–177PubMedCrossRefGoogle Scholar
  3. 3.
    Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228PubMedCrossRefGoogle Scholar
  4. 4.
    Kollef MH (2001) Hospital-acquired pneumonia and de-escalation of antimicrobial treatment. Crit Care Med 29:1473–1475PubMedCrossRefGoogle Scholar
  5. 5.
    Rello J, Vidaur L, Sandiumenge A, Rodríguez A, Gualis B, Boque C, Diaz E (2004) De-escalation therapy in ventilator-associated pneumonia. Crit Care Med 32:2183–2190PubMedGoogle Scholar
  6. 6.
    Leone M, Bourgoin A, Cambon S, Dubuc M, Albanèse J, Martin C (2003) Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med 31:462–467PubMedCrossRefGoogle Scholar
  7. 7.
    Morel J, Casoetto J, Jospé R, Aubert G, Terrana R, Dumont A, Molliex S, Auboyer C (2010) De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit. Crit Care 14:R225PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Heenen S, Jacobs F, Vincent JL (2012) Antibiotic strategies in severe nosocomial sepsis: why do we not de-escalate more often? Crit Care Med 40:1404–1409PubMedCrossRefGoogle Scholar
  9. 9.
    Shime N, Kosaka T, Fujita N (2013) De-escalation of antimicrobial therapy for bacteraemia due to difficult-to-treat Gram-negative bacilli. Infection 41:203–210PubMedCrossRefGoogle Scholar
  10. 10.
    Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernández-Delgado E, Herrera-Melero I, Ortiz-Leyba C, Márquez-Vácaro JA (2014) De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 40:32–40PubMedCrossRefGoogle Scholar
  11. 11.
    Mokart D, Slehofer G, Lambert J, Sannini A, Chow-Chine L, Brun JP, Berger P, Duran S, Faucher M, Blache JL, Saillard C, Vey N, Leone M (2014) De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study. Intensive Care Med 40:41–49PubMedCrossRefGoogle Scholar
  12. 12.
    Niederman MS (2006) De-escalation therapy in ventilator-associated pneumonia. Curr Opin Crit Care 12:452–457PubMedCrossRefGoogle Scholar
  13. 13.
    Silva BN, Andriolo RB, Atallah AN, Salomão R (2013) De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev 3:CD007934Google Scholar
  14. 14.
    Calandra T, Cohen J, International Sepsis Forum Definition of Infection in the ICU Consensus Conference (2005) The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 33:1538–1548PubMedCrossRefGoogle Scholar
  15. 15.
    American Thoracic Society; Infectious Diseases Society of America (2005) Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416CrossRefGoogle Scholar
  16. 16.
    Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O’Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG (2010) Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 50:133–164PubMedCrossRefGoogle Scholar
  17. 17.
    Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE (2010) Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 50:625–663PubMedCrossRefGoogle Scholar
  18. 18.
    Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC (2005) Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 41:1373–1406PubMedCrossRefGoogle Scholar
  19. 19.
    Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG, CONSORT Group (2012) Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 308:2594–2604PubMedCrossRefGoogle Scholar
  20. 20.
    Renyi A (1953) On the theory of order statistics. Acta Math Acad Sci Hungar 4:191–231CrossRefGoogle Scholar
  21. 21.
    Ellenberg JH (1994) Selection bias in observational and experimental studies. Stat Med 13:557–567PubMedCrossRefGoogle Scholar
  22. 22.
    Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055–2064PubMedCrossRefGoogle Scholar
  23. 23.
    Leibovici L (2009) Non-antibiotic treatment for bacterial infections: how to validate chance findings. Clin Microbiol Infect 15:298–301PubMedCrossRefGoogle Scholar
  24. 24.
    Retamar P, Portillo MM, López-Prieto Rodríguez-López F, de Cueto M, García MV, Gómez MJ, Del Arco A, Muñoz A, Sánchez-Porto A, Torres-Tortosa M, Martín-Aspas A, Arroyo A, García-Figueras C, Acosta F, Corzo JE, León-Ruiz L, Escobar-Lara T, Rodríguez-Baño J (2012) Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis. Antimicrob Agents Chemother 56:472–478PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH (2000) The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 118:146–155PubMedCrossRefGoogle Scholar
  26. 26.
    Kerry SM, Bland JM (1998) Trials which randomize practices II: sample size. Fam Pract 15:84–87PubMedCrossRefGoogle Scholar
  27. 27.
    Garcin F, Leone M, Antonini F, Charvet A, Albanèse J, Martin C (2010) Non-adherence to guidelines: an avoidable cause of failure of empirical antimicrobial therapy in the presence of difficult-to-treat bacteria. Intensive Care Med 36:75–82PubMedCrossRefGoogle Scholar
  28. 28.
    Martin-Loeches I, Deja M, Koulenti D, Dimopoulos G, Marsh B, Torres A, Niederman MS, Rello J, EU-VAP Study Investigators (2013) Potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: the interaction of ecology, shock and risk factors. Intensive Care Med 39:672–681PubMedCrossRefGoogle Scholar
  29. 29.
    Leone M, Malavieille F, Papazian L, Meyssignac B, Cassir N, Textoris J, Antonini F, La Scola B, Martin C, Allaouchiche B, Hraiech S (2013) Routine use of Staphylococcus aureus rapid diagnostic test in patients with suspected ventilator-associated pneumonia. Crit Care 17:R170PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2014

Authors and Affiliations

  • Marc Leone
    • 1
    • 2
  • Carole Bechis
    • 1
  • Karine Baumstarck
    • 3
  • Jean-Yves Lefrant
    • 4
  • Jacques Albanèse
    • 5
  • Samir Jaber
    • 6
  • Alain Lepape
    • 7
  • Jean-Michel Constantin
    • 8
  • Laurent Papazian
    • 2
    • 9
  • Nicolas Bruder
    • 10
  • Bernard Allaouchiche
    • 11
  • Karine Bézulier
    • 12
  • François Antonini
    • 1
  • Julien Textoris
    • 2
  • Claude Martin
    • 1
  • For the AZUREA Network Investigators
  1. 1.Service d’anesthésie et de réanimationHôpital NordMarseilleFrance
  2. 2.Unité de Recherche sur les Maladies Infectieuses et Tropicales ÉmergentesCentre National de la Recherche Scientifique–Unité Mixte de Recherche 7278, Aix Marseille UniversitéMarseilleFrance
  3. 3.Unité d’Aide Méthodologique à la Recherche Clinique et EpidémiologiqueAix Marseille UniversitéMarseilleFrance
  4. 4.Service des Réanimations Pôle Anesthésie Réanimation Douleur UrgenceCHU NîmesNîmesFrance
  5. 5.Hôpital La ConceptionMarseilleFrance
  6. 6.Hôpital Saint-EloiMontpellierFrance
  7. 7.Hôpitaux Lyon SudLyonFrance
  8. 8.Réanimation polyvalenteHôpital universitaire EstaingClermont-FerrantFrance
  9. 9.Hôpital NordMarseilleFrance
  10. 10.Hôpital la TimoneMarseilleFrance
  11. 11.Hôpital Edouard HerriotLyonFrance
  12. 12.Centre d’Investigation Clinique 9502Aix Marseille Université, Assistance Publique Hôpitaux de MarseilleMarseilleFrance

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