Abstract
Purpose
Antibiotic de-escalation is promoted to limit prolonged exposure to broad-spectrum antibiotics, but proof that it prevents the emergence of resistance is lacking. We evaluated determinants of antibiotic de-escalation in an attempt to assess whether the latter is associated with a lower emergence of antimicrobial resistance.
Methods
Antibiotic treatments, starting with empirical beta-lactam prescriptions, were prospectively documented during 2013 and 2014 in a tertiary intensive care unit (ICU) and categorized as continuation, de-escalation or escalation of the empirical antimicrobial treatment. Determinants of the de-escalation or escalation treatments were identified by multivariate logistic regression; the continuation category was used as the reference group. Using systematically collected diagnostic and surveillance cultures, we estimated the cumulative incidence of antimicrobial resistance following de-escalation or continuation of therapy, with adjustment for ICU discharge and death as competing risks.
Results
Of 478 anti-pseudomonal antibiotic prescriptions, 42 (9 %) were classified as escalation of the antimicrobial treatment and 121 (25 %) were classified as de-escalation, mainly through replacement of the originally prescribed antibiotics with those having a narrower spectrum. In multivariate analysis, de-escalation was associated with the identification of etiologic pathogens (p < 0.001). The duration of the antibiotic course in the ICU in de-escalated versus continued prescriptions was 8 (range 6–10) versus 5 (range 4–7) days, respectively (p < 0.001). Mortality did not differ between patients in the de-escalation and continuation categories. The cumulative incidence estimates of the emergence of resistance to the initial beta-lactam antibiotic on day 14 were 30.6 and 23.5 % for de-escalation and continuation, respectively (p = 0.22). For the selection of multi-drug resistant pathogens, these values were 23.5 (de-escalation) and 18.6 % (continuation) respectively (p = 0.35).
Conclusion
The emergence of antibiotic-resistant bacteria after exposure to anti-pseudomonal beta-lactam antibiotics was not lower following de-escalation.
Similar content being viewed by others
References
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent J-L, Moreno R, The Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup (2013) Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228
Dellit TH, Owens RC, McGowan JE, 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 develo** an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44:159–177
Kollef MH (2001) Hospital-acquired pneumonia and de-escalation of antimicrobial treatment. Crit Care Med 29(7):1473–1475
Kollef MH (2001) Optimizing antibiotic therapy in the intensive care unit setting. Crit Care 5:189–195
Niederman MS (2006) De-escalation therapy in ventilator-associated pneumonia. Curr Opin Crit Care 12:452–457
Silva BNG, Andriolo RB, Atallah AN, Salomao R (2013) De-escalation of antimicrobial treatment for adults with sepsis, severe sepsis or septic shock (review). Cochrane Database Systematic Rev 3:CD007934 doi:10.1002/14651858
Tabah A, Cotta MO, Garnacho-Montero J, Schouten J, Roberts JA, Lipman J, Tacey M, Timsit JF, Leone M, Zahar JR, De Waele J, on behalf of the Working Group for Antimicrobial Use in the ICU (2015) A systematic review of the definitions, determinants and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. doi:10.1093/cid/civ1199
Garnacho-Montero J, Escoresca-Ortega A, Fernandez-Delgado E (2015) Antibiotic de-escalation in the ICU: how is it best done? Curr Opin Infect Dis 28:193–198
Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernandez-Delgado E, Herrera-Melero I, Ortiz-Leyba C, Marquez-Vacaro JA (2014) De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 40:32–40
Knaak E, Cavalieri SJ, Elsasser GN, Preheim LC, Gonitzke A, Destache CJ (2013) Does antibiotic de-escalation for nosocomial pneumonia impact intensive care unit length of stay? Infect Dis Clin Pract 21(3):172–176
Giantsou E, Liratzopoulos N, Efraimidou E, Panopoulou M, Alepopoulou E, Kartali-Ktenidou S, Manolas K (2007) De-escalation therapy rates are significantly higher by bronchoalveolar lavage than by tracheal aspirate. Intensive Care Med 33:1533–1540
Gonzalez L, Cravoisy A, Barraud D, Conrad M, Nace L, Lemarié J, Bollaert P-E, Gibot S (2013) Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients. Crit Care 17:R140
Mokart D, Slehofer G, Lambert J, Sannini A, Chow-Chine L, Brun J-P, Berger P, Duran S, Faucher M, Blanche J-L, Saillard C, Vey N, Leone M (2014) De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results of an observational study. Intensive Care Med 40:41–49
Leone M, Bechis C, Baumstarck K, Lefrant J-Y, Albanèse J, Jaber S, Lepape A, Constantin J-M, Papazian L, Bruder N, Allaouchiche B, Bézulier K, Antonini F, Textoris J, Martin C, for the AZUREA network investigators (2014) De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med 40:1399–1408
Steurbaut K, Colpaert K, Gadeyne B, Depuydt P, Vosters P, Danneels C, Benoit D, Decruyenaere J, De Turck F (2012) COSARA: integrated service platform for infection surveillance and antibiotic management in the ICU. J Med Syst 36:3765–3775
De Bus L, Diet G, Gadeyne B, Leroux-Roels I, Claeys G, Steurbaut K, Benoit D, De Turck F, Decruyenaere J, Depuydt P (2014) Validity analysis of a unique infection surveillance system in the intensive care unit by analysis of a data warehouse built through a workflow-integrated software application. J Hosp Infect 87:159–164
De Bus L, Saerens L, Gadeyne B, Boelens J, Claeys G, De Waele JJ, Benoit DD, Decruyenaere J, Depuydt PO (2014) Development of antibiotic treatment algorithms based on local ecology and respiratory surveillance cultures to restrict the use of broad-spectrum antimicrobial drugs in the treatment of hospital-acquired pneumonia in the intensive care unit: a retrospective analysis. Crit Care 18:R152
Saag MS. Gilbert DN CH, Eliopoulos GM, Moellering RC (2012) The Sanford guide to antimicrobial therapy. 23rd edition of the Belgian/Luxembourg version 2012–2013. Antimicrobial Therapy Inc., Sperryville
Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL (2012) Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281
R-GNOSIS (2011) Resistance in Gram-Negative Organisms: Studying Intervention Strategies. Available at: http://www.r-gnosis.eu/. Accessed 14 March 2016
Andersen PK, Abildstrom SZ, Rosthoj S (2002) Competing risk as a multi-state model. Stat Methods Med Res 11:203–215
Pepe M, Mori M (1993) Kaplan-Meier, marginal or conditional probability curves in summarizing competing risk failure time data? Stat Med 12(8):737–751
Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD (2004) A note on competing risks in survival data analysis. Br J Cancer 91(4):1229–1235
Gray RJ (1998) A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154
(2015) R Foundation for Statistical Computing. R: a language and environment for statistical computing (version 3.2.2). Available at: http://www.R-project.org
cmprsk-package. Available at: https://cran.r-project.org/web/packages/cmprsk/cmprsk.pdf. Accessed 14 March 2016
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(6):R225
De Waele JJ, Ravyts M, Depuydt P, Blot SI, Decruyenaere J, Vogelaers D (2010) De-escalation after empirical meropenem treatment in the intensive care unit: fiction or reality? J Crit Care 25:641–646
Álvarez-Lerma F, Alvarez B, Luque P, Ruiz F, Dominguez-Roldan J-M, Quintana E, Sanz-Rodriguez C, The ADANN Study Group (2006) Empiric broad-spectrum antibiotic therapy of nosocomial pneumonia in the intensive care unit: a prospective observational study. Crit Care 10:R78
McCullough AR, Rathboneb J, Parekh S, Hoffmann TC, Del Mar CB (2015) Not in my backyard: a systematic review of clinicians’ knowledge and beliefs about antibiotic resistance. J Antimicrob Chemother 70:2465–2473
Joung MK, Lee JA, Moon SY, Cheong HS, Joo EJ, Ha YE, Sohn KM, Chung SM, Suh GY, Chung DR, Song JH, Peck KR (2011) Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care 15(2):R79
Armand-Lefèvre L, Angebault C, Barbier F, Hamelet E, Defrance G, Ruppé E, Bronchard R, Lepeule R, Lucet JC, El Mniai A, Wolff M, Montravers P, Plésiat P, Andremonta A (2013) Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother 57(3):1488–1495
Carlier M, Roberts JA, Stove V, Verstraete AG, Lipman J, De Waele JJ (2015) A simulation study reveals lack of pharmacokinetic/pharmacodynamic target attainment in de-escalated antibiotic therapy in critically ill patients. Antimicrob Agents Chemother 59(8):4689–4694
Weiss E, Zahar JR, Lesprit P, Ruppe E, Leone M, Chastre J, Lucet JC, Paugam-Burtz C, Brun-Buisson C, Timsit JF, De-escalation study Group (2015) Elaboration of a consensual definition of de-escalation allowing a ranking of beta-lactams. Clin Microbiol Infect 21(7):649.e1–649.e10
Madaras-Kelly K, Jones M, Remington R, Hill N, Huttner B, Samore M (2014) Development of an antibiotic spectrum score based on veterans affairs culture and susceptibility data for the purpose of measuring antibiotic de-escalation: a modified Delphi approach. Infect Control Hosp Epidemiol 35(9):1103–1113
Acknowledgments
This research project is funded by the IWT (Institute for the Promotion of Innovation through Science and Technology in Flanders) (project IWT–TBM COSARA–project number 060517). LDB received a Clinical Research Grant from Ghent University Hospital, Belgium (project number KW/1394/INT/001/001). JDW is a senior Clinical Investigator with the Research Foundation Flanders (FWO).
Authors' contributions
LDB and PD conceived the study, participated in its design and coordination, analyzed the data, and drafted the manuscript; WD, JC, LDB, KV, and BG performed data acquisition and analyses; WD, JC, BG, KV, JB, GC, JDW, and JD critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Additional information
Take-home message: The results of this study do not confirm the expected favorable effect of de-escalation of anti-pseudomonal beta-lactam antibiotic treatment on the selection of antimicrobial resistance. De-escalation should therefore not be considered to be a safe strategy underpinning an unlimited empirical use of broad-spectrum combination therapy. Future research to determine the most optimal de-escalation strategy and by extension the most optimal antibiotic strategy reducing overall antibiotic exposure and antimicrobial selection pressure is essential.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
De Bus, L., Denys, W., Catteeuw, J. et al. Impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in ICU patients: a retrospective observational study. Intensive Care Med 42, 1029–1039 (2016). https://doi.org/10.1007/s00134-016-4301-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-016-4301-z