EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study

Belén Gutiérrez-Gutiérrez, Jesús Sojo-Dorado, José Bravo-Ferrer, Nienke Cuperus, Marlieke de Kraker, Tomislav Kostyanev, Lul Raka, George Daikos, Jan Feifel, Laura Folgori, Alvaro Pascual, Herman Goossens, Seamus O'Brien, Marc J M Bonten, Jesús Rodríguez-Baño, EURECA project team, Belén Gutiérrez-Gutiérrez, Jesús Sojo-Dorado, José Bravo-Ferrer, Nienke Cuperus, Marlieke de Kraker, Tomislav Kostyanev, Lul Raka, George Daikos, Jan Feifel, Laura Folgori, Alvaro Pascual, Herman Goossens, Seamus O'Brien, Marc J M Bonten, Jesús Rodríguez-Baño, EURECA project team

Abstract

Introduction: The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE.

Methods: A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case-control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies.

Ethics and dissemination: Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship.

Trial registration number: NCT02709408.

Keywords: antimicrobial therapy; carbapenem-resistance; complicated intraabdominal infections; complicated urinary tract infections; healthcare-associated pneumonia; outcome.

Conflict of interest statement

Competing interests: JR-B has been a scientific advisor for AstraZeneca, Merck and InfectoPharm, and speaker at accredited educational courses supported by Merck. AP has been a speaker for Merck and B Braun; he has been a scientific advisor for Merck and has received unrestricted research grants from B Braun and Astra Zeneca. MJMB has been a speaker for Pfizer. SO is an employee of AstraZeneca.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Study design according to targeted objectives. BAT, best available therapy; CRE, carbapenem-resistant Enterobacteriaceae; CSE, carbapenem-susceptible Enterobacteriaceae.
Figure 2
Figure 2
Decision tree for patient enrolment. BSI, blood stream infection; CRE, carbapenem-resistant Enterobacteriaceae; CSE, carbapenem-susceptible Enterobacteriaceae; cUTI, complicated urinary tract infection; eCRF, electronic case report form; IAI, intra-abdominal infection; PN, pneumonia.
Figure 3
Figure 3
Sample size required for each study. CRE, carbapenem-resistant Enterobacteriaceae; CSE, carbapenem-susceptible Enterobacteriaceae.

References

    1. World Health Organization (WHO). Antimicrobial resistance: global report on surveillance, 2014. (accessed 23 Jun 2016).
    1. Tzouvelekis LS, Markogiannakis A, Psichogiou M et al. . Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012;25:682–707. 10.1128/CMR.05035-11
    1. Falagas ME, Tansarli GS, Karageorgopoulos DE et al. . Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis 2014;20:1171–5. 10.3201/eid2007.121004
    1. Rodríguez-Baño J, Cisneros JM, Cobos-Trigueros N et al. . Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology. Enferm Infecc Microbiol Clin 2015;33:337.e1–337.e21. 10.1016/j.eimc.2014.11.009
    1. Tumbarello M, Viale P, Viscoli C et al. . Predictors of mortality in bloodstream infections caused by KPC-producing Klebsiella pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55:943–50. 10.1093/cid/cis588
    1. Qureshi ZA, Paterson DL, Potoski BA et al. . Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56:2108–13. 10.1128/AAC.06268-11
    1. Daikos GL, Tsaousi S, Tzouvelekis LS et al. . Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58:2322–8. 10.1128/AAC.02166-13
    1. Infectious Diseases Society of America (IDSA). White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens. Clin Infect Dis 2012;55:1031–46. 10.1093/cid/cis688
    1. Kostyanev T, Bonten MJ, O'Brien S et al. . Innovative medicines initiative's new drugs for bad bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance. J Antimicrob Chemother 2016;71:290–5. 10.1093/jac/dkv339
    1. Rex JH, Eisenstein BI, Alder J et al. . A comprehensive regulatory framework to address the unmet need for new antibacterial treatments. Lancet Infect Dis 2013;13:269–75. 10.1016/S1473-3099(12)70293-1
    1. Charlson ME, Pompei P, Ales KL et al. . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. 10.1016/0021-9681(87)90171-8
    1. Versporten A, Bielicki J, Drapier N et al. . The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother 2016;71:1106–17. 10.1093/jac/dkv418
    1. Garner JS, Jarvis WR, Grace Emori T et al. . CDC definitions for nosocomial infections. Am J Infect Control 1988;13:128–40. 10.1016/0196-6553(88)90053-3
    1. Friedman ND, Kaye KS, Stout JE et al. . Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137:791–7. 10.7326/0003-4819-137-10-200211190-00007
    1. American College of Chest Physicians/Society of Critical Care Medicine: Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74. 10.1097/00003246-199206000-00025
    1. Goldstein B, Giroir B, Randolph A. International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2–8. 10.1097/01.PCC.0000149131.72248.E6
    1. Rhee JY, Kwon KT, Ki HK et al. . Scoring systems for prediction of mortality in patients with intensive care unit-acquired sepsis: a comparison of the Pitt bacteremia score and the Acute Physiology and Chronic Health Evaluation II scoring systems. Shock 2009;31:146–50. 10.1097/SHK.0b013e318182f98f
    1. Vincent JL, Moreno R, Takala J et al. . The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ disfunction failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–10. 10.1007/BF01709751
    1. Singer M, Deutschman CS, Seymour CW et al. . The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801–10. 10.1001/jama.2016.0287
    1. Duncan H, Hutchison J, Parshuram CS. The pediatric early warning system score: a severity of illness score to predict urgent medical need in hospitalized children. J Crit Care 2006;21:271–8. 10.1016/j.jcrc.2006.06.007
    1. Knaus WA, Draper EA, Wagner DP et al. . APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818–29. 10.1097/00003246-198510000-00009
    1. Slater A, Shann F, Pearson G. PIM2: a revised version of the Paediatric Index of mortality. Intensive Care Med 2003;29:278–85. 10.1007/s00134-002-1601-2
    1. Tumbarello M, Trecarichi EM, De Rosa FG et al. . Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 2015;70:2133–43. 10.1093/jac/dkv086
    1. Palacios-Baena ZR, Oteo J, Conejo C et al. . Comprehensive clinical and epidemiological assessment of colonisation and infection due to carbapenemase-producing Enterobacteriaceae in Spain. J Infect 2016;72:152–60. 10.1016/j.jinf.2015.10.008
    1. Beyersmann J, Wolkewitz M, Allignol A et al. . Application of multistate models in hospital epidemiology: advances and challenges. Biom J 2011;53:332–50. 10.1002/bimj.201000146
    1. Akaike H. A new look at the statistical model identification. IEEE Trans Automatic Control 1974;19:716–23. 10.1109/TAC.1974.1100705

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