Prognostic factors of Escherichia coli bloodstream infections, in the face of emerging multi-resistance. Severity score and therapeutic implications – SEPTICOLI

Escherichia coli is the first causative agent among community-acquired bacteraemia and the 5th among hospital-acquired bacteraemia. E. coli bloodstream infections (BSI) account for an overall mortality rates ranging from 5% to nearly 30%. The determinants associated with severe outcome and death remain poorly understood. The epidemiology of E. coli BSI has recently changed dramatically with the global emergence of multiresistant strains producing extended-spectrum ß-lactamases (ESBL). Outcome is worse in case of ESBL-E. coli, which may be due to the intrinsic virulence of ESBL-E. coli or to a delayed adequate empirical antibiotic therapy because of multiresistance. In a previous study conducted 10 years ago, we found that host-factors and portal of entry outweigh bacterial determinants to predict the severity of E. coli bacteraemia. Whether this is still the case now with the epidemiological explosion of ESBL producing strains is unknown. Additionally, the last 10 years have witnessed a major progress in genomics with the wide availability of relatively cheap whole genome sequencing (WGS) techniques and pipelines for sequence analysis. Finally, predicting the severity of an infection as soon as the initial clinical assessment is of major importance to provide the best care, while limiting unnecessary hospitalizations and costs. Yet, no simple clinical score exists to predict the severity of E. coli infections.
In a translational approach, we will include during a maximum of one year 500 adults with E. coli BSI hospitalized in one of the 7 hospitals participating in this study. Precise clinical data will be collected at inclusion (visit 1) and 28 days after inclusion or upon patient’s discharge (if before day 28) (visit 2). The primary endpoint of the study is death from E. coli BSI at visit 2.
The first aim is to determine risk-factors for death at visit 2, including clinical and bacteriological factors determined by WGS in the era of the global emergence of ESBL producing E. coli. Risk-factors associated with an infection by an ESBL producing E. coli as well as risk-factors associated with death will be analysed for clinical and bacteriological factors both in a univariate analysis followed by a multivariate logistic regression model. If a sufficient number of ST131 strains are identified, we will also determine risk-factors for infection by an ST131 group. By analysing precisely the antibiotic received as empirical therapy, the resistance patterns of E. coli, patient outcome and risk-factors established for both ESBL carriage and death, we will determine whether initial treatment was appropriate, and based on the epidemiology of resistance we will discuss appropriate empirical therapy. The second aim is to determine virulence characteristics of ESBL strains both at the genome and phenotypic level thanks to a mouse model of septicaemia, and compare them to the clinical data. The third aim, based on the clinical risk factors identified in the first part of the work, we will establish and evaluate a simple clinical severity score named COLISCORE, which aim is to help clinician evaluate patients’ severity upon initial clinical evaluation and particularly to detect patients at risk of severe outcome.
The study will be organised into 4 work packages (WP) under the scientific responsibility of Pr Agnès Lefort, WP1 will coordinate and organise the dissemination of the work, WP2 “PATIENTS” will organise the patients inclusions and clinical data collection, WP3 “LAB” will perform microbiological analyses (phenotypic, genome sequencing, intrinsic virulence testing in a mouse model) and WP4 “STATS” will perform the statistical analysis, modelling and evaluation of the COLISCORE.
The ultimate goal of this work is to have a clinical impact on patients’ management, by understanding the determinants of patient severity due to E. coli BSI in the context of current major epidemiological changes.