Next-Generation Sequencing Diagnostics of Bacteremia in Sepsis (Next GeneSiS-Trial) - Study Protocol for a Prospective, Observational, Non-interventional, Multicenter, Clinical Trial

Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime in patients with sepsis. In this context, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. Especially the concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach.

Next GeneSiS is a prospective, observational, non-interventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis (according to recent sepsis definitions [sepsis-3]) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological testings. Moreover, the clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients´ management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first three days after onset (as assessed by (1.) death of the patient or lack of improvement of the patient´s clinical condition (in terms of an inadequate decrease of SOFA-score) or (2.) persistent high procalcitonin levels).

This prospective, observational, non-interventional, multicenter study trial for the first time investigates the performance as well as the clinical value of a NGS based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication.

Two sets of blood cultures (2x aerobic / 2x anaerobic) will be collected at study inclusion (=Onset) as well as 72 hours afterwards (=72h). In parallel, plasma samples for NGS-based measurements need to be obtained as described previously. Further blood samples for NGS-based measurements can be collected whenever physicians order blood cultures (2x aerobic / 2x anaerobic) because of the clinical suspicion of a bloodstream infection (BSI) within the first 3 days after study inclusion. Results of microbiological routine diagnostics in specimens different from blood (e.g. body fluid, tissue, bronchoalveolar lavage, endotracheal aspirate) will be used for further analyses when they are obtained within a timeframe of ≤72 hours prior or after the timepoints for NGS-based measurements. Clinical data collection and (if possible) PCT measurements will be performed at Onset as well as at 72h after study inclusion. The final outcome evaluation of patients will be performed at 28 days.