Background

Multi-drug resistant (MDR) bacterial pathogens clearly pose an important challenge to our society at multiple levels: in humans, MDR pathogens are increasingly detected and associated with significant morbidity, mortality and health care costs. Similarly, in veterinary medicine, MDR bacteria lead to a high economic burden and constitute a reservoir for dangerous zoonoses representing a serious public health concern. The spread of many bacterial pathogens is complex, and understanding the most important routes of transmission is a precondition for effective countermeasures. A better understanding of transmission events and dynamics between compartments (animals and humans) would be a critical guide to containment. We anticipate that a shared surveillance database between human and veterinary medicine coupled to state-of-the-art automated phylogenetic analysis will enable a more complete and detailed surveillance of MDR pathogens and generate actionable results for public health policy.Objective of the project:The main goal is to connect human and veterinary microbiology laboratories through a shared framework for near real-time molecular epidemiology of MDR bacterial pathogens, which will allow to perform transmission and outbreak surveillance between different species and the environement.

Specific aims include:

• Implementation of an active surveillance system using methicillin resistant Staphylococcus aureus (MRSA) as a proof-of-concept, which can be expanded to many other one-health related MDR pathogens.
• Continuous development of a highly flexible surveillance tool, which allows to incorporate molecular epidemiological data from whole genome sequencing (WGS) and important metadata information.
• Development of a semi-automated modelling tool to assess transmission rates between geographic locations, hospitals, communities, and species over time and space.
• Preparation for expansion with different other species including carbapenemase-producing Enterobacteriacea.
• Connection to international databases for global surveillance.

Approaches and methods

WGS data from different institutions (human outbreak typing data from USB, CHUV, HUG and from animals of VetSuisse) will be combined in a common database. As a basis for the development of the web interface and underlying database, http://nextstrain.org and PanGenome.ch will be adapted for bacteria and the Swiss context. We will design a database that allows upload of new sequences and metadata by different sites. This will be developed jointly by SIB experts in software development and bioinformatics, and the Neher Group at the Biozentrum who created NextStrain. The uploaded data will be automatically assessed for sequence quality and metadata consistency. In particular, USB, an ISO-accredited NGS facility for routine microbiology diagnos-tics, will provide the quality control tools and verify/biocurate the uploaded strains and metadata on a regular basis, in collaboration with SIB (via the competence center for biocuration). The award-winning phylogenetic analysis and visualization tool NextStrain (Open Science Award by NIH and Wellcome Trust) will be adapted to intuitively display metadata collected at the various study sites (e.g. time of isolation, geographical origin, species, screening vs. invasive, phenotypic resistance information). Moreover, state-of-the-art phylogenetic tools will by used to infer timetrees and transmission rates. The implementation will be tested with a broad collection of already WGSed MRSA isolates from Switzerland (WP2-3). During the project, MRSA isolates will be prospectively sequenced and added to the database while the analysis pipelines is rerun whenever new data is added (WP4).National and international cooperations envisaged: The establishement of a Swiss wide, scalable and flexible database for molecular epidemiology would allow to monitor different MDR pathogens in near real-time. Importantly, combining both animal and human isolates with geographic and phylogenic data will allow modelling the exchange rates between different hosts. Special attention will be devoted to ensure that genomes can also be analysed in a global context by comparing with existing databases such as BIGSdb, potentially contributing to global monitoring of MDR pathogens.

Timeframe and mile stones

• WP1: Functional specification – assess the needs of clinical microbiologists, veterinarians & researchers regarding the planned surveillance database
• WP2: Knowledge and data representation with tool implantation with retrospective MRSA data – define structured database and implement the tools
• WP3: Impact study with MRSA retrospective data – assess the impact of the surveillance system with MRSA retrospective data. Semi-automated tools provided by the surveillance database including time tree analysis within the cohort.
• WP4: Validation studies with prospective MRSA – extend to individual prospective MRSA projects for validation
• WP5: Release and dissemination to other partners – ensure the produced data are reusable by 3rd party tools and resources.

Expected benefit and possible applications of results

The framework will allow exchanging relevant molecular epidemiological data – thereby enabling a one Health surveillance system for the transmission of MDR pathogens between different species and environments. The detailed information on relevant strains would be interesting for various stakeholders: (i) human and animal microbiologists could better understand transmission routes and develop new prevention strategies at the most critical cross-points, (ii) public health authorities would have a near real-time surveillance tool for a detailed assessment and tracking of single strains but also large scale outbreaks, (iii) basic researchers could access the database and use the available WGS data to develop more complex transmission models, which go beyond an automated surveillance. The proposed initial proof-of-concept study with a focus on MRSA isolates is planned to be expanded to other MDR pathogens e.g. carbapenemase or mcr-1 positive Enterobacteriacea.