The research and development pipeline of therapeutic interventions and vaccines effective against WHO critical priority Enterobacterales spp.: a horizon scanning review and implications for policy and research

<strong>Background:</strong> In 2019 the World Health Organization (WHO) labelled anti-microbial resistance (AMR) as one of the biggest global public health threats. Despite this, ongoing concerns exist about the rising burden of resistant bacterial infections and mortality and an insufficient research and development pipeline. Among resistant bacterial organisms, the Enterobacterales genus has been highlighted as a critical priority for research and development by the WHO 2024 bacterial priority pathogens list. <strong>Aims and Objectives:</strong> The aim of this horizon scanning review was to systematically identify and assess the state of the research and development pipeline of therapeutic agents and vaccines effective against 3^rd generation cephalosporin-resistant and carbapenem-resistant Enterobacterales since the WHO classified them as a critical priority pathogen in 2017. <strong>Methods:</strong> Biomedical databases, including Embase and MEDLINE (OVID), clinical trial repositories from the Cochrane CENTRAL database, clinical trial registers, and grey literature sources, were systematically searched for randomised controlled trials of therapeutic interventions and vaccines that target or are effective against Enterobacterales registered or published between 01.01.2017 and 01.06.2024. Data relating to investigational compound development was extracted and categorised based on the type of intervention to map the research and development pipeline. <strong>Results:</strong> Our search strategy identified a total of 9783 records. From these records, 58 unique agents were identified. Of these, 17 were antibiotics, 13 were novel beta-lactamase inhibitors in combination with antibiotics already approved for clinical use, 12 were vaccines and 16 other interventions were identified. Overall, 60% of research and development was initially led by small to medium-sized enterprises, with 81% of development in high-income countries. Based on our analysis, 24% of the pipeline was discontinued, and only 12% reached market approval. Currently, 47% of the active pipeline consists of interventions in phase I. When combined with previous analyses of drug progression through the clinical trial pipeline, our results suggest that 12 novel therapeutic interventions and five vaccines effective against Enterobacterales are predicted to become available for clinical use in the next five years. <strong>Conclusion:</strong> Our horizon scanning review of the research and development pipeline targeting Enterobacterales, and historical clinical drug development success rates suggests that the current pipeline is insufficient to address the increasing burden of AMR-related morbidity and mortality due to Enterobacterales. Future policies targeting AMR must focus on providing financial support for small and medium-sized enterprises, prioritising the development of effective vaccines, and ensuring equitable global access and distribution of newly approved therapeutic and preventative interventions.