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Background: Despite the extensive use of antibiotics and the growing challenge of antimicrobial resistance, there has been a lack of substantial initiatives aimed at diminishing the prevalence of infections in nursing homes and enhancing the detection of urinary tract infections (UTIs)., Objective: This study aims to systematize and enhance efforts to prevent health care-associated infections, mainly UTIs and reduce antibiotic inappropriateness by implementing a multifaceted intervention targeting health care professionals in nursing homes., Methods: A before-and-after intervention study carried out in a minimum of 10 nursing homes in each of the 8 European participating countries (Denmark, Greece, Hungary, Lithuania, Poland, Slovakia, Slovenia, and Spain). A team of 4 professionals consisting of nurses, doctors, health care assistants, or health care helpers are actively involved in each nursing home. Over the initial 3-month period, professionals in each nursing home are registering information on UTIs as well as infection and prevention control measures by means of the Audit Project Odense method. The audit will be repeated after implementing a multifaceted intervention. The intervention will consist of feedback and discussion of the results from the first registration, training on the implementation of infection and prevention control techniques provided by experts, appropriateness of the diagnostic approach and antibiotic prescribing for UTIs, and provision of information materials on infection control and antimicrobial stewardship targeted to staff, residents, and relatives. We will compare the pre- and postintervention audit results using chi-square test for prescription appropriateness and Student t test for implemented hygiene elements., Results: A total of 109 nursing homes have participated in the pilot study and the first registration audit. The results of the first audit registration are expected to be published in autumn of 2024. The final results will be published by the end of 2025., Conclusions: This is a European Union-funded project aimed at contributing to the battle against antimicrobial resistance through improvement of the quality of management of common infections based on evidence-based interventions tailored to the nursing home setting and a diverse range of professionals. We expect the intervention to result in a significant increase in the number of hygiene activities implemented by health care providers and residents. Additionally, we anticipate a marked reduction in the number of inappropriately managed UTIs, as well as a substantial decrease in the overall incidence of infections following the intervention., International Registered Report Identifier (irrid): DERR1-10.2196/60099., (©Ana García-Sangenís, Daniela Modena, Jette Nygaard Jensen, Athina Chalkidou, Valeria S Antsupova, Tina Marloth, Anna Marie Theut, Beatriz González López-Valcárcel, Fabiana Raynal, Laura Vallejo-Torres, Jesper Lykkegaard, Malene Plejdrup Hansen, Jens Søndergaard, Jonas Kanstrup Olsen, Anders Munck, András Balint, Ria Benko, Davorina Petek, Nina Sodja, Anna Kowalczyk, Maciej Godycki-Cwirko, Helena Glasová, Jozef Glasa, Ruta Radzeviciene Jurgute, Lina Jaruseviciene, Christos Lionis, Marilena Anastasaki, Agapi Angelaki, Elena Petelos, Laura Alvarez, Marta Ricart, Sergi Briones, Georg Ruppe, Ramon Monfà, Anders Bjerrum, Carl Llor. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.09.2024.)