Implementation strategy modifications: An applied multi-site comparison using ERIC and FRAME-IS for the “Fluoroquinolone Restriction for the Prevention of <i>Clostridioides difficile</i> infection Trial” (FIRST)

Background: infection (FIRST) trial as case studies. Methods: FIRST was a multisite fluoroquinolone pre-prescription restriction intervention delivered via the electronic health record. We partnered with multidisciplinary stakeholders at each site to co-design and adapt the intervention using pre-planned implementation strategies. Multiple data sources (interviews, meeting notes, implementation diaries) collected iteratively over two years were analyzed to identify strategy modifications. Strategies were coded using Expert Recommendations for Implementing Change (ERIC) conceptual clusters, and modifications were documented using the Framework for Reporting Adaptations and Modifications to Evidence-Based Implementation Strategies (FRAME-IS). Modified strategies were categorized as planned or unplanned and contextualized via thematic content analysis. Results: Across 458 total modifications, the most modified strategies focused on facilitating stakeholder engagement, adapting to local contexts, and using evaluative approaches to improve EBP uptake/sustainment. Planned modifications (n=330, 72%) outnumbered unplanned modifications (n=157, 34%). Rural and community hospitals required more unplanned modifications (average 41 vs. 31 for academic centers), while sites with prior restrictive intervention experience had higher planned-to-unplanned ratios (3.1:1 vs. 1.6:1). Academic hospitals with trainee rotations required ongoing education and higher strategy modifications. All modifications maintained EBP core fidelity. Site-specific patterns organizational characteristics were linked to modification intensity and type, including absorptive capacity, prior experience, relational coordination, rurality, and educational requirements. Conclusions: Integrating ERIC and FRAME-IS enabled systematic documentation of implementation strategy modifications across diverse settings. Planned:unplanned modification ratios provided novel insights into organizational absorptive capacity and implementation preparedness. Standardized implementation approaches inadequately address critical organizational differences, requiring context-sensitive strategy selection and intensity calibration. This work advances implementation science methodology by demonstrating how systematic modification documentation can inform tailored implementation support. Trial Registration: ClinicalTrials.gov Identifier: NCT03848689.