Previously, successful antimicrobial stewardship (AS) approaches were described. There is currently no standardized operational approach to developing and implementing successful AS interventions. Concomitant vancomycin and piperacillin-tazobactam use (CVPTU) for more than 48 hours at Vanderbilt University Medical Center (VUMC) declined considerably from 2015 to 2019. Researchers examined the interventions that resulted in this shift and developed a model to guide future intervention development and planning. Adult admissions at VUMC were assessed for CVPTU from January 2015 to August 2019. The primary outcome, the percentage of admissions getting CVPTU for more than 48 hours, was assessed using statistical process control charts. To evaluate the potential intensity and effects of these changes associated with successful change during this time period and to identify guiding principles for the development of future initiatives, the researchers developed the Three Antimicrobial Stewardship E’s (TASE) framework and the Association between Stewardship Interventions and Intended Results (ASIR) analysis. The average monthly percentage of admissions getting CVPTU decreased from 4.2 to 0.7%. Over the course of 8 time periods, the researchers found 4 with high intervention intensity, 3 with moderate intervention intensity, and one with low intervention intensity. Throughout, continuous AS education at the provider level was present. The most significant reduction in CVPTU and lasting prescribing practice changes occurred after the creation and dissemination of division and department algorithms, as well as reinforcement via computerized provider order entry sets. The TASE framework and ASIR analysis highlighted critical interventions and strategies for effecting and maintaining change at VUMC. More research is needed to confirm the framework’s efficacy as a tool for designing stewardship interventions at the institution and others.