A Novel Metric for Quantifying the Sustainability of Phage-Mediated Bacterial Suppression

<jats:p>The global spread of antimicrobial-resistant (AMR) bacteria represents one of the greatest threats to modern medicine, making the development of novel therapeutic strategies urgent. Phage therapy, which exploits bacteriophages (phages, viruses that infect and kill bacteria) has regained attention as a therapeutic approach for multidrug-resistant infections. One critical determinant of treatment outcome is the capacity of phages to sustain bacterial growth suppression; however, no metric has existed to directly quantify the duration of effective lytic activity. Here, we propose the Sustainability Index (SusI), a novel metric that quantifies both the duration and extent of phage-mediated bacterial growth suppression, restricted to the primary lysis period from lysis initiation to resistance emergence. Evaluation of individual phages and two-phage cocktails against both laboratory and clinical isolates of Escherichia coli demonstrated that SusI provides information independent of the Virulence Index, which primarily reflects bactericidal activity during the initial phase of infection, and serves as a complementary metric to the Suppression Index, which may incorporate behavior beyond primary lysis. Cocktails composed of phages targeting different receptor specificities consistently exhibited higher SusI values, consistent with the notion that multifaceted selective pressure delays resistance emergence. Furthermore, in a mouse model of systemic infection established by intraperitoneal administration, cocktails with higher SusI values demonstrated superior therapeutic efficacy. These results confirm SusI as a practical metric for rational phage cocktail design. As phage therapy advances toward clinical implementation, standardized quantitative metrics such as SusI are expected to facilitate evidence-based selection of therapeutic phages across diverse pathogens and infection conditions.</jats:p>