Large scale phage-antibiotic combination studies reveal key combinations for urinary tract infection and urosepsis treatments

Abstract The growing problem of AMR infections in healthcare has prompted the search for alternative treatments, with increasing interest in bacteriophages. However, most bacteriophage-antibiotic interactions are incompletely understood, and the benefits of combining them remains context dependent. In this study, we screened thousands of phage-antibiotic combinations to assess interaction outcomes in clinical E. coli and K. pneumoniae isolates. By integrating bacteriophages into an existing, scalable clinical MIC determination platform, we identified shifts in antibiotic MIC and susceptibility, revealing patterns of additivity and antagonism. Overall, interactions showed a species-specific profile; additive interactions predominated, particularly for E. coli . Hierarchical clustering highlighted frequent positive interactions between β-lactams and Tequatroviruses. Notably, closely related phages sometimes displayed divergent phenotypes, indicating that interaction outcomes cannot be inferred solely from taxonomic relatedness or genomic similarity. Taken together, these results establish a foundation for rational, evidence-based development of phage-antibiotic therapies to restore and broaden treatment options against multidrug-resistant infections.