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While wastewater is understood to be a critically important reservoir of antimicrobial resistance due to the presence of multiple antibiotic residues from industrial and agricultural runoff, there is little known about the effects of antibiotic interactions in the wastewater on the development of resistance. We worked to fill this gap in quantitative understanding of antibiotic interaction in constant flow environments by experimentally monitoring E. coli populations under subinhibitory concentrations of combinations of antibiotics with synergistic, antagonistic, and additive interactions. We then used these results to expand our previously developed computational model to account for the effects of antibiotic interaction. We found that populations grown under synergistic and antagonistic antibiotic conditions exhibited significant differences from predicted behavior. E. coli populations grown with synergistically interacting antibiotics developed less resistance than predicted, indicating that synergistic antibiotics may have a suppressive effect on resistance development. Furthermore E. coli populations grown with antagonistically interacting antibiotics showed an antibiotic ratio-dependent development of resistance, suggesting that not only antibiotic interaction, but relative concentration is important in predicting resistance development. These results provide critical insight for quantitatively understanding the effects of antibiotic interactions in wastewater and provide a basis for future studies in modelling resistance in these environments., (© 2023. The Author(s).)