Interaction Tolerance Detection Test for Understanding the Killing Efficacy of Directional Antibiotic Combinations

Combination treatments are commonly prescribed for enhancing drug efficacy, as well as for preventing the evolution of resistance. The interaction between drugs is typically evaluated near the MIC, using growth rate as a measure of treatment efficacy. However, for infections in which the killing activity of the treatment is important, measurements far above the MIC are needed. In this regime, the killing rate often becomes weakly concentration dependent, and a different metric is needed to characterize drug interactions. We evaluate the interaction metric on killing using an easy visual assay, the interaction tolerance detection test (iTDtest), that estimates the survival of bacteria under antibiotic combinations. We identify antibiotic combinations that enable the eradication of tolerant bacteria. Furthermore, the visualization of the antibiotic interactions reveals directional drug interactions and enables predicting high-order combination outcomes, therefore facilitating the determination of optimal treatments.