SPARK: Systematic Profiling of Antibiotic-Phage Response Kinetics

Phage therapy is, in practice, combination therapy: phage are almost always added to an ongoing antibiotic regimen, yet the combination is rarely designed to have a specific interaction pattern. Interactions can be antagonistic, additive or synergistic and cannot be inferred from either agent alone. Here we introduce SPARK, a method which quantifies phage antibiotic interaction from growth curves as the integrated deviation of observed growth from the growth expected under Bliss independence. We profiled 42 combinations spanning the ESKAPE pathogens and Escherichia coli with twelve antibiotics. We show that i) synergy and antagonism are resolvable within a single high-throughput assay, with the interaction determined by the phage antibiotic bacteria pairing; ii) 21 clinical Staphylococcus aureus isolates differ among themselves as widely as the seven species do; and, iii) interactions change between a few hours and two days, several reversing direction. Overall, SPARK needs only a plate reader and the analysis is performed with a specific openly available web tool.