Strain-dependent variability in pharmacodynamic interactions for phage-antibiotic combinations in Pseudomonas aeruginosa

OBJECTIVE: Phage and antibiotics are routinely used in combination and offer the potential to enhance treatment outcomes through synergistic drug effects. Given the increasing therapeutic use of phages, it is important to evaluate whether antibiotic-phage interactions vary among bacterial strains. METHODS: We performed a systematic quantitative analysis of phage-antibiotic pharmacodynamic interaction effects for a panel of nine clinical Pseudomonas aeruginosa strains and six antibiotics using a lytic Pbunavirus phage. To this end, we performed bacterial growth profiling for a range of antibiotic and phage concentrations using optical density measurements. We applied a mathematical general pharmacodynamic interaction model to quantify bidirectional concentration-dependent phage-antibiotic interaction effects on antibiotic sensitivity. RESULTS: For all tested antibiotics, phage-antibiotic treatments consistently decreased the sensitivity towards phage, whereas the presence of phage increased the sensitivity for aztreonam, colistin, and meropenem for almost all nine bacterial strains. Between ciprofloxacin and phage, strong antagonistic interactions were observed as was high variability among strains. In contrast, the sensitivity towards amikacin and ceftazidime exhibited divergent strain-specific interaction effects with both increases and decreases in the presence of phage. CONCLUSIONS: In conclusion, the current study highlights the importance of considering strain-specific variability in antibiotic-phage interaction effects, which underscores the need for personalized treatment strategies to select optimal combinations of antibiotics and phages.