A semi-mechanistic Pharmacokinetic/Pharmacodynamic model for quantifying phage-antibiotic synergy against Pseudomonas aeruginosa

Multidrug-resistant (MDR) Pseudomonas aeruginosa is among the top three pathogens urgently needing new treatments. Phage therapy offers an alternative to antibiotics by auto-dosing and by targeting bacteria that are resistant to conventional antibiotics, and combining phages with antibiotics may overcome shortcomings of monotherapy. We developed a novel semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model based on static in vitro time-kill data evaluating ciprofloxacin (CIPRO; 0-128 µg/mL) and bacteriophage PEV31 (0.01-100 MOI) individually and in combination against MDR P. aeruginosa strain FADDI-PA001. Additionally, a Shiny-based interactive application was designed to simulate and visualize the impact of varying concentrations of phage and antibiotic treatments, facilitating real-time regimen optimization. Monotherapy with either CIPRO or PEV31 inhibited bacterial growth for less than 8 h before regrowth occurred; complete eradication was achieved only at high CIPRO concentrations (64 and 128 µg/mL). In combination (with CIPRO doses above 2 µg/mL), PEV31 and CIPRO acted synergistically, reducing bacterial levels below 102 CFU/mL at 24 h. The final PK/PD model which included a phage-bacteria-interaction term and implemented CIPRO's effect as a power-model successfully captured the observed time-kill-data for both monotherapy and combination therapy. These promising findings support further in vivo validation and mechanistic studies to advance combination therapy for MDR pathogens. Our integrated approach paves way for clinical translation.