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

Abstract

Background: ultidrug-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.

Research design and methods: 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.

Results: 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.

Conclusions: 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.