A semi-mechanistic pharmacokinetic/pharmacodynamic model for quantifying phage-antibiotic synergy against Pseudomonas
Omar Assafiri1, Qixuan Hong1, Sandra Morales2
1Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
Background:
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.
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.
Insights
Combination therapy with bacteriophage PEV31 and ciprofloxacin (CIPRO) shows synergistic effects against multidrug-resistant Pseudomonas aeruginosa. This approach may overcome antibiotic resistance and pave the way for clinical translation.
Area of Science:
- Microbiology
- Pharmacology
- Bioinformatics
Background:
- Multidrug-resistant (MDR) *Pseudomonas aeruginosa* is a critical threat requiring novel therapeutic strategies.
- Phage therapy presents an alternative to antibiotics, with potential for synergistic effects when combined with conventional antimicrobials.
Purpose of the Study:
- To develop and validate a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for evaluating combination therapy of ciprofloxacin (CIPRO) and bacteriophage PEV31 against MDR *P. aeruginosa*.
- To create an interactive application for simulating and optimizing phage-antibiotic treatment regimens.
Main Methods:
- A semi-mechanistic PK/PD model was developed using *in vitro* time-kill data.
- Bacteriophage PEV31 and ciprofloxacin were tested individually and in combination against MDR *P. aeruginosa* strain FADDI-PA001.
- A Shiny-based application was used to simulate treatment outcomes.
Main Results:
- Monotherapy with CIPRO or PEV31 resulted in transient bacterial inhibition with subsequent regrowth.
- Combination therapy demonstrated synergistic effects, reducing bacterial levels below 102 CFU/mL at 24 hours when CIPRO concentrations exceeded 2 µg/mL.
- The developed PK/PD model accurately captured time-kill data for both monotherapy and combination treatments.
Conclusions:
- The synergistic activity of PEV31 and CIPRO supports further *in vivo* studies for MDR pathogen treatment.
- This integrated modeling approach shows promise for the clinical translation of phage-antibiotic combination therapies.
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