Modeling Phage-Antibiotic Synergy, Innate Immunity, and Phage Resistance in Multidrug-Resistant Acinetobacter baumannii.

Background/

Objectives

Antimicrobial resistance has been recognized as a major global health threat, with multidrug-resistant Acinetobacter baumannii identified as one of the most critical pathogens. To address the limitations of conventional antibiotics, phage therapy has been proposed as a complementary or alternative intervention. In this study, experimental data were integrated into a deterministic differential-equation-based model to capture phage-bacteria-antibiotic-host immune system interactions.

Methods

The model extended a previous phage-host immune system synergy framework by incorporating phage-antibiotic synergy and a time-dependent reduction in phage adsorption as a phenomenological representation of population-level reduction in phage susceptibility. This formulation does not explicitly model the molecular mechanisms or evolutionary emergence of resistance. In vitro observations of phage-induced resensitization to ceftazidime informed model parameterization, while remaining parameters were estimated from experimental observations or literature values. Simulations evaluated bacterial dynamics under phage-only, antibiotic-only, and immunity-only conditions, as well as combined therapeutic scenarios.

Results

Model predictions indicated the greatest bacterial reduction when phages, antibiotics, and host innate immunity acted together. Phage-antibiotic synergy further enhanced predicted bacterial clearance, particularly for ceftazidime-resistant populations, while a population-level reduction in phage susceptibility was predicted approximately 4 h post-infection, consistent with experimental observations. Combined scenarios involving continuous antibiotic infusion, phage plus host immunity, or low-dose antibiotic regimens predicted accelerated bacterial declines when synergistic interactions were active.

Conclusions

This framework integrates experimental observations with mathematical modeling to explore therapeutic interactions and temporal changes in phage susceptibility, while assessing parameter sensitivity and guiding future experimental and preclinical studies.