Phage-antibiotic therapy under density dependent bacterial defenses

TL;DR

This paper develops a mathematical model to analyze phage therapy effectiveness against bacteria, considering bacterial social defenses, immune response, and antibiotics, revealing conditions for successful bacterial suppression and oscillations.

Contribution

It introduces a comprehensive mathematical model incorporating bacterial social defenses, immune response, and antibiotics to evaluate phage therapy efficacy.

Findings

Phages destabilize bacterial growth equilibria, aiding immune suppression.

Oscillations can occur but generally lead to minimal bacterial populations.

Combination therapy with antibiotics enhances bacterial suppression.

Abstract

Phage therapy is an alternative treatment method for bacterial infections. It has shown particular promise in reducing bacterial load while preventing antibiotic resistance. Here, we develop a mathematical model of a bacterial infection within a host to study phage therapy. It incorporates interactions between phages, bacteria, the immune system, and antibiotics. Additionally, the model includes bacterial social dynamics that provide protection from treatments and the innate immune response. We analytically and numerically identify all of the equilibria of the model and derive insights regarding the overall effectiveness of phage therapy. Without phage therapy, the model exhibits bistability: bacteria populations above a threshold grow and become entrenched, while those below it can be effectively suppressed by the immune system. We find that that phages destabilize the former equilibrium, and thus in combination with the immune system are able to suppress the bacteria. We conducted bifurcation analyses, which show that the equilibrium with a suppressed population of bacteria can become unstable. In this scenario, the system undergoes oscillations. However, these oscillations -- which can be exacerbated by social dynamics -- lead to minuscule bacterial populations, and thus, in practice, phage therapy is widely effective across the parameter space. We also demonstrate how suppression can be further improved by the addition of periodic dosing of antibiotics in a combination therapy.