Modeling and Optimizing Treatments of Bacterial Infections by Phage and Phage-Antibiotic Combinations*

The spread of antibiotic-resistant pathogens is a global threat to public health. As such, there is growing interest in alternative antimicrobials including phage, or viruses that only infect bacteria. However, phage therapy has shown inconsistent efficacy in clinical trials, possibly due to heterogeneity in the host immune response. By combining nonlinear population models and animal experiments, we have shown that host immunity can work synergistically with phage to cure an acute respiratory infection. Nonetheless, phage therapy could still fail when phage resistance is high. In such cases, we consider two strategies proposed to enhance the robustness of phage therapy: combining phage with antibiotics and combining different strains of phage (phage cocktail). Our model predicts that host immunity is also required for the efficacy of phage-antibiotic combinations. Finally, we discuss applications of optimal control theory to optimize the dosing and composition of single phage and phage cocktail therapy, and opportunities to extend findings to application of phage therapy to complex spatial environments.