Reapproaching old treatments: considerations for PK/PD studies on phage therapy for bacterial respiratory infections

Antibiotic resistant bacterial respiratory infections are a significant global health burden, and new therapeutic strategies are needed to control the problem. For bacterial respiratory infections, this need is emphasized by the rise in antibiotic resistance and a lean drug development pipeline. Bacteriophage (phage) therapy is a promising alternative to antibiotics. Phage are viruses that infect and kill bacteria. Because phage and antibiotics differ in their bactericidal mechanisms, phage are a treatment option for antibiotic resistant bacteria. Here, we review the history of phage therapy and highlight recent pre-clinical and clinical case reports of its use for treating antibiotic resistant respiratory infections. The ability of phage to replicate while killing the bacteria is both a benefit for treatment and a challenge for pharmacokinetic (PK) and pharmacodynamic (PD) studies. In this review, we will discuss how the phage lifecycle and associated bidirectional interactions between phage and bacteria can impact treatment. We will also highlight PK/PD considerations for designing studies of phage therapy to optimize the efficacy and feasibility of the approach.