In vivo assessment and optimization of phage PK/PD for the treatment of pulmonary Mycobacterium abscessus infection

Nontuberculous mycobacteria (NTM) are environmental bacteria that cause serious pulmonary infections in people with underlying lung diseases. One of the most common NTMs associated with pulmonary disease is Mycobacterium abscessus (Mabs). Mabs is highly drug resistant, and it is the most difficult NTM to treat. The therapeutic use of bacteriophage (phage), which are viruses that infect and kill bacteria, is a potential alternative to antibiotics for treating drug resistant bacteria including Mabs. Recent compassionate use cases where NTM disease was treated with phage, highlight the potential for phage to be a new therapeutic option for Mabs infection. At the same time, the recent cases emphasize the need to better understand and improve the approach of using phage to treat Mabs infection. Phage dosing in the recent Mabs treatment cases was performed without knowledge of in vivo phage exposure over time (pharmacokinetics, PK) or the impact of phage on the Mabs burden (pharmacodynamics, PD). For any bacterial infection, knowledge of phage PK/PD, which differs from traditional small molecule PK/PD, is minimal. This R01 proposal addresses this significant gap in knowledge. Using a Mabs isolate and phage from recent clinical cases and a mouse lung infection model, we will perform the first in vivo PK/PD studies of phage therapy to treat Mabs infection. Time course PK/PD data, along with pathology, spatial analysis of phage and Mabs localization in the lung, and respiratory function data, will be used to develop an in silico quantitative systems pharmacology (QSP) model that describes in vivo interactions between phage, Mabs, and the host. With the aid of phage PK/PD knowledge we will also systematically investigate different phage dosing strategies to optimize phage treatment and improve therapeutic outcome. In Aim 1, we will evaluate PK/PD of phage delivered via the intravenous (IV) route or intratracheal (IT) route. In Aim 2, we will evaluate the PK/PD of liposome-encapsulated phage. Liposome encapsulation may help target phage to macrophages, which serve as an intracellular niche for Mabs, and it may shield phage from host clearance or inactivation. In Aim 3, we will evaluate the effect on phage PK/PD of combining phage with antibiotic drug treatment. The results of these Aims will provide mechanistic insights into interactions between phage, Mabs, host, and antibiotic and they will support our long-term objective of using QSP modeling to promote translation of phage therapy for Mabs infection to successful use in the clinic.