Reapproaching Old Treatments: Considerations for PK/PD Studies on Phage Therapy for Bacterial Respiratory Infections

Abstract

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 preclinical 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.

Palmitic Amide Triggers Virus Life Cycle via Enhancing Host Energy Metabolism

“…It is estimated that 10 24 genes are shuttled from viruses to hosts each year, which indicates that the viruses may be a major source of genetic creativity ( Dennehy, 2014 ). The knowledge about the process of virus infection is first obtained from bacteriophages (phages) ( Sharma et al, 2017 ; Schmalstig et al, 2021 ). During the phage infection, the first step for phage infection is the interaction between phages and the receptors on its host cells ( Schmalstig et al, 2021 ).…”

“…The knowledge about the process of virus infection is first obtained from bacteriophages (phages) ( Sharma et al, 2017 ; Schmalstig et al, 2021 ). During the phage infection, the first step for phage infection is the interaction between phages and the receptors on its host cells ( Schmalstig et al, 2021 ). The tail protein of phages would degrade the cell wall of bacteria and the genomic nucleotide acids of phages are injected into the host cells ( Schmalstig et al, 2021 ).…”

“…During the phage infection, the first step for phage infection is the interaction between phages and the receptors on its host cells ( Schmalstig et al, 2021 ). The tail protein of phages would degrade the cell wall of bacteria and the genomic nucleotide acids of phages are injected into the host cells ( Schmalstig et al, 2021 ). The subsequent replication strategy of phage can be classified into virulent or template phage ( Howard-Varona et al, 2017 ).…”

“…The subsequent replication strategy of phage can be classified into virulent or template phage ( Howard-Varona et al, 2017 ). In the lytic cycle of phages, the phages utilize the machinery of hosts to complete the replication of viral genomes and the assembly of virions ( Schmalstig et al, 2021 ). At present, it has been well characterized that the infecting phage must transmit its genome out of the viral particle and into the cytoplasm of host cell ( Weaver, 2012 ; Cumby et al, 2015 ; Schmalstig et al, 2021 ).…”

“…In the lytic cycle of phages, the phages utilize the machinery of hosts to complete the replication of viral genomes and the assembly of virions ( Schmalstig et al, 2021 ). At present, it has been well characterized that the infecting phage must transmit its genome out of the viral particle and into the cytoplasm of host cell ( Weaver, 2012 ; Cumby et al, 2015 ; Schmalstig et al, 2021 ). However, it remains unknown whether any other components, such as metabolites, are packaged in the virions and transmitted into the host cells along with the viral genomes to initiate the virus life cycle.…”