Hydrogels for Local and Sustained Delivery of Bacteriophages to Treat Wound Infections.

Bacteriophages (phages) are viruses that specifically target and kill bacteria, serving as a promising therapeutic to combat multidrug-resistant (MDR) pathogens such as Pseudomonas aeruginosa (Pa). However, delivering adequate concentrations of active phages directly to the infection site over sufficient times to eradicate infections remains an outstanding challenge to phage therapy (PT). Here we present "HydroPhage", a biocompatible hydrogel system for the sustained release of high-titre phages to effectively treat infections caused by MDR pathogens. We develop injectable hydrogels comprised of hyaluronic acid (HA) and polyethylene glycol (PEG) crosslinked through static covalent thioether bonds and hemithioacetal-based dynamic covalent crosslinks (DCC), which encapsulate phages at concentration up to 1011 PFU per mL gel, and achieve sustained release over a week with more than 60% total phage recovery. In a preclinical mouse model of extended wound infection, we demonstrate enhanced bacterial clearance compared to intravenous treatment. Thus, using hydrogels for local and sustained delivery of phage may represent an effective approach to eradicating MDR infections broadly.

Phage Therapy for Respiratory Infections: Opportunities and Challenges.

We are entering the post-antibiotic era. Antimicrobial resistance (AMR) is a critical problem in chronic lung infections resulting in progressive respiratory failure and increased mortality. In the absence of emerging novel antibiotics to counter AMR infections, bacteriophages (phages), viruses that infect bacteria, have become a promising option for chronic respiratory infections. However, while personalized phage therapy is associated with improved outcomes in individual cases, clinical trials demonstrating treatment efficacy are lacking, limiting the therapeutic potential of this approach for respiratory infections. In this review, we address the current state of phage therapy for managing chronic respiratory diseases. We then discuss how phage therapy may address major microbiologic obstacles which hinder disease resolution of chronic lung infections with current antibiotic-based treatment practices. Finally, we highlight the challenges that must be addressed for successful phage therapy clinical trials. Through this discussion, we hope to expand on the potential of phages as an adjuvant therapy in chronic lung infections, as well as the microbiologic challenges that need to be addressed for phage therapy to expand beyond personalized salvage therapy.

The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.

With the increasing prevalence of antimicrobial-resistant bacterial infections, there is great interest in using lytic bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of intravenously administered bacteriophage in uninfected mice. A single dose of LPS-5, an antipseudomonal bacteriophage recently used in human clinical trials, was administered intravenously to both wild-type BALB/c and neutropenic ICR mice. Phage concentrations were assessed in peripheral blood and spleen at 0.5, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance is only minimally affected by neutropenia. Indeed, the half-life of phages in blood in BALB/c and ICR mice is 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that substantial functional inactivation of circulating phages occurs over time. These data indicate that circulating factors, but not neutrophils, inactivate intravenously administered phages.