Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going?

Abstract

Purpose: Widespread antibiotic-resistant bacteria are threatening the arsenal of existing antibiotics. Not only are antibiotics less likely to be effective today, but their extensive use continues to drive the emergence of multidrug-resistant pathogens. A newold antibacterial strategy with bacteriophages (phages) is under development, namely, phage therapy. Phages are targeted bacterial viruses with multiple antibacterial effector functions, which can reduce multidrug-resistant infections within the human body. This review summarizes recent phage therapy clinical trials and patient cases and outlines the fundamentals behind phage treatment strategies under development, mainly through bench-to-bedside approaches. We discuss the challenges that remain in phage therapy and the role of phages when combined with antibiotic therapy. Methods: This narrative review presents the current knowledge and latest findings regarding phage therapy. Relevant case reports and research articles available through the Scopus and PubMed databases are discussed. Findings: Although recent clinical data suggest the tolerability and, in some cases, efficacy of phage therapy, the clinical functionality still requires careful definition. The lack of well-controlled clinical trial data and complex regulatory frameworks have driven the most recent human data generation on a singlepatient compassionate use basis. These cases often include the concomitant use of antibiotics, which makes it difficult to draw conclusions regarding the effectiveness of phages alone. However, human data support using antibiotics as phage potentiators and resistance breakers; thus, phage adjuvants are a promising avenue for near-term clinical development. Current knowledge gaps exist on the appropriate routes of administration, phage selection, frequency of administration, dosage, phage resistance, and pharmacokinetic and pharmacodynamic properties of the phages. In addition, we highlight that some phage therapies have mild adverse effects in patients. Implications: Although more translational research is needed before the clinical implementation is feasible, phage therapy may well be pivotal in safeguarding humans against antibiotic-resistant infections.

Combination ofin vivophage therapy data within silicomodel highlights key parameters for treatment efficacy

“…Despite many encouraging data from both ancient literature and recent compassionate treatments, phage therapy remains underexploited, notably because of ambiguous results from clinical trials (Luong et al, 2020). Indeed, the translation from in vitro to clinical conditions remains unmet, in particular because using phages as a drug requires a specific method to elaborate a rational scheme for safe and optimal administration.…”

Encapsulation and Delivery of Therapeutic Phages

“…Despite the numerous advancements in the preparation of phages for clinical applications, each route of administration represents its individual challenges (25). These include the stability of phage preparations, target-site specific delivery, as well as the antibody-mediated inactivation of phages and their clearance by the reticuloendothelial system of the recipient (26,27,28). To optimise the efficacy and delivery of phages, formulations for therapeutic phages are under constant development (29,30,31).…”

The Age of Phage: Friend or Foe in the New Dawn of Therapeutic and Biocontrol Applications?

“…While little evidence exists displaying any inherent toxicity associated with phage virions and potential anaphylactic immune responses, toxicity associated with impurities in phage preparations can pose an issue, although this can be minimized through proper phage purification [192,193]. In humans, treatment of various infections with phage administered via oral, superficial, intramuscular, or intravenous routes have been reported in different countries, and any apparent side effects were often minor or localized in nature [4,194,195]. Another benefit to the use of bacteriophages is that they are naturally sourced and highly abundant in a variety of environmental locations [3].…”