Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches

Abstract

Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.

Figure 1. Development and implementation of phage therapy.

(A) A summary of the key steps in phage therapy development and clinical implementation. The process typically begins with phage identification and selection, including phage bank establishment (sourcing, storage, and characterization of phages), followed by susceptibility testing (using spot tests, plaque assays, efficiency of plating [EOP] assays, and growth kinetics studies). The manufacturing phase involves phage propagation (using selected bacterial strains in liquid- or solid-based systems) and rigorous purification with quality control measures (including endotoxin removal and standardized quality protocols). The therapeutic administration phase encompasses clinical applications (considering various administration routes and dosing strategies) and therapeutic monitoring (tracking treatment efficacy, patient response, and monitoring for potential resistance development and adverse events). Note that these steps are not universally applied in all phage therapies. (B) Phage therapy approaches can be personalized to individual patients (patient-specific phage preparation), fixed (preformulated), or administered as a hybrid of the two approaches. The hybrid model represents an intermediate approach combining elements of both personalized and fixed phage therapy strategies.

Figure 2. Gaps in phage therapy through the perspective of a drug development pipeline.

The drug development pathway consists of three major phases: lead discovery and optimization, preclinical development, and clinical development. In lead discovery and optimization, key areas requiring further research include phage cocktail design (understanding phage host range and phage-phage interactions), phage-antibiotic interactions (investigating both synergistic and antagonistic effects), and genomic engineering (developing phage genomic editing techniques and synthetic phage genomes). Preclinical development encompasses in vitro studies (focusing on phage stability), in vivo studies (addressing formulation for delivery and phage pharmacology), and toxicity tests (evaluating toxicity pathways and dose-response models). The clinical development phase involves multiple critical components: establishment of manufacturing processes, regulatory review and approval procedures, safety monitoring protocols, optimization of dosage and duration regimens, efficacy evaluation, and postrelease monitoring. Addressing these knowledge gaps will be necessary for successful implementation of clinical phage therapy and to broaden applications for phage-based strategies.