Phage Therapy: Considerations and Challenges for Development

Bacteriophage therapy (phage therapy) involves the use of live, lytic bacteriophages to treat bacterial infections via bacterial cell lysis. Lytic bacteriophages mediate their antimicrobial effect by way of specific attachment to bacterial cell wall receptors, injection of bacteriophage DNA into the bacterium, recruitment of bacterial host cell machinery for bacteriophage protein production, and subsequent lysis of the bacterial cell with release of bacteriophage progeny [1, 2]. Phage therapy has a century-old origin [3], and while the interest in this treatment modality waned with the development of antibiotics, medical practice in some Eastern European countries has continued the clinical use of phage therapy. The emergence of multidrug-resistant (MDR) bacterial infections has renewed interest in phage therapy [2, 4]. However, published data in the English literature on controlled trials of phage therapy that rigorously measure safety and efficacy are sparse. In addition to the potential for phage therapy to treat MDR bacterial infections, some of the proposed benefits of phage therapy include the reduced risks of drug interactions between antibiotics and other medications, avoidance of antibiotic toxicities, and the prospects of retained activity in the presence of biofilms [5–7]. Concerns with phage therapy can include the potential for transduction of genetic material to the microbiome, such as virulence factors or genes that confer antibiotic resistance; development of bacterial resistance to the phage; and rapid release of endotoxin due to bacterial cell lysis [2, 7, 8]. Data that address these concerns are important to advance product manufacturing and evaluation of phage therapy products in controlled clinical trials. The Office of Vaccines Research and Review (OVRR) within the Center for Biologics Evaluation and Research at the US Food and Drug Administration regulates the evaluation of investigational bacteriophages for infectious diseases indications. OVRR reviews information regarding the composition, manufacture, and control of investigational bacteriophages and protocols for planned clinical studies of phage therapy within the regulatory framework for biological products. In this issue, Dufour et al [9] present comparative in vitro data on endotoxin release (ER) during bacterial cell lysis after exposure to bacteriophages in order to address one of the clinical safety concerns of phage therapy. The authors measured ER, metabolic growth, and cell viability of 2 pathogenic Escherichia coli strains over 180 minutes following exposure to bacteriophages, β-lactam antibiotics, or amikacin. While bacterial cell growth and the number of metabolically active cells decreased faster after exposure to bacteriophage than to β-lactam antibiotics, the cumulative endotoxin concentrations were higher in the β-lactam–treated bacterial strains than in either the amikacinor bacteriophage-treated strains. Amikacinand bacteriophage-treated strains produced similar concentrations of endotoxin and exhibited a greater decrease in metabolically active cells than the β-lactam–treated strains. The authors state that their study provides novel data regarding ER that may occur with phage therapy but acknowledge that the in vivo relevance of the study findings may be limited. Bacteria–bacteriophage interactions in the context of active infection and the human immune system involve complexities that are not easily reproduced in vitro. In transitioning the study of phage therapy from the bench to the clinic, issues to be considered include product composition, mode of administration, and the underlying disease (including site of infection). Since bacteriophages replicate only in the presence of their host bacteria, first-in-human data with phages in healthy participants may not address safety concerns that are unique to bacteriophage–bacteria interaction in the setting of active infection, such as tolerability of therapy, immune response to therapy, and ER. Assessment of bacteriophage pharmacokinetics and pharmacodynamics in otherwise healthy patients who are colonized by the target strain(s) may provide some insights, such as the E D I T O R I A L C O M M E N T A R Y Head1=Head2=Head1=Head2/ Head1