The role of regulated clinical trials in the development of bacteriophage therapeutics

Abstract

Antibiotic resistance is now recognized as a major, global threat to human health and the need for the development of novel antibacterial therapies has become urgent. Lytic bacteriophages (phages) targeting individual bacterial pathogens have therapeutic potential as an alternative or adjunct to antibiotic use. Bacteriophage therapy has been used for decades, but clinical trials in this field are rare, leaving many questions unanswered as to its effectiveness for many infectious diseases. As a consequence bacteriophage therapy is not used or accepted in most parts of the world. The increasing need for new antimicrobial therapies is driving the development of bacteriophage therapies for a number of diseases but these require the successful completion of large-scale clinical trials in accordance with US FDA or European EMA guidelines. Bacteriophages are considered as biological agents by regulatory authorities and they are managed by biological medicinal products guidelines for European trials and guidelines of the division of vaccines and related product applications in the USA. Bacteriophage therapy is typically an ‘active’ treatment requiring multiplication in the bacterial host and therefore the factors that govern its success are different from those of conventional antibiotics. From the pharmacokinetic and pharmacodynamic points of view, time of treatment, dosage depending on the site of infection and the composition of the bacteriophage formulation (single vs multiple strains) need careful consideration when designing clinical trials. Scientific evidence regarding inflammatory effects, potential for gene transfer and phage resistance, need to be evaluated through such trials. However purity, stability and sterility of preparations for human use can be addressed through Good Manufacturing Practises to reduce many potential safety concerns. In this review we discuss the potential for the development of bacteriophage therapy in the context of critical aspects of modern, regulated clinical trials.

Therapeutic Potential of Staphylococcal Bacteriophages for Nasal Decolonization of <i>Staphylococcus aureus</i> in Mice

“…Here, we examined phage K alone, and together with 44AHJD as a cocktail, for activity against S. aureus isolates that represented highly virulent, antibiotic-resistant, and genetically diverse strains. This established that the therapeutic potential of phages is improved as part of a cocktail, which supports previous literature reports [33,36].…”

“…It has been shown earlier that a phage cocktail significantly reduces the frequency of mutation in bacteria in comparison to the use of a single phage preparation [33]. Therefore, a greater chance of successful treatment of bacterial infections may be expected by combining multiple phages with varied host specificities.…”

Paenibacilluslarvae-Directed Bacteriophage HB10c2 and Its Application in American Foulbrood-Affected Honey Bee Larvae

“…It is important to ensure that the phages selected do not exhibit generalized transduction or possess gene sequences with significant homology to antibiotic resistance genes and genes for other bacterial virulence factors (9,10). Moreover, it is critical that the therapeutic phages lyse relevant strains of the targeted bacteria and spare bacteria of the bee microbiome and the habitat of the hives.…”

Synthetic biology platform technologies for antimicrobial applications

“…Recently, Ando et al described a high-throughput method for engineering novel phage specificity in a modular manner. These synthetic phages can be inexpensively and rapidly evaluated for clinical use, easing the path for regulatory approval and advancing the therapeutic potential of phage-based treatments [34,[44][45][46].…”