Invasive bacteriophages between a bell and a hammer: a comprehensive review of pharmacokinetics and bacterial defense systems

Bacteria and phages have co-evolved, developing bacterial immune systems that defend against phage infections. This ongoing evolutionary arms race has led to exploring phages as potential therapeutic alternatives. The sustainability of phage therapy depends on a comprehensive understanding of phage pharmacokinetics and bacterial defense mechanisms. While several studies show that phages generally exhibit good distribution across most organs, some experiments involving phage administration to humans or animals have not always succeeded. This failure can be attributed to the role of innate and adaptive immunity in neutralizing phages, despite phage therapy's limited clinical application. The immune adaptations bacteria develop in response to phage attacks provide time for them to evolve stronger defenses, raising concerns about the long-term efficacy of phage therapy. This review highlights the importance of understanding the interplay between phage pharmacokinetics and bacterial defenses to ensure the future success of phage therapy.