Animal Models to Translate Phage Therapy to Human Medicine

Abstract

Phagotherapy, the use of bacteriophages to fight bacterial infections as an alternative to antibiotic treatments, has become of increasing interest in the last years. This is mainly due to the diffusion of multi-drug resistant (MDR) bacterial infections that constitute a serious issue for public health. Phage therapy is gaining favor due to its success in agriculture and veterinary treatments and its extensive utilization for human therapeutic protocols in the Eastern world. In the last decades, some clinical trials and compassionate treatments have also been performed in the Western world, indicating that phage therapy is getting closer to its introduction in standard therapy protocols. However, several questions concerning the use of phages in human therapeutic treatments are still present and need to be addressed. In this review, we illustrate the state of art of phage therapy and examine the role of animal models to translate these treatments to humans.

Animal Models in the Evaluation of the Effectiveness of Phage Therapy for Infections Caused by Gram-Negative Bacteria from the ESKAPE Group and the Reliability of Its Use in Humans

“…These studies may provide the critical information necessary to evaluate the safety and efficiency of a specific therapy in humans. Properly constructed animal models, including both vertebrates and invertebrates, provide a broader view of the mechanism of phage therapy on a living organism, give information on the impact on the immune system (possible interactions with immune system components, e.g., phagocytes), gut microbiota, infected tissue, and allow estimation of the scale of safety, tolerability, and observation of the possible side effects of the preparation used [44][45][46]. In vitro studies will never fully provide valuable information on drug metabolism, tissue distribution, and bioavailability.…”

“…Another invertebrate described in the publications is Drosophila melanogaster (fruit fly), which may be useful in testing the safety and/or toxicity of phage preparations and their pharmacokinetics after oral administration [55] or assessing the therapeutic effects of phages after injection [56]. Overall, invertebrate studies are relatively inexpensive, easy to perform, and quick, yet they provide a lot of important information on the therapeutic and prophylactic effects as well as the safety of phage use [44]. Despite many advantages, invertebrate organisms are very different from mammals, including humans, and have many limitations when it comes to translating therapies to humans.…”

“…The zebrafish model is also used to ascertain the effects of phage therapy [44,84]. Pseudomonas aeruginosa infection is an important complication in cystic fibrosis, which contributes to the high mortality rate of patients [89].…”

Considerations for Phage Therapy Against Mycobacterium abscessus

“…Recent reviews about clinical trials describe results of phage therapy to treat chronic otitis, infected burn wounds, diarrhea, diabetic foot ulcers, venous leg ulcers, urinary tract infections, or gastrointestinal disorders caused by Staphylococcus aureus , A. baumannii , Pseudomonas aeruginosa , and the Enterobacteriaceae family with different results ( Furfaro et al, 2018 ; Altamirano and Barr, 2019 ), but no clinical trial using bacteriophages against mycobacteria has been performed. Finally, Brix et al (2020) summarized different animal models used to study phage therapy, including Caenorhabditis elegans , Drosophila melanogaster , Galleria mellonella , zebrafish, quail, chicken, rabbit, hamster, and mouse.…”

Bacteriophage and Endolysin Encapsulation Systems: A Promising Strategy to Improve Therapeutic Outcomes

“…In recent decades, the emergence of multidrug-resistant bacterial pathogens has spurred clinicians and researchers to look for alternative therapeutic options, which mainly includes phages. Phages have been evaluated in various animal models and clinical trials to establish their clinical relevance in treating drug-resistant bacterial infections (Abdelkader et al, 2019;Brix et al, 2020;Pirnay and Kutter, 2020). Based on the results of previous studies, these entities are considered as fascinating future antimicrobial agents.…”