Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection

Abstract

Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being “GMP-like”) targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally “phage therapy 2.0” has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial–academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.

Cost-effectiveness of a bone substitute delivering gentamicin in the treatment of chronic osteomyelitis of long bones: Protocol for the CONVICTION randomized multicenter study

“…They have the ability to replicate themselves in their host, and can be deliver locally. This lysin, can destroy the bacteria; it also has anti-biofilm properties ( 23 ). Phage therapy is a potentially innovative approach for patients with bone and joint infection, but there are major drawbacks: (i) few phages are available at this time, targeting only few bacteria such as S. aureus or P. aeruginosa ; (ii) it is necessary to identify the pathogen(s) responsible for the infection before the surgery, to select active phages after determining phage susceptibility.…”

Les virus au service de la santé : les bactériophages

“…Toutes les IOA ne semblent pas être de bonnes indications de la phagothérapie. Les phages ont été utilisés avec succès pour traiter des IOA chroniques, comme des ostéites post-traumatiques ou les ostéomyélites [19]. Les infections associées à la pose de prothèses articulaires représentent également une bonne indication de la phagothérapie, notamment lorsqu'il s'agit d'une infection chronique chez des patients pour qui l'explantation de la prothèse aboutirait à une perte importante de fonction [20].…”

Phage-antibiotic synergy: cell filamentation is a key driver of successful phage predation

“…In this context, phage therapy is more than ever regaining scientific and medical interests after several decades of exclusive use of antibiotics. In Europe, since January 2018, phage magistral preparations have been approved and applied in Belgium [4], whereas in others countries, compassionate usage has been approved in combination with different antibiotics [5,6]. Note that a genetically modified bacteriophage has been successfully used recently for the treatment of an immunocompromised cystic fibrosis young patient, dying from a Mycobacterium abscessus infection [7].…”

“…In this context, phage therapy is more than ever regaining scientific and medical interests after several decades of exclusive use of antibiotics. In Europe, since January 2018, phage magistral preparations have been approved and applied in Belgium [4], whereas in others countries, compassionate usage has been approved in combination with different antibiotics [5,6].…”