Preparation and pharmacokinetic evaluation of Staphylococcus phage COP-80B for treatment of periprosthetic joint infections in a mouse model

TL;DR

This study shows that local administration of phage COP-80B effectively targets knee tissue in mice, while systemic delivery fails, and confirms the safety of the phage treatment.

Contribution

A scalable production method for pharmaceutical-grade phage COP-80B and pharmacokinetic data from a mouse model for periprosthetic joint infections.

Findings

Local phage administration sustains phage presence in knee tissue for several days.

Systemic administration does not deliver phages to the intra-articular space.

Phage COP-80B administration shows no toxic effects in mice.

Abstract

•Rapid and scalable production method yields pharmaceutical-grade phage preparation.•Local phage administration results in sustained phage presence in the knee tissue.•Systemic phage administration fails to deliver phages to the periarticular tissue.•No observable toxic effects after phage COP-80B administration in mice.

Rapid and scalable production method yields pharmaceutical-grade phage preparation.

Local phage administration results in sustained phage presence in the knee tissue.

Systemic phage administration fails to deliver phages to the periarticular tissue.

No observable toxic effects after phage COP-80B administration in mice.

Phage therapy has recently attracted significant attention as a potential treatment for periprosthetic joint infections, yielding promising outcomes in several compassionate use cases. The absence of standardized treatment protocols is partly attributable to insufficient pharmacokinetic data regarding relevant phage administration routes and dosages. Another neglected aspect is the scalable manufacturing of pharmaceutical-grade phage preparations for preclinical testing. In this study, we address both challenges and present a scalable phage production process for the Staphylococcus epidermidis-specific phage COP-80B We prepared a highly purified phage suspension, as verified through qPCR, HPLC, NTA and short-read sequencing, which was used in a preclinical pharmacokinetic study in an uninfected mice model. Using a plaque assay, we determined phage concentrations in mouse organs over time after intraperitoneal and intra-articular application of 109 phages. Intra-articularly administered phages persisted in the periarticular tissue for several days, entered the systemic circulation and were subsequently cleared from the liver and spleen. Conversely, intraperitoneally administered phages did not reach the intra-articular space. No adverse events and no changes in hematological parameters were observed in mice after phage application by either route, confirming the safety of a single-dose application. Our results emphasize the importance of local phage administration for sustained presence in periarticular tissue and provide valuable pharmacokinetic data to support the development of optimized treatment protocols for periprosthetic joint infections.

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