Bacteriophage Therapy for Orthopaedic Infections and the Bench-to-Bedside Pipeline
July 3, 2025
As bacteriophage therapy begins to demonstrate early promise in the management of periprosthetic joint infections (PJIs), attention is shifting toward the complex scientific and translational questions that must be addressed to move these treatments from isolated compassionate-use cases into broader clinical practice.
At the University of Pittsburgh Department of Orthopaedic Surgery, Kenneth Urish, MD, PhD, associate professor of orthopaedic surgery, and his team have built one of the most comprehensive orthopaedic bacteriophage programs in the country. But their ongoing work highlights just how much remains to be solved in terms of translating bacteriophage therapy into practice as another standard of care or weapon in the clinical armamentarium against PJI.
The Challenge of Phage Matching and Phenotypic Variation
Unlike antibiotics, which can often be applied empirically, bacteriophage therapy requires precise matching between phage and bacterial isolate. One of the biggest challenges identified in Dr. Urish’s lab and that of others working in the phage therapy space is the level of bacterial phenotypic variation that exists even within the same infection site in the same person.
“We’ve learned that where you obtain the bacterial sample from really matters. The bacteria living in the synovial fluid may not be identical to bacteria in the deep tissue or on the implant surface. We’ve had cases where susceptibility testing on one isolate would have led us to select the wrong phage entirely,” says Dr. Urish.
These differences are driven in part by changes in bacterial surface structures, particularly wall teichoic acids, which serve as the primary binding sites for many bacteriophages. Variability in wall teichoic acid glycosylation patterns may determine whether a given phage can successfully attach and infect its target.
Supported by a National Institutes of Health R01 grant, Dr. Urish and colleagues are actively investigating how these glycosylation changes influence phage susceptibility.
“We’re trying to understand at a molecular level why one isolate is susceptible while another from the same patient may not be. That has huge implications for how we screen and select phages,” says Dr. Urish.
Laboratory Modeling of Resistance and Phage Adaptation
In the laboratory, Dr. Urish and his colleagues are using in vitro growth inhibition systems to better understand how bacteria develop resistance under phage pressure, and how phages may be adapted in response. The approach is conceptually similar to how minimum inhibitory concentration (MIC) assays are performed for antibiotics but tailored to phage dynamics.
“We’ll plate out the bacteria with phage, and for 24 hours you’ll often see good growth inhibition,” says Dr. Urish. “But if you wait longer, you may see some bacteria eventually grow through that phage pressure. Those are the organisms starting to escape.”
The lab then recycles those breakthrough bacterial populations, culturing them again with the same phage across multiple sequential passages. Each cycle allows the team to observe how bacterial populations evolve and whether phage activity can be maintained or adjusted.
“It’s very much like a predator-prey system,” says Dr. Urish. “We’re watching how the bacteria respond to the phage, and how the phage might continue to suppress or fail, depending on the mutations that emerge.”
This iterative model allows Dr. Urish’s team to characterize resistance mechanisms, evaluate the durability of candidate phages, and ultimately refine which phages or phage combinations are most likely to remain effective against evolving infections.
Personalizing Phage Therapy for Each Infection
This variability has led Dr. Urish to advocate for highly individualized phage therapy models, particularly in orthopaedics where infections may persist for years and involve diverse bacterial subpopulations.
“The standard approach of growing one isolate from synovial fluid and picking a phage based on that is not sufficient. We need to sample multiple compartments like the joint fluid, tissue, bone, and screen across those isolates to ensure we’re selecting phages that cover the entire spectrum of bacterial phenotypes present in that patient,” says Dr. Urish.
Dr. Urish and his colleagues maintain an extensive internal isolate library, coupled with partnerships that provide access to larger phage banks across the country. This infrastructure allows for rapid matching of phages to individual patient infections but also highlights the logistical challenges that would need to be addressed for broader clinical scalability.
Manufacturing and Regulatory Infrastructure
Unlike traditional antibiotics, bacteriophage preparations present complex regulatory and manufacturing challenges. Phages are classified as biologic agents, subject to FDA oversight. Dr. Urish and colleagues currently operate under individual emergency use Investigational New Drug (IND) approvals for each case which require extensive documentation, quality assurance, and oversight for every treatment administered.
“We’re averaging about six months from initial referral to actual phage administration. That timeline reflects the complexity of isolate screening, phage matching, production, sterility testing, and regulatory submissions,” says Dr. Urish.
Production capacity also remains a challenge. While small-scale laboratory preparations are sufficient for individual cases, large-scale manufacturing would require standardized, GMP-compliant facilities capable of producing phage preparations that meet strict purity and safety criteria.
“We’re working closely with external manufacturing partners to scale up production capabilities,” says Dr. Urish.
Dr. Urish’s program is creating the necessary framework to eventually be able to conduct formal clinical trials that will provide the data necessary to potentially achieve broader regulatory approval.
“Emergency use cases have allowed us to build clinical experience. But ultimately, we need prospective, controlled trials to fully validate safety, efficacy, and reproducibility,” says Dr. Urish.
The Future of Phage Therapy in Orthopaedics
Looking ahead, Dr. Urish anticipates that bacteriophage therapy will likely find its initial role as a salvage option for complex refractory PJIs cases where multiple surgeries and antibiotics have failed, and amputation is being considered. However, as safety and efficacy data accumulate, there is the potential for expansion into earlier stages of infection management.
“This isn’t about replacing antibiotics. It’s about adding a new layer of precision to how we manage infections, particularly infections that don’t respond to standard therapies,” says Dr. Urish.
The long-term vision includes developing national phage libraries, real-time diagnostic screening platforms, and integrated multidisciplinary teams capable of delivering personalized phage therapy within standard orthopaedic care pathways.
“We have a lot of the pieces in place with our laboratory capacity, the regulatory framework, and the clinical experience we’ve gained so far. The next step is to systematically bring these together through well-designed trials that can move the field forward,” says Dr. Urish.
References and Further Reading
