Bacteriophage Therapy in Orthopaedic Periprosthetic Infections – Developing a Phage Therapy Program at UPMC and the University of Pittsburgh
July 2, 2025
Periprosthetic joint infections (PJIs) remain among the most challenging complications in orthopaedic surgery. While the lifetime risk of infection following total joint replacement remains low at about 1%, the absolute number of cases continues to rise as joint replacement procedures become increasingly common. For the subset of patients who develop a PJI, the clinical consequences can be profound and life-altering. Revision surgeries, extended hospitalizations, long-term intravenous antibiotics, impaired mobility, and, in some cases, limb amputation or death represent the difficult and often devastating outcomes these infections can lead to.
Why Bacteriophages Are Being Reconsidered
As the global problem of antimicrobial resistance and multi-drug resistant organisms continues, researchers are increasingly looking to alternative therapeutic strategies to manage complex infections. Among these approaches, bacteriophage therapy has reemerged as a serious candidate. First identified in the early twentieth century, bacteriophages are viruses that preferentially infect and lyse bacteria and were widely studied and even used clinically early on in parts of Europe, before the age of antibiotics was jumpstarted by Alexander Fleming and colleagues with the discovery of penicillin. However, with the identification and widespread adoption of antibiotics, research into bacteriophages faded into relative obscurity.
“We’ve known about bacteriophages for decades, but the antibiotic era pushed interest away. Now, with increasing numbers of infections that no longer respond to antibiotics, bacteriophages are receiving renewed attention,” says Kenneth L. Urish, MD, PhD, associate professor of Orthopaedic Surgery in the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine.
The biology of bacteriophages offers different advantages over antibiotics. Unlike broad-spectrum antibiotics, bacteriophages exhibit narrow specificity, targeting individual bacterial species or subpopulations. More importantly for orthopaedic applications, they have the ability to infect and replicate inside bacteria embedded within biofilm, the structured colonies of bacteria that form on implant surfaces and are highly resistant to conventional treatments designed to eradicate them.
From Metabolic Tolerance to Bacteriophage Therapy
Before entering the field of bacteriophage therapy, Dr. Urish’s laboratory in the Department of Orthopaedic Surgery had been focused on studying bacterial metabolic tolerance, how bacteria survive prolonged antibiotic exposure without necessarily developing traditional genetic resistance. His early work examined how bacterial populations persist in a dormant or metabolically altered state under antibiotic pressure, particularly within biofilms that form on orthopaedic implants.
“That work gave us a deep understanding of why these infections are so difficult to treat,” says Dr. Urish. “We were looking at how the physiology of bacteria allows them to evade antibiotics even when those drugs are technically active against them.”
This prior research provided an entry point into exploring alternative therapies capable of disrupting biofilms and persistent bacterial populations. Bacteriophages, with their unique life cycle and ability to penetrate biofilms, offered a mechanistically distinct strategy.
As antimicrobial resistance continues to accelerate due to adaptation, less than optimal antimicrobial stewardship, the lack of support and research for new antibiotics, and the rampant use of antibiotics in commercial food production putting pressure on therapeutic options for challenging infections like complex PJI cases, Dr. Urish and his colleagues began establishing the foundation for a clinical bacteriophage program.
First Compassionate Use Case – An Infection with No Antibiotic Options
As Dr. Urish and his colleagues were developing the laboratory capabilities to study bacteriophages, a clinical referral arrived that served as the program’s first treatment case. Although the laboratory was primarily focused on metabolic tolerance research at the time, they had begun assembling the microbiology infrastructure needed for phage matching. The request to evaluate a complex, treatment-resistant infection prompted an accelerated clinical application of their early work and creating the basis for what would become the team’s formalized compassionate use program.
“When I was first approached about this, I was aware of bacteriophages, but like most physicians, I considered them experimental and largely theoretical. Then the first patient walked into clinic,” says Dr. Urish.
The patient was an older adult who had a highly complex case involving a well-fixed hip and knee prosthesis supported by a long plate along the femur and complicated by a multi-drug resistant Pseudomonas infection. Despite nearly two years of intravenous antibiotics, the infection persisted, no other antibiotic options were possible, and surgical options were deemed too high-risk given the patient’s age and comorbidities.
“At that point, palliative care had been consulted. There were no other treatment options being offered. And the timing was extraordinary. If the patient had presented to my clinic two weeks earlier, I wouldn’t have had anything to offer him either. But we had just begun developing our bacteriophage program,” says Dr. Urish.
This became the first compassionate-use case for bacteriophage therapy undertaken by Dr. Urish and his colleagues. With cultures obtained from the patient, Dr. Urish and the team performed bacteriophage sensitivity screening using their in-house phage library, identifying two candidate phages active against the patient’s isolate. The patient was treated under expanded-access U. S. Food and Drug Administration (FDA) provisions, receiving bacteriophage injections every three to six months over a two-year period. While the cultures never fully cleared, the patient remained clinically asymptomatic, ambulatory, and independent.
“This case was not about eradication, per se. It was more about clinical control and about preserving his quality of life. We created a kind of ‘demilitarized zone’ within the infection, suppressing bacterial activity enough so he could maintain function without systemic illness,” says Dr. Urish.
How the Program Was Built: A Unique Phage Therapy Infrastructure
Following the success of this initial case, Dr. Urish and his colleagues moved to develop a comprehensive bacteriophage program within the Department of Orthopaedic Surgery.
“We essentially became our own microbiology lab for phage therapy. The clinical microbiology labs don’t perform these tests, so we had to build that capacity ourselves,” says Dr. Urish.
Dr. Urish’s program is one of only a handful of centers in the United States working in bacteriophage therapy, and the only one currently dedicated to orthopaedic infections. The program maintains a growing isolate library and collaborates with other research centers to obtain diverse bacteriophage candidates.
“We’ve developed a complete pipeline now, from patient referral, to isolate acquisition, to phage matching, to production. In most other centers, phages are shipped in, and the clinical site is largely passive. Here, we can carry the entire process from start to finish,” says Dr. Urish.
The program also partners with outside institutions to source phages for less common pathogens. While Dr. Urish’s laboratory focuses primarily on Staphylococcus aureus, which is a frequent pathogen in PJIs, the network includes collaborators with phage libraries targeting Staphylococcus epidermidis, Pseudomonas, and other species.
Early Success and Program Growth
Dr. Urish and his colleagues have now received national and international referrals, with patients traveling from as far away as Hawaii, Canada, and Florida to seek care.
“We’re treating the most complex salvage cases in patients who have failed multiple surgeries, exhausted antibiotic options, and in many cases are facing amputation or worse,” says Dr. Urish.
While still early, these compassionate use cases provide critical real-world experience as Dr. Urish and his team work to transition bacteriophage therapy into broader clinical trials. With their infrastructure and ability to treat patients through compassionate-use protocols, Dr. Urish and the team are helping lead the advance of phage therapy for difficult to treat infections.
