Our systematic review indicates that personalized bacteriophage therapy, grounded in modern biotechnological advances, serves as an effective adjunctive treatment for PJI. It not only demonstrates substantial clinical efficacy but also offers the advantage of a low-risk profile. Integrating observational analyses from various existing clinical studies on this treatment, we find that bacteriophage therapy is emerging as a critical adjunctive treatment, particularly in cases involving resistant complex bacteria or recurrent infections. It is increasingly indispensable in managing prosthetic joint infections. The following sections will provide a detailed discussion on these aspects:

In the treatment of PJI, one of the primary challenges is biofilm formation. Biofilms are highly organized polymeric structures composed of bacterial communities and extracellular matrix (ECM), adhering to surfaces of human tissues and implants. These structures are formed by the secretion of polysaccharides, proteins, lipids, and extracellular DNA (eDNA) [36]. Additionally, bacteria within the biofilm matrix can exist in various metabolic states, making it difficult to obtain accurate bacteriological evidence [37]. The physical separation of the biofilm and the varied states of the bacteria within pose significant challenges to conventional treatment [38]. Furthermore, bacteria can acquire antimicrobial resistance (AMR) through various mechanisms. Factors influencing bacterial resistance include overuse and misuse of antibiotics, which accelerate this process. Currently, the rate of increasing bacterial resistance surpasses the development of new antibiotics [39, 40]. According to the Global Antimicrobial Surveillance System (GLASS), antimicrobial resistance has been reported among 500,000 individuals across 22 countries. The severity of AMR is particularly pronounced in low- and middle-income countries due to inadequate surveillance, limited access to antibiotics, and insufficient laboratory capabilities [41]. These multiple factors collectively complicate the treatment of prosthetic joint infections with conventional antibiotics alone, often necessitating comprehensive, multidisciplinary interventions at medical centres.

Currently, the treatment guidelines and expert consensus for PJI emphasize a multidisciplinary approach involving orthopaedic surgeons, infectious disease specialists, internists, microbiologists, pharmacists, and rehabilitation physicians [42]. Treatment strategies are categorized based on the duration of clinical symptoms into acute and chronic infections. Acute infections may be managed with the Debridement, Antibiotics, and Implant Retention (DAIR) protocol, while chronic infections often require revision surgery (one/two stage revision) [43]. For refractory PJI or cases where joint reconstruction is unfeasible, alternative salvage procedures such as amputation, resection arthroplasty, and arthrodesis are considered [44]. Regardless of whether the infection is acute or chronic following primary replacement surgery, antibiotic therapy tailored to bacteriological evidence and the patient’s individual condition is an essential component of PJI management. Currently, research has compiled microbiological data on PJI, with Staphylococcus species (including Staphylococcus aureus and coagulase-negative Staphylococci) are the most common pathogens in PJI, accounting for approximately 40-60% of cases. Other Gram-positive pathogens (such as Streptococci and Enterococci) account for 10-20%, and Gram-negative bacilli for 5-20%. Moreover, the microbiological profile of infections varies between hip and knee prostheses due to differences in location and surgical techniques [45,46,47]. Joint aspiration and biopsy to obtain definitive bacteriological evidence are crucial for antibiotic selection. Systemic administration of antibiotics is indispensable for effective antibacterial treatment. However, most antibiotics cannot achieve sufficient local drug concentrations, necessitating their local application when required, which may include local injection, intra-articular catheter delivery, or combining with a carrier substance [48, 49]. In summary, a personalized approach to the selection of antibiotics, their administration routes, and treatment duration is advocated [50, 51]. In the coming years, knee and hip revision surgeries are projected to increase by 43–182%. This suggests that without improvements in current prevention and treatment strategies, the number of infections will likely rise [5]. Additionally, literature reports indicate that even with systematic SAT, the success rate is not 100%. Most patients receiving bacteriophage therapy are those for whom antibiotic treatments have failed. For these patients, bacteriophage therapy serves as an adjunct to both conservative and surgical treatments, aiming to enhance the success rate of suppressive antibiotic therapy [52, 53]. Therefore, it is essential and urgent to continue research and innovation in this therapeutic approach to address the ongoing challenges. This review, in screening clinical cases of treating PJI, found that in dealing with high treatment difficulty, the existence of multiple drug-resistant and recurrent PJI, and other complex cases, the trend of multiple medical institutions reusing bacteriophages has become increasingly apparent.

Bacteriophages are abundantly present in natural environments and exhibit high specificity towards bacteria, making them of significant research interest. Regarding their mechanism of action, traditionally, it is believed that the primary mechanism of phages involves interacting with receptors on the host cell surface and using endolysins (peptidoglycan hydrolases) to inject their genome into the target bacteria. The replication method then depends on whether the phage is virulent or temperate. Virulent phages replicate through the lytic cycle, producing new phages while killing the bacteria, and temperate phages usually have two pathways: the lytic cycle and the lysogenic cycle. In the lysogenic cycle, the phage genome, known as a prophage, integrates with the host genome, replicating as part of the bacterial chromosome or as an independent plasmid. Under favorable conditions, the prophage can switch to the lytic cycle, releasing new phages and killing the host bacteria [54, 55] (Fig. 3). As research on phages has progressed, additional bactericidal mechanisms have been discovered, such as reducing biofilm surface polymers via enzymatic action, lowering bacterial virulence, and assisting the host immune system in bacterial clearance [56,57,58]. Bacteriophages can also intervene in bacterial dissemination by expressing phage-carried sporulation genes during infection, affecting the formation of bacterial spores to counteract bacterial defense mechanisms mediated by dormancy, thereby intervening in bacterial spread [59]. In the clinical studies included in this review, bacteriophage therapy demonstrated significant efficacy to control the disease, with 39 out of 42 patients showing substantial symptom relief. Regarding treatment safety, three patients experienced adverse reactions such as fever and chills. Overall, these adverse reactions were relatively mild, and they alleviated after reducing or discontinuing bacteriophage treatment. These reactions are likely due to potential bacterial residual cell wall component into the phage preparation, or could be due to bacterial lysis in vivo or to the host’s immune response. These mechanisms require further readership to clearly understand the pathophysiology of such symptoms.

A schematic representation of the lytic cycle and lysogenic life cycle and the general processes of bacteriophages. Although the lysogenic cycle of temperate bacteriophages does not immediately cause bacterial lysis, it can induce genetic remodeling and, under suitable conditions, may transition into the lytic cycle, leading to bacterial destruction and replication of the bacteriophage. And the lytic cycle of virulent bacteriophages produces lysins that degrade the bacterial cell wall, rapidly leading to facilitates dissemination of themselves

Of course, bacteriophage therapy also has certain limitations. Its highly specific mechanism of action is like a double-edged sword. Each type of phage has a host range and is only effective against specific bacterial strains. This specificity means not all phages are suitable for treating PJI. Therefore, clinical phage preparations require accurate bacteriological evidence from the patient to ensure the selected phage can lyse the target bacteria. This requirement restricts the scalability of standardized phage preparations [60]. Additionally, studies have shown that bacteria can develop resistance to phages by altering or suppressing the expression of their receptors [61]. From the results of this review, several limitations are evident. First, there is a predominance of case studies, with few large-scale clinical trials. This raises questions about the ability to statistically evaluate and describe the combined results. The differences in study types may also introduce biases in assessing clinical efficacy and adverse events. Second, all patients received standardized antibiotic therapy alongside phage treatment. Antibiotics and phages may have synergistic effects. Additionally, in some studies, patients underwent surgical treatment concurrent with bacteriophage therapy. These factors could confound the assessment of bacteriophage therapy’s efficacy. Furthermore, in most case reports, there is a lack of uniform standards regarding the source, formulation, drug concentration and dosage, administration route, administration frequency, and treatment duration of bacteriophages, the lack of standardization makes it difficult to draw definitive conclusions. Although the results of this review do not differ significantly from previously published systematic reviews, caution is still needed in evaluating and confirming these data due to the lack of large-scale clinical experiments and standardized experimental designs.

Recently, several new phage research clinical teams have been established in Europe. In Belgium, PHAGEFORCE, a multidisciplinary initiative, has been established by the “Multidisciplinary Phage Task Force” to standardize bacteriophage therapy and prospectively collect data. In France, the “PHAGEinLYON” clinic program has also been established to provide pharmaceutical-grade phages to patients with severe infections and systematically collect treatment metrics [13]. Additionally, new concepts for phage treatment of PJI are being implemented. For example, the Center of Reference for Infection of Osteoarticular Complexes (CRIOAc) at the Croix-Rousse Hospital has innovatively proposed the concept of “PhagoDAIR” which involves injecting a cocktail of active bacteriophages during open or arthroscopic DAIR surgery, with promising clinical outcomes [21, 25]. Currently, various antibacterial methods inspired by bacteriophages, including bacteriophages themselves, their enzymes and derivatives, effects mediating biofilm destruction, and enhancing antibiotic sensitivity, may lead to more commercialized products. Despite our limited understanding of most bacteriophage functions, the potential of this vast field remains immense. Regarding clinical research, given the potential efficacy of bacteriophage therapy for refractory PJI, larger-scale clinical controlled studies should be conducted according to current clinical practice guidelines to support the safety and effectiveness of bacteriophage therapy. In the future, as the limitations of conventional treatments become more apparent and foundational research and clinical applications of bacteriophage therapy progress, new discoveries are likely to emerge, facilitating the clinical translation of bacteriophage therapy and ushering in a new era for the treatment of PJI.