Abstract
Background
Periprosthetic Joint Infection (PJI) following hip and knee arthroplasty is a catastrophic complication in orthopaedic surgery. It has long been a key focus for orthopaedic surgeons in terms of prevention and management. With the increasing incidence of antibiotic resistance in recent years, finding more targeted treatment methods has become an increasingly urgent issue. Bacteriophage Therapy (BT) has emerged as a promising adjunctive treatment for bone and joint infections in recent years. It not only effectively kills bacteria but also demonstrates significant anti-biofilm activity, garnering substantial clinical interest due to its demonstrated efficacy and relatively low incidence of adverse effects.
Purpose
This review aims to systematically evaluate the efficacy and safety of bacteriophage therapy in treating PJI following hip and knee arthroplasty, providing additional reference for its future clinical application.
Methods
Following predefined inclusion and exclusion criteria, our team conducted a systematic literature search across seven databases (PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, CNKI, and WanFang Database). The search was conducted up to May 2024 and included multiple clinical studies on the use of bacteriophage therapy for treating PJI after hip and knee arthroplasty to assess its efficacy and safety.
Results
This systematic review included 16 clinical studies after screening, consisting of 15 case reports and one prospective controlled clinical trial, involving a total of 42 patients with PJI treated with bacteriophage therapy. The average patient age was 62.86 years, and 43 joints were treated, with patients undergoing an average of 5.25 surgeries. The most common pathogen in these infections was Staphylococcus aureus, accounting for 18 cases. 33 patients received cocktail therapy, while nine were treated with a single bacteriophage preparation. Additionally, all patients underwent suppressive antibiotic therapy (SAT) postoperatively. All patients were followed up for an average of 13.55 months. There were two cases of recurrence, one of which resulted in amputation one year postoperatively. The remaining patients showed good recovery outcomes. Overall, the results from the included studies indicate that bacteriophage therapy effectively eradicates infectious strains in various cases of PJI, with minimal side effects, demonstrating promising clinical efficacy.
Conclusion
In the treatment of PJI following hip and knee arthroplasty, bacteriophages, whether used alone or in combination as cocktail therapy, have shown therapeutic potential. However, thorough preoperative evaluation is essential, and appropriate bacteriophage types and treatment regimens must be selected based on bacteriological evidence. Future large-scale, randomized controlled, and prospective trials are necessary to validate the efficacy and safety of this therapy.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Periprosthetic joint infection (PJI) is a catastrophic complication after joint replacement surgery and has consistently posed a challenging problem for orthopaedic surgeons. Despite advances in surgical techniques and innovative use of antibiotics, the overall incidence of PJI remains at 0.97% for total hip arthroplasty (THA) and 1.03% for total knee arthroplasty (TKA). According to previous surveys, PJI is the most common reason for revision surgery in TKA (25%) and the third most common reason for revision in THA (15.4%) [1, 2]. Further study have compared the impact of different aetiologies on the incidence of PJI following primary joint replacement surgery, revealing that patients with rheumatoid arthritis have a higher incidence compared to those with osteoarthritis [3]. Additionally, PJI is associated with a relatively high mortality and complication rate, which significantly affects patient prognosis. Literature reports a 90-day mortality rate of 0.9% for PJI, with postoperative complication rates of 31.3% for knee joints and 19.6% for hip joints [4], some studies also have reported a five year mortality rate for PJI as high as 26%, comparable to the mortality rates of several common malignancies such as prostate and breast cancer [5]. In terms of healthcare costs, PJI also imposes a substantial financial burden on both patients and society. For example, in the United States, the annual hospital costs related to hip and knee PJI are projected to reach $1.85 billion by 2030 [6].
Currently, once PJI is suspected or diagnosed, various treatment options are available. However, patients almost invariably require additional surgery combined with prolonged antibiotic therapy. Traditional treatment methods are often limited in effectiveness against multidrug-resistant bacteria, and the presence of complex bacterial strains further complicates treatment. Moreover, the side effects of antibiotic therapy add to the patient’s risk. Therefore, there is an urgent need to discover new therapeutic strategies to address these challenges.
Bacteriophages (also known as Phage) are natural viruses that are ubiquitous in the environment and specifically infect and lyse bacteria. They exhibit high specificity and generally do not affect the body’s normal microbiota [7]. Leveraging this advantage, the use of bacteriophages as a method to combat bacteria has gradually emerged as a novel clinical option for bacterial diagnosis and treatment. Bacteriophage therapy has been shown to be effective against infections in various organs and systems, including the pulmonary, urinary, skin wounds, intestinal, and musculoskeletal systems [8,9,10,11,12,13,14]. In the field of PJI after joint replacement, from a diagnostic perspective, studies have compared the use of bacteriophage-based detection methods with traditional microbial cultures in sonicate fluid (SF) samples from patients undergoing revision surgery for suspected PJI. Results indicate that bacteriophage-based methods are faster and more sensitive, demonstrating clear advantages [15]. From a therapeutic perspective, a series of foundational studies on bacteriophage treatment for device-related infections have shown promising progress. In in vitro experiments, studies analyzed the bacteriophage activity against Staphylococcus aureus isolates from PJI cases, showing that at least one bacteriophage inhibited planktonic bacterial growth in 97% of the samples [16]. In animal studies, research applied phage-coated implants to treat joint infection models in mice. The findings revealed that implants containing bacteriophages were effective in both treating and preventing infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains [17]. Other studies utilized bacteriophage-derived lysins in in vitro models and mouse prosthetic joint infection models, finding that bacteriophage products effectively reduced bacterial presence on peri-prosthetic tissues and implant surfaces [18]. Therefore, bacteriophage therapy shows significant potential in the clinical management of PJI, leveraging its high specificity and low side effects to target specific bacteria effectively and act rapidly against antibiotic-resistant strains.
Currently, a growing number of clinical studies are focusing on the efficacy and mechanisms of bacteriophage therapy in managing PJI. Thus, this review aims to systematically evaluate the efficacy and safety of bacteriophage therapy in treating PJI following hip and knee arthroplasty, providing further insights for its future clinical applications.
Materials and methods
Literature search strategy
In May 2024, we conducted a systematic search of the literature on the role of bacteriophages in managing PJI based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [19]. Specifically, we formulated our search strategy based on the PICO framework, which includes predefined parameters for Population, Intervention, Comparison, Outcome, and Study Design. The study population consisted of patients with PJIs following hip or knee arthroplasty. The intervention involved the use of bacteriophages (or derived biological agents like lysins) administered through various routes. The comparison, where applicable, was against traditional standard treatment regimens such as antibiotic therapy alone. The primary outcomes were infection clearance rates and clinical recovery. The search was conducted by two authors who screened seven databases (PubMed, Embase, Web of Science, Cochrane Library, Clinical Trials, CNKI, and WanFang Database). Various search terms were employed, including “hip arthroplasty,” “knee arthroplasty,” “bacteriophage therapy,” and “postoperative infection” (for detailed search strategies, see the appendix). Additionally, we manually searched the reference lists of relevant articles to ensure all pertinent studies were included. The search covered the period from the inception of the databases to the present.
Inclusion and exclusion criteria
Inclusion criteria: Clinical studies involving bacteriophage therapy for infections following hip or knee arthroplasty; these include case reports, retrospective studies, and prospective studies. The studies must provide detailed treatment protocols and outcome evaluations. Exclusion criteria: Studies of low relevance (e.g., those not involving the treatment of infections following hip or knee arthroplasty); animal experiments and laboratory studies; articles not peer-reviewed; studies that are incomplete or lack critical data; review articles and other types of publications.
Data extraction and quality assessment
Key information was extracted from the included studies, including: study design (case reports, retrospective studies, prospective studies); the number of patients and their demographic characteristics; the type of infection and information on pathogens; treatment protocols (types of bacteriophages, routes of administration, dosages, and treatment duration); treatment outcomes (improvement in clinical symptoms, eradication of bacterial infection, and follow-up duration); and safety and adverse effects (complications). The search results were downloaded into Zotero 6.0 for evaluation. After removing duplicates, titles and abstracts were screened for eligibility. Full texts of the studies that met the eligibility criteria were reviewed and data were extracted. This culminated in the formation of this systematic review (Fig. 1).
Results
Studies characteristics (table 1)
A total of 16 studies were included, of which 15 were case reports and one was a prospective controlled study, involving a total of 42 patients. Among the included studies, six were from the USA, five from France, one from Germany, one from the Netherlands, one from Latvia, and one from Italy. The study participants were mostly patients over 60 years old, with an average age of 62.86 years. They had undergone hip or knee arthroplasty, with an average of 5.25 surgeries (calculated from reports that included surgical counts). The studies involved a total of 43 joints (29 hips and 14 knees), including one report where the same patient had infections in both the hip and knee on the same side. Details are provided in Table 1.
Sample description (table 2)
In all case reports, patients had a history of multiple surgeries, including debridement, one-stage revision, and two-stage revision arthroplasty. Among the infectious pathogens, the most common was Staphylococcus aureus, with a total of 18 cases, followed by Staphylococcus epidermidis with 16 cases, and Pseudomonas aeruginosa with five cases. Furthermore, regarding the use of bacteriophages, all reports specified the types of bacteriophages used for treatment. However, the details on bacteriophage types, timing of use, routes of administration, dosages, dosing frequencies, and duration of use varied among the reports. Of the 42 patients, 33 received bacteriophage cocktail therapy, and nine were treated with a single bacteriophage preparation. Additionally, all patients received suppressive antibiotic therapy postoperatively. Regarding routes of administration, some reports mentioned the use of intravenous injection or combined intra-articular administration. In some cases, bacteriophages were administered solely intra-articularly, either by direct injection into the joint cavity before wound closure during surgery or by continuous infusion through a drainage tube. Additionally, phage-loaded carrier the Defensive Antibacterial Coating (DAC®) hydrogel were applied to the prosthesis surface, and in some studies, oral administration was used. In the use of combination antibiotics, the types of antibiotics were adjusted in real-time based on the patient’s disease progression. Most case reports mentioned that patients received at least six weeks of suppressive antibiotic therapy postoperatively. The simplified treatment flowchart and specific methods included in these studies in Fig. 2; Table 2.
Effectiveness and safety of treatment (table 2)
Patients included in the 16 studies were followed up for an average of 13.55 months (considering only reports with recorded follow-up durations), with two cases of recurrence observed. Among the 19 patients detailed in the case reports, one underwent amputation due to poor infection control one year post-surgery, while the others had favourable recovery outcomes. Statistical results from prospective clinical studies indicated that the overall response rate for patients treated with a combination of bacteriophages and antibiotics was 95.5%, with one patient experiencing infection recurrence during follow-up. Regarding adverse reactions, case reports documented one patient experiencing fever and chills; three patients developed liver function abnormalities attributed to bacteriophage therapy, with one patient recovering after discontinuation of treatment without life-threatening consequences. Additionally, two patients exhibited kidney function abnormalities, though these could not be definitively attributed to bacteriophage therapy alone due to concurrent antibiotic use. In the prospective controlled study, one patient was transferred to the control group due to evidence of other pathogens and a lack of bacteriophage titer in mid-sampling tests, which was considered a failure of bacteriophage therapy, while two patients experienced fever reactions.
Synthesized analysis
Overall, the aggregated results from the included studies suggest that bacteriophage therapy is effective in eradicating infectious strains in various cases of prosthetic joint infections. Notably, it shows significant clinical efficacy against complex multi-drug-resistant bacteria. Compared to conventional antibiotic-only treatments, bacteriophage therapy is better tolerated, has fewer side effects, and lacks reports of severe adverse reactions on a large scale. This highlights its specific bactericidal mechanisms as a prominent advantage in combating multi-drug-resistant strains.
Discussion
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.
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.
Conclusions
Bacteriophage therapy has demonstrated good efficacy in various complex infection cases, particularly those caused by antibiotic-resistant strains. Given the growing issue of antibiotic resistance, its specificity and low side effects make bacteriophage therapy a promising alternative treatment. However, factors such as the type of infection, the patient’s underlying conditions, and the treatment regimen can also affect the efficacy of bacteriophage therapy. Additionally, the small sample sizes of current studies, along with inconsistencies in bacteriophage sources, preparation methods, and administration routes, may also affect the outcomes. Future research requires standardized phage formulations and the inclusion of large sample sizes, randomized controlled trials, and prospective studies to further explore their efficacy and mechanisms.
References
Kamath AF, Ong KL, Lau E et al (2015) Quantifying the Burden of Revision Total Joint Arthroplasty for Periprosthetic Infection. J Arthroplasty 30:1492–1497. https://doi.org/10.1016/j.arth.2015.03.035
Sangaletti R, Zanna L, Akkaya M et al (2023) Periprosthetic joint infection in patients with multiple arthroplasties. Bone Joint J 105–B:294–300. https://doi.org/10.1302/0301-620X.105B3.BJJ-2022-0800.R1
Zhao H, Li L, Wang H-Y et al (2024) Efficacy analysis of clinical serological indicators in the diagnosis of postoperative periprosthetic joint infection in patients with rheumatoid arthritis or osteoarthritis. Int Orthop 48:1945–1952. https://doi.org/10.1007/s00264-024-06171-y
Yang C, Ji B, Li G et al (2024) Ninety-day postoperative mortality and complications in continuous and unselected single-stage revisions for chronic periprosthetic joint infection. Int Orthop 48:1691–1700. https://doi.org/10.1007/s00264-024-06152-1
Piuzzi N, Klika A, Lu Q et al (2024) Periprosthetic joint infection and immunity: current understanding of host-microbe interplay. J Orthop Res 42:7–20. https://doi.org/10.1002/jor.25723
Premkumar A, Kolin DA, Farley KX et al (2021) Projected Economic Burden of Periprosthetic Joint Infection of the hip and knee in the United States. J Arthroplasty 36:1484–1489e3. https://doi.org/10.1016/j.arth.2020.12.005
Taha M, Abdelbary H, Ross F, Carli A (2018) New innovations in the treatment of PJI and Biofilms-Clinical and preclinical topics. Curr Rev Musculoskelet Med 11:380–388. https://doi.org/10.1007/s12178-018-9500-5
Köhler T, Luscher A, Falconnet L et al (2023) Personalized aerosolised bacteriophage treatment of a chronic lung infection due to multidrug-resistant Pseudomonas aeruginosa. Nat Commun 14:3629. https://doi.org/10.1038/s41467-023-39370-z
Leitner L, Ujmajuridze A, Chanishvili N et al (2021) Intravesical bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomised, placebo-controlled, double-blind clinical trial. Lancet Infect Dis 21:427–436. https://doi.org/10.1016/S1473-3099(20)30330-3
Johri AV, Johri P, Hoyle N et al (2023) Case report: successful treatment of recurrent E. Coli infection with bacteriophage therapy for patient suffering from chronic bacterial prostatitis. Front Pharmacol 14:1243824. https://doi.org/10.3389/fphar.2023.1243824
Karn SL, Bhartiya SK, Pratap A et al (2024) A Randomized, Placebo-controlled, double-blind clinical trial of bacteriophage cocktails in chronic wound infections. Int J Low Extrem Wounds 15347346231226342. https://doi.org/10.1177/15347346231226342
Khanal D, Chang RYK, Hick C et al (2021) Enteric-coated bacteriophage tablets for oral administration against gastrointestinal infections. Int J Pharm 609:121206. https://doi.org/10.1016/j.ijpharm.2021.121206
Ferry T, Onsea J, Roussel-Gaillard T et al (2024) Bacteriophage therapy in musculoskeletal infections: from basic science to clinical application. EFORT Open Rev 9:339–348. https://doi.org/10.1530/EOR-24-0042
Uyttebroek S, Chen B, Onsea J et al (2022) Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review. Lancet Infect Dis 22:e208–e220. https://doi.org/10.1016/S1473-3099(21)00612-5
Suster K, Cör A (2022) Fast and specific detection of staphylococcal PJI with bacteriophage-based methods within 104 sonicate fluid samples. J Orthop Res 40:1358–1364. https://doi.org/10.1002/jor.25167
DePalma B, Nandi S, Chaudhry W et al (2022) Assessment of Staphylococcal Clinical isolates from Periprosthetic Joint Infections for potential bacteriophage therapy. J BONE JOINT SURGERY-AMERICAN VOLUME 104:693–699. https://doi.org/10.2106/JBJS.21.00958
Kaur S, Harjai K, Chhibber S (2016) In vivo Assessment of Phage and Linezolid Based Implant Coatings for Treatment of Methicillin Resistant S. aureus (MRSA) mediated Orthopaedic device related infections. https://doi.org/10.1371/journal.pone.0157626. PLOS ONE 11:
Sosa B, Niu V, Turajane K et al (2020) 2020 John Charnley Award: the antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection. BONE JOINT J 102B:3–10. https://doi.org/10.1302/0301-620X.102B7.BJJ-2019-1590.R1
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097
Ferry T, Leboucher G, Fevre C et al (2018) Salvage Debridement, Antibiotics and Implant Retention (DAIR) with local injection of a selected cocktail of bacteriophages: is it an option for an Elderly Patient with Relapsing Staphylococcus aureus Prosthetic-Joint infection? Open Forum Infect Dis 5:ofy269. https://doi.org/10.1093/ofid/ofy269
Patey O, McCallin S, Mazure H et al (2018) Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on Osteoarticular infections. https://doi.org/10.3390/v11010018. Viruses 11:
Tkhilaishvili T, Winkler T, Müller M et al (2019) Bacteriophages as adjuvant to antibiotics for the Treatment of Periprosthetic Joint Infection caused by Multidrug-Resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 64. https://doi.org/10.1128/AAC.00924-19
Doub JB, Ng VY, Johnson AJ et al (2020) Salvage bacteriophage therapy for a chronic MRSA prosthetic joint infection. Antibiotics 9. https://doi.org/10.3390/antibiotics9050241
Ferry T, Kolenda C, Batailler C et al (2020) Phage therapy as adjuvant to conservative surgery and antibiotics to salvage patients with relapsing S. Aureus prosthetic knee infection. Front Med 7. https://doi.org/10.3389/fmed.2020.570572
Ferry T, Batailler C, Petitjean C et al (2020) The potential innovative use of bacteriophages within the DAC(®) hydrogel to treat patients with knee megaprosthesis infection requiring Debridement antibiotics and Implant Retention and Soft tissue Coverage as Salvage Therapy. Front Med (Lausanne) 7:342. https://doi.org/10.3389/fmed.2020.00342
Cano EJ, Caflisch KM, Bollyky PL et al (2021) Phage therapy for limb-threatening prosthetic knee Klebsiella pneumoniae infection: Case Report and in Vitro characterization of anti-biofilm activity. Clin Infect Dis 73:E144–E151. https://doi.org/10.1093/cid/ciaa705
Doub JB, Ng VY, Wilson E et al (2021) Successful treatment of a recalcitrant staphylococcus epidermidis prosthetic knee infection with intraoperative bacteriophage therapy. Pharmaceuticals 14. https://doi.org/10.3390/ph14030231
Ferry T, Kolenda C, Batailler C et al (2021) Case Report: arthroscopic debridement antibiotics and Implant Retention with Local Injection of Personalized Phage Therapy to Salvage a Relapsing Pseudomonas Aeruginosa prosthetic knee infection. Front Med (Lausanne) 8:569159. https://doi.org/10.3389/fmed.2021.569159
Neuts A-S, Berkhout HJ, Hartog A, Goosen JHM (2021) Bacteriophage therapy cures a recurrent Enterococcus faecalis infected total hip arthroplasty? A case report. Acta Orthop 92:678–680. https://doi.org/10.1080/17453674.2021.1968714
Ramirez-Sanchez C, Gonzales F, Buckley M et al (2021) Successful treatment of staphylococcus aureus prosthetic joint infection with bacteriophage therapy. Viruses 13. https://doi.org/10.3390/v13061182
Schoeffel J, Wang EW, Gill D et al (2022) Successful use of salvage bacteriophage therapy for a recalcitrant MRSA knee and hip prosthetic joint infection. Pharmaceuticals 15. https://doi.org/10.3390/ph15020177
Racenis K, Rezevska D, Madelane M et al (2022) Use of phage cocktail BFC 1.10 in Combination with Ceftazidime-Avibactam in the treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report. Front Med 9. https://doi.org/10.3389/fmed.2022.851310
Cesta N, Pini M, Mulas T et al (2023) Application of phage therapy in a case of a chronic hip-prosthetic joint infection due to Pseudomonas aeruginosa: an Italian real-life experience and in Vitro Analysis. Open Forum Infect Dis 10. https://doi.org/10.1093/ofid/ofad051
Fedorov E, Samokhin A, Kozlova Y et al (2023) Short-term outcomes of phage-antibiotic combination treatment in adult patients with periprosthetic hip joint infection. Viruses 15. https://doi.org/10.3390/v15020499
Doub JB, Chan B, Johnson AJ (2023) Salphage: salvage bacteriophage therapy for a chronic Enterococcus faecalis prosthetic joint infection. IDCases 33:e01854. https://doi.org/10.1016/j.idcr.2023.e01854
Limoli DH, Jones CJ, Wozniak DJ (2015) Bacterial extracellular polysaccharides in Biofilm formation and function. https://doi.org/10.1128/microbiolspec.MB-0011-2014. Microbiol Spectr 3:
Visperas A, Santana D, Klika AK et al (2022) Current treatments for biofilm-associated periprosthetic joint infection and new potential strategies. J Orthop Res 40:1477–1491. https://doi.org/10.1002/jor.25345
Molina-Manso D, del Prado G, Ortiz-Pérez A et al (2013) In vitro susceptibility to antibiotics of staphylococci in biofilms isolated from orthopaedic infections. Int J Antimicrob Agents 41:521–523. https://doi.org/10.1016/j.ijantimicag.2013.02.018
Abushaheen MA, Muzaheed, Fatani AJ et al (2020) Antimicrobial resistance, mechanisms and its clinical significance. Dis Mon 66:100971. https://doi.org/10.1016/j.disamonth.2020.100971
Ghosh D, Veeraraghavan B, Elangovan R, Vivekanandan P (2020) Antibiotic resistance and epigenetics: more to it than meets the Eye. Antimicrob Agents Chemother 64. https://doi.org/10.1128/AAC.02225-19
(2022) Global Antimicrobial Resistance and Use Surveillance System (GLASS) report 2022. World Health Organization
Walter N, Rupp M, Baertl S et al (2022) Periprosthetic joint infection: patients benefit from a multidisciplinary team approach. Bone Joint Res 11:8–9. https://doi.org/10.1302/2046-3758.111.BJR-2021-0499
Kapadia BH, Berg RA, Daley JA et al (2016) Periprosthetic joint infection. Lancet 387:386–394. https://doi.org/10.1016/S0140-6736(14)61798-0
Leitner L, Posch F, Amerstorfer F et al (2020) The Dark side of Arthroplasty: competing risk analysis of failed hip and knee arthroplasty with Periprosthetic Joint infection. J Arthroplasty 35:2601–2606e1. https://doi.org/10.1016/j.arth.2020.04.078
Triffault-Fillit C, Ferry T, Laurent F et al (2019) Microbiologic epidemiology depending on time to occurrence of prosthetic joint infection: a prospective cohort study. Clin Microbiol Infect 25:353–358. https://doi.org/10.1016/j.cmi.2018.04.035
Manning L, Metcalf S, Clark B et al (2020) Clinical characteristics, etiology, and initial management strategy of newly diagnosed Periprosthetic Joint infection: a Multicenter, prospective observational cohort study of 783 patients. Open Forum Infect Dis 7:ofaa068. https://doi.org/10.1093/ofid/ofaa068
Tsai Y, Chang C-H, Lin Y-C et al (2019) Different microbiological profiles between hip and knee prosthetic joint infections. J Orthop Surg (Hong Kong) 27:2309499019847768. https://doi.org/10.1177/2309499019847768
Gonzalez Moreno M, Trampuz A, Di Luca M (2017) Synergistic antibiotic activity against planktonic and biofilm-embedded Streptococcus agalactiae, Streptococcus pyogenes and Streptococcus oralis. J Antimicrob Chemother 72:3085–3092. https://doi.org/10.1093/jac/dkx265
Steadman W, Chapman P, Schuetz M et al (2023) Local antibiotic delivery options in prosthetic joint infection. https://doi.org/10.3390/antibiotics12040752. ANTIBIOTICS-BASEL 12:
Miller R, Higuera CA, Wu J et al (2020) Periprosthetic Joint Infection: a review of Antibiotic Treatment. JBJS Rev 8:e1900224. https://doi.org/10.2106/JBJS.RVW.19.00224
Nelson SB, Pinkney JA, Chen AF, Tande AJ (2023) Periprosthetic Joint infection: current clinical challenges. Clin Infect Dis 77:e34–e45. https://doi.org/10.1093/cid/ciad360
Prendki V, Ferry T, Sergent P et al (2017) Prolonged suppressive antibiotic therapy for prosthetic joint infection in the elderly: a national multicentre cohort study. Eur J Clin Microbiol Infect Dis 36:1577–1585. https://doi.org/10.1007/s10096-017-2971-2
Escudero-Sanchez R, Senneville E, Digumber M et al (2020) Suppressive antibiotic therapy in prosthetic joint infections: a multicentre cohort study. Clin Microbiol Infect 26:499–505. https://doi.org/10.1016/j.cmi.2019.09.007
Salmond GPC, Fineran PC (2015) A century of the phage: past, present and future. Nat Rev Microbiol 13:777–786. https://doi.org/10.1038/nrmicro3564
Dy RL, Richter C, Salmond GPC, Fineran PC (2014) Remarkable mechanisms in microbes to resist phage infections. Annu Rev Virol 1:307–331. https://doi.org/10.1146/annurev-virology-031413-085500
Roach DR, Donovan DM (2015) Antimicrobial bacteriophage-derived proteins and therapeutic applications. Bacteriophage 5:e1062590. https://doi.org/10.1080/21597081.2015.1062590
Shahed-Al-Mahmud M, Roy R, Sugiokto FG et al (2021) Phage φAB6-Borne depolymerase combats Acinetobacter baumannii Biofilm formation and infection. Antibiot (Basel) 10. https://doi.org/10.3390/antibiotics10030279
Kolenda C, Josse J, Medina M et al (2020) Evaluation of the activity of a combination of three bacteriophages alone or in Association with antibiotics on Staphylococcus aureus embedded in Biofilm or internalized in Osteoblasts. Antimicrob Agents Chemother 64. https://doi.org/10.1128/AAC.02231-19
Schwartz DA, Rodríguez-Ramos JA, Shaffer M et al (2023) Human-gut Phages Harbor Sporulation genes. mBio 14:e0018223. https://doi.org/10.1128/mbio.00182-23
Huang Y, Wang W, Zhang Z et al (2022) Phage products for fighting Antimicrobial Resistance. https://doi.org/10.3390/microorganisms10071324. Microorganisms 10:
Garb J, Lopatina A, Bernheim A et al (2022) Multiple phage resistance systems inhibit infection via SIR2-dependent NAD(+) depletion. Nat Microbiol 7:1849–1856. https://doi.org/10.1038/s41564-022-01207-8
Acknowledgements
None.
Funding
Open access funding provided by Hospices Civils de Lyon.
Author information
Authors and Affiliations
Contributions
The first and corresponding authors contributed to the study conception and design. Material preparation, data collection, analysis and the draft of the manuscript were performed by the first author. All authors commented on previous versions of the manuscript and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare that this research was conducted in the absence of any financial interests or personal relationships that could be construed as a potential conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Yang, S., Mukh, A.A., Abdelatif, E. et al. Bacteriophage therapy as an innovative strategy for the treatment of Periprosthetic Joint Infection: a systematic review. International Orthopaedics (SICOT) (2024). https://doi.org/10.1007/s00264-024-06295-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00264-024-06295-1