Periprosthetic joint infection (PJI) remains one of the most common and devastating complications following arthroplasty. As advances in surgical innovations, education, and experience in arthroplasty continue to play a key role in reducing failure modes, such as mechanical failures and wear-related issues, PJIs have become more prominent. From a materials perspective, innovations in bone cement and cementing techniques,1 as well as the development of highly cross-linked polyethylene,2 have contributed to improved outcomes. Furthermore, while longer-term studies are awaited to determine the durability of these results, advances in technology and surgical techniques,3 along with the resultant improvements in precision of component positioning and preoperative planning,4 have shown a promising trend in reducing the incidence of other failure modes, such as instability,5 thereby making PJIs more prominent as a clinical challenge. This complication often necessitates revision surgery and long-term antibiotic treatment, leading to substantial morbidity and healthcare costs, with a recent study highlighting an in-hospital mortality rate of 3.5% among 52,286 patients treated for PJI.6 Despite recent developments in the diagnosis and treatment of PJIs, patients often experience lasting functional deficits and a high risk of PJI recurrence, suggesting that even the “winners are losers” in this battle against PJI.7 Balancing the latest research advances with practical clinical applications is crucial to improving outcomes for these patients.
The diagnosis of PJI is inherently complex and requires a multifaceted approach. There is no single standalone test with sufficient specificity or sensitivity to confirm or exclude the diagnosis of PJI. However, recent advances in diagnostic methods have shown the potential to enhance the reliability of PJI detection. For instance, synovial fluid neutrophil extracellular traps (SF-NETs) have emerged as a promising biomarker, potentially improving diagnostic accuracy, particularly in culture-negative and antibiotic-pretreated cases.8 A recent study demonstrated an area under the curve (AUC) of 0.971 for SF-NETs, with sensitivity and specificity surpassing traditional markers, including ESR, CRP, synovial white blood cell count (WBC), and polymorphonuclear neutrophil percentage (PMN%).8 In addition, some patients, such as those with rheumatoid arthritis (RA), may present additional diagnostic challenges due to underlying inflammation. In these patients, adjusted thresholds for these markers could enhance diagnostic efficacy.9
Additionally, a calprotectin lateral flow immunoassay has been proposed to aid in diagnosing PJI in patients who do not meet the European Bone and Joint Infection Society (EBJIS) criteria for positive infection. A calprotectin level of > 50 mg/l showed high sensitivity (96.2%), specificity (90.9%), positive predictive value (92.6%), and negative predictive value (95.2%) for diagnosing infection.10 Nevertheless, EBJIS criteria remain the diagnostic criterion of choice. Histopathological analysis also contributes to PJI diagnosis, and it is important for orthopaedic surgeons to recognize its value. Although the number of samples (typically between three and six tissue specimens)11 contributes to the accuracy of the diagnosis, the crucial point is ensuring that histopathology is performed as part of the diagnostic process.
Microbiological culture remains a cornerstone in the diagnosis of PJI, although its sensitivity is not always optimal due to factors such as biofilm formation and intracellular persistence.12 Recent efforts to optimize tissue pretreatment methods, such as tissue-mechanical homogenization (T-MH) and tissue-dithiothreitol (T-DTT) treatment, have shown promise in improving microbial detection. Fang et al12 demonstrated that T-MH had the highest sensitivity for detecting microorganisms, and combining it with T-DTT, a method requiring no special equipment, could further enhance bacterial yield in PJI diagnosis, underscoring the role of optimizing microbiological preanalytics to improve culture results.
Molecular diagnostics, particularly next-generation sequencing (NGS), have been reported as promising adjunctive tools for diagnosing PJI, particularly in culture-negative cases. NGS can identify a broad range of pathogens by sequencing all DNA in a sample, with reported sensitivity rates up to 89% (metagenomic NGS) in such challenging cases.13 Despite its advantages, NGS remains supplementary to traditional methods due to concerns such as false positives and lack of consistent superiority in specificity over cultures.14 Cell-free DNA NGS (cfDNA NGS) further reduces turnaround time and detects antimicrobial resistance genes, potentially guiding more targeted treatments.13 While promising, these technologies should complement established diagnostics, particularly in complex or inconclusive cases.
The integration of artificial intelligence (AI) into the diagnosis and management of PJI is promising. Through natural language processing (NLP), AI has shown potential in automating data extraction from electronic health records, thus enhancing diagnostic accuracy and efficiency.15 Moreover, AI-driven predictive algorithms can help to identify patients at risk of developing PJI,16 assisting surgeons in making informed preoperative decisions. Machine-learning models, such as artificial neural networks, have demonstrated the ability to predict PJI following revision total knee arthroplasty by analyzing a range of risk factors.17 Additionally, AI frameworks applied to imaging methods, such as dynamic bone scintigraphy, have shown superior diagnostic performance compared to traditional methods, offering a potential tool for accurate PJI diagnosis and improving patient outcomes.18
The appearance and organization of bacterial biofilm on a prosthesis is a critical step in the pathogenesis of PJI. Biofilms pose a substantial challenge, often necessitating revision arthroplasty due to their resistance to eradication without surgical intervention. However, biofilm is not the sole reason for the persistence of infection. Small colony variants and intracellular persistence, which are closely linked to biofilm, also play an important role in chronic infections.19 This issue is becoming increasingly relevant as more caution is advised regarding the use of rifampicin between stages of staged operations, as it remains one of the few antibiotics effective against intracellular staphylococci. Recent advances, however, offer a promising outlook on biofilm management. Halicin, the first antimicrobial agent identified through a deep-learning AI approach, has demonstrated effectiveness against various bacterial strains.20 Higashihira et al21 reported positive findings on the efficacy of halicin against Staphylococcus aureus biofilms on orthopaedic substrates and recommended further in vitro studies to validate these results.21 Additionally, Lin et al22 found that ethylenediaminetetraacetic acid-normal saline irrigation (EDTA-NS) disrupted S. aureus biofilms both in vivo and in vitro, even without additional antibiotic therapy. Finally, although the use of hydrogen peroxide has been largely abandoned in the UK due to risks of gas embolism, reconsidering its use in hip and knee arthroplasty has been proposed due to its benefits in combating and disrupting bacterial biofilm.23 This could represent a further avenue in reducing the burden of biofilm in PJI.23
The administration of antibiotics in the treatment of PJI remains a key component of the management strategy. Recent advances in local antibiotic administration, particularly intraosseous (IO) delivery and continuous local antibiotic perfusion (CLAP), show promise in improving outcomes.
CLAP has gained attention as a delivery system for orthopaedic infections by maintaining high local concentrations of antibiotics at the site of infection for extended periods. This technique, distinct from catheter-based methods,24 utilizes negative pressure to direct antibiotics to the infected area while minimizing dead space and mitigating systemic side effects.25 However, recent studies indicate that high concentrations of gentamicin can negatively impact bone cell viability and mineralization potential. While gentamicin’s cellular toxicity is well documented,26 these findings highlight the need for further investigation into optimal dosage and duration to balance efficacy with cellular health.27
IO antibiotic delivery provides markedly higher local antibiotic concentrations compared with traditional intravenous (IV) routes, achieving ten- to 15-fold higher levels around the knee in primary arthroplasty.28 This method enhances targeted local drug delivery and has shown potential in reducing early PJI risk in THA and TKA,29 potentially representing a promising adjunct in managing established PJIs. Similarly, topical antibiotics, including vancomycin powder, aim to deliver high local concentrations at the surgical site. While some studies suggest a reduction in PJI risk,30 these results are confounded by the concurrent use of antiseptic strategies such as povidone-iodine lavage. Potential antibiotic resistance and variable outcomes indicate the need for more robust evidence before recommending routine use.30
Extended systemic antibiotic administration has traditionally been central to PJI management. However, recent findings have suggested that adequate surgical debridement with high local concentrations of targeted antibiotics during first-stage revision surgery can achieve high success rates without prolonged systemic therapy. A review of two-stage revision hip arthroplasties showed a 91% success rate with no statistically significant effect of the duration of IV antibiotics (less than 48 hours, less than five days, or over five days).31 The evolving landscape in PJI management emphasizes the need for tailored approaches that optimize local drug delivery while minimizing systemic toxicity.32
The debridement, antibiotics, and implant retention (DAIR) protocol is a key approach for managing acute PJI, aiming to retain the prosthesis and reduce morbidity. Double DAIR, or staged DAIR, has been proposed to enhance infection control through phased interventions.33 However, the current evidence supporting its effectiveness is limited and not robust. While some observational studies suggest potential benefits,34 these findings are not backed by high-level evidence and results across studies have been inconsistent. Infection-specific imaging advances, such as the bacteria-specific hybrid tracer (99mTc-UBI29-41-Cy5), could offer promising support by precisely identifying infection locations, thereby improving the efficacy of debridement and infection control.35
Recent research underscores the complexity and scope of revision surgery for PJI, revealing that ‘real-world’ revision and reinfection rates are often underestimated. Resl et al36 highlighted this issue by analyzing the German joint registry, stressing the need to appreciate the full scale of PJI and its consequences. Exchange arthroplasty, the cornerstone of surgical management for PJI, can be performed as either a single-stage or two-stage procedure. Histological analysis is widely used during the reimplantation phase of revision surgery; however, a recent study suggests that it may not reliably predict persistent infection.37 Additionally, the type of spacer used in a two-stage exchange remains a topic of debate. Wu et al38 reported that while both prosthetic and cement spacers are effective for treating chronic knee PJI, prosthetic spacers were associated with better range of motion and patient-reported outcome measures (PROMs). However, the single-stage approach has recently gained attention with fewer procedures, reduced morbidity and mortality, shorter hospital stays, lower healthcare costs, and comparable or even superior outcomes in select patient groups.39,40
Salvage procedures may become necessary in severe PJI cases where reconstruction is not feasible. In addition to traditional surgical management, bacteriophage therapy could represent a revolutionary approach for treating refractory infections. Although still in its early stages and complicated to access, recent studies have suggested promising outcomes in bone and joint infections treated with phages.41 Further research is needed to fully understand their efficacy, but phage therapy holds the potential to greatly alter the management of severe PJIs in the future.
Recent advances in the diagnosis, management, and prevention of PJI offer promising avenues to improving patient outcomes. Continued research and the integration of innovative technologies are essential to overcoming the challenges posed by PJI. By harmonizing cutting-edge research with practical clinical applications, we can move closer to minimizing the burden of this complex and devastating complication.
References
1. Barrack RL , Mulroy RD Jr , Harris WH . Improved cementing techniques and femoral component loosening in young patients with hip arthroplasty. A 12-year radiographic review . J Bone Joint Surg Br . 1992 ; 74-B ( 3 ): 385 – 389 . Crossref PubMed Google Scholar
2. de Steiger R , Lorimer M , Graves SE . Cross-linked polyethylene for total hip arthroplasty markedly reduces revision surgery at 16 years . J Bone Joint Surg Am . 2018 ; 100-A ( 15 ): 1281 – 1288 . Crossref PubMed Google Scholar
3. Fontalis A , Kayani B , Plastow R , et al. A prospective randomized controlled trial comparing CT-based planning with conventional total hip arthroplasty versus robotic arm-assisted total hip arthroplasty . Bone Joint J . 2024 ; 106-B ( 4 ): 324 – 335 . Crossref PubMed Google Scholar
4. Mancino F , Fontalis A , Kayani B , Magan A , Plastow R , Haddad FS . The current role of CT in total knee arthroplasty . Bone Joint J . 2024 ; 106-B ( 9 ): 892 – 897 . Crossref PubMed Google Scholar
5. Bendich I , Vigdorchik JM , Sharma AK , et al. Robotic assistance for posterior approach total hip arthroplasty is associated with lower risk of revision for dislocation when compared to manual techniques . J Arthroplasty . 2022 ; 37 ( 6 ): 1124 – 1129 . Crossref PubMed Google Scholar
6. Reinhard J , Lang S , Walter N , et al. In-hospital mortality of patients with periprosthetic joint infection demographic, comorbidity, and complication profiles of 52,286 patients . Bone Jt Open . 2024 ; 5 ( 4 ): 367 – 373 . Crossref PubMed Google Scholar
7. Haddad FS . Even the winners are losers . Bone Joint J . 2017 ; 99-B ( 5 ): 561 – 562 . Crossref PubMed Google Scholar
8. Cai Y , Liang J , Chen X , et al. Synovial fluid neutrophil extracellular traps could improve the diagnosis of periprosthetic joint infection . Bone Joint Res . 2023 ; 12 ( 2 ): 113 – 120 . Crossref PubMed Google Scholar
9. Wang Y , Li G , Ji B , et al. Diagnosis of periprosthetic joint infections in patients who have rheumatoid arthritis . Bone Joint Res . 2023 ; 12 ( 9 ): 559 – 570 . Crossref PubMed Google Scholar
10. Macheras GA , Argyrou C , Tzefronis D , et al. Intraoperative calprotectin lateral flow immunoassay can assist decision-making between one- and two-stage revision total hip arthroplasty for patients with suspected periprosthetic joint infection . Bone Joint J . 2024 ; 106-B ( 5 ): 118 – 124 . Crossref PubMed Google Scholar
11. Sigmund IK , Yeghiazaryan L , Luger M , Windhager R , Sulzbacher I , McNally MA . Three to six tissue specimens for histopathological analysis are most accurate for diagnosing periprosthetic joint infection . Bone Joint J . 2023 ; 105-B ( 2 ): 158 – 165 . Crossref PubMed Google Scholar
12. Fang X , Zhang L , Cai Y , et al. Effects of different tissue specimen pretreatment methods on microbial culture results in the diagnosis of periprosthetic joint infection . Bone Joint Res . 2021 ; 10 ( 2 ): 96 – 104 . Crossref PubMed Google Scholar
13. Indelli PF , Ghirardelli S , Violante B , Amanatullah DF . Next generation sequencing for pathogen detection in periprosthetic joint infections . EFORT Open Rev . 2021 ; 6 ( 4 ): 236 – 244 . Crossref PubMed Google Scholar
14. Kildow BJ , Ryan SP , Danilkowicz R , et al. Next-generation sequencing not superior to culture in periprosthetic joint infection diagnosis . Bone Joint J . 2021 ; 103-B ( 1 ): 26 – 31 . Crossref PubMed Google Scholar
15. Lisacek-Kiosoglous AB , Powling AS , Fontalis A , Gabr A , Mazomenos E , Haddad FS . Artificial intelligence in orthopaedic surgery: exploring its applications, limitations, and future direction . Bone Joint Res . 2023 ; 12 ( 7 ): 447 . Crossref PubMed Google Scholar
16. Kuo FC , Hu WH , Hu YJ . Periprosthetic joint infection prediction via machine learning: comprehensible personalized decision support for diagnosis . J Arthroplasty . 2022 ; 37 ( 1 ): 132 – 141 . Crossref PubMed Google Scholar
17. Klemt C , Yeo I , Harvey M , et al. The use of artificial intelligence for the prediction of periprosthetic joint infection following aseptic revision total knee arthroplasty . J Knee Surg . 2024 ; 37 ( 2 ): 158 – 166 . Crossref PubMed Google Scholar
18. Nie L , Sun Z , Shan F , Li C , Ding X , Shen C . An artificial intelligence framework for the diagnosis of prosthetic joint infection based on 99mTc-MDP dynamic bone scintigraphy . Eur Radiol . 2023 ; 33 ( 10 ): 6794 – 6803 . Crossref PubMed Google Scholar
19. Sendi P , Rohrbach M , Graber P , Frei R , Ochsner PE , Zimmerli W . Staphylococcus aureus small colony variants in prosthetic joint infection . Clin Infect Dis . 2006 ; 43 ( 8 ): 961 – 967 . Crossref PubMed Google Scholar
20. Stokes JM , Yang K , Swanson K , et al. A deep learning approach to antibiotic discovery . Cell . 2020 ; 180 ( 4 ): 688 – 702 . Crossref PubMed Google Scholar
21. Higashihira S , Simpson SJ , Morita A , et al. Halicin remains active against staphylococcus aureus in biofilms grown on orthopaedically relevant substrates . Bone Joint Res . 2024 ; 13 ( 3 ): 101 – 109 . Crossref PubMed Google Scholar
22. Lin J , Suo J , Bao B , et al. Efficacy of EDTA-NS irrigation in eradicating staphylococcus aureus biofilm-associated infection . Bone Joint Res . 2024 ; 13 ( 1 ): 40 – 51 . Crossref PubMed Google Scholar
23. Farhan-Alanie OM , Kennedy JW , Meek RMD , Haddad FS . Is it time to reconsider the use of hydrogen peroxide in hip and knee arthroplasty . Bone Joint J . 2023 ; 105-B ( 2 ): 97 – 98 . Crossref PubMed Google Scholar
24. Whiteside LA , Roy ME . One-stage revision with catheter infusion of intraarticular antibiotics successfully treats infected THA . Clin Orthop Relat Res . 2017 ; 475 ( 2 ): 419 – 429 . Crossref PubMed Google Scholar
25. Himeno D , Matsuura Y , Maruo A , Ohtori S . A novel treatment strategy using continuous local antibiotic perfusion: a case series study of a refractory infection caused by hypervirulent Klebsiella pneumoniae . J Orthop Sci . 2022 ; 27 ( 1 ): 272 – 280 . Crossref PubMed Google Scholar
26. Chang Y , Goldberg VM , Caplan AI . Toxic effects of gentamicin on marrow-derived human mesenchymal stem cells . Clin Orthop Relat Res . 2006 ; 452 : 242 – 249 . Crossref PubMed Google Scholar
27. Yamamoto Y , Fukui T , Sawauchi K , et al. Effects of high antibiotic concentrations applied to continuous local antibiotic perfusion on human bone tissue-derived cells . Bone Joint Res . 2024 ; 13 ( 3 ): 91 – 100 . Crossref PubMed Google Scholar
28. Chin SJ , Moore GA , Zhang M , Clarke HD , Spangehl MJ , Young SW . The AAHKS Clinical Research Award: intraosseous regional prophylaxis provides higher tissue concentrations in high bmi patients in total knee arthroplasty: a randomized trial . J Arthroplasty . 2018 ; 33 ( 7S ): S13 – S18 . Crossref PubMed Google Scholar
29. Parkinson B , McEwen P , Wilkinson M , et al. Intraosseous regional prophylactic antibiotics decrease the risk of prosthetic joint infection in primary TKA: a multicenter study . Clin Orthop Relat Res . 2021 ; 479 ( 11 ): 2504 – 2512 . Crossref PubMed Google Scholar
30. Mancino F , Gant V , Meek DRM , Haddad FS . Vancomycin powder in total joint replacement . Bone Joint J . 2023 ; 105-B ( 8 ): 833 – 836 . Crossref PubMed Google Scholar
31. Petrie MJ , Panchani S , Al-Einzy M , Partridge D , Harrison TP , Stockley I . Systemic antibiotics are not required for successful two-stage revision hip arthroplasty . Bone Joint J . 2023 ; 105-B ( 5 ): 511 – 517 . Crossref PubMed Google Scholar
32. Ferguson J , Bourget-Murray J , Stubbs D , McNally M , Hotchen AJ . A comparison of clinical and radiological outcomes between two different biodegradable local antibiotic carriers used in the single-stage surgical management of long bone osteomyelitis . Bone Joint Res . 2023 ; 12 ( 7 ): 412 – 422 . Crossref PubMed Google Scholar
33. McQuivey KS , Bingham J , Chung A , et al. The double DAIR: A 2-stage debridement with prosthesis-retention protocol for acute periprosthetic joint infections . JBJS Essent Surg Tech . 2021 ; 11 ( 1 ): e19.00071-e19.00071 . Crossref PubMed Google Scholar
34. Perez BA , Koressel JE , Lopez VS , Barchick S , Pirruccio K , Lee GC . Does a 2-stage debridement result in higher rates of implant retention compared with single debridement alone? J Arthroplasty . 2022 ; 37 ( 7S ): S669 – S673 . Crossref PubMed Google Scholar
35. Welling MM , Warbroek K , Khurshid C , et al. A radio- and fluorescently labelled tracer for imaging and quantification of bacterial infection on orthopaedic prostheses: a proof of principle study . Bone Joint Res . 2023 ; 12 ( 1 ): 72 – 79 . Crossref PubMed Google Scholar
36. Resl M , Becker L , Steinbrück A , Wu Y , Perka C . Re-revision and mortality rate following revision total hip arthroplasty for infection . Bone Joint J . 2024 ; 106-B ( 6 ): 565 – 572 . Crossref PubMed Google Scholar
37. Straub J , Staats K , Vertesich K , Kowalscheck L , Windhager R , Böhler C . Two-stage revision for periprosthetic joint infection after hip and knee arthroplasty . Bone Joint J . 2024 ; 106-B ( 4 ): 372 – 379 . Crossref PubMed Google Scholar
38. Wu B , Su J , Zhang Z , et al. Prosthetic spacers in two-stage revision for knee periprosthetic joint infection achieve better function and similar infection control . Bone Joint Res . 2024 ; 13 ( 6 ): 306 – 314 . Crossref PubMed Google Scholar
39. Lenguerrand E , Whitehouse MR , Kunutsor SK , et al. Mortality and re-revision following single-stage and two-stage revision surgery for the management of infected primary knee arthroplasty in England and Wales: evidence from the National Joint Registry . Bone Joint Res . 2022 ; 11 ( 10 ): 690 – 699 . Crossref PubMed Google Scholar
40. Haddad FS , Sukeik M , Alazzawi S . Is single-stage revision according to a strict protocol effective in treatment of chronic knee arthroplasty infections? Clin Orthop Relat Res . 2015 ; 473 ( 1 ): 8 – 14 . Crossref PubMed Google Scholar
41. Suh GA , Ferry T , Abdel MP . Phage therapy as a novel therapeutic for the treatment of bone and joint infections . Clin Infect Dis . 2023 ; 77 ( Suppl 5 ): S407 – S415 . Crossref PubMed Google Scholar
Author contributions
A. Fontalis: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Writing – original draft, Writing – review & editing
W. Wignadasan: Data curation, Investigation, Methodology, Resources, Validation, Writing – original draft, Writing – review & editing
B. Kayani: Investigation, Methodology, Supervision, Validation, Writing – review & editing
F. S. Haddad: Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing
Funding statement
The authors received no financial or material support for the research, authorship, and/or publication of this article.
Data sharing
All data generated or analyzed during this study are included in the published article and/or in the supplementary material.
Social media
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