What’s New in Musculoskeletal Infection

Periprosthetic joint infection (PJI) continues to be a devastating complication after total joint arthroplasty (TJA) and remains one of the most common causes for revision TJA. Projections are clear that primary TJA will continue to increase annually and, with it, PJI. In 2022, there was an emphasis on the global economics of PJI management, whereas, in 2023, the literature attempted to provide a more granular look at the financial burden of PJI. Wixted et al. analyzed the direct costs of PJI at a tertiary referral center, including the costs of relevant ancillary services, and demonstrated that the failure of successful reimplantation and the need for additional surgical procedures more than doubled the direct costs of PJI management ($38,865 compared with $79,223)1. Additionally, Charalambous et al. assessed cost drivers of 2-stage exchange for PJI treatment and found that age, illicit drug use, the Elixhauser comorbidity index, and number of surgical procedures before reimplantation were all associated with an increased cost of PJI treatment and that failure to clear infection was associated with a >50% increase in total costs at 2 years after treatment2. In 2023, the psychosocial impact of PJI was also highlighted. Shichman et al. demonstrated that the sequelae of PJI decreased patient-reported quality of life, social satisfaction, and mental health, with approximately 1 of 4 patients regretting their initial decision to undergo primary TJA3. Das et al. demonstrated that patients who underwent spacer placement for PJI after TJA had a disproportionately higher incidence of mental health disorders following a surgical procedure compared with aseptic revisions and primary TJA, urging surgeons to consider collaborative management with mental health professionals in the treatment of PJI4. Not only are mental health disorders a consequence of PJI, but they are also likely a risk factor. Harmer et al. demonstrated that depression and anxiety were associated with an increased risk of any infection, and specifically with an increased risk of PJI after revision total knee arthroplasty (TKA)5. Two-stage exchange continues to be considered the mainstay treatment of PJI, although 1-stage treatment is gaining popularity. In an Australian cost-utility analysis using a Markov model, Okafor et al. found that opting for an index 2-stage revision instead of a 1-stage revision when there is no compelling indication for 2-stage exchange is not likely to be cost-effective6. In the United States, most surgeons are utilizing 2-stage exchange, with 75% of American Association of Hip and Knee Surgeons (AAHKS) survey respondents reporting the use of 2-stage exchange rather than 1-stage exchange and with the majority of surgeons handling <20 PJI cases per year7. Despite this, the use of single-stage exchange is increasing across the globe, with a single high-volume European center reporting a >30% increase in 1-stage exchange from 2008 to 20218. Fehring et al. reported a 99% reimplantation rate after 2-stage exchange at their specialized PJI referral center, which is far better than the previously published reimplantation rates9. This work highlights the potential benefit of a national network of specialized PJI centers with experienced revision surgeons performing high-volume procedures to treat infection and with multidisciplinary consultants familiar with the special needs of patients with PJI. The complex surgical management and the devastating economic, physical, and psychosocial burdens of PJI make concerted research efforts crucial moving forward. Prevention Although areas of new research and technology continue to focus on the development of novel diagnostics and treatment strategies for PJI, improvement in the prevention of this catastrophic complication is the best way that we can help our patients. Unfortunately, despite all of our scientific advances in prevention, a recent national database analysis of >500,000 patients undergoing TJA showed that we have made little impact in lowering our PJI rates following total hip arthroplasty (THA) and TKA from 2005 to 201910. Nevertheless, there have been several impactful articles in 2023 on the prevention of PJI. The optimal perioperative irrigation solutions continue to be debated, with many options including dilute povidone-iodine, chlorhexidine, and acetic acid-based commercial compounds. A recent systematic review and meta-analysis of 13 papers found a reduction in PJI rates with povidone-iodine, but no difference between povidone-iodine and chlorhexidine11. A study of 3,232 patients who underwent primary THA or TKA found a significant reduction in PJI rates with the use of dilute povidone-iodine12, adding to the existing literature supporting its use. Chlorhexidine still plays a role in the prevention of PJI, with data showing the effectiveness of preoperative application via cloth wipes13. Although obesity is a clear risk factor for PJI, much research has focused on optimizing this high-risk cohort to prevent infection. Many patients are now taking glucagon-like peptide-1 (GLP-1) receptor agonists, so the impact of this class of medications on infection rates and complications requires further analysis. One database study on patients undergoing TKA found that those taking semaglutide had lower rates of PJI, but a higher risk of medical complications and hypoglycemic events, postoperatively14. In obese patients, a recent randomized controlled trial found no difference in PJI rates in patients receiving either negative-pressure wound therapy or an occlusive silver-impregnated dressing15. We continue to work with our dental colleagues to help to prevent PJI in patients who require both THA or TKA and dental procedures. Although other studies have failed to show a benefit to routine dental screening prior to elective arthroplasty16, 1 study found a reduction in PJI rates within the first month after the surgical procedure17. Another study in the Journal of the American Dental Association found no benefit to routine antibiotic prophylaxis for PJI prevention prior to dental procedures following THA and TKA18. Despite minimal change in our PJI rates in recent years, further research must continue to emphasize prevention. With advances in artificial intelligence, machine learning may also play a role going forward to aid perioperative health optimization and guide surgical planning to help to predict and prevent PJI19. Diagnosis Advances in the diagnosis of PJI involved several key areas: the utility of rapid and point-of-care (POC) testing, clinical testing of novel serum and synovial fluid laboratory markers (including ratios of a combination of markers), and the exploration of next-generation sequencing and testing of machine learning models. In testing prior to revision TJA, a fast POC synovial C-reactive protein (CRP) cassette test with a minimum cutoff value of ≥8 mg/L had very good accuracy for the diagnosis of chronic PJI20. This POC test had comparable sensitivity and slightly lower specificity when compared with a laboratory method (threshold, 2.7 mg/L). A prospective study of a rapid D-lactic acid strip test demonstrated comparable sensitivity and specificity with 2 different leukocyte esterase (LE) strip tests in a synovial fluid analysis for PJI21. In a retrospective study of PJI diagnosis, Akçaalan et al. studied the utility of the large unstained cell percentage (%LUC) for reimplantation in 2-stage exchange arthroplasty for PJI22. When a predictive cutoff value of 1.75% for the %LUC was used, sensitivity was 69.2% and specificity was 73%. In examining the synovial absolute neutrophil count23, an optimal threshold for synovial absolute neutrophil count of 1,415.5 cells/μL was associated with an area under the receiver operating characteristic curve (AUC) of 0.930 for a diagnosis of chronic knee PJI. A threshold for the synovial absolute neutrophil count of 2,247 cells/μL showed an AUC of 0.905 for a diagnosis of chronic hip PJI. In a literature review of serum presepsin in PJI24, studies demonstrated AUC values ranging from 0.86 to 0.926. These values were higher than the AUCs for CRP in each of their respective studies, yet further study is needed to explore this emerging biomarker. Tarabichi et al. found that plasma D-dimer was noninferior to serum CRP with respect to PJI diagnosis25. When examining PJI caused by indolent organisms, D-dimer demonstrated the highest sensitivity at 93.8%. In a retrospective study of revision TJA, the CRP/albumin ratio and CRP/fibrinogen ratio were significantly higher in patients with PJI and showed better sensitivity and specificity than CRP for diagnosing PJI26. In another study, there were excellent AUCs for the CRP/albumin ratio (0.931) and the CRP/lymphocyte ratio (0.935)27. In an emerging technology, isothermal microcalorimetry improved time to PJI detection by nearly 2 days when compared with conventional cultures, along with better diagnostic accuracy, particularly in patients taking chronic antibiotics28. In a pilot study, mass spectrometry-based proteomic profiling of sonicated fluid differentiated Staphylococcus aureus-associated PJI from non-infectious failure after arthroplasty29. Metagenomic next-generation sequencing also showed promise in PJI detection, especially in patients with polymicrobial infection and/or culture-negative results30. Early work has also been presented utilizing a machine-learning-based analytical approach, based on 18 preoperative blood biochemical tests, to discriminate between PJI and aseptic cases31. Surgical Treatment Research published in the past year continues to clarify the role of each of the 3 major treatment options for PJI: DAIR (debridement, antibiotics, and implant retention), 2-stage exchange, and 1-stage exchange. DAIR The timing of DAIR procedures continues to show importance in the literature. A prospective multicenter study showed an overall success rate of DAIR procedures without suppressive antibiotics of 45% (85 of 189), with the highest success in patients treated for infection <1 month from the primary TKA32. Dislocation following DAIR for hip PJI was shown to be high at 19.9% in 151 patients treated for hip PJI. In patients who had components exchanged that increased hip stability, there was an elevenfold decrease in dislocation. Thus, techniques to increase hip stability are recommended in DAIR for hip PJI, regardless of intraoperative stability testing33. Acute PJI is a devastating complication following aseptic revision arthroplasty. One study found DAIR procedures with antibiotic suppression to be a viable option in these situations, with 80% survivorship free from revision for infection at 5 years34. A study comparing first-stage treatment with an antibiotic-loaded spacer and a DAIR procedure without the use of antibiotic-loaded cement showed similar rates of acute kidney injury (17.9% compared with 14.7%), suggesting that use of intravenous antibiotics rather than antibiotic bone cement is an independent risk factor for acute kidney injury in the treatment of PJI35. A 2-Stage Exchange Previous research has suggested a high rate of spacer retention in patients who undergo a planned 2-stage exchange for periprosthetic hip or knee infection. Treatment at a specialized PJI center appears to improve the rate of reimplantation to 99% (386 of 390) in these patients9. The necessity of intramedullary dowels in knee spacers was clarified by a recent study, which showed a 31% positive culture rate from femoral and tibial canals at the time of resection36. In a study of 203 patients who underwent 2-stage exchange for the treatment of periprosthetic knee infection, the success rate was 74%. Risk factors for failure were found to be male sex and a positive intraoperative culture at the time of reimplantation37. Poor outcomes continue to be seen with the treatment of fungal knee PJI, with 1 study showing infection-free survival at 2 years of 64% for treatment with 2-stage exchange combined with antifungal therapy38. A 1.5-Stage Exchange A 1.5-stage exchange for treatment of PJI, in which an articulating spacer is used for definitive management, has garnered recent interest among surgeons39,40. Two studies compared this treatment modality with traditional 2-stage exchange and showed comparable infection-free survivorship, lower cost, and similar pain scores, thus making it a reasonable treatment option in high-risk patients being treated for PJI39,40. Another study looking at retained hip spacers showed acceptable survivorship free of reinfection of 86% at 5 years, but showed high rates of stem loosening, subsidence, and unplanned reoperation for these patients, and those authors thus recommended limited use in healthy patients with higher functional demands41. A 1-Stage Exchange Although a prospective, multicenter, randomized study comparing 1-stage exchange with 2-stage exchange is ongoing in the United States, results are not yet available. However, 1-stage exchange continues to gain enthusiasm as a treatment for PJI, despite varied results. One study comparing DAIR, 1-stage exchange, and 2-stage exchange for PJI treatment showed the lowest risk of reoperation and no increase in mortality at 1 year in the 1-stage exchange cohort8. A retrospective study showed 92.7% survivorship free from revision for infection after 1-stage treatment for periprosthetic hip infection and massive bone loss with a cemented modular femoral stem42. Antibiotic Therapy Antibiotic Prophylaxis In a prospective, randomized controlled multicenter trial of 4,239 patients, vancomycin as an adjunct to cefazolin prophylaxis did not decrease the risk of surgical-site infection in patients without methicillin-resistant S. aureus (MRSA) colonization who were undergoing hip or knee arthroplasty43. In a retrospective cohort study of 2,451 TJAs, Kurcz et al. found no increased rate of allergic reaction with cefazolin prophylaxis in patients allergic to penicillin compared with patients without a penicillin allergy44. The rate of PJI was lower with cefazolin administration than with other antibiotics. A national database study of 22,558 patients who underwent TKA demonstrated increased risk of PJI in patients with a history of alcohol abuse, diabetes, and rheumatoid arthritis who underwent colonoscopy without antibiotic prophylaxis45. Antibiotic-Loaded Bone Cement In a retrospective cohort study of 9,366 patients undergoing primary TKA, Cieremans et al. reported that the use of gentamycin or tobramycin antibiotic-loaded bone cement did not decrease infection rate compared with no antibiotic-loaded bone cement46. In contrast, a cost-utility analysis within the single-payer Canadian health-care system showed that routine use of antibiotic-loaded bone cement in primary TKA was more cost-effective than use of antibiotic-free bone cement47. Based on German Arthroplasty Registry data on 13,612 intracapsular femoral neck fractures treated with arthroplasty, cemented fixation with antibiotic-loaded bone cement was associated with a lower risk of PJI compared with uncemented fixation in hemiarthroplasty, but not in THA48. In a retrospective cohort study of 52 two-stage revisions for the treatment of PJI after TKA, articulating spacers with only 1 g of vancomycin per bag of cement were associated with 88.5% survival of the reimplanted joint at 5-year follow-up and a 14% rate of acute kidney injury, which resolved without intervention in all cases49. Antibiotics at the Operative Site According to a prospective study of 1,659 patients who underwent primary TJA, 1 g of intra-articular vancomycin decreased the risk of acute postoperative PJI in patients who underwent TKA, but not in patients who underwent THA, without increasing the risk of local or systemic vancomycin toxicity50. In a retrospective cohort study of 68 patients undergoing primary TKA or THA, Burns et al. found that 1 g of intra-articular vancomycin resulted in therapeutic levels of vancomycin within the joint for 48 hours without ototoxicity or nephrotoxicity51. A single-blinded randomized controlled trial of 20 patients undergoing primary THA demonstrated that intraosseous administration of vancomycin prophylaxis resulted in higher local tissue and lower serum concentrations of vancomycin compared with intravenous administration52. In an institutional database study of 299 two-stage revision THAs, high-dose targeted antibiotics in cement beads placed locally at the time of the first stage followed by ≤5 days of intravenous antibiotics yielded similar outcomes as longer courses of intravenous antibiotics53. Extended Oral Antibiotic Administration Villa et al. reported no improvement in the PJI rate with >24 hours of postoperative oral antibiotic prophylaxis in a retrospective cohort study of 178 aseptic revision TJAs54. In a retrospective cohort study of 444 two-stage revision TJAs for PJI, the 1-year reinfection rate when oral antibiotics were administered for ≤2 weeks following reimplantation was equivalent to that for a longer oral antibiotic course55. An institutional joint registry study of 45 acute infections after revision TJAs showed that suppressive antibiotic therapy following treatment with irrigation and debridement and postoperative intravenous antibiotics yielded 5-year survivorship free of reoperation for infection of 70%34. Basic Science ORS ICM on Musculoskeletal Infection 2023 The Orthopaedic Research Society (ORS) held an International Consensus Meeting (ICM) on Musculoskeletal Infection in 202356. Many basic-science challenges were addressed, including attempts at standardizing measures of efficacy for in vitro infection studies. Because biofilms play important roles in persistent musculoskeletal infections, the consensus experts suggested that, rather than relying on the gold-standard microbiological outcome of colony-forming units (CFUs), multiple orthogonal outcome measures should be used to determine bacterial loads: spectroscopy, reagent-based assays, reporter assays, microscopy, and quantitative real-time polymerase chain reaction (qRT-PCR). It was also agreed that full eradication (and not a 1.5-log [approximately 30-fold] reduction in CFUs) might be necessary to show in vivo clinical benefit in some biofilm and implant-associated infections. Questions about a standardized combination panel of organisms for in vitro testing (including methicillin-sensitive S. aureus [MSSA], MRSA, Staphylococcus epidermidis, Group B streptococci, Escherichia coli, Pseudomonas aeruginosa, Cutibacterium acnes, and Candida albicans) could not reach consensus, given concerns for competition between the organisms. The ICM group recommended against using the current ASTM International standards for construction of biofilms for in vitro testing in musculoskeletal infection. Novel Models of Chronic Infection and Effects on Metabolism In an interesting in vivo investigation of the effect that MSSA PJI has on mitochondrial function, Bouji et al. demonstrated marked dysfunction and decreased oxygen consumption in ATP (adenosine triphosphate) synthesis in the PJI model compared with controls57. In an eloquent model of the race-for-the-surface hypothesis, the idea that bacterial and host cells compete to cover the surface of orthopaedic implants at the time of implantation, Xie et al. showed that the bulk of the competition for the implant surface ended by 3 hours after implantation58. This has implications for the study of further host-pathogen interactions and the effect of early use of antimicrobial agents on the initial colonization of orthopaedic implants. Animal Models of PJI and Osteomyelitis Dao et al. demonstrated reproducible murine models of osteomyelitis using free S. aureus and biofilm suspension S. aureus through a needle-based inoculum and through a model of holes drilled into tibial bone, both with and without associated metal implants59. Similar work by Irwin et al. on a rat model of PJI with a biofilm inoculum on a custom prosthetic pin led to mature and reproducible biofilm in the knee joint space and in the bone60. Other Topics Hand and Upper Extremity Hemoglobin A1c screening has become universal in the practice of TJA. A Veterans Affairs elective hand surgical practice developed a hemoglobin A1c screening program prior to elective hand procedures and used a cutoff of <8% for elective surgical procedures. They compared patients who underwent a surgical procedure before and after the screening program was implemented. Unlike in arthroplasty, there was no difference in infectious complications in the hand practice before and after screening was implemented61. Tai et al. analyzed a cohort of patients who underwent irrigation and debridement for PJI after total elbow arthroplasty. Of the cohort of 26 patients, 17 (65%) had treatment failure at the 2-year follow-up. Failure was more likely in patients with a longer duration of symptoms and polymicrobial infections62. Trauma Cortez et al. analyzed the Surgical Implant Generation Network Surgical Database for patients who underwent intramedullary nailing for open femoral and tibial shaft fractures. The authors found that patients who underwent delayed debridement had a greater risk of infection at 30 days. For each 6-hour delay, there was an additional 0.17% risk of infection. The authors recommended expeditious debridement for open fractures when possible63. Solasz et al. reviewed patients with operatively treated fractures to determine factors associated with infection after the surgical procedure. The risk factors identified were high body mass index; Black or Hispanic race; higher American Society of Anesthesiologists (ASA) class; tobacco, alcohol, and drug use; and lower-extremity fractures64. Foot and Ankle A single-institution registry of patients who underwent total ankle arthroplasty was reviewed for patients who experienced periprosthetic ankle infection to establish risk factors. Of the total of 1,863 patients, 19 (1%) experienced infection. There was a higher proportion of diabetes and smoking in the infection group than the no-infection group65. Zhang et al. tested the Mayo Periprosthetic Joint Infection Risk Score for validation in the total ankle arthroplasty population. The authors reported that when a Mayo score of >5 was used as the criterion for high risk for PJI, the sensitivity of the test was 90% and the specificity was 84.3%66. Spine Rudic et al. queried the PearlDiver database to determine the incidence of and risk factors for postoperative infection after instrumented spinal fusion for adolescent idiopathic scoliosis. Patients with non-idiopathic scoliosis were excluded. In the cohort of 9,801 patients, the infection rate was 0.4% at 7 days, 1.9% at 30 days, and 2.7% at 90 days. Obesity and male sex were identified as independent risk factors for surgical site infection67. In a retrospective cohort study analyzing patients who underwent posterior spinal fusion for surgical site infection, Higashi et al. compared patients who received vancomycin suspended in fibrin glue in the surgical site before closure with patients who did not. Treatment with vancomycin suspended in fibrin glue was significantly associated with lower odds of surgical site infection (odds ratio, 0.2 [95% confidence interval, 0.05 to 0.85]; p = 0.03)68. HIV (Human Immunodeficiency Virus) Bahoravitch et al. showed a strong association between use of antiretroviral therapy and development of periarticular osteonecrosis in the HIV-positive population69. Chowdary et al. used propensity score matching in a national database to compare HIV-positive patients with HIV-negative patients who underwent THA. There was no difference in the rates of postoperative pneumonia, wound dehiscence, or surgical site infections between the HIV-positive patients and the HIV-negative matched cohort70.