What’s New in Musculoskeletal Infection

Musculoskeletal infection continues to be the most devastating complication after orthopaedic surgery. It is a burden for all involved: painful for patients, challenging for physicians, and costly for the health-care system. A tremendous amount of research has been devoted in 2022 to understanding and solving many problems associated with musculoskeletal infection. The intent of this article is to highlight key studies that augment current knowledge regarding prevention, diagnosis, and treatment. Although the majority of infection research has been in the field of hip and knee arthroplasty, this article will also cover landmark studies in other subspecialties from the past year. A substantial body of research was dedicated to the psychosocial effect of periprosthetic joint infection (PJI) on patients. Furdock et al. showed that 20% of patients who underwent 2-stage exchange for PJI presented with Patient-Reported Outcomes Measurement Information System (PROMIS) depression scores consistent with major depressive disorder, compared with 7% of patients who underwent aseptic revision. After treatment, depression scores improved in both cohorts1. In a study utilizing the PearlDiver Database, Das et al. reported that the risk of depressive, anxiety, bipolar, psychotic, and stress disorders was significantly higher in patients who underwent spacer placement for PJI than in patients who underwent aseptic revision2. In another study, Lueck et al.3 demonstrated that patients who undergo spacer insertion for PJI experience a significant decline in psychological health as determined by the 36-Item Short Form Health Survey4 (SF-36) and Hospital Anxiety and Depression Scale5 (HADS). Similar findings were also reported in the Girdlestone population using PROMIS Global Physical and Mental Health surveys6. It is not surprising that treatment regret with respect to having undergone primary total joint arthroplasty (TJA) is a phenomenon experienced by 28% of patients who underwent hip and knee arthroplasty and experienced PJI that required 2-stage exchange, as discussed by Sequeira et al.7. Prevention Although we still search for ways to improve our treatment outcomes for PJI, most surgeons would agree that prevention is the most important step in the management of this very difficult problem. Several recent studies have tried to identify the optimal irrigation solution to prevent PJI in primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). A retrospective review of >30,000 cases demonstrated a reduction in PJI rates with the use of dilute povidone-iodine solution8. Another basic science study found that povidone-iodine, sodium hypochlorite, and acetic acid-based irrigants all demonstrated eradication of all bacterial growth in <2 minutes of contact9. Five of 7 trials in a recent systematic review and meta-analysis found a benefit in reducing PJI rates with the use of topical vancomycin powder and povidone-iodine solution, but the studies were of poorer quality with varying dosing and also found higher rates of wound complications in those patients receiving vancomycin powder alone10. A systematic review and meta-analysis published last year specifically on the use of vancomycin powder did find a reduction in PJI rates; however, the quality of those studies were poor as well11. The optimal irrigation solution, which should balance bactericidal activity with lack of inhibition of wound-healing, still has not been conclusively determined. Further prospective randomized clinical trials are needed to answer this important question. Similarly, much research has focused on the optimal dressing to prevent PJI, especially in high-risk patients. Although negative-pressure wound therapy and silver-impregnated dressings both have data supporting their use, a recent randomized controlled trial found no difference between the 2 dressings in obese patients12. Over the last few years, orthopaedic surgeons have made great progress in optimizing modifiable risk factors prior to arthroplasty, specifically with weight loss before the surgical procedure. With more patients undergoing bariatric surgery to optimize their weight, a recent study found that patients who underwent bariatric surgery actually had higher rates of reoperation for PJI after TKA relative to a matched cohort with high body mass index (BMI), suggesting that underlying malnutrition may play a role13. Likewise, patients who underwent bariatric surgery prior to THA had higher rates of implant failure and dislocation than patients with naturally low or high BMI14. Other perioperative protocols continue to be evaluated to reduce the risk of PJI. A prospective cohort study in >1,200 patients who underwent primary TKA found that those who wiped the surgical area with chlorhexidine the night before the surgical procedure had lower infection rates15. The optimal venous thromboembolic prophylaxis continues to be debated. A recent study found that patients taking lower-dose aspirin (81 mg twice daily) had lower rates of PJI than patients taking a higher dose (325 mg twice daily)16. Intraoperatively, many surgeons prefer the use of helmets, but concerns exist with regard to the potential contamination of the fan. One study suggested that the fan should run for 3 minutes prior to entering the operating room to decrease the risk of contamination17. We have made great strides reducing the rates of PJI following primary TKA and THA over the last decade, but there is more work to be done. Further prospective research on prevention of PJI should focus on continuing to improve our patient optimization and perioperative protocols. Diagnosis Advances in the diagnosis of PJI involved several key areas: clinical testing of novel serum and synovial fluid laboratory markers, the predictive value of testing prior to reimplantation in chronic PJI, and the exploration of diagnostic imaging modalities. In a single-institution study of 7,661 patients, Aichmair et al. assessed the predictive value of serum interleukin (IL)-6, which has a shorter half-life than C-reactive protein (CRP), in early-onset PJI after THA and TKA18. IL-6 levels measured on postoperative day 3 demonstrated no significant difference in patients who underwent THA or TKA with and without early-onset PJI. In a retrospective case-control study, Yan et al. investigated superoxide dismutase (SOD) as a potential novel serum biomarker in the diagnosis of PJI after TKA19. The authors concluded that serum SOD represents a promising marker, including in a subgroup analysis in culture-negative PJI. In a prospective study of synovial pH, Theil et al. compared this value with other traditional markers of chronic PJI after THA and TKA20. Synovial pH was found to be a useful adjunct parameter to established synovial markers such as synovial leukocyte count and differential, but showed low sensitivity. Grzelecki et al. sought to determine the utility of a rapid, off-label strip test that detects D-lactic acid in synovial fluid in the diagnosis of PJI21. In their prospective study of revision THA and TKA, the authors found good accuracy, with comparable sensitivity and specificity to leukocyte esterase (LE) strip tests. Another study examined the proteomic profiling of sonicated fluid to further support this potential avenue to differentiate PJI from noninfectious arthroplasty failure22. A study of serum and synovial markers of early PJI found that false-negative rates were significantly higher for synovial white blood-cell counts and synovial neutrophil percentage in patients treated with antibiotics within 2 weeks compared with untreated patients23. With respect to reimplantation arthroplasty algorithms, Shao et al. evaluated the diagnostic effectiveness of serum CRP, erythrocyte sedimentation rate (ESR), plasma D-dimer, and fibrinogen obtained prior to performing second-stage revision or spacer exchange24. The authors reported that plasma fibrinogen had the highest area under the receiving operating characteristic curve (AUC) value of 0.831, followed by serum CRP (0.829) and ESR (0.795); plasma D-dimer had the lowest AUC value of 0.716. The authors of another study concluded that routine use of alpha-defensin in the workup prior to a second-stage arthroplasty for PJI may not be warranted25. In a retrospective study of triple-phase bone scanning in the setting of potential PJI, semiquantitative criteria showed no advantage in PJI diagnosis26. The authors observed no significant difference between visual analysis and semiquantitative measurement in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Triple-phase bone scanning demonstrated good clinical diagnostic efficacy when the time interval from prosthesis implantation to bone scanning was >1 year. Surgical Treatment Published research in the past year continues to clarify the role of each of the 3 major treatment options for PJI: irrigation and debridement, 2-stage exchange, and 1-stage exchange. Irrigation and Debridement The timing of debridement, antibiotics, and implant retention (DAIR) continues to show importance in the literature. A comparison study between DAIR and 2-stage revision within 12 weeks of the index arthroplasty showed comparable success rates of each technique at the 6-year follow-up, supporting the importance of timing with regard to performing DAIR27. DAIR continues to appear to be an acceptable treatment in management of early PJI (within 30 days) after revision arthroplasty; however, failure rates are increased in cases of antibiotic mismatches, multiple DAIR procedures, or a prolonged interval (>30 days) from the index procedure to the DAIR28. The addition of antibiotic-loaded calcium sulfate beads has not been shown to reduce the incidence of recurrent PJIs following DAIR29. A registry-based cohort study showed no difference in re-revision rates of an initial 2-stage exchange compared with a 2-stage exchange following a failed DAIR30. Two-Stage Exchange The results of 2-stage exchange continue to show improved success rates when compared with DAIR for chronic knee PJI. A multicenter study with a minimum 5-year follow-up of PJI in knees showed an infection eradication rate of 89%. High mortality, 33% in 1 study, continues to be seen during the course of 2-stage treatment31. The eradication rates of PJI in knees were similar to those seen in PJI in hips32. The risk factors for reinfection following 2-stage exchange for PJI were elevated CRP levels at the time of diagnosis and infection with methicillin-sensitive Staphylococcus aureus (MSSA)33. The use of a short course of oral antibiotics (<2 weeks) has been shown to decrease the 1-year reinfection rate following 2-stage exchange arthroplasty for PJI34. Failed 2-stage exchange remains a large financial burden on the health-care system. Patients undergoing successful 2-stage exchange for hip PJI without a further surgical procedure incurred approximately $40,000 less total costs than those requiring further surgical procedures following reimplantation35. High-dose antibiotic cement spacers for the treatment of PJI were found to be independent risk factors for acute kidney injury, which had a rate of 22.7% following the first stage of a planned 2-stage exchange versus 6.6% following a 1-stage exchange36. A study comparing knee spacer types (new femoral component, cement-on-cement, and static) found no difference in the odds of infection clearance and showed increased range of motion and improved ambulatory status prior to reimplantation utilizing the new-femoral-component spacer design37. Although downtrending serum markers can be reassuring prior to reimplantation, there do not appear to be values for ESR or CRP that significantly predict failed 2-stage exchange for PJI; thus, pre-reimplantation aspiration is recommended to help to guide management38. One-Stage Exchange Although a prospective, multicenter, randomized study comparing 1-stage exchange with 2-stage exchange is ongoing in the United States, the results are not yet available. However, 1-stage exchange continues to gain enthusiasm as a treatment for PJI despite varied results. One study showed a re-revision rate for infection of 20% at 8 years in 1-stage exchange for streptococcal hip PJI39. The design of constructs used in 1-stage exchange for PJI also appear to vary among institutions. A study comparing 1-stage exchange utilizing a metal femoral component and an all-polyethylene tibial component compared with 2-stage exchange showed improved infection-free survival at 2 years (85% compared with 75%) and overall lower postoperative complication rates40. Implant design (hinged compared with non-hinged TKA) in 1-stage exchange did not show significantly different functional outcomes across cohorts, and the designs showed an overall infection control rate of 91% at a mean follow-up of 6 years41. Antibiotic Therapy Antibiotic Prophylaxis A prospective, multicenter study of 1,838 patients who underwent primary TJA demonstrated that a weight-adjusted preoperative dose of cephalosporin was associated with lower surgical site infection risk compared with alternative antibiotics administered at or after the time of incision42. Prophylactic antibiotic administration for >24 hours was not associated with a decreased risk of surgical site infection. In patients who underwent TJA and were at high risk for PJI, extended oral antibiotic prophylaxis for 7 days with cefadroxil, trimethoprim-sulfamethoxazole, or clindamycin was found to be a cost-effective measure to decrease the rate of PJI43. Two studies concluded that extended oral antibiotic prophylaxis (for 7 days in 1 study and a mean of 11 days in the other) with cefadroxil or cephalexin after aseptic revision TKA results in a significantly lower rate of PJI at 90 days44,45. However, the same extended postoperative antibiotic regimen as in the latter study (mean, 11 days) after aseptic revision THA did not confer any decreased risk of PJI46. Antibiotics and PJI Based on a multicenter study evaluating the species and antibiotic resistance profiles of infecting organisms in PJI after TKA, the most effective empiric antibiotic regimen once culture results have been obtained is vancomycin for infections that occur <1 year after the surgical procedure and cefazolin for infections that occur later47. A prospective, randomized controlled trial demonstrated that the use of an antibiotic spacer with 2 g of vancomycin and 2.4 g of tobramycin per bag of PALACOS cement (Heraeus Medical) in the treatment of PJI is an independent risk factor for acute kidney injury, particularly in patients with chronic kidney disease36. In patients who underwent failed surgical treatment for PJI, chronic oral antibiotic suppression yielded 67% reoperation-free survival at a median follow-up of 50 months48. Patients with THA or gram-positive infections had increased likelihood of success with suppressive antibiotic therapy. Another approach following multiple failed surgical treatments for PJI is 1-stage revision with intra-articular antibiotic infusion, reported to have an 87.6% rate of survival free from reoperation for infection at a 7-year follow-up49. A multicenter study found that, in patients who met the definition of culture-negative PJI but had no histologic signs of infection, antibiotic therapy could be withheld without infection recurrence at the 2-year follow-up50. Antibiotic Resistance In an international, multicenter study of 218 patients, the use of gentamycin-loaded bone cement in primary TJA did not increase the prevalence of resistance to gentamycin or other antibiotics among infecting organisms in patients who developed PJI51. Conversely, in patients who received ≥2 weeks of oral antibiotics following reimplantation in 2-stage revision for PJI, there was increased resistance to the oral antibiotic among the infecting organisms causing recurrent PJI52. However, as novel resistant organisms causing reinfection were not recorded as the same species as the original infecting organism in this study cohort, it is difficult to conclude that selective pressure from oral antibiotics induced new drug resistance. The antimicrobial resistance profile of coagulase-negative staphylococci isolated from cases of PJI after TKA was found to differ significantly between tertiary referral centers, even ones in geographic proximity to one another53. As a result, continuous antibiotic susceptibility testing is essential to optimize antibiotic therapy and stewardship. Other Topics Animal and In Vitro PJI Models Ibrahim et al. presented data showing reproducible results with an ingrowth hip hemiarthroplasty model for gram-negative PJI in rats. The model allows weight-bearing, shows predictable biofilm formation, and provides a clinically relevant animal model for challenging PJI cases54. Visperas et al. presented a novel rabbit model for knee PJI with consistent biofilm production and reproducible response to sham compared with antibiotic treatments55. Small animal models of musculoskeletal infection often require general anesthetic, and hypothermia in murine models is common during general anesthesia. Constant et al. demonstrated that peri-anesthetic hypothermia in rodents creates a significant risk of both greater infection burden and mortality in these models, complicating the interpretation of results across all small animal studies examining infection and outcomes56. In an effort to understand the precise timing and biology of Pseudomonas aeruginosa biofilm production, Spake et al. reported on a polyetheretherketone (PEEK) disc model for in vitro biofilm creation57. Their model allowed for consistent imaging and quantification of biofilm production and has implications for understanding the variables associated with biofilm production across multiple species. Genetics, Genomics, and Novel Therapeutics The sequencing of pathogens to understand the individual genotype has started to become relevant to both research and clinical treatment of orthopaedic infections in the past few years. Trobos et al. presented data from a unique study that attempted to correlate genomic bacterial data with patient outcomes in PJI. They analyzed 111 staphylococcal strains obtained from patients during surgical treatment of PJI and correlated genomic data with a binary infection-treatment outcome (infection was resolved or unresolved). Staphylococcus epidermidis ST2 caused the majority of relapses and was associated with both multidrug resistance and strong biofilm production. Similarly, the S. aureus strains with the strongest biofilm production were the most likely to cause unresolved infection58. Small-colony variants in S. aureus are present in varying degrees and can predict the likelihood of invasion into osteoblasts in an in vitro model of bacterial isolates obtained from patients with diagnosed PJI, potentially helping to identify those at risk for persistent infection59. On the host side, CCR2 (C-C motif chemokine receptor 2) mediates chemotaxis for macrophages and neutrophils during inflammatory responses. In a murine model of orthopaedic implant-associated infection, CCR2-deficient mice were found to have significantly reduced myeloid inflammatory cells in draining lymph nodes compared with the control wild-type mice60. In a study evaluating the ability of orthopaedic infections to co-opt our own immune regulatory system for survival benefits, as malignancies also often do, Warren et al. analyzed periprosthetic tissue from patients undergoing revision hip or knee arthroplasty for immune checkpoints related to apoptosis (PD-1 [programmed cell death-1] and its ligand PD-L1). Patients were separated into those with aseptic diagnoses (16 patients) and those with PJI (15 patients), and were further evaluated on the basis of recurrence of infection. PD-L1 expression was upregulated (p = 0.039) in PJI cases (25%) compared with aseptic cases (8%), and it was upregulated (p = 0.039) in the recurrent PJI cases (68%) compared with the remaining PJI cases (15%). Those in whom expression of PD-L1 was >20% had an odds ratio of 15 for reinfection compared with controls (p = 0.092). Although the numbers are small, the series suggests immune checkpoint upregulation as a potential mechanism for recurrent or persistent orthopaedic infection61. In a mouse model of femoral osteomyelitis, Kobayashi et al. tested zoledronic acid and anti-RANKL (receptor activator of nuclear factor kappa-B ligand) monoclonal antibody to assess osteoprotective effects against the erosive and necrotic changes of the untreated infection. The anti-RANKL monoclonal antibody outperformed zoledronic acid and showed some promise in preventing further osteonecrosis associated with osteomyelitis62. Carbon-infiltrated carbon nanotube (CICNT) surfaces mimic antimicrobial surface textures found in nature and have been shown previously to have a minimal effect on osseointegration. Morco et al. performed an in vitro study of 2 different CICNT types in a biofilm model, showing that both stainless steel substrate and carbon substrate CICNTs were able to reduce biofilm burden by 60% to 80% (p < 0.0001) compared with controls. Applications abound for future orthopaedic implant coatings63. Bacteriophages DePalma et al. described a series of staphylococcal isolates from patients with PJI and their response to available bacteriophages. They found that small-colony variants were present in 24% of the isolates and that none of these isolates had growth inhibition by the bacteriophages64. Totten and Patel reported on bacteriophage activity against 122 clinical isolates of S. aureus from patients with orthopaedic implant infections, finding successful bacteriophage infection in 73% of the planktonic bacteria and 100% of the biofilm bacteria65. Šuster and Cör assessed and compared bacteriophage K DNA methods for identifying staphylococcal infections with high sensitivity and specificity in a relatively short 3 to 4-hour time frame that could dramatically shorten the diagnosis for patients with orthopaedic infections66. Sports and Biomechanics Sorensen et al. presented biomechanical data on tensile strength of tendon grafts affected by varying S. epidermidis infectious bioburden and found that infection led to a significantly decreased peak load to failure for the tendon grafts compared with controls (p = 0.043). The increasing burden led to an even lower peak to failure (p = 0.0005 at 10,000 colony-forming units)67. Further adding to the data supporting vancomycin use in anterior cruciate ligament (ACL) reconstruction, Tong et al.68 presented in vivo data from a rat model supporting specific times and concentrations for vancomycin soaking of the ACL graft. Truong et al.69 presented findings that vancomycin-soaked grafts are highly cost-effective for ACL reconstruction. Trauma and Infection To understand bacterial associations with polymicrobial infection, Gitajn et al.70 retrospectively reviewed >400 fracture-associated deep infections that required operative debridement. They found that methicillin-resistant S. aureus (MRSA), MSSA, and coagulase-negative staphylococcal species represented the majority of monomicrobial infections (71%). Gram-negative rods, gram-positive rods, and anaerobes were much more likely to be found in polymicrobial infections. Specific organisms from the Enterobacter, Enterococcus, and Pseudomonas genera were found to have the highest frequency in polymicrobial infections70. For necrotizing soft-tissue infections, Heath et al. found that early administration of clindamycin as part of the antibiotic regimen conferred a substantial limb-salvage benefit after controlling for multiple other factors71. Spine Vicente-Sánchez et al. presented compelling data showing a significant decrease in the incidence of early surgical site infections in spine surgery following the implementation of surgical care bundles in 2012 (4.2% compared with 1.9%; p = 0.006)72. Karamian et al. used a retrospective 3-to-1 case-control matched study to evaluate the effect of early surgical site infections on patients after thoracolumbar fusion. Although the surgical site infection group had a higher rate of early readmission and reoperation, both groups had similar improvements in patient-reported outcomes with no differences at 1 year, suggesting that, if appropriately managed, surgical site infection after spine surgery does not lead to prolonged disability or worse clinical outcomes73. Foot and Ankle Conti et al. reported on a series of 11 patients undergoing 2-stage revision total ankle arthroplasty for chronic PJI, showing a 63% reoperation rate after reimplantation and 1 below-the-knee amputation to control infection, but a majority of patients who were ambulatory at the final follow-up74. Winkler et al. retrospectively reviewed 583 amputations for diabetic foot osteomyelitis to determine the relation of limb loss to lesion location and other comorbidities, finding that patients with more proximal lesions and those with substantial peripheral vascular disease had a significantly higher chance of major amputation above the ankle joint75. Evidence-Based Orthopaedics The editorial staff of JBJS reviewed a large number of recently published studies related to the musculoskeletal system that received a higher Level of Evidence grade. In addition to articles cited already in this update, 4 other articles relevant to infection are appended to this review after the standard bibliography, with a brief commentary about each article to help guide your further reading, in an evidence-based fashion, in this subspecialty area. Evidence-Based Orthopaedics Blom AW, Lenguerrand E, Strange S, Noble SM, Beswick AD, Burston A, Garfield K, Gooberman-Hill R, Harris SRS, Kunutsor SK, Lane JA, MacGowan A, Mehendale S, Moore AJ, Rolfson O, Webb JCJ, Wilson M, Whitehouse MR; INFORM trial group. Clinical and cost effectiveness of single stage compared with 2 stage revision for hip prosthetic joint infection (INFORM): pragmatic, parallel group, open label, randomised controlled trial. BMJ. 2022 Oct 31;379:e071281. In a prospective, randomized controlled trial, Blom et al. evaluated 140 patients with PJI of the hip and compared 1-stage with 2-stage exchange arthroplasty. There was no difference in the presumed infection eradication rate between the groups, but patients who underwent 1-stage exchange had fewer complications (8% compared with 27%; p = 0.01). Additionally, 1-stage exchange was also more cost-effective. According to this study, surgeons should consider 1-stage exchange arthroplasty for candidate patients with PJI in order to minimize complication rates and cost of the treatment. Kruse CC, Ekhtiari S, Oral I, Selznick A, Mundi R, Chaudhry H, Pincus D, Wolfstadt J, Kandel CE. The use of rifampin in total joint arthroplasty: a systematic review and meta-analysis of comparative studies. J Arthroplasty. 2022 Aug;37(8):1650-7. In a systematic review and meta-analysis that included 22 studies analyzing the effect of addition of rifampin to PJI surgical treatment, Kruse et al. reported a significant reduction in failure rates when rifampin was used (26.0%) compared with the standard of care (35.9%); the odds ratio was 0.61 (95% confidence interval, 0.43 to 0.86). However, this effect was only seen with exchange arthroplasty and rifampin did not appear useful when implants were retained. As noted by Kruse et al., for appropriate candidates with PJI, the addition of rifampin to the antibiotic regimen after exchange arthroplasty may improve infection eradication rates. Ma N, Gogos S, Moaveni A. Do intrawound antibiotics reduce the incidence of surgical site infections in pelvic and lower-limb trauma surgery? A systematic review and meta-analysis. J Orthop Trauma. 2022 Nov 1;36(11):e418-24. In a systematic review and meta-analysis that focused on patients with skeletal trauma to the lower extremity and the pelvis treated with surgical fixation, Ma et al. examined the effect of the addition of topical vancomycin to intravenous antibiotic therapy. The meta-analysis did not show a significant benefit of topical vancomycin with regard to the reduction of surgical site infections. Although Ma et al. did not find a significant benefit of using topical vancomycin in their study, further research is necessary to determine whether it may play a role in preventing infection in patients with skeletal trauma treated with surgical fixation. Xiao M, Money AJ, Pullen WM, Cheung EV, Abrams GD, Freehill MT. Outcomes after resection arthroplasty versus permanent antibiotic spacer for salvage treatment of shoulder periprosthetic joint infections: a systematic review and meta-analysis. J Shoulder Elbow Surg. 2022 Mar;31(3):668-79. Xiao et al. performed a systematic review and meta-analysis comparing patients with shoulder PJI treated with either permanent resection arthroplasty or a permanently retained antibiotic spacer. Although infection eradication rates were similar (82% for the resection arthroplasty and 85% for the antibiotic spacer), patients treated with a permanent antibiotic spacer had significantly better forward flexion and higher American Shoulder and Elbow Surgeons scores. According to this study, surgeons should make an effort to implant a spacer in patients with chronic shoulder PJI when it is possible to help to maximize function.