What’s New in Musculoskeletal Infection

Periprosthetic joint infection (PJI) remains the most dreaded complication after total joint arthroplasty (TJA). As reimbursement for joint replacement continues to decline1-3, fewer orthopaedic surgeons take on this challenging and time-consuming practice. Indeed, in a recent study, Keely Boyle et al. found that 16% of knee arthroplasty revisions, including revisions for infection, were performed at a different center than the one in which the index procedure was performed. Illgen et al. used the American Joint Replacement Registry (AJRR) to show that, in hips, the migration rate for PJI ranges from 28.6% to 46.6%, depending on the size of the hospital5. This places a major portion of the responsibility of PJI care on a few specialized surgeons. Therefore, understanding the economics of PJI care has been a hot topic this year. In a study utilizing the National Inpatient Sample (NIS), Premkumar et al. projected that, by 2030, the annual hospital costs related to PJI of the hip and knee will equal $1.85 billion in the United States6. In another study from a single institution, the cost of care for a PJI after a 2-stage total knee arthroplasty (TKA) was more than 5 times the cost of care of an uncomplicated primary TKA for an age-matched and body mass index (BMI)-matched cohor t7. Comparing the cost of operative treatment for PJI of the hip and knee with that of aseptic revision, Yao et al.8 showed that the PJI treatment had costs that were double those of the aseptic treatment. Unintended hospitalization during the 2-stage exchange process was shown to add >$20,000 in costs to patient care, which is concerning because less than one-half of the patients who underwent resection for PJI had a successful 2-stage exchange within 1 year9. Using a Markov model, Antonios et al. showed the cost-effectiveness of adding a planned second debridement, antibiotics, and implant retention (DAIR) procedure to treat PJI10. Efforts to reduce failure in PJI treatment will continue to be an important topic in research. Prevention Although originally spoken to Philadelphians to increase fire awareness in the 1700s, Benjamin Franklin’s famous quote, “An ounce of prevention is worth a pound of cure,” certainly still applies to PJI. With the substantial clinical and financial burden of PJI, resources should be focused, not just on treatment, but on optimizing strategies to prevent infection. Many studies published on this topic at this time will help to guide orthopaedic surgeons and their perioperative management of patients undergoing total hip arthroplasty (THA) and TKA, while prompting more prospective studies to answer important questions. Preoperative Staphylococcus aureus screening is controversial. In a recent systematic review and meta-analysis with 32 studies, Ribau et al. identified a marked reduction in infection with decolonization prior to elective THA and TKA11. However, in a randomized controlled trial (RCT) of 613 patients, Rohrer et al. did not find a difference in PJI rates with nasal decolonization, but they did have a small sample size12. Further adequately powered studies are needed to determine whether screening and selective treatment or universal decolonization is the most clinically and cost-effective method. Perioperative optimization of patients undergoing THA and TKA continues to be a topic of research. Although hemoglobin A1c has long been used as a marker for glycemic control over a 3-month period, recent studies have examined serum fructosamine, which measures glycemic control over a 2 to 3-week period. A large, multicenter, retrospective analysis found that patients with preoperative fructosamine levels of >293 µmol/L had higher rates of PJI and mortality following THA13. Another study found that patients with type-2 diabetes undergoing treatment with metformin had reduced rates of PJI, complications, and 1-year revision rates when compared with those not taking metformin14. Identifying high-risk patients with diabetes preoperatively and optimizing their glycemic control could help to prevent PJI and is an area of active research. Preoperative nutrition status was also a topic of focus. Using the National Surgical Quality Improvement Program (NSQIP) database, Statz et al.15 showed that preoperative serum albumin of <3.5 g/dL was the strongest predictor of postoperative infection in patients who underwent THA, when compared with diabetes, smoking, and BMI of ≥40 kg/m2. In a separate study, Johnson et al. reported similar results in patients who underwent TKA16. There are many intraoperative variables that surgeons can control to help to reduce the risk of PJI. In a recent RCT of patients who underwent shoulder arthroplasty, Morris et al.17 found that the use of laminar flow was associated with reduced bacterial colony-forming units above the surgical field, but further clinical data are needed. Several recent studies have focused on studying the optimal irrigation solution for the prevention of PJI. In a meta-analysis of 8 RCTs, Kobayashi et al. identified a significant reduction in rates of PJI with dilute povidone-iodine over saline solution alone18. Two other articles, both with large sample sizes, confirmed the benefits of povidone-iodine irrigation19,20. In an American Association of Hip and Knee Surgeons (AAHKS) award-winning paper from the 2021 meeting, Premkumar et al. also found that dilute povidone-iodine and hydrogen peroxide can eradicate methicillin-susceptible S. aureus (MSSA) biofilm; however, the authors did not find success with saline solution, vancomycin, or bacitracin-polymyxin irrigation21. Although vancomycin powder has been shown to reduce the incidence of postoperative infection in the spine literature, a recent systematic review of 9 studies failed to identify a benefit to the routine use of topical vancomycin for infection prevention in primary THA and TKA22. Finally, negative-pressure wound therapy, or incisional vacuum-assisted closure, have increased in popularity for THA and TKA. Doman et al. found that using negative-pressure wound therapy, rather than silver-impregnated dressings, resulted in a reduced infection rate in high-risk patients, particularly those patients taking stronger, non-aspirin anticoagulation23. In a meta-analysis of RCTs, Ailaney et al. found a significant reduction in infection rate among patients who underwent revision THA and TKA with negative-pressure wound therapy, but found no difference in the infection rate among patients who underwent primary arthroplasty, although they did find a higher incidence of blistering24. Diagnosis Scientific advances in the diagnosis of PJI involved 3 main areas: (1) benchmarking newer methods of testing and laboratory marker ratios compared with traditional testing, (2) the introduction of novel biomarkers, and (3) an exploration of newer diagnostic testing modalities. Synovial fluid antibody testing, through a commercially available assay, provided no additional clinical benefit when compared with traditional cultures for PJI diagnosis in revision hip and knee arthroplasty25. Furthermore, the antibody testing had low sensitivity and a high rate of discordance with culture. In other studies, α-defensin was compared with leukocyte esterase: although both tests provided high diagnostic utility for PJI and supported the 2018 International Consensus Meeting PJI algorithm’s classification of them as equivalent tests26, in 1 study, Shohat et al. suggested that leukocyte esterase may be more valuable because of its low cost and point-of-care availability27. The C-reactive protein/albumin ratio (CAR) was linked to postoperative complications such as PJI after TJA28 and reinfection and readmission after single-stage revision for PJI29. An analogous ratio of albumin-to-globulin demonstrated utility in the diagnosis of PJI30. When comparing preoperative aspiration cultures with intraoperative culture data in a paper that won the James A. Rand Young Investigator’s Award, Boyle et al. found that aspiration culture had favorable sensitivity and specificity for diagnosing PJI when compared with tissue culture for the majority of PJI organisms, especially for monomicrobial aspiration results. The authors recommended collecting multiple tissue culture samples to maximize the chance of identifying an underlying polymicrobial PJI31. In another study, Li et al. described a sensitivity of aspiration culture of 81.29% compared with intraoperative synovial fluid cultures32. In patients with discordant PJI results, 60% were polymicrobial, and no intraoperative synovial fluid culture growth was found in 40% of the PJI cases. These authors recommended that a synovial fluid specimen be taken for a second culture test, especially with polymicrobial organisms and/or Streptococcus species in preoperative aspiration culture results. A number of specific biomarkers showed promise in the diagnosis of PJI, including synovial soluble tumor necrosis factor receptor 2 (sTNF-R2)33, synovial fluid interleukin-1 beta (IL-1β) (especially in combination with the polymorphonuclear [PMN] percentage)34, and calprotectin (of note, calprotectin did not reliably differentiate PJI from rheumatoid arthritis in this study)35. In 1 study, a calprotectin point-of-care test showed high sensitivity and specificity (>95%) in the diagnosis of PJI after TKA36. D-dimer in plasma was found to be a better marker for PJI after revision knee arthroplasty than after revision hip arthroplasty37. There was continued interest in exploring novel modalities for diagnosing PJI, including bacteriophage-based methods using sonicated fluid samples38. This technique has demonstrated high specificity and sensitivity, with rapid diagnostic times compared with traditional culturing methods. Surgical Treatment Irrigation and Debridement A single DAIR procedure continues to show high failure rates. Survivorship in 1 study at 2 years was 52.4%. Patients with staphylococcal infections showed higher failure rates regardless of the chronicity of symptoms39. Supplementation of DAIR procedures with the use of intraosseous antibiotic delivery appears to increase success rates, with a rate of 92.3% reported at a mean follow-up of 16 months40. A second DAIR procedure continues to show superior results to a single DAIR procedure for PJI. McQuivey et al. found success rates of 87% and 90% at a mean follow-up of 3.5 years in 2 studies from the same institution41. In cases of extensive instrumentation in revision TKA, irrigation and debridement with chronic suppression was shown to be as effective as a 2-stage exchange at a mean of 3.2 years (62.5% compared with 67.7%)42. Predictive algorithms such as KLIC and CRIME80 were externally validated for predicting failure of DAIR for the treatment of acute PJI43. Adjunctive antiseptic irrigation solutions are commonly used in DAIR procedures and other procedures for PJI. Siddiqi et al.44 reviewed studies on the most common additive solutions used and acknowledged that there is a paucity of high-quality research to guide surgeons in their use. Two-Stage Exchange A systematic review of the results of 2-stage exchange for PJI showed a high success rate of 95.4% at 2 years; however, this success rate dropped to 89.8% if patients had follow-up of 5 years, suggesting a need for further studies reporting long-term follow-up45. A positive frozen section at the time of reimplantation was shown to be an independent risk factor for treatment failure in patients undergoing a 2-stage exchange46. A plasma D-dimer test prior to reimplantation was a poor predictor of success after a second-stage exchange47. Partial 2-stage exchange for periprosthetic hip infection, in which the femoral stem is retained, has gained in popularity in recent years. In 1 study, Yishake et al. showed an 85.7% success rate at 4 years utilizing this technique; however, further long-term studies are needed to clarify the utility of this technique48. Two-stage exchange continues to show the highest success rates (65%) for the treatment of fungal PJI when compared with DAIR procedures (15%)49. The rate of PJI following megaprosthesis reconstruction remains high at 17%, with a 35% failure rate of subsequent management regardless of treatment type (DAIR, 2-stage, single-stage)50. Acute kidney injury remains common following the first stage of a 2-stage exchange, with 2 separate studies citing acute kidney injury rates of 14% and 33% following 2-stage exchange arthroplasty for PJI51,52. One-Stage Exchange Although 1-stage exchange continues to gain enthusiasm as a treatment for PJI, the results have remained varied. In a study examining single-stage exchange for Enterococcus PJI, Rossmann et al. showed a reinfection rate of 37.5% at 22 months, with older age and male sex associated with higher risk of failure in this cohort53. Massive femoral bone loss (greater than Paprosky IIIA) and previous revision surgical procedures were also associated with a higher risk of subsequent septic failure following a single-stage exchange in a different study; thus, a 2-stage exchange is recommended in these instances54. One-stage exchange to treat periprosthetic hip infection in patients ≤45 years of age showed a survival rate free of revision for infection of 76.9% at a minimum 10-year follow-up55. In another study, 25 of 26 patients did not have a recurrence of infection following a single-stage exchange revision TKA for infection or associated bone loss at the 2-year follow-up56. In a study examining single-stage exchange for PJI around the rotating-hinge knee implants, Ohlmeier et al. showed infection-free survival of 90% at 6 years57. One-stage revision for culture-negative infection was shown to be as effective as 2-stage revision, with comparable failure rates of 16.7% and 20%, suggesting that culture-negative infection may not be an exclusion criterion for a single-stage exchange58. Antibiotics Perioperative Antibiotics Using a break-even cost analysis, Pagani et al. found that preoperative allergy testing of patients undergoing elective TJA for penicillin or cephalosporin allergy was cost-effective in preventing PJI59. Preoperative penicillin allergy testing of patients who underwent primary TJA and had a self-reported penicillin allergy was calculated to potentially have saved up to $37 million in 202060. By updating the institutional definition of severe penicillin allergy, standardizing preoperative antibiotic administration, and referring patients for allergy evaluation, Jones et al. were able to increase the likelihood that patients who underwent primary TJA and had a documented penicillin allergy received cefazolin for antibiotic prophylaxis61. Interestingly, none of the patients with a documented severe allergy to penicillin had an allergic reaction to cefazolin. There was no increased risk of acute PJI following primary TJA with 1 preoperative dose of prophylactic antibiotics compared with 24-hour dosing in a retrospective cohort study of 3,317 patients62. In a single-institution, retrospective cohort study of 1,047 patients, Feder et al. found an increased risk of PJI when prophylactic intravenous vancomycin administration was incomplete prior to primary TJA incision or tourniquet inflation, which occurred in nearly one-half of all patients who had been given vancomycin63. A 7 to 14-day course of postoperative oral antibiotics following primary TJA in patients with a BMI of ≥40 kg/m2 did not decrease the risk of PJI within 90 days postoperatively or wound complications in a single-center, retrospective cohort study of 650 cases64. Vancomycin Powder In a study of 18,299 primary TJAs, the use of intra-articular and subcutaneous vancomycin powder with dilute povidone-iodine lavage did not change the distribution of the PJI infecting organism type65. Lawrie et al. prospectively studied the intra-articular administration of 1 g of vancomycin and 600 mg of tobramycin during cementless TKA. They found that therapeutic concentrations of intra-articular antibiotics persisted for 24 hours postoperatively without resulting systemic toxicity66. Intraosseous Antibiotics In a retrospective cohort study of 1,060 patients undergoing primary TKA, Park et al. observed a sixfold decrease in PJI at a minimum 90-day follow-up with intraosseous vancomycin compared with intravenous vancomycin as an adjunct to intravenous cefazolin administered to all patients67. In a multicenter, retrospective cohort study of 1,906 patients who underwent a primary TKA, Parkinson et al. found a lower risk of PJI within 1 year postoperatively with prophylactic antibiotics administered intraosseously and intravenously compared with those administered only intravenously68. There were no adverse events due to intraosseous antibiotic administration. Similarly, there was no increased risk of acute renal insufficiency, vancomycin flushing syndrome (also known as “red man” syndrome), or neutropenia with prophylactic intraosseous vancomycin in a single-surgeon series of 631 primary TKAs evaluated retrospectively69. Antibiotic Resistance In a single-institution cohort study, Klasan et al. found an increase in the prevalence of antibiotic-resistant, coagulase-negative staphylococci among the infecting organisms in PJI after TKA from 2006 to 201870. Coagulase-negative staphylococci developed resistance to newer antibiotics, such as teicoplanin, fosfomycin, and tetracycline, but not to vancomycin. However, among infecting organisms collectively, there was no change in the prevalence of antibiotic resistance over the same time frame. In another single-center, retrospective study, Ludwick et al. reported that, in patients who underwent 2-stage revision for culture-positive PJI, 3.5% of infecting organisms developed antibiotic resistance by the time of reimplantation71. Other Topics Spine In a prospective, propensity-matched, cohort analysis, Abola et al. compared patients undergoing spine surgery who did or did not receive postoperative antibiotic prophylaxis and found no difference in the rate of infection with either sensitive or resistant organisms72. Kreitz et al. retrospectively reviewed 15,011 patients who underwent spine surgery to determine whether a preoperative epidural corticosteroid injection was a risk factor for postoperative surgical site infection. They found that, overall, there was no association between epidural corticosteroid injection and infection after decompression. However, there was a significant increase (p = 0.025) in the rate of infection after fusion for patients who received a preoperative epidural steroid injection (2.68%) compared with those who did not (1.69%)73. Hand Comparing smokers with nonsmokers who underwent open reduction and internal fixation for distal radial fractures, Galivanche et al. showed that smokers had a significantly higher rate of postoperative infection (OR, 1.73 [95% confidence interval (CI), 1.26 to 2.39])74. Farley et al. performed a retrospective study in patients who underwent carpometacarpal joint arthroplasty to compare adverse outcomes between opioid-naïve patients and patients who had used opioids preoperatively. The authors found that patients who use >10 oral morphine equivalents had a higher rate of surgical site infection (OR, 2.02 [95% CI, 1.59 to 2.54])75. Bäcker et al. performed a multicenter, prospective, comparative study to determine the effect of preoperative antibiotic administration prior to elective hand surgery and found no difference in the postoperative infection rate between patients who received antibiotic prophylaxis and those who did not76. Native Joint Septic Arthritis Russo et al. performed a systematic review on 2-stage exchange for native septic arthritis of the hip and knee. Using 21 studies comprising 435 procedures, the authors found an eradication rate of 93.3% at mean follow-up of 53.7 months77. Bettencourt et al. analyzed 215 patients with a history of septic arthritis of the native knee who underwent TKA. These patients were matched by age, sex, BMI, and the year of the surgical procedure with control patients who underwent TKA. At 10 years, the infection-free survivorship was 90% for the patients with a history of septic arthritis and 99% for the control group78. In another study of 201 patients with a history of native hip or knee septic arthritis who underwent TJA, Tan et al. found a 12.1% rate of PJI. There was no difference in the rate between patients who had 1-stage or 2-stage TJA, and the timing of TJA after the diagnosis of septic arthritis had no effect on the PJI rate79. Human Immunodeficiency Virus (HIV) HIV is the deadliest pandemic of our time due to the suppressive effect of the virus on the immune system. Orthopaedic surgeons often consider HIV a risk factor for infection after a surgical procedure. Rajcoomar et al. retrospectively reviewed 102 THAs in patients who had HIV but not hemophilia and found only 5 postoperative infections. All of the infections were found in patients who had not yet initiated or were noncompliant with antiretroviral therapy80. In another study evaluating patients in a low-income nation who had HIV but not hemophilia and were not intravenous drug users who underwent THA (n = 102) or TKA (n = 20), at a mean follow-up of 4 years and 3 months, only 1 patient who underwent THA developed a deep infection, and 1 patient who underwent TKA developed a superficial surgical site infection81. In a PearlDiver database study analyzing 729,101 patients who underwent THA, those with HIV taking antiretroviral therapy and those with HIV not taking antiretroviral therapy were matched 1:1:1 to patients without HIV. The 1-year PJI rates were slightly higher in those not taking antiretroviral therapy (5.3%) than those taking antiretroviral therapy (4.2%), but both approached the rate seen in the population without HIV (3.8%)82. PJI Registries As PJI complicates only 1% to 2% of hip and knee arthroplasty cases, large numbers are needed clinically to test hypotheses and make improvements in care. For primary and revision cases, large national registries provide sufficient data to allow the analysis of treatments that have small impacts and to allow subgroup analysis of populations that would otherwise be too small to study. A multinational group, the Global Arthroplasty Infection Association (GAIA), has proposed the formation of a prospective joint infection registry across multiple countries83. Modeled after the Bone and Joint Infection Registry in the United Kingdom, a standardized submission process would allow participation in prospective trials with large numbers of patients with PJI across the world. Future clinical advancements in PJI treatment and prevention depend on large data sets with diverse populations, and a global registry has the potential to drive improvements in the years to come. Basic and Translational Science In a study from the AO Research Institute in Switzerland84, Foster et al. investigated the performance of antibiotic-loaded hydrogel (poly[N-isopropylacrylamide] grafted hyaluronic acid) compared with antibiotic-loaded polymethylmethacrylate (PMMA) in a sheep model of implant-associated chronic infection. The hydrogel loaded with vancomycin and gentamicin produced local concentrations of antibiotics that were 10 to 100 times above those of the PMMA group. The hydrogel also showed reasonable biodegradability. Four of 5 sheep in both groups had an absence of infection at the time of euthanasia, suggesting an in vivo performance of the hydrogel similar to that of the current standard of care. In a similar animal study, Harrison et al.85 used a chitosan and polyethylene glycol paste loaded with mannitol, amikacin, and vancomycin in treating implant-associated S. aureus infections in rabbit models. Compared with chitosan paste without mannitol, antibiotic-loaded PMMA, and vancomycin powder alone, the chitosan paste with mannitol led to a sustained release of local antibiotics and similar bacterial control and was completely degraded by 3 weeks. Development of Animal Models for PJI In 2021, there were large leaps forward in PJI basic science, as 2 groups reported the independent creation of a robust and reproducible animal model for hip and knee PJI. Investigators at the University of Ottawa reported on a high-fidelity model of PJI that developed after the animals underwent hip hemiarthroplasty with cemented implants86, showing predictable infection progression after the surgical procedure using in vivo photoluminescent imaging of the S. aureus organisms. Reliable creation of biofilm on the prosthetic femoral head was seen in all animals. Investigators at the University of Pittsburgh reported on the creation of a rabbit model of implant-associated infection87. The injection of S. aureus bacteria into a predrilled tunnel, followed by the implantation of a small metal screw, led to predictable increases in inflammatory markers, radiographic implant-associated osteolysis, and histologic evidence of infection. 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, 3 other articles relevant to musculoskeletal infection surgery 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 Bernard L, Arvieux C, Brunschweiler B, Touchais S, Ansart S, Bru JP, Oziol E, Boeri C, Gras G, Druon J, Rosset P, Senneville E, Bentayeb H, Bouhour D, Le Moal G, Michon J, Aumaître H, Forestier E, Laffosse JM, Begué T, Chirouze C, Dauchy FA, Devaud E, Martha B, Burgot D, Boutoille D, Stindel E, Dinh A, Bemer P, Giraudeau B, Issartel B, Caille A. Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection. N Engl J Med. 2021 May 27;384(21):1991-2001. In an open-label RCT, 410 patients from 28 separate French medical centers who underwent appropriate surgical treatment for PJI were randomized to receive either 6 or 12 weeks of appropriate postoperative antibiotic therapy. Failure was defined as persistent infection or recurrent infection with an identical organism as that for the index procedure. The 6-week antibiotic therapy regimen proved to be noninferior to the 12-week regimen, with a recurrence rate of 18.1% for the 6-week group compared with 9.4% for the 12-week group. Reducing the duration of antibiotic exposure in infected patients may improve compliance and result in less selection pressure for resistant organisms. Grewal G, Polisetty T, Boltuch A, Colley R, Tapia R, Levy JC. Does application of hydrogen peroxide to the dermis reduce incidence of Cutibacterium acnes during shoulder arthroplasty: a randomized controlled trial. J Shoulder Elbow Surg. 2021 Aug;30(8):1827-33. In order to determine the effectiveness of hydrogen peroxide treatment in reducing Cutibacterium acnes infection, 60 patients undergoing a shoulder arthroplasty, performed by a single fellowship-trained surgeon, received standard skin preparation and preoperative antibiotic prophylaxis and were randomized to receive the control treatment or hydrogen peroxide dermal exposure after incision. Culture specimens were obtained from the skin, dermis, and glenohumeral joint. The overall culture positivity rate was 20%, and all positive cultures were C. acnes. There was no significant difference between patients who received the control treatment and those who received the hydrogen peroxide dermal treatment. C. acnes is a indolent and stubborn bacterium that frequently complicates shoulder arthroplasty. It is important to continue to search for methods to eliminate the colonization of this bacterium in order to prevent deep PJI in this vulnerable population. Villa JM, Pannu TS, Theeb I, Buttaro MA, Oñativia JI, Carbo L, Rienzi DH, Fregeiro JI, Kornilov NN, Bozhkova SA, Sandiford NA, Piuzzi NS, Higuera CA, Kendoff DO. International organism profile of periprosthetic total hip and knee infections. J Arthroplasty. 2021 Jan;36(1):274-8. In an international collaboration of 7 major institutions, Villa et al. demonstrated that S. aureus and Staphylococcus epidermidis remain the 2 most frequently encountered organisms involved in PJI worldwide. Resistant infections were most common in Russia and Germany. The United Kingdom and Uruguay had the lowest frequency of multi-organism infections. Future research should focus on more effective methods for the prevention of staphylococcal PJI.