The incorporation of antibiotics within polymethylmethacrylate (PMMA) has been widely used over recent decades for managing infection following skeletal trauma. Early research helped to clarify which antibiotics in which formulations were potentially clinically effective, with a common application of managing “dead space” following debridement of bone and soft tissue, addressing established infection as well as preventing deep infection. As the microbiology involved in these infections evolves, along with the antibiotics available, we have need for continued research into this important area of orthopaedics.
In the September 15, 2021 issue of JBJS, Levack et al. report on their investigation into the suitability of alternative antibiotics (amikacin, meropenem, minocycline, and fosfomycin) for use in PMMA beads, with a particular focus on thermal stability and in vitro elution characteristics. Tobramycin was also used to validate the study methodology. Minimum inhibitory concentrations of the antibiotics were tested against S. aureus, E. coli, and Acinetobacter baumannii. Antibiotic-laden PMMA beads of different sizes were tested, with antibiotic elution determined using high-performance liquid chromatography with mass spectrometry.
The authors found that amikacin was comparable to tobramycin with respect to heat stability and elution. Meropenem showed favorable elution kinetics and thermal stability in the initial 7 days.
The investigators emphasize that “The data presented are intended to generate further study of these antibiotics to better identify potential areas of clinical utility,” and they rightly point out that their data are not intended for clinical decision-making, “as antibiotic dosages and in vivo applications, specifically with biofilms, have not been evaluated.” Nonetheless, these new data involving the characteristics of amikacin and meropenem are intriguing. Moreover, this study serves as a great reminder of the need to regularly reevaluate established therapies as research techniques, pharmacology, and clinical conditions (such as evolving microbial pathogens) continue to change.
Marc Swiontkowski, MD
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 14 subspecialties. Click here for a collection of all such OrthoBuzz specialty-update summaries.
This month, co-author Thomas K. Fehring, MD summarizes the 5 most compelling findings from the >90 studies highlighted in the recently published “What’s New in Musculoskeletal Infection.”
Albumin and Complication Risk
–One recent study evaluated the effect of albumin levels on complications following primary and revision total joint arthroplasties (shoulder, elbow, wrist, hip, knee, ankle, or fingers). Patients with lower albumin levels preoperatively were at significantly increased risk for infection, pneumonia, sepsis, and other adverse outcomes compared with patients with normal albumin levels.
Antibiotic Prophylaxis and SSI Risk
–A retrospective cohort study using data from 436,724 total hip arthroplasty (THA) and 862,918 total knee arthroplasty (TKA) procedures examined antibiotic prophylaxis patterns and surgical site infection (SSI) risk1. Patients who received IV antibiotics other than cefazolin preoperatively had a higher risk of SSI.
Corticosteroid Injections and PJI
– A study using a large national database found that patients who underwent TKA and received a postoperative intra-articular corticosteroid injection (5,628 of 166,946 TKAs, 3.4%) had a significantly higher rate of periprosthetic joint infection (PJI) compared with a matched control cohort who did not receive an injection2.
–A multicenter randomized controlled trial found that a 3-month course of microorganism-directed oral antibiotics significantly reduced the rate of failure from further infection after 2-stage revision of THA or TKA for chronic PJI3. Among 185 patients, treatment success was achieved for 87.5% of the patients who received 3 months of antibiotics vs 71.4% of those who did not.
Oral Antibiotics in Revision Arthroplasty
–Another multicenter randomized controlled trial evaluated the utility of adding rifampin to conventional antimicrobial therapy in cases of staphylococcal PJI treated with debridement and retention of the implant4. No significant advantage of adding rifampin to standard antibiotic therapy was found.
- Zastrow RK, Huang HH, Galatz LM, Saunders-Hao P, Poeran J, Moucha CS. Characteristics of antibiotic prophylaxis and risk of surgical site infections in primary total hip and knee arthroplasty. J Arthroplasty. 2020 Sep;35(9):2581-9. Epub 2020 Apr 18.
- Roecker Z, Quinlan ND, Browne JA, Werner BC. Risk of periprosthetic infection following intra-articular corticosteroid injections after total knee arthroplasty. J Arthroplasty. 2020 Apr;35(4):1090-4. Epub 2019 Nov 16.
- Yang J, Parvizi J, Hansen EN, Culvern CN, Segreti JC, Tan T, Hartman CW, Sporer SM, Della Valle CJ; Knee Society Research Group. 2020 Mark Coventry Award: microorganism-directed oral antibiotics reduce the rate of failure due to further infection after two-stage revision hip or knee arthroplasty for chronic infection: a multicentre randomized controlled trial at a minimum of two years. Bone Joint J. 2020 Jun;102-B(6_Supple_A):3-9.
- Karlsen ØE, Borgen P, Bragnes B, Figved W, Grøgaard B, Rydinge J, Sandberg L, Snorrason F, Wangen H, Witsøe E, Westberg M. Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial. J Orthop Surg Res. 2020 Aug 28;15(1):365.
Among >100,000 total hip arthroplasty (THA) patients ≥55 years of age whose data resides in a Canadian arthroplasty database, the 15-year cumulative incidence of periprosthetic joint infection (PJI) was 1.44%, according to a study by the McMaster Arthroplasty Collaborative in the March 18, 2020 issue of JBJS.
In addition to finding that the overall risk of developing PJI after THA has not changed over the last 15 years in this cohort, the authors found the following factors associated with increased risk of developing a PJI:
- Male sex (absolute increased risk of 0.48% at 10 years)
- Type 2 diabetes (absolute increased risk of 0.64% at 10 years)
- Discharge to a convalescent-care facility (absolute increased risk of 0.46% at 10 years)
The authors view the third bulleted item above as “a surrogate marker of frailty and poorer general health.”
Patient age, surgical approach, surgical setting (academic versus rural), use of cement, and patient income were not associated with an increased risk of PJI. Nearly two-thirds of PJI cases occurred within 2 years after surgery, and 98% occurred within 10 years postoperatively.
The authors conclude that these and other substantiated findings about PJI risk factors “should be reviewed with the patient during preoperative risk counseling.”
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Thomas K. Fehring, MD, co-author of the July 17, 2019 “What’s New in Musculoskeletal Infection,” selected the five most clinically compelling findings—all focused on periprosthetic joint infection (PJI)—from among the more than 90 noteworthy studies summarized in the article.
Preventive Irrigation Solutions
–An in vitro study by Campbell et al.1 found that the chlorine-based Dakin solution forms potentially toxic precipitates when mixed with hydrogen peroxide and chlorhexidine. The authors recommend that surgeons not mix irrigation solutions in wounds during surgery.
–A clinical evaluation by Stone et al. showed that alpha-defensin levels in combination with synovial C-reactive protein had high sensitivity for PJI diagnosis, but the alpha-defensin biomarker can lead to false-positive results in the presence of metallosis and false-negative results in the presence of low-virulence organisms.
–In an investigation of next-generation molecular sequencing for diagnosis of PJI in synovial fluid and tissue, Tarabichi et al. found that in 28 revision cases considered to be infected, cultures were positive in only 61%, while next-generation sequencing was positive in 89%. However, next-generation sequencing also identified microbes in 25% of aseptic revisions that had negative cultures and in 35% of primary total joint arthroplasties. Identification of pathogens in cases considered to be aseptic is concerning and requires further research.
–A multicenter study found that irrigation and debridement with component retention to treat PJI after total knee arthroplasty had a failure rate of 57% at 4 years.2
–Findings from an 80-patient study by Ford et al.3 challenge the assumption that 2-stage exchanges are highly successful. Fourteen (17.5%) of the patients in the study never underwent reimplantation, 30% had a serious complication, and of the 66 patients with a successful reimplantation, only 73% remained infection-free. Additionally 11% of the patients required a spacer exchange for persistent infection.
- Campbell ST, Goodnough LH, Bennett CG, Giori NJ. Antiseptics commonly used in total joint arthroplasty interact and may form toxic products. J Arthroplasty.2018 Mar;33(3):844-6. Epub 2017 Nov 11.
- Urish KL, Bullock AG, Kreger AM, Shah NB, Jeong K, Rothenberger SD; Infected Implant Consortium. A multicenter study of irrigation and debridement in total knee arthroplasty periprosthetic joint infection: treatment failure is high. J Arthroplasty.2018 Apr;33(4):1154-9. Epub 2017 Nov 21.
- Ford AN, Holzmeister AM, Rees HW, Belich PD. Characterization of outcomes of 2-stage exchange arthroplasty in the treatment of prosthetic joint infections. J Arthroplasty.2018 Jul;33(7S):S224-7. Epub 2018 Feb 17.
Prior to performing a primary total joint arthroplasty, patient optimization is both possible and recommended. However, when a patient with a periprosthetic joint infection (PJI) comes in to your office, opportunities for patient optimization are limited. At that point, the patient’s BMI, kidney/liver values, and HgbA1c/fructosamine levels are not going to be dramatically improved prior to any procedure to eradicate the infection and/or salvage the implant. Still, for the purposes of care optimization and prognostic guidance, it is important to identify specific patient or wound characteristics that may help us flag patients who are at increased risk for failure after treatment of a PJI.
That was the goal of the case-control study by Citak et al. in the June 19, 2019 edition of The Journal. The authors compared 91 patients who experienced a failed 1-stage revision total knee arthroplasty that was performed to treat a PJI to a matched cohort who had a successful 1-stage revision to treat a PJI. (The authors defined “failure” as any subsequent surgical procedure regardless of reason.)
A bivariate logistic analysis revealed that patients who had a history of a previous 1-stage (OR 29.3; p< 0.001) or 2-stage (OR 5.8; p <0.001) exchange due to PJI, or who had Streptococcus (OR 6.0; p = 0.013) or Enterococcus (OR 17.3; p = 0.023) isolated from their wound were at increased risk of reinfection compared to the control group. Just as important, the authors found that patient body weight of 100 kg or above and history of deep vein thrombosis (DVT) were the only patient comorbidities related to an increased risk of a failed revision.
While these findings may not be surprising in light of previous data on this topic, they are important in aggregate. Patients whose wounds contain isolated enterococci or streptococci may not be ideal candidates for 1-stage PJI revision surgery. Additionally, the authors highlight that patients who have failed two or more attempts at a 1-stage revision should be considered for a 2-stage protocol.
While many of the patients in this study who failed the 1-stage revision may have also failed a 2-stage revision, ongoing research comparing the two protocols should help further clarify whether certain infections are more amenable to successful treatment with one protocol or the other. In the meantime, studies such as this add valuable data that surgeons can use to guide patient care and provide meaningful patient education for shared decision-making about how to treat these difficult infections.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
Despite a bevy of research and intense clinical focus, definitively diagnosing periprosthetic joint infections (PJIs) remains a major challenge in many patients. There is no single test that can confirm a PJI diagnosis with absolute accuracy, and surgeons often encounter clinical factors that make the diagnostic challenge even more complex. One such scenario is when a surgeon cannot aspirate enough fluid for culture from the affected joint of a patient who may have a PJI. In such situations, important microbiological data that would come from culturing synovial fluid are unavailable, leaving treating surgeons information-poor.
In the June 5, 2019 issue of The Journal, Li et al. provide surgeons with data about a controversial solution to this so-called “dry-tap” problem. The lead author performed aspirations on nearly 300 joints that were suspicious for periprosthetic infection. Eighty-two of those aspirations (29%) yielded ≤1.0 mL of synovial fluid. In those “dry-tap” cases, 10 mL of saline solution was injected into the joint, which was then reaspirated.
When comparing cultures from the aspirates that were the result of a saline lavage to those in which no lavage was performed, the authors found overlapping 95% confidence intervals in sensitivity, specificity, positive predictive value (PPV), and negative predictive value. However, the specificity (0.991 vs 0.857) and PPV (0.987 vs 0.889) were higher in the nonlavage cohort, even if those differences did not reach statistical significance. In addition, no significant differences were found between the groups in terms of relative frequencies of specific pathogen types.
Although the authors conclude that this lavage-and-reaspiration technique “is not necessarily inappropriate,” it is important to note that no post-hoc power analysis was performed, and therefore type II error needs to be considered because the study was probably underpowered. In addition, the International Consensus Meeting (ICM) recommends against lavaging a “dry” joint to obtain fluid for culture, largely because the injected saline will dilute results if a leukocyte esterase strip test or cell count is subsequently performed as part of the PJI-diagnosis process. Still, the authors point out that the data supporting the ICM’s recommendations against this practice are relatively weak, and the specificity and sensitivity data from this study are quite satisfactory.
So does this give us another option for determining whether a periprosthetic joint infection is present in patients from whom little or no synovial fluid can be obtained? Maybe. But this technique requires further investigation before it becomes widely implemented in practice. Without validation, it risks becoming just one more variable that could reinforce our own confirmation biases in these challenging cases. With further validation, however, it could allow pre-revision collection of valuable and accurate culture information from “dry” joints.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
The US FDA has approved the Synovasure Alpha Defensin Lateral Flow Test Kit for helping detect periprosthetic joint infection (PJI) in the synovial fluid of patients being evaluated for revision joint replacement.
Alpha defensins are proteins released by neutrophils in early response to infection. OrthoBuzz previously summarized a 2018 JBJS study that found this rapid alpha defensin test to have 96.9% overall accuracy.
In the FDA news release about the approval, Tim Stenzel, MD, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, said the test provides health care professionals with additional information that “could potentially reduce patient risk by avoiding unnecessary revision operations for replacement joints.”
In a Commentary on the 2018 JBJS study, Garth Ehrlich, PhD and Michael Palmer, MD said the device is a “substantive advance,” but not “a panacea.” For one thing, metallosis would still need to be ruled out with MRI, because that noninfectious etiology triggers a false-positive result with this rapid test. Synovasure is also likely to miss detection of slow-growing, chronic bacterial pathogens such as Proprionibacterium acnes, the commentators said.
The Synovasure test kit received approval through the FDA’s de novo premarket pathway, which is reserved for “low- to moderate-risk devices of a new type,” according to the agency.
Despite what seems like a new, high-quality study being published on the topic every week or so, orthopaedic surgeons still have an extremely hard time determining whether a prosthetic hip or knee is infected or not. We have an array of available tests and the relatively easy-to-follow criteria for a periprosthetic joint infection (PJI) from the Musculoskeletal Infection Society (MSIS), but a large number of these patients still fall into the gray zone of “possibly infected.” This predicament is especially thorny in patients who received antibiotics just prior to the diagnostic workup, which interferes with the accuracy of many tests for PJI.
In the April 17, 2019 issue of The Journal, Shahi et al. remind orthopaedic surgeons about a valuable tool that can be used in this scenario. Their retrospective study looked at 121 patients who had undergone revision hip or knee arthroplasty due to an MSIS criteria-confirmed periprosthetic infection. Shahi et al. sought to determine which diagnostic tests were least affected by prior antibiotic administration. The authors found that erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, synovial white blood cell (WBC) count, and polymorphonuclear neutrophil (PMN) percentage were all significantly lower in the 32% of patients who had received antibiotics within 2 weeks of those tests, compared with the 68% who did not receive antibiotics. The only test that was found not to be significantly affected by the prior admission of antibiotics was the urine-based leukocyte esterase strip test.
Considering the ease and rapidity with which a leukocyte esterase test can be performed and evaluated (at a patient’s bedside, with immediate results), its low cost, and the fact that it is included in the MSIS criteria, these findings are very important and useful. While we would prefer that patients with a possibly infected total hip or knee not receive antibiotics prior to their diagnostic workup, previous antibiotic exposure remains a relatively common scenario. The findings from this study can assist us in those difficult cases, and they add further evidence to support the value and reliability of the easy-to-perform leukocyte esterase test.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
Quick and accurate: that’s what orthopaedic surgeons want in diagnostic tools to help them determine whether patients presenting with pain after total joint arthroplasty have an infection. A prospective Level I study by Gehrke et al. in the January 3, 2018 issue of The Journal of Bone & Joint Surgery determined that a new lateral flow version of the Synovasure Alpha Defensin Test meets those requirements.
Alpha defensin is a protein secreted by neutrophils in response to bacterial infection, prior to the development of specific immune responses. Earlier research established alpha defensin in synovial aspirates to be an excellent biomarker for periprosthetic joint infection (PJI). The original ELISA-based alpha defensin test is usually sent out for 24-hour processing, limiting its intraoperative utility. However, the lateral flow version of the test (akin to an over-the-counter pregnancy test) was approved for use in Europe—and its results are available in 10 to 15 minutes.
Gehrke et al. compared the rapid test’s results to the diagnostic criteria promulgated by the Musculoskeletal Infection Society (MSIS). According to MSIS criteria, there were 76 joints with PJI among 191 study subjects on whom 195 joint aspirations were performed. Using that as the benchmark for diagnosis, the authors analyzed results from the rapid alpha defensin tests and found the following performance:
- 92.1% sensitivity
- 100% specificity
- 100% positive predictive value
- 95.2% negative predictive value
- 96.9% overall accuracy
Although the rapid test does not provide information about the identity of specific pathogens, the authors conclude that it “enables surgeons to start proper therapy without delay.” That ability comes at a price, however. In Germany, where this study was performed, each rapid test costs about 400 Euros, which is nearly $500 US.
In a commentary on the study, Garth Ehrlich and Michael Palmer cite another possible cost with the rapid-test scenario. Prior to using any alpha defensin test, physicians must rule out metallosis with MRI, because that non-infectious entity triggers false-positive results.
The percentage of periprosthetic joint infections (PJIs) among patients requiring revision arthroplasty of the hip and knee is increasing. PJIs have important clinical implications both for revision surgical procedures as well as pre- and postoperative management. Any extra help we can get making a PJI diagnosis outside of the obvious (where the patient presents with a draining wound) would be most welcome.
In the September 6, 2017 issue of The Journal, Shahi et al. present compelling data from a prospective study suggesting that serum D-dimer levels may help diagnose PJI—and thereby help determine the optimal timing of component reimplantation. The authors determined that 850 ng/mL was the optimal threshold value for D-dimer in diagnosing PJI. Moreover, with sensitivity of 89% and specificity of 93%, this test outperformed the widely used ESR and CRP tests, which until now have proven to be the “best” tools we have at our disposal.
Ideally, after these results are confirmed in larger populations of patients undergoing revision arthroplasty, the serum D-dimer test—inexpensive and almost universally available—will be used in all high-volume joint replacement centers. The continued pursuit of diagnostic and treatment methodologies for patients with suspected PJI is definitely warranted, given the increasing number of patients requiring arthroplasty and combined lifetime knee- and hip-replacement revision rates hovering around 10% to 12%. The identification of D-Dimer elevation as a potentially more accurate diagnostic tool than our currently available tests is a welcome contribution.
Marc Swiontkowski, MD