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Diagnosing Infection in “Dry” Prosthetic Joints

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

FDA Approves Rapid Alpha-Defensin Test for PJI

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.

Which Germs Cause Pelvic Prosthesis Infections?

Prosthetic infections involving total hip or knee implants are bad enough, but infections involving pelvic endoprostheses following tumor resection can be particularly devastating, often necessitating multiple surgical interventions. And, such infections are disconcertingly common, affecting an estimated 11% to 53% of pelvic endoprostheses.

Findings from a retrospective multisite cohort study by Sanders et al. in the May 1, 2019 issue of The Journal of Bone & Joint Surgery reveal more about the specific microorganisms underlying those infections—and may offer insight into how to prevent them.

The authors analyzed 70 patients who underwent pelvic endoprosthetic reconstruction following a tumor resection. Eighteen patients (26%) developed an infection, and in 14 out of those 18 cases, the infection was determined to be polymicrobial. Cultures from 12 of the 18 patients (67%) were positive for a member of the Enterobacteriaceae family of gram-negative bacteria, which includes Escherichia coli. More generally, microorganisms associated with intestinal flora appeared 32 out of the 42 times that any microorganism was isolated.

At the latest follow-up (median follow-up was 66 months), 9 of the 18 patients still had the original implant, although 2 of those patients had a fistula and another 2 were receiving suppressive antibiotics. Of the remaining 9 patients who had the original implant removed, 3 had a second implant in situ.

The authors emphasize how different these pelvic endoprosthetic infections are from infections related to joint arthroplasty. The close proximity of incisions for periacetabular tumor resection to the gut and other highly colonized areas might contribute to these infections, they speculate. Sanders et al. say the findings of this study may prompt surgeons to employ additional surgical-site antiseptic measures before and during these surgeries and “may justify the use of a broader spectrum of [systemic] antibiotic prophylaxis aimed at gram-negative bacteria.”  They also suggest that investigations into “selective gut decontamination” might yield additional information about how to prevent infections in this surgical setting.

Diagnosing PJI: When The “Urine Dipstick” Outperforms Conventional Labs

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

Rabbit Study Suggests Antibiotic-Releasing Implant Coating Could Cut Infection Risk

A study by Miller et al. in the February 20, 2019 issue of JBJS provides preclinical proof of concept that antibiotic-loaded coatings on orthopaedic implants could eventually reduce the incidence of implant-associated infection.

The researchers used in vivo bioluminescence imaging (BLI) and ex vivo analysis of colony-forming units (CFUs) to show the efficacy of an implant coating that released linezolid-rifampin over a 7-day period. Through a parapatellar arthrotomy, researchers reamed the femoral canal of 12 rabbits and inoculated the canals with a bioluminescent strain of MRSA. They then inserted a surgical grade titanium peg into each canal. All of the pegs were coated with a nanofiber coating; 6 of the pegs were loaded with the antibiotic coating and 6 were not.

Implants coated without antibiotics were associated with significantly increased in vivo BLI signals and significantly increased knee width, relative to implants with the antibiotic-releasing coatings. The animals were killed on day 7, and ex vivo analysis of CFUs isolated from soft tissue, bone, and implant specimens showed significantly increased CFUs in the specimens without the antibiotic-releasing coating, while CFUs were undetectable in the implants with antibiotics.

This larger-animal model to assess bacterial burden employed a clinically used orthopaedic implant and replicated a medial parapatellar arthrotomy in humans. According to the authors, the coating used is “highly versatile, and the polymers or drug concentrations could be modified for more rapid or longer release.” This rabbit model should be amenable to studying additional antibiotic-releasing strategies for possible translation to clinical research in humans.

Musculoskeletal Infections: Oral Antibiotics Not Inferior to IV

OrthoBuzz occasionally receives posts from guest bloggers. In response to a recent New England Journal of Medicine studythe following commentary comes from Daniel Leas, MD and Joseph R. Hsu, MD.

Deep infections continue to be one of the most resource-intensive problems that orthopaedic surgeons face. Long-standing dogma has favored 6 or more weeks of intravenous (IV) antibiotics, resulting in increased healthcare costs during both the inpatient and outpatient treatment periods.

To explore the possibility of utilizing targeted oral antibiotics as an alternative, effective treatment for musculoskeletal infections, the OVIVA (Oral versus Intravenous Antibiotics) multicenter research collaboration conducted a prospective, randomized controlled trial. A total of 1,054 patients with deep musculoskeletal infections were randomized to oral or IV arms for 6 weeks of antibiotic treatment and followed for 1 year to determine treatment efficacy. The primary end point was treatment failure within 1 year, defined as the presence of predefined clinical symptoms of deep infection, microbiologic evidence of continued infection, or histologic presence of microorganisms or inflammatory tissue. Secondary outcomes included catheter-associated complications, discontinuation of therapy, and Clostridium difficile diarrhea.

Of the 1,054 patients enrolled, 909 patients were included in the final analysis. Treatment failure occurred in 14.6% of patients treated with IV antibiotics and 13.2% of patients in the oral-therapy group. This -1.4% difference indicated noninferiority based on the predetermined 7.5% noninferiority margin. Secondary outcomes between the groups differed only in catheter-related complications being more common in the IV group (9.4% vs 1.0% in the oral group).

These findings and conclusions should challenge us to re-evaluate the basis for extended IV antibiotics to treat complex musculoskeletal infections, and to consider a greater role for oral antibiotics for such infections. Further study of this question focused on patients with retained hardware is warranted.

Daniel P. Leas, MD is a PGY-5 orthopaedic resident at Carolinas Medical Center.

Joseph R. Hsu, MD is a Professor of Orthopaedic Trauma and Vice Chair of Quality at the Atrium Health Musculoskeletal Institute.

Extended Oral Antibiotics May Cut PJI Risk When Risk Factors Aren’t Modifiable

Periprosthetic joint infections (PJIs) create a significant burden for patients, surgeons, and healthcare systems. That is why so much research has gone into how best to optimize certain patients preoperatively—such as those with obesity, diabetes, or kidney disease—to decrease the risk of these potentially catastrophic complications. Still, it is not always possible or feasible to optimize every “high-risk” patient who would benefit from a total hip or knee replacement, and therefore many such patients undergo surgery with an increased risk of infection. In such cases, surgeons need additional strategies to decrease PJI risk.

In the December 19, 2018  issue of JBJS, Inabathula et al. investigate whether providing high-risk total joint arthroplasty (TJA) patients with extended postoperative oral antibiotics decreased the risk of PJI within the first 90 days after surgery. In their retrospective cohort study, the authors examined >2,100 total hip and knee replacements performed at a single suburban academic hospital. The patients in 68% of these cases had at least one risk factor for infection. Among those high-risk patients, about half received 7 days of an oral postoperative antibiotic, while the others received only the standard 24 hours of postoperative intravenous (IV) antibiotics.

Relative to those who received IV antibiotics only, those who received extended oral antibiotics experienced an 81% reduction in infection for total knee arthroplasties and a 74% reduction in infection for total hip arthroplasties. I was stunned by such large reductions in infection rates obtained simply by adding an oral antibiotic twice a day for 7 days. Most arthroplasty surgeons go to great lengths to decrease the risk of joint infection by percentages much less than that.

While further investigations are needed and legitimate concerns exist regarding the propagation of antimicrobial-resistant organisms from medical antibiotic misuse, these data are very exciting.  I agree with Monti Khatod, MD, who, in his commentary on this study, says that “care pathways that aim to improve modifiable risk factors should not be seen as obsolete based on the findings of this paper.” Furthermore, the study itself is at risk for treatment and selection biases that could greatly influence its outcomes. Nevertheless, getting a successful result in these patients is challenging and, if validated with further data, this research may help surgeons obtain better outcomes when treating high-risk patients in need of hip or knee replacements.

Chad A. Krueger, MD
JBJS Deputy Editor for Social Media

Routine Diagnostic Tests for Periprosthetic Joint Infection Demonstrate a High False-Negative Rate

 
Background:
Current guidelines recommend serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as the first-line testing for evaluation of suspected periprosthetic joint infection, in addition to synovial white blood-cell (WBC) count and polymorphonuclear percentage. However, the sensitivity and other diagnostic measures of these tests and the influence of organisms on these inflammatory markers remain inadequately investigated.

Disrupting “Quorum Sensing” Could Help Fight Biofilms

Biofilm for OBuzzThis post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

A biofilm is a complex combination of extracellular carbohydrates, proteins, lipids, and one or more species of bacteria that may adhere to an orthopaedic implant and surrounding tissue (see related OrthoBuzz post). Staphylococci bacteria are believed to account for more than 50% of all biofilm infections of medical devices.

Researchers recently summarized what we know about the biofilm formation process.1 In the attachment phase, free-floating bacteria attach to a prosthetic surface via proteins. Extracellular DNA from autolysis add to the mix. Then begins the irreversible attachment phase, during which the initial bacteria are incarcerated while more free-floating bacteria are added. During this phase, autoinducers are expressed, which serve as inter- and intrabacterial signals.

In the presence of an adequate quorum of bacteria, the maturation phase begins, during which the bacterial population cohesively shifts from replication to expression of virulence factors such as secretion systems, toxins, or biofilm formation. A mature biofilm is immune-resistant, although bacterial replication decreases. In the dispersal phase bacteria become planktonic again, potentially available to repeat the process.

Once a biofilm has formed, antibiotic administration becomes problematic because of the toxicity of the high doses needed to treat biofilm colonies. An underlying challenge with pharmacologic intervention is the variety of quorum-sensing communication pathways between bacterial species. The authors suggest that a future biofilm-fighting strategy may be to force bacteria into biofilm-forming behavior before they reach the necessary critical density to become virulent, although this notion remains unexplored. Researchers are investigating other possible strategies to disrupt the quorum-sensing communication among bacteria that enable them to behave as a “social” group.

Reference

  1. Mooney JA, Pridgen EM, Manasherob R, Suh G, Blackwell HE, Barron AE, Bollyky PL, Goodman SB, Amanatullah DF. Periprosthetic bacterial biofilm and quorum sensing. J Orthop Res. 2018 Sep;36(9):2331-2339. doi: 10.1002/jor.24019. Epub 2018 May 24.

Surgical Infection Prevention: Local Antibiotic Powders Beat IV Agents in Rats

Culture for OBuzzWhen it comes to preventing infections associated with orthopaedic procedures, the question of which antibiotic to use is only one of several concerns. How and where to administer antibiotics is another relevant question, not only in terms of infection-fighting effectiveness but also in terms of combatting the proliferation of antibiotic-resistant microbes.

In the September 19, 2018 issue of The Journal of Bone & Joint Surgery, Sweet et al. report on findings from a study in rats that compared the infection-prevention efficacy of intravenous (IV) cefazolin (n = 20) and IV vancomycin (n = 20) with local application of 4 antimicrobials—vancomycin powder (n = 20), cefazolin powder (n = 20), tobramycin powder (n = 20), and dilute Betadine lavage (n = 20).

The researchers induced infection by surgically implanting a polytetrafluoroethylene vascular graft near each rat’s thoracic spine and inoculating it with methicillin-sensitive Staphylococcus aureus (MSSA). After 7 days, all of the rats in each of the IV cefazolin, IV vancomycin, and Betadine lavage groups had grossly positive cultures for MSSA, “with bacterial colonies too numerous to count.” Ninety percent of the rats in the local cefazolin-powder group also had positive cultures, but the infection rates with vancomycin and tobramycin powder were much lower than those with the other four approaches (p <0.000001).

In addition to the main “disclaimer” about this study (namely, that its findings cannot be extrapolated to clinical practice in humans), the authors caution that “the effect of locally applied antibiotics on the emergence of resistant organisms is unknown,” while citing evidence that systemic administration of antibiotics is “associated with the emergence of resistant organisms at an alarming rate.”

Sweet et al. say they plan to follow up this study with a similar model to investigate the efficacy of local antimicrobials against the more problematic methicillin-resistant Staphylococcus aureus (MRSA)—and they suggest further that “clinical studies should be considered to determine the relative clinical efficacy of local versus systemic antibiotics for surgical infection prophylaxis in humans.”