Vancomycin Powder May Thwart Spinal Fusion
Prompted by relatively high infection rates associated with surgical treatment of pediatric spinal conditions such as scoliosis and spinal-deformity surgery in immunocompromised adults, spine surgeons have led “deep dive” clinical research into the possible benefits of local, intrawound antibiotic therapy. Consequently, the administration of antibiotic powder around the spine’s posterior elements and internal-fixation devices has become fairly widespread. But are there possible downsides to this approach that can impact patient outcomes?
This important question is addressed in the basic-science study by Ishida et al. in the October 2, 2019 issue of The Journal. The authors analyzed the fusion-specific impact of varying concentrations of intrawound vancomycin and tobramycin in a well-characterized rat model of posterolateral fusion performed with syngeneic iliac-crest allograft plus clinical bone-graft substitute. Ishida et al. found that a high dose of vancomycin (71.5 mg/kg, about 5 times higher than spine surgeons typically use) but not tobramycin had detrimental effects on fusion-mass formation in this model, as demonstrated by micro-computed tomography and histological analysis.
We now need further clinical research from the spine community to determine the optimal doses and types of intrawound antibiotics in this setting. Based on the currently available data, power calculations should be performed when designing future trials focused on this question. There seems to be little remaining doubt that locally delivered antibiotics help limit surgical-site and deep infections in spinal surgery. The impact of antibiotics on fusion rates must now be investigated further.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Stop Adding Antibiotics to Irrigation Solutions
The rate of adoption of knowledge gleaned from multiple well-done randomized clinical trials into medical practice is disappointingly slow. This has been well-documented in cardiovascular medicine, and the examples in orthopaedic surgery are embarrassingly similar. A corollary phenomenon exists with the slow rate of transfer of information from basic science studies to orthopaedic clinical practice.
These “disconnects” occur largely because we tend to adopt the practices of our residency faculty, often without any rational inquiry. Having been an oral examiner for the Part II ABOS Oral Boards, I frequently asked, “Why did you decide on that approach to the patient’s problem?” And I often heard in response, “That’s the way it was done in my residency.”
In the September 18, 2019 issue of The Journal, Goswami et al,. report findings from a well-designed in vitro study demonstrating that the common practice of adding the antibiotics polymyxin and bacitracin to irrigation solution to lower the risk of infection is not based on sound evidence. While adding antibiotics might make intuitive sense, according to these authors, it is “a futile exercise.”
After testing 8 different irrigation solutions for efficacy against S. aureus and E. coli and for toxicity to musculoskeletal cells, Goswami et al. concluded that “our results provide further support for the use of dilute povidone-iodine because of its bactericidal properties, relatively limited toxicity,… and modest cost.” They go on to say that their findings bring into question the widespread usage of polymyxin-bacitracin.
Certainly, we need to assemble more evidence from additional research to identify the optimal irrigation solution for orthopaedic surgery, but in the interim, we should probably stop using polymyxin-bacitracin. Doing so would have the added benefits of lowering costs and not exacerbating the serious problem of antimicrobial resistance. There are many areas of clinical practice where we have no evidence either for against a particular approach. But when we do have solid evidence, even if it’s from an in vitro study, we should work together to improve the rates of adoption into clinical practice.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
What’s New in Musculoskeletal Infection 2019
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.
PJI Diagnosis
–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.
Treating PJI
–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.
References
- 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.
Failure Factors after 1-Stage Exchange TKA
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
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 study, the 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.
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