Infection and Risk Factors in Today’s Orthopedic ORA Pro/Con Debate

Debate #1Routine Use of

Antibiotic-loaded Bone Cement

in Primary TKA

ProMike Reed, MD, FRCS

Northumbria, UK

ConAntonia Chen, MD, MBA

Boston, MA

Debate #2Use of

Vancomycin Sprinkle

in TJA

ProCarlos Higeura-Rueda, MD

Weston, FL

ConThorston Seyler, MD, PhD

Durham, NC

Debate #3Gut or Joint Microbiome:

Which is the most promising frontier

in PJI research?

JointMatthew Dietz, MD

Morgantown, WV

GutAlberto Carli, MD, MS

New York, NY

Evidence: We’ve got a tremendous amount of evidence on antibiotic-loaded cement and whether to use it or not, which really begins with the Scandinavian registries. Henry Makow first gave us this indication, based on 92,000 Scandinavian patients having hip replacements and 43,000 patients using knee replacement, which has been followed by the Norwegians, and the Finnish.

Then we’ve got two Australasian registries. In New Zealand, they found an increase in the risk of infection of used antibiotic-loaded cement. What I would say is that the study is relatively small, only 65,000 patients, when compared to other registries. It also produced some interesting data, claiming that the parental antibiotics have no function, which causes pause. The issue with the Australian registry is that there’s been such a change in practice towards using antibiotic-loaded cement.

The data I would like to highlight is unpublished and pulled from the national joint registry of England and Wales. It is massive and includes 730,000 patients—almost one million—which shows a significant risk reduction for both revisions for infection and overall revision.

In favor: Mike Reed

Antibiotic Resistance: I think people are concerned about antibiotic resistance. There’s quite a lot of work on this, but I would like to refer to Jay Parvizi’s paper, which shows that using antibiotic-loaded cement over a long period of time doesn’t affect the antibiotic profile of any bugs that grew. Subsequently, in infections, using high-dose, local antibiotic cement, we looked at the resistance pattern in great detail, and what we found was no difference in the number of resistant infections generated. In fact, there were slightly fewer, but not significantly fewer.

In Europe, we have very low rates of antibody resistance compared to the US, and we’ve obviously been doing this for a very long time. Also, the papers and data on this subject have shown no difference.

Cost Effectiveness: A 2014 article in the Bone & Joint Journal, “The economics of using prophylactic antibiotic-loaded cement in total knee replacement,” talks about the cost of antibiotic-loaded cement. It does note depending on the type of cement used, its cost ranges between USD $2,000 and USD $100,000 dollars per infection that it prevents, which is actually quite costly. I think we’d all agree on that.

In infections, using high-dose, local antibiotic cement, we looked at the resistance pattern in great detail, and what we found was no difference in the number of resistant infections generated.”

Debate #1: Routine Use of Antibiotic-loaded Bone Cement in Primary TKA

Evidence: Antibiotics have a good role in our lives. As our studies have shown, antibiotic-loaded cement can actually be beneficial, cost-saving, decrease the risk of infection, and can reduce revisions. All of these things are great. But in registries, we don’t know why a patient gets antibiotic cement—is it every single patient or selective patients? My thought process, going across the board, is not every chin strap is for everyone. You want to individualize medicine. That’s the trend and where we’re heading in the future of personalized medicine. So, why shouldn’t antibiotics be used in all patients?

Some studies show that there’s no difference in infection rates. These are smaller studies, but they can identify patients who have received antibiotics, and identified that superficial infection rates weren’t different, as indicated by the New Zealand general registry, which showed that an increase or use of antibiotic-loaded cement had an increased risk of PJI.

So, I will put my caveat out there that I do use antibiotics in cement in primary total joints at certain times, but mostly for high-risk patients. How do you define a high-risk patient? It really depends, but diabetic patients are typically high-risk immunosuppressed patients patients and

Against: Antonia Chen

those with malignant tumors, hemophilia, inflammatory arthropathies, and a prior history of infection can also be classified as high-risk patients. There’s a time and place for antibiotics but, it doesn’t have to be for every single patient.

Antibiotic Resistance: What is the problem with using antibiotic-loaded cement in every patient? Well, antibiotic resistance is something we’re all careful about. You have to be. We’re good at antibiotic stewardship because we understand that it will affect the future and the next generation. If we create resistance now, will it be a problem later? Now, granted, it’s a low dose in primaries, so that becomes a different error. I’m talking specifically to those who do revisions. For example, if you reference Thorsten Seyler’s data on acute kidney injury, the micro-organism profile changed over time, and it’s something to be careful about. I like my patients’ kidneys. I don’t want them on dialysis. I don’t want them to have to go in for a kidney replacement. So, it can happen to vulnerable patients.

Cost Effectiveness: Cost means a lot. We use a system where money pays for things. But if you look at all these studies, cost is based on the prevention of infection. The infection rate in our hospital is .05 percent, and I think in many of our instances, it’s probably very low. So, to go from a .05 to a .04 is not really a statistical blip or a big change. I know these studies are looking at case-by-case prevention of infection, which can save USD $2,000. I can save USD $100,000, depending on the patient. But will that patient actually become infected, even with the use of antibiotic-loaded cement? Is it really cost-saving? Yes, if you look at it from a research perspective. In the grand scheme of things, even if antibiotic cement is used or not. I’m not sure if cost savings pairs out in the grand scheme of things.

Debate #1: -continued-

In 2020, we’re expecting to spend approximately 1.6 billion dollars just on this condition, so prevention is extremely important. I treat a lot of infections, and when you look at the evidence, after you get a PJI, your chances of successfully treating it are 80 percent, at best. Dr. Parvizi’s paper shows that if you get a PJI, it’s a life-changing event. Your five-year survivorship is probably lower than if you get prostate, colon, or breast cancer. You have a 26 percent chance of dying if you get a PJI within five years of an infection, which is pretty dramatic. And it’s even worse when the cultures are negative, and we have a misdiagnosis of persistent infection.

Looking at a recent paper from Bryan Springer and all the registries show about a 1.5 to 2 percent increase in every single registry in the incidents of PJI per year. If you have vancomycin powder in addition to IV vancomycin, your chances of that implant being colonized, at least in this study, are close to zero, and again, you can see the difference if you use systemic vancomycin, which is the equivalent of the antibiotic prophylactic. Now, when you look at the paper from 2017, “Interwound vancomycin powder in the clinical setting,” they had two groups: one that used vancomycin powder and another group without it. It’s very clear that there’s a difference in terms of the incident of PJI. There’s

also the paper from Dr. Chambers, which shows a 50 percent reduction, specifically in the revision cases, when they use vancomycin powder. So, in conclusion, previous work supports the clinical use of interwound vancomycin powder, mainly in high-risk cases. I, certainly, disagree that you have to use it for every single case, but there is clear evidence, especially in the revision setting, where it’s beneficial.

In favor: Carlos Higuera-Rueda

In a rat model of a contaminated intra-articular implant, use of intra-articular vancomycin powder in combination with systemic vancomycin completely eliminated MRSA bacterial contamination. Animals treated with systemic vancomycin alone had persistent MRSA contamination.”

A commentary by Carlos A. Higuera, MD, islinked to the online version of this article atjbjs.org.

Intra-Articular Vancomycin Powder EliminatesMethicillin-Resistant S. aureus in a Rat Model of a

Contaminated Intra-Articular ImplantAdam I. Edelstein, MD, Joseph A. Weiner, BS, Ralph W. Cook, BS, Danielle S. Chun, BA, Emily Monroe, MD, Sean M. Mitchell, BS,

Abhishek Kannan, BS, Wellington K. Hsu, MD, S. David Stulberg, MD, and Erin L. Hsu, PhD

Investigation performed at the Department of Orthopaedic Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois

Background: Periprosthetic joint infection following hip and knee arthroplasty leads to poor outcomes and exorbitantcosts. Topical vancomycin powder has been shown to decrease infection in many procedures such as spine surgery. Therole of vancomycin powder in the setting of total joint arthroplasty remains undefined. Our aim was to evaluate the efficacyof intra-articular vancomycin powder in preventing infection in a rat model of a contaminated intra-articular implant.

Methods: Thirty-two female Sprague-Dawley rats underwent knee arthrotomy and implantation of a femoral intramed-ullary wire with 1 mm of intra-articular communication. The knee joint was also inoculated with 1.5 · 107 colony formingunits (CFU)/mL of methicillin-resistant Staphylococcus aureus (MRSA). Four treatment groups were studied: (1) no anti-biotics (control), (2) preoperative systemic vancomycin, (3) intra-articular vancomycin powder, and (4) both systemicvancomycin and intra-articular vancomycin powder. The animals were killed on postoperative day 6, and distal femoralbone, joint capsule, and the implanted wire were harvested for bacteriologic analysis. Statistical analyses were performedusing Wilcoxon rank sum and Fisher exact tests.

Results: There were no postoperative deaths, wound complications, signs of vancomycin-related toxicity, or signs ofsystemic illness in any of the treatment groups. There were significantly fewer positive cultures in the group that receivedvancomycin powder in combination with systemic vancomycin compared with the group that received systemic vanco-mycin alone (bone: 0% versus 75% of 8, p = 0.007; Kirschner wire: 0% versus 63% of 8, p = 0.026; whole animal: 0%versus 88% of 8, p = 0.01). Only animals that received both vancomycin powder and systemic vancomycin showedevidence of complete elimination of bacterial contamination.

Conclusions: In a rat model of a contaminated intra-articular implant, use of intra-articular vancomycin powder incombination with systemic vancomycin completely eliminated MRSA bacterial contamination. Animals treated with sys-temic vancomycin alone had persistent MRSA contamination.

Clinical Relevance: This animal study presents data suggesting that the use of intra-articular vancomycin powder forreducing the risk of periprosthetic joint infections should be investigated further in clinical studies.

Periprosthetic joint infections are rare but devastatingcomplications of joint replacement surgery. They occurafter approximately 1% of primary hip and knee ar-

throplasties and up to 5% of revisions1-6. As the utilization ofhip and knee arthroplasty is expected to rise dramatically, theincidence of periprosthetic joint infection is expected to

Disclosure: No outside funding was provided for this study. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the onlineversion of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arenaoutside the submitted work.

Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewedby an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication.Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.

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COPYRIGHT � 2017 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

J Bone Joint Surg Am. 2017;99:232-8 d http://dx.doi.org/10.2106/JBJS.16.00127

Debate #2: Use of Vancomycin Sprinkle in TJA

Antibody stewardship is considered best practice. By adding vancomycin powder in the wound, you’re violating the number-one rule that we do every day. Again, it’s generally accepted that exposure to antibiotics increases the likelihood of the emergence of track resistance. There’s plenty of data out there and recommendations across the board, not only in the US, but worldwide.

There’s so much evidence in spine surgery. Let’s look at spine surgery. One prospective randomized trial; nineteen retrospective studies with a significant bias. The one prospective trial found no difference in infection rates. So, I don’t think there’s enough evidence to support the routine use of it. More importantly, updated CDC and WHO guidelines strongly recommend against the use of topical antibiotics, and this is a strong recommendation despite low evidence.

Let’s look at the expected cost of preventive strategies for periprosthetic joint infection. If your one complication read exceeds 1.1 percent, then a local vancomycin sprinkle in a wound becomes a very inefficient cost strategy. So, you may want to look at other approaches, such as an antibiotic-loaded cement with a lower release and fewer complications.

Be aware of your knee complications with vancomycin powder in the wound, such as seroma, wound drainage, and even anaphylaxis.

REBUTTALHIGHLIGHT

Seyler: If you sprinkle vancomycin powder in the wound, you’re not going to reach that implant-bone interface. A better way to deliver it would be an antibiotic cement. Higuera-Rueda: I agree that if the implant is contaminated, it’s probably better to have the delivery of the antibiotics by way of cement.

Against: Thorston Seyler

Debate #2: -continued-

The joint is the most promising microbiome when we’re trying to explore treatments and modalities to address prosthetic joint infection. Our pure culture paradigm is now considered our gold standard in terms of addressing or diagnosing prosthetic joint infection. However, this leads to a significant problem for us in that we have a 20 to 30 percent culture negative rate.

And we can attribute this to any number of different issues, whether it’s prior antibiotic use, the presence of biofilm, or that we’re growing the bugs incorrectly or that the bugs just don’t want to grow for us. In infections, we’ve demonstrated the existence of these polymicrobial infections. However, unfortunately, given our limitations and our culture methods, we’re only able to grow out that more dominant species that will overtake and overwhelm and lead us to a likely incorrect or incomplete diagnosis.

However, with the development of scientific methods, we now have meta-genomics where we can go ahead and use the genomics and piece together those A’s, G’s, C’s, and T’s to give us a more complete picture of what’s occurring in the joint microbiome, to give us more complete answers as to what’s occurring with our prosthetic joint infection. And if you look at it, this is important

because the microbial cells outnumber the human cells on our body 10 to one. And so, it’s a microbe world, and we’re just living in it. And if you look at it, specifically, in terms of the microbiome, 99 percent of our DNA genes are made of microbe cells, not human cells, and so, my opponent will tell you that most of those are in the gut. However, I’ll argue that the most important ones are likely in our joint, and I would argue that while the gut is, certainly, part of the inflammatory process, it likely reflects changes that might be occurring elsewhere within the body.

Whenever we looked at infected patients, we saw common occurrences of MRSA and MSSA. But we also saw in those primary knee arthroplasty patients that five out of the seven of the patients had the existence of some type of organisms. Ones that you wouldn’t expect to commonly be present within the joint. And then also, when we’re looking at next-generation sequencing, looking at live bacteria within the joint, 35 percent did demonstrate some type of microbes within the joint and these are all consistent with the microbiome. And so, if you ask me, which microbiome is more important, I will tell you that the joint is the more important one.

Joint: Matthew Dietz

I would argue that while the gut is, certainly, part of the inflammatory process, it likely reflects changes that might be occurring elsewhere within the body.”

Debate #3: Gut or Joint Microbiome: Which is the Most Promising Frontier in PJI Research?

We know that PJIs are a big problem. We definitely understand that the path of physiology is difficult and the ideas that we have some form of contamination either at surgery or around the time of surgery. We know there is biofilm and the problem of how to get rid of it. We also know we’re dealing with a unique space, a periprosthetic space, divided into an articular space, which is relatively immune privileged. And then, an intermediaryspace, which has lots of cells.But the fact is, we’ve been treating infections for a long time, almost 50 years, around joints. And our treatment and prevention is around one hypothesis: killing bacteria. As an orthopedic surgeon, when I do a knee replacement, I have nine different opportunities to kill bacteria.

Paper after paper has shown that after all of this, you can still detect some bacteria that grows if you culture these wounds, or culture just before you close. So, the answer is yes, there are bacteria there, and we’ve been trying to kill them with many different powerful antibiotics, and we really haven’t made a dent in the treatment rates, so we have to look at something else. We have to look toward enhancing the human response. And in 2018, you are what you eat. The gut microbiome has obviously been shown to be essential in

inflammatory response. You might say we need some better research.

I’m going to quote some journals, and those journals have really short names because their impact factors are so big. Beginning with Cell, 2014. When you take mice and remove their microbiome, it clearly shows that they’re more sensitive to a variety of different infections. When you rescue their microbiome with feces or with probiotics, they can immediately fight off infection. In Science Review 2016, “Looking at multiple modes of cancer in mice” clearly shows that when you rescue their microbiome and look at their neutrophils, the neutrophils are older, and there are fewer of them. Now, do the same thing in humans and sickle cell patients who are getting penicillin V to prevent life-threatening sepsis, their neutrophils are older, there are fewer neutrophils as well, and when you take them off antibiotics, the neutrophils return. It’s compelling human evidence.

From the basic science hypothesis to the clinical sphere to the orthopedic risk factors to the actual documented mouse model in well-controlled situations, the gut microbiome has an automatic, significant response, and I think that’s the next frontier in PJI.

Gut: Alberto Carli

We have to look toward enhancing the human response. And in 2018, you are what you eat. The gut microbiome has obviously been shown to be essential in inflammatory response.”

Debate #3:-continued-

ReduceRevisions.org is an initiative focused on supporting orthopedic professionals by identifying and communicating best-in-class protocols, experiences, technologies, and global data for reducing TJA revisions and sharing that information in a way that measurably improves outcomes. To learn more, visit ReduceRevisions.org.

This supplement is sponsored by Heraeus Medical, the manufacturer and supplier of the PALACOS® bone cement portfolio. To learn more, visit Heraeus-Medical-USA.com.