(48:52):

That's the whole point about the psychological issue related to culture-negative cements. And it's 21st century, you can't just say, "Culture doesn't isolate organism in 35% of the cases." And in this one, it is really important, because look, he's already got an amputation on the other side. He works, actually. This is a Vietnam vet that actually works. And he's a very decent citizen who's done everything right. Now, you're going to put him through an operation. And this operation's already had a two-stage exchange. So, another two-stage exchange and this guy carries about 40% failure rate. And you're going to increase the chances of failure even further because you don't know what the organism is.

Dr. Parvizi (00:01):

Hi, everyone. My name is Jay Parvizi. I'm an orthopedic surgeon from Philadelphia. And thank you all for being here. But if in the middle of the talk you're all baking or you are running out short of oxygen, we'll try to bring some oxygen capsules in. I don't know why the room is so small, but thank you all for attending. And then, today, we are going to have three talks, followed by case presentation. And afterwards, we'll obviously be entertaining your questions related to infection. I assume you're all here to hear about infection, right? You're all looking very blank. It is through the infection one, isn't it? No.

(00:41):

Well, we got to change the subject. We got to talk about fibromyalgia. So, we are going to get started. I'll have a 10-minute talk that lays the ground as to why infection is important. And then we're going to have two 20-minute talks why great faculty up here. And then the case presentation, and then discussions. Perfect.

(01:04):

So, the faculty, we have Dr. Cortes-Penfield. He's an actually infectious disease specialist from University of Nebraska. Thank you for being here. I know you are not used to seeing orthopedic surgeons in the room, but I promise you, they're not all going to get drunk, at least not during the session.

Dr. Cortes-Penfield (01:24):

Like a minnow in a shark tank. Pleasure to meet you all.

Dr. Parvizi (01:27):

And then we have Collin Mudrick. He's an orthopedic surgeon from Richmond, Virginia. Collin, very nice to have you here.

Dr. Mudrick (01:34):

Thank you for having me.

Dr. Parvizi (01:36):

So, that's the agenda, which we talked about. So, we're going to do a poll, correct? All right. What's the most common cause of acute failure in the arthoplasty? So, those who answer the septic loosening, pain and instability, they can leave now. No. Obviously, infection is the most common cause of failure of knees and hips, actually, where instability used to be the most common cause of hip replacement. Now, based on all registry data, infection is the number one cause of failure of total joint arthoplasty. SSI is a terrible problem because it leads to patient dissatisfaction, increased length of stay, increased cost, mortality. And because of that, a lot of organizations have come together, trying to come up with guidelines for prevention of infection.

(02:30):

But infection prevention is a little tough because each patient has their own immune system. Bacterial microbes have different levels of virulence. Each surgery is different between different people. Some bacteria have the ability to form biofilm. And that's why the conceptual formula of CDC was put together. And basically, what CDC has told us is that SSI is a balance between the bioburden and immune threshold of the host. Reduced bioburden enhance the immune threshold. You will make a difference to SSI prevention. But that's not easy to do because your skin has up to 2 million bacteria per square centimeter. We are doing surgery in, definitely, a non-sterile environment. Your goal is to try to take those microbes down to as little as possible. And sometimes, with implants, you only need 10 or 20 microbes to be able to cause an infection.

(03:26):

And then we are dealing with the issue of microbiome. There is three or four microbes to every mammalian cell in our body. We basically are drowning in a pool of microbes. And it's amazing that we don't see more infection than we do today. So, between 2000 and 2014, there will be over a million total joint replacements being performed and continue to be going up and up. And there has been some predictions that, by year 2030, we might be doing closer to 1.5 million joint replacements.

(04:00):

The incidence of infection after joint replacement is really not very well-known because it depends on how you define infection, how much follow-up you have, how truthful you are with the date, etc. But it can be between 1 to 4% after primaries. And it can occur in about third of the cases after revisions. And if you look at these projection studies that I did with Steve Kurtz many years ago, we used the NI database, we predict that the incidence of infection was going to be on an exponential rise. At the time, ourselves and others were skeptical of this projection. But we've gone back and looked at that data, and unfortunately, we had actually under-predicted the incidence of infection, and infection is actually on even a steeper rise.

(04:44):

If you're those people that's looking at literature coming out registry database related to infection, I would urge you to stop reading them. They mean nothing. Registry database cannot be looking at infection. They just don't contain enough granular data to give us any signals about infection. And because of that, a lot of the highly respected journals will not publish data coming out of registry related to infection.

(05:12):

But then, on top of that, there is this thing so-called the aseptic cases that are actually infected. The more you look for infection, the more you will see. This was a study from our institution that we found about 12% of aseptic cases were actually infected, that were either not investigated preoperatively or the metrics that we used to define infection versus aseptic was obviously very crude. Unfortunately, some of us in this room that deal with infection see these pictures not infrequently. And there is also the issue of death following joint replacements. And this particular graph that we published a while ago shows that the five-year mortality of prosthetic joint infection is very similar to some of these common cancers, including breast cancer, melanoma, prostate, etc. If you are asking a number, 75% survivorship after five years. PJI, 75% survivorship after five years. And again, the projection about the cost, well, these are expensive procedures. You'll ask anybody who treats infection, they're extremely difficult to treat, very costly, long stay in the hospital, very expensive to treat them, both from surgical as well as medical perspective. So, this particular projection showed 1.85 billion by year 2030.

(06:42):

So, that's basically the base of where we are in terms of infection. It is a very, very important problem. 20, 25 years ago when I was doing research and being on the podium, nobody would listen to me, and they still don't. And there would be nobody in the room, or if there were, two or three people, you would walk out of the room and people would say, "Why are you wasting your time with infection? I've never seen one. This is not a problem." Now, we've all come to realize that infection is probably one of the most deadly complications of joint replacement. And we should make every effort to try to minimize that as much as possible.

(07:22):

So, I'm going to pass the presentation to Collin. Collin is going to talk about the diagnosis where we've been and where we're going. And as you all know, diagnosis of infection is a very challenging problem that still continues to baffle many of us in this room. Collin, thank you.

Dr. Mudrick (07:38):

Thank you, Dr. Parvizi. And thanks to Medscape for hosting this event tonight. I want to thank Dr. Cortes-Penfield, coming from Nebraska. He's probably one of the smarter guys in the room. And obviously, Dr. Parvizi has truly been instrumental in getting us to where we are today, from not only a diagnostic perspective but a treatment perspective. So, it's really an honor to be on a panel with you, Dr. Parvizi.

(08:02):

But if you'll go back with me just for a minute this is back the 1930s. So, at this time, pneumonia was the third biggest killer in the U.S. It was a public health crisis. And both the diagnosis as well as the treatment were quite difficult. To just take you quickly through how they would diagnose, you would have a patient present to the ER. You would take their sputum. You would inoculate a mouse's peritoneum, and you would allow this to incubate, and then mix this with anti-serum afterwards. And after a one or two-day process, maybe have a diagnosis. So, obviously, in the meantime, patients were getting sick and dying.

(08:49):

And the other problem was this is pre-antibiotics. So, there weren't a lot of great treatments for pneumonia at the time. Luckily, there was a guy named Rufus Cole, who was, I think, the Dr. Parvizi of the 1930s with MetLife, which is an insurance company. The reason they were involved is that they had paid out $25 million in death benefits the year before. So, they had a vested interest in finding a treatment. And so, together, what they were able to do was, number one, discover there was about five subtypes of pneumonia, which was hugely important because this allowed them to direct treatment towards those subtypes. And so, they took the mortality rate from 25% down to about 7% using this technology of the time. And I think the reason I mention this is I think there's a parallel to what we are experiencing today and what we've seen over the past 10 years and we've been in just a renaissance period of being able to better diagnose and better treat these infections. And we're not there 100% yet, but we have certainly made some big strides.

(10:02):

So, this is a bit of a busy slide. But I think the big takeaway is to mention biofilm. I think most people in the room have heard of biofilms. But the pathogens that we fight against are very good at creating these biofilms, which is an extracellular matrix that prevents antibiotics, as well as our immune system, to fight them. And the scary part about it is that we know at least in vitro that they can form in 24 to 48 hours. In vivo, I think we're still figuring that out. But needless to say, it can happen quickly and are very difficult to treat.

(10:42):

So, again, despite everything that's been done, there's not a single gold standard test today in 2022. However, we are significantly closer, and there have been some various distinct algorithms that we will go over briefly today that I think are very important as practicing surgeons in treating these diseases. And so, a quick history. In 2011, the MSIS produced their recommendations, which were pretty amazing back then, because there hadn't been a lot of consensus to this point where they identified major and minor criteria. This was then adopted by the ICM in 2013 with a few minor tweaks.

(11:28):

And so, this really, at the time, became a gold standard for diagnosis. And this is near and dear to me because I was a fellow in 2014 and we were at a tertiary care facility, which was somewhat of a proverbial dumping ground for infections usually about 4:00 on a Friday. So, that's how we spent most of our weekends. But this criteria was incredibly helpful for us in treating these. And fast forward five years later again, from the work of Dr. Parvizi and colleagues, this has been refined even further to the point where we not only have specific cutoffs, we also have a scoring system, which makes it very easy and idiot-proof, which is helpful for me. It makes it easy to be able to look at a chart and apply these numbers.

(12:17):

And so, you can see, in looking at sensitivity, we went from 80% to almost 98%, which was a huge increase and has really decreased the false negatives. And that's the problem that we've been facing for a long time. And we'll go over each of these individually, as we move through. But as Dr. Parvizi mentioned infection in total neuroplasty is number one in terms of failure for acute and usually in the top two or three for chronic failure in both hip and knee surgery. And so, it's obviously a big deal. And that's why we're here talking about it today.

(12:58):

In the clinic, as we're seeing patients, we're seeing people with painful joints. And there's a lot of different diagnoses that are swirling in our brain. And there are obvious ones, aseptic loosening and stability, as some of the people mentioned on the pole there, are some that are less obvious, such as metallosis and other component malposition. But I think the point being is that, every time you see a knee or a hip that has pain or is not functioning well, infection should be on your mind. And even if it seems obvious that it may be aseptic loosening, it may not be. So, I think the key again is to treat every painful joint that you work up as potential infection. I'm sorry.

(13:45):

So, again, history and physical exam are obviously very important. I think if you look at the picture on the right on the top, everybody here would agree that that's an infected joint. There's an obvious open wound. There's infected hardware that's exposed. So, that's not a hard one.

(14:02):

The top left, I think again most people would agree that that is a loose tibia. So, we know that, I think, maybe the more challenging part there is, is it from a mechanical cause? Is the patient overweight? Is it malposition? Or, is there an underlying cause such as infection that's causing it? But again, everybody would agree on the fact that it needs surgery.

(14:25):

Now, the bottom two cases are an X-ray that may look pretty normal or an incision that looks pretty normal. And these may be further out from surgery, but they come to you as a second opinion two years out from surgery and have lack of range of motion or they hurt all of the time. And those people are the ones that your radar goes up a little bit and you may need to consider that it may be a possibility of an infection. And again, the algorithm I mentioned is very helpful in these cases in moving in a stepwise fashion of making a diagnosis.

(15:04):

So, this is proposed in 2018. Again, I know this is a little bit of a busy algorithm, but is actually very simple. And we'll break it down just into three separate sections. First, before we get there, to mention, there are also a lot of markers that a lot of us are familiar with. There's ESR, CRP. There's PMN percentage by blood cell count. Now, over the past five to 10 years, we've also had new markers that have continued to, I guess, allow us to hone in our diagnoses.

(15:39):

So, you go back to that clinical suspicion. You see that patient that is painful and/or lack of range of motion, or there's something that has your antenna up. CRPSR plus or minus a D-dimer are very easy lab values to get. Almost every lab in the country can perform these. I think it is worth mentioning that CRP is reported differently depending on the lab. So, this is milligrams per deciliter. Occasionally, it's milligrams per liter. It's good to know your lab and how they report it. You have an accurate number.

(16:16):

So, I think this is again an easy test. And occasionally, you'll see somebody that's obvious. There's a hot red swollen joint, you know that it's infected. So, you don't need to send them to get these labs. You already know and can aspirate. But somebody that comes in with an already painful knee and it's not obviously infected, they're not going to be real happy about you just coming at them with an 18-gauge needle and shoving it into their joint. And I think there's morbidity associated with that. So, in those cases that are a little more equivocal, I think getting these lab values can really help direct you. I think we all know CRP is probably the most sensitive of these serum biomarkers, followed by D-dimer and ESR. But when you get a panel of them, if any one of them is elevated, then I think it's prudent to go ahead and aspirate that joint because your suspicion is high. I think it's also worth mentioning that there is occasion where somebody may have high normal levels, but if you have a really high suspicion, let's say, they're a gastric bypass patient or immunocompromised in some way and you have suspicion, I think it's still probably a decent idea to aspirate to help you dictate further treatment.

(17:28):

So, I think this is one of the big cruxes that I find incredibly helpful in diagnosing these was the minor criteria. So, the ESR and CRP, that's relatively straightforward. You get an aspirate, and so then what do you do? And the scoring system and this panel has been very helpful in trying to get to a place where you can move forward. So, the synovial white count of 3,000 cells, leukocyte esterase, which is again something you can get in clinic, and then a PMN of greater than 80%, these are all numbers that we now have cutoffs that, again, are a little more sensitive than what they previously were and are helping us determine. And alpha defense, as I mentioned earlier, again, is another marker that carries a lot of weight. You can see that it gives you three points on the scale but, again, is something that can be very helpful in moving forward.

(18:27):

So, it's obvious, if you get a eight, you have an idea you've got a diagnosis of infection. But there are other cases where you are in the gray zone. So, you maybe have a score of four, or you have somebody that has an ESR and a CRP that are high, but you have a dry tap. So, what do you do next? And that's a case that happens relatively frequently. So, I think this is the second part of the algorithm. But if you have a dry tap, I think there's always a case to be made to make a second tap if you are suspicious. And I think, whether it's ultrasound-guided or other image guided, I think that may be even more beneficial to try to find a fluid collection to get. And if you can't get that, I think nuclear medicine scan, as well as potential PET scans can be helpful.

(19:16):

I think, on the other side of that, if you have a case for, let's say, that loose tibia that we saw earlier, so you're planning on surgery and you still are in that in-between zone, this is the third part that's an intraoperative scoring system, which again, you get there and sometimes you're unsure. And I think this is a helpful tool to be able to use while you're in the operating room. And that's essentially looking at the possibility or the exposure of purulence, of a positive histology, and a single positive culture. These, again, in those equivocal cases, can help you direct which direction you're going to go.

(20:00):

I think another point that's incredibly important and, again, very helpful worth mentioning, and I know Dr. Parvizi is very involved with this as well, but the cases where you are less than 90 days from surgery. So, the guidelines that have been proposed, most of them are based on post-90-day values. And we know that, in the first 90-day period, these values are different. Originally, there were values that were proposed that were fairly significantly higher than these that are listed here. And it was very helpful, but again, we were probably getting some false negatives. So, these were revised and are now lower and have a little bit of a higher sensitivity for these acute phase problems.

(20:47):

So, a few things that, again, despite where we are, we have incredible diagnostic tools at our fingertips today. There are still clinical challenges that all of us see that treat infections. And I think one of them is when someone comes in at four, five weeks post-op and their knee is obviously hot and red and swollen. And so, clinically, you think there's an infection. You aspirate and there's purulence. So, now, you've got a sample that you send off. And what do you do in that situation? Do you move forward with surgery because the patient's getting sicker? Do you wait for a culture, treat them with antibiotics until you have a culture, and then make your decision? And then, when you make that decision, do you do an I&D with a poly exchange? Do you go with a one stage exchange or a two stage resection? And again, those are all dictated by the information that you have. And sometimes, you don't have all of the pieces of the information.

(21:52):

I think, again, on the chronic side, elevated labs that are culture negative are another significant challenge that we have, where all your radar, your antenna are up for a possible infection. But nothing is growing. Or in the case of confounding factors, such as a metallosis or somebody, that's a rheumatoid. So, the numbers can be again a little confusing. I think that the tools which Dr. Cortes-Penfield is going to talk about a little bit today again continue to evolve and are giving us the ability to diagnose bugs earlier and maybe more accurately and faster that, again, clinically will help us to dictate where we're going to head with our next steps. So, I think, with that note, I don't want to take any of Dr. Cortes-Penfield's thunder. But I'll turn it over to him. And thank you for your attention.

Dr. Cortes-Penfield (22:56):

Sure. So, let's start off with a quick poll here. Which of the following organisms you guys think is the commonly isolated by culture in prosthetic joint infection? All right. So, I have to lean forward to see, but it looks like almost everyone said Staph aureus. And you guys are right on the money. So, while the most common causes of PJI vary a little bit, on both the timing and the specific joint infection, a consistent finding is that Staphylococci are most prevalent throughout, Staph aureus and coagulase-negative Staph, with a minority of cases being caused by Strep, other Gram-positive organisms, Gram-negative organisms, anaerobes, and then rarely, fungi or other non-bacterial isolates. I will call out of course P. acnes or now Cutibacterium acnes, C. acnes, is a predominant pathogen in shoulder arthoplasty specifically, just because of the microbiome of the human shoulder.

(23:59):

Antimicrobial resistance affects both antibiotic prophylaxis, what antibiotics we use to treat, and eventually, our outcomes. We know that methicillin-resistant Staph aureus has been on the rise in the U.S. for quite a while. It's half in some regions more than half of isolates. Well, it remains fortunately rare in Europe. Good for the Europeans. Resistance is emerging in Gram-negatives, particularly in the Enterobacteriaceae, which are essentially all of your non-Pseudomonas Gram-negatives in Pseudomonas and in Acinetobacter. And then multidrug resistance is a huge problem in E.coli, CLABSI, and pneumonias probably public enemy number one in terms of having carbapenamase and extensive drug resistance, as well as Pseudomonas. And these really limit our treatment options.

(24:44):

So, what I'm going to talk to you guys about mostly is the tools that we have at our disposal to establish a microbiologic diagnosis, rather than just, is there a PJI? So, what's causing PJI? And those are two separate questions. And both are worth answering. Now, let's ask another question. Which of the following do you guys think is the highest sensitivity for isolating the causative agent of PJI? All right. So, it looks the answers are all over the place, with syndromic testing being the most common option.

(25:17):

I would say you guys are right, unless you voted for number one, because most of these technologies, other than routine cultures, are in the first couple years of development. They're in early stages. And really, if you look at the literature, the thing that's been examined is, what is the value of routine cultures versus next-generation sequencing? And next-generation sequencing certainly seems to be improving diagnosis. So, it's probably not routine culture, but we have many emerging technologies. And I think it's going to be very interesting to see over the next couple of years what additive value each one has.

(25:54):

All right. So, why do I care what bug I'm treating? Well, first of all, it can inform your operative planning. I don't tell surgeons what surgery to do, but if I'm asked, I love to weigh in on the prognosis. And I can tell you as an ID doc that Staph aureus polymicrobial infection, and to a lesser extent, Candida and mycobacterial infections, are associated with a pretty dismal diagnosis with implant retention. In fact, for Staph aureus and polymicrobial infections, there are multiple retrospective studies indicating that they're an independent risk factor for treatment failure of care.

(26:25):

It can inform my management. So, both the selection of the primary antibiotics I'm using, whether or not I need to add Rifampin, for retained Staphylococcal infections. It might inform what kind of local antibiotics you guys are putting in your cement spacers. So, for example, if we isolate Candida, you might be thinking of adding for econazole, instead of just vancomycin and aminoglycoside. And it's going to inform our duration of therapy, knowing particularly that retained Staphylococcal infections would require three to six months of therapy. And in high-risk patients, some would say most patients, serious consideration should be given to indefinite suppressive therapy.

(27:01):

So, what methods do we have to diagnose PJI? Well, for a long time, what we had was routine cultures. And we know that they're not so good. So, preoperative aspirations have about a 72% sensitivity for PJI. Lower in hips versus knees, probably due to the difficulty of getting an adequate sample. We know that, even when you take patients to the OR and get tissue samples, as well as synovial fluid, the culture negative rate varies from study to study, but frequently is about 35%. And we know that our culture negative PJIs are more common in infections that arise late versus in the early postoperative period and more likely arise in patients who have infection of a revision arthoplasty, rather than PJI of the index arthoplasty. And that's important because late infection and revision arthoplasty are again two independent risk factors for treatment failure. So, we know that the folks in whom we don't know what we're treating are set up for failure.

(27:59):

Now, there are a few simple things that you can take home to your practice without any new technology that will improve the yield of your cultures. First off is to get and send multiple cultures, ideally, five to six. That's what the literature says is probably optimal in terms of sensitivity. Send large volumes of tissue. If there's a leader of pus and I see a swab that you sent from the OR, I will have an aneurysm, I'd send the whole bottle of pus because we know that that improves the diagnostic yield.

(28:27):

For what it's worth, there was a large cohort study out of Mayo just published earlier this year that looked at the value of AFB and fungal cultures. And the diagnostic yield are very low. And that's not surprising because Candida grows really well in normal bacterial cultures and mycobacterial PJI is rare. Based on that study, those authors recommended that you really only send fungal and AFB cultures in folks who've had a prior treatment failure with a culture negative infection, folks who are seriously immunocompromised but have hematologic malignancy or solid organ transplant or folks who've recently had a systemic or invasive Candida or mycobacterial infection that might have seated the joint.

(29:09):

Other things you can do with your routine cultures. You can and should inoculate synovial fluid and/or tissue, which can just be macerated in the lab, into blood culture bottles. This doesn't require any new technology. You just need to sit down with your hospital's microbiology lab director and say, "This is a thing we need to do. Here's the literature." And inoculating joint fluid and tissue into blood culture bottles substantially improves the sensitivity of cultures. Interestingly, it also seems to reduce culture contamination rates, so we get fewer irrelevant coag-negative Staph. And it improves the time to microbiologic diagnosis down to about 24 hours.

(29:48):

You can also do implant sonication. And there is data, again from Mayo, where they've pioneered both techniques and found the implant sonication versus inoculating synovial fluid and tissue into blood culture bottles similarly improves the sensitivity of your cultures. If you don't do sonication, again, this is something your lab probably has the equipment they need to do. There's something fancy that's required for this. You need a vortex or you need a sonicator. You need a centrifuge. Even at a smaller community center, they probably have this equipment in the lab. And this also modestly improves the sensitivity of standard tissue cultures from the 60s to the mid-80s. You can also sonicate cultures if you're trying to demonstrate that you've eradicated infection in someone undergoing a two-stage exchange. Unfortunately, while it's very specific, it's not terribly sensitive.

(30:46):

So, cultures can get us to a pretty good spot, about 85 to 90%. But that's still leaving 10 to 15% of folks with a culture-negative PJI. And that's probably because we can't always get good operative samples, or we are seeing patients who've previously been given courses of antibiotics. And those have made the cultures negative. And we're just dealing with something that's really hard to grow in culture. Our anaerobes, some of our non-Staph, non-Strep, non-Gram-negatives, more unusual organisms. And this, I think, is where PCR technology can really help. And we have a couple options. We can do next-generation sequencing or metagenomics, which can be targeted or shotgun. I'll explain those in a moment. Or we can do multiplex syndromic PCR panels.

(31:35):

So, there's potentially two different approaches to metagenomics. There's targeted metagenomics. And the concept here is ribosomes have been around for a while. Everybody's got them, even if you're a bacteria. And so, we know that ribosomal RNA is something that we can go looking for, regardless of what the pathogen is going to be. And then we can look at tiny variations in those sequences to figure out what organism is in there. There's also something called shotgun metagenomics, which is essentially I'm just throwing a bunch of primers into that reaction. I'm going to try and amplify every piece of DNA that's in there. I'm going to screen out the stuff that's human DNA from my patient. And then whatever's left, I'll sequence and I'll find the bug that way.

(32:16):

And then you can do what's called syndromic or multiplex PCRs. And this is essentially a product where the manufacturer and its scientists have curated a list of gene targets for specific bugs that they know typically cause that infectious syndrome. They can go for both a specific species and look for specific genes that indicate antibiotic resistance. This is a great approach because the technology exists already. It's been deployed from many other infectious syndromes. One potential downside is that what it's looking for is limited to this pre-made list of targets. And so, you might miss some particularly unusual rare microorganism.

(33:01):

Here's some recently published data from just a couple months ago in joint bone surgery that looked at about 300 patients with ICM-defined PJI. And specifically, the 28% of those who had a culture-negative PJI, they took those samples. They did targeting metagenomics or next-gen sequencing on them. And they found that, in about two-thirds of cases, they could identify an organism. And this plot that you're looking at on the right is showing you both how often each bug was detected and with what abundance. So, the x-axis is the frequency of detection within that sample. The Y-axis is the amount of DNA that was present.

(33:43):

And what I want to call your attention to is, yes, they found all sorts of things. They found a whole bunch of things which we don't typically think of as pathogens, Ralstonia polymonus, but however, there were the same standout organisms that showed up again and again at high frequency. And they are things that we know typically cause PJI, coag-negative, Staph aureus, Acidobacteria, Gram-negatives. And so, these probably were true pathogens.

(34:09):

This is the same data presented in a slightly different way. Notably, this next-gen sequencing approach is highly, highly sensitive. It can pick up even intestinal amounts of DNA. And so, perhaps, not surprisingly, it was routinely picking up multiple different organisms. However, a consistent finding is that one of those was far and way more abundant. There was way much a whole lot more DNA for one pathogen and then a small amount of these other bugs. And so, the cool thing is because this is quantitative, we actually have some information to distinguish what is likely sample culture contamination versus what is truly a pathogen that needs to be targeted with therapy.

(34:53):

So, what about these syndromic pathogens? Again, they focus on things that we know are typical causes of a certain infectious syndrome. And we can not only identify specific species, but we can look at specific antibiotic resistance targets to immediately inform optimal therapy. There are a whole bunch of these that are already in routine practice. We've got one for rapid identification of blood cultures for meningitis, for gastroenteritis, for upper and lower respiratory tract infections. These other syndromic panels are pretty consistently very high sensitivity and specificity in mid to high-90s. So, we know that this platform works for infections at other sites. And in May of this year, we just got a new FDA approval for a 39 target joint infection panel, which we're going to talk about over the next couple slides.

(35:48):

So, this is BioFire's target. BioFire's panel, it's got a bunch of targets, which you can see here, going after both Gram-positive and Gram-negative bacteria, as well as Candida albicans. It's also got a couple antibiotic specific resistance targets like mecA for MRSA and vanA for vancomycin-resistant Enterococcus. I do want to point out it is missing two important things. It is missing Cutibacterium acnes, which is a bummer because that's one of the leading causes of shoulder arthoplasty infection. And it's missing Staphylococcus epidermis, which is a real bummer because that's the number one or number two cause of arthoplasty infection in general. This is reportedly due to issues with specificity, just because these bacteria exist at very high counts in the skin. My hope is, perhaps, we'll get a new iteration that has quantitative PCR. We can look at the CT value and distinguish real from not real infection. But for the moment, those are two important limitations, I would say, to what is otherwise a really comprehensive pathogen list.

(36:55):

This is a poster from IDWeek 2018, where they took about 900 synovial fluid samples. And they ran BioFire on all of them, compared them to what the cultures had shown. If you look at this graph on the left here, the dark green is what was found in cultures. The light green is what the BioFire detected that was not grown in culture. And then the yellow bars are the false negatives, so the culture was positive and the BioFire didn't pick anything up. What we saw was the majority of the BioFire PCR assay results were concordant with the cultures. And when they yielded additional organisms, the scientists could then do follow-up PCR with a second method and found that, indeed, that DNA was there. So, probably, the BioFire was right.

(37:43):

This is a similar poster from IDWeek a couple years later in 2020, where they've then expanded their set to about 1,500 samples. And you can see the same thing. So, the blue bars are the yield of the routine culture. And the BioFire panel is providing some additional yield for each organism. Very high sensitivity and specificity compared to culture, very high rates of agreement. And interestingly, there's a substantial detection of one or more organisms.

(38:17):

This is the most recent data. This is from IDWeek 2022, just a couple weeks ago, where these authors really focused on time to initiation of targeted therapy and how often the bone and joint panel was able to optimize or change what antimicrobials we were actually giving. They looked at both native and prosthetic joints. They had 42 patients. I noticed a couple things here. First, they reduced the number of culture-negative infections by about a third. And they found that, when the culture was positive, the large majority of those patients could have had more targeted therapy based on the BioFire PCR results. A substantial number, 39%, would've been targeted based on the negative culture results. And overall, the transition to targeted therapy could have started over two days earlier, versus waiting for the final culture and susceptibilities. So, this technology can both improve time to optimal therapy and the rate at which we're actually giving targeted versus empiric antimicrobials.

(39:25):

Now, the BioFire product does not actually have any peer-reviewed data yet, all posters I've been showing you. There is a similar technological platform that's got approval, not by the FDA, but it's available in Europe. And they have some peer-reviewed data. That's why I'm presenting this to you now. Again, they did a cohort of about 57 patients. They ran this multiplex PCR panel on all those samples. And they were able to reduce the rate of culture-negative infections by about a fifth, with a very high rate of concordance between the culture results and the PCR when both were positive. So, it is telling you what you're going to find in the cultures and a substantial minority of cases that are culture-negative. It's going to be able to give you a specific bug to target. Thank you.

Dr. Parvizi (40:23):

Thank you, Dr. Cortes. How are you all doing? I know the room is small. Enough oxygen? Perfect. We're going to present a case that's going to be for 10 minutes. And for those of you who want to come, there are some seats over here. And then, your questions. There's a lot of questions that have come through the web, but also, we are here to really answer your questions, anything you may have. So, let me pick your brain, Collin, Nicolas. This is one of actually my cases, 65-year-old gentleman, had that right below the knee amputation. He's a diabetic. He smokes. He's allergic to vancomycin because he lost his hearing after administration of vancomycin for a prolonged period of time. He's actually a Vietnam vet. That's how he lost his right leg. He also sustained the fraction on the left side, which was treated in traction. Then, he undermined the knee replacement on the left side back in 1999. Unfortunately, got infected, needed two-stage exchange for MRSA PJI.

(41:33):

Since 2000, and I think he came to us in 2016 or so, he's been having an area of a scar right in the middle of his femur that continues to drain rotational perialum material. Then he takes antibiotics and then dries up. And he's got pain. And this is what his knee looks like on the left. So, Collin, I think you'll agree this is loose, right?

Dr. Mudrick (42:00):

I would agree. Yes, sir.

Dr. Parvizi (42:02):

And it's drifting into various deformity. And he's actually having problem wearing this prosthetic on the right side. He can't put much weight on this side. So, as you said earlier for diagnosis, any painful prosthesis is infected unless proven otherwise. And then you nicely took us through the steps. You would do serology first, ESR, CRP. If you want to do a D-dimer, you can. If you don't, you don't have to. And then if ESR and CRP is elevated or if ESR and CRP is normal but you have a high index of suspicion, you told us that the next step would be aspiration, right?

Dr. Mudrick (42:44):

Yes, sir.

Dr. Parvizi (42:44):

So, that's step number two. If aspiration is dry, you would do a repeat aspiration. So, I think it's very important we get that straight in this room. Serology, aspiration, repeat aspiration. Nowhere in there we've talked about bone scan or PET scan. And I see a lot of patients referred to me they have had an Indian label bone scan, but they haven't had their joint aspirated. So, I think that's really a mistake in algorithm. So, we did ESR marginally because 30 is the threshold for chronic. CRP, and very nicely, Collin told us, that come in two different... I don't know why, Nicolas. I have no idea why they're still reporting a milligram per liter, milligram per deciliters. It's confusing. I have no idea. But this is milligram per liter. So, 10 is the threshold for milligram per liter, or one for milligram per deciliter. D-dimer is 290, but that's elevated. But it doesn't matter. If CRP is elevated and D-dimer is elevated, that's still two points. It's not four points. It's still two points. Cell count 4,500. I think 3,000 is the... So, we've got three points there. We have two points there. That's five. And then we have another three points for the synovial neutral differential. So, would you agree, Nicolas, this is infected?

Dr. Cortes-Penfield (44:10):

This gentleman has a definite infection.

Dr. Parvizi (44:12):

So, we send this for culture. And because he's had multiple treatments, so we asked him to keep the culture for 14. How long should we keep the culture?

Dr. Cortes-Penfield (44:24):

That's a great question, a little bit of debate. But there are some evidence that prolonged holds of cultures will modestly increase yield of cultures, long being 10 to 14 days.

Dr. Parvizi (44:34):

14 days, yeah. So, routinely though, five is probably what the lab does, right?

Dr. Cortes-Penfield (44:40):

Unless you talk to the lab, they're probably going to throw away the sample at day five.

Dr. Parvizi (44:43):

At day five. So 14, and then if you suspect mycobacterium or, maybe, fungi, you would do longer?

Dr. Cortes-Penfield (44:51):

Yeah, it depends on what you're really thinking about. Candida will grow right away. Some of the more unusual fungi will take weeks. Mycobacteria, unless they're that specific rapid-growers, are going to take weeks.

Dr. Parvizi (45:03):

Perfect. So, one of the things about molecular test, we're going to come to that in a second, but one of the things that excites me about molecular testing, two things. One is actually you get the results much faster. I don't have to wait 21 days to know that the patient has mycobacteria. Over that matter, 14 days to find out if they have C. acne. The second thing, which is what I really would like you to weigh in. And I know we are diverting it a little bit here, but I really would like to pick your brain on that now. A lot of the criticism I hear is that molecular testing is going to lead to a huge, huge over-utilization of antibiotics. And we heard that in the AMR meeting that I had.

(45:47):

I would argue it's exactly the opposite, because what do we do right now for culture-negatives? My institution gives them broader spectrum Gram-positive, broader spectrum Gram-negative. Some of them with complex, they even give them additional antimicrobial. And perhaps, they even cover fungi, right? But if you sent a sample for molecular testing and you isolate the C. acne, isn't it fair to say that that will reduce the antibiotic stewardship?

Dr. Cortes-Penfield (46:17):

Yeah. So, our culture-negative regimens are incredibly broad. It's hard to imagine how you'd be expanding coverage based on any positive result from the BioFire. Essentially, what it can do is target therapy for you. I would say, as long as you are sending it appropriately, as long as you are not sending this PCR panel in patients who don't have clinical suspicion of infection, this can only help us optimize antibiotic therapy.

Dr. Mudrick (46:46):

I'm curious, along those lines of one of your slides, Nico, is you had E. coli in the top right. And is that a condition of poor surgeon hand hygiene? How do you explain that being such an outlier?

Dr. Cortes-Penfield (47:04):

I think that E. coli just grows really vigorously. And so, when we find it, we find a lot of it. I'm not here to cast aspersions or blame.

Dr. Mudrick (47:13):

I'm just curious.

Dr. Cortes-Penfield (47:14):

If you do enough surgeries, you're going to get some infections. But that is an interesting feature of the next-gen sequencing. We don't have it with the syndromic panel yet, but they can offer actual quantitation, which, like I mentioned, and this is important because they're so sensitive, they always find a bunch of things, that is really going to help us distinguish what is real and something I need to treat and what is low-level contamination, not the cause of the patient's infection.

Dr. Parvizi (47:41):

So, Collin, what are you going to do?

Dr. Mudrick (47:44):

So, again, as we've said, I think we've identified PJI by score, and we don't have a culture. And so, I think, if we have the availability of syndromic PCR next-gen, I think that's what I would do now. Before this panel, I don't know. I probably would've treated it and given broad spectrum antibiotics. But I think we have a better way of potentially identifying...

Dr. Parvizi (48:09):

Right, know what it is. Because I think this is a complex operation. Fortunately, the components are loose. But we don't always have that luxury, because they come in with long cemented stems, all the way down to the ankle and they're infected. You've got to yank those out. So, the question is, what am I going to put in the cement? And what am I going to give them postoperatively? And in 21st century, you're telling a patient, "I'm going to yank out these well-fixed components. I'm going to put an antibiotic cement spacer. I'm going to give you six weeks of intravenous antibiotics. And then I'm going to put you through a second operation that is about 20% failure rate." Aren't they entitled to ask, "What antibiotic are you going to put in the cement if you don't know what my organism is?"

(48:52):

That's the whole point about the psychological issue related to culture-negative cements. And it's 21st century, you can't just say, "Culture doesn't isolate organism in 35% of the cases." And in this one, it is really important, because look, he's already got an amputation on the other side. He works, actually. This is a Vietnam vet that actually works. And he's a very decent citizen who's done everything right. Now, you're going to put him through an operation. And this operation's already had a two-stage exchange. So, another two-stage exchange and this guy carries about 40% failure rate. And you're going to increase the chances of failure even further because you don't know what the organism is.

Dr. Mudrick (49:36):

So, yeah, I think the other challenge, too, as you mentioned, is that there's a draining sinus at the mid-thigh. And so, yes, you have an aspirate from the joint. But again, there's another source that hopefully it's the same bug, but is it communicating or not with the joint itself.

Dr. Parvizi (49:53):

With joint. And I think most of us in this room, the surgeons will agree. I don't know how to go back. You will agree that there is a little bit of an involucrum at the area where he's... You see, there's a dead bone there, right? Nicolas, do you agree?

Dr. Cortes-Penfield (50:06):

Mm-hmm.

Dr. Parvizi (50:07):

There's a dead bone. So, there's an involucrum. There's suspicious radiolucency at the tip of that femoral stem. So, obviously, infected, score of eight. So, you just answered this question. I don't think we'll go through this. I think all of us in this room agrees that we would do the D, syndromic molecular testing. There's really nothing else here is going to help. Bone scan, well, I know it's infected. Repeat aspiration, you don't need it because you've already made the diagnosis. You could potentially send tissue samples and wait for a long period of time, etc. But I think molecular testing is really... And in fact, we did and just did pick up MRSA, his old infection. I have no idea why culture didn't, by the way, but he had been on and off antibiotics a lot. I think that does... Is it fair to say?

Dr. Mudrick (50:58):

As someone who does ortho ID at a tertiary referral center, that is the bane of my existence. And again, I'm not casting aspersions, but it's typically someone who comes up with an infection. It's questionable whether it's superficial surgical site infection or it's a deep infection. We give a couple weeks of Keflex to hope it will go away. We got unlucky it did not go away. And then by the time that they get aspirated, there's nothing for me to try.

Dr. Cortes-Penfield (51:23):

Can I ask you, if let's say that's happened, is there an ideal time to stop those and wait, let's say, it's not a festering infection, or is that still to be determined?

Dr. Mudrick (51:34):

Yeah. So, that's a key point. Anyone in whom you've decided to operate, unless there's evidence of sepsis or systemic infection, it's totally okay to hold antibiotics until it's time to give perioperative antibiotic therapy. I would say, as to how long to be off antibiotics to attempt a repeat culture, I can't give you a good evidence-based answer. If you talk to Ravi Darwish, who wrote the vertebral osteo guidelines, he would say at least two weeks. But I think that's expert opinion level.

Dr. Parvizi (52:08):

So, we went ahead. And actually, there was infection at the tip. We resected that bone, did an osteotomy, did an antibiotic cement spacer, added our VC, plenty of vancomycin, except this gentleman has sensitivity to vanco. So, I think we actually did a lot of daptomycin here as well, and then went back and replanted it. So, I think this is just one case that highlights the issues you face with the culture-negative cases.