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Biofilm Matters
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Biofilm Matters
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Language: EN.
Segment:0 .
IAN KENNEDY: In our series. I'm Ian Kennedy, I'm an orthopedic surgeon from Glasgow. I'll be helping deliver these quarterly webinars, each covering a different aspect of musculoskeletal infection. I would encourage you all to join BAJIS. It's currently free of charge and we'll keep you updated on all our other upcoming education events.
IAN KENNEDY: If you have any questions for the speakers throughout the webinar, please type these into the Q&A box at the bottom of your screen and I'll go through these at the end of each talk. So our first session today is going to focus on periprosthetic joint infection. And joining me as co-host is someone with a vast amount of experience in this area is current British Hip Society President, Professor Dominic Meek.
IAN KENNEDY: So over to yourself Prof.
DOMINIC MEEK: Thanks very much, Ian. So we've got fantastic speakers with a huge amount of experience tonight, and I'm going to start with introducing Mr Jason Webb, who's a consultant orthopedic surgeon based in Bristol. He's one of the leading, the country's leading hip surgeons, an international reputation for the prevention and treatment of prosthetic joint infection.
DOMINIC MEEK: And he's an interest in fundamental science research for infection, particularly in antibiotic bone, cement and biofilms. So it's a great pleasure to ask him to give us his talk in biofilm matters. Thanks very much.
JASON WEBB: Thank you very much, Dominic, for those kind words. And thank you for inviting me to take part in this. And so here we go.
JASON WEBB: I hope everyone can see that. So, yeah, if tonight is a dinner party and the menu, I think I'm a slightly odd, quirky, unusual starter that may suit everyone's taste, but I think we're going to have a very satisfying and tasty main course from Lizzie and Lee. I'm sure puddings are going to leave everyone extremely satisfied. So yeah, as Dominic said, I'm an orthopedic surgeon in Bristol.
JASON WEBB: These are my disclosures. And my background in this is though though, although my clinical practice is in prosthetic joint infection, my research background interest is in the sort of basic sciences and biofilm mediated techniques of management. I'm the surgical lead for our regional PJI clinic and Lizzie is the microbiology lead and the real lead so you'll hear from her next.
JASON WEBB: And because of my sort of research background in MI, I was invited at the consensus meeting to be in a rare group, the work group of the BIOFILM work group, which of over 800 inverted comma experts involved with that whole process, the BIOFILM group was only 28. Now, fortunately, the majority were basic scientists and microbiologists, so they knew what they were dealing with,
JASON WEBB: and then I think there were a couple of interested amateurs, such as myself, surgeons in that group. But from that, of vital importance is, you know, the group that came back started to the UK PJI Consensus Group, and then that's evolved into BAJIS, which is vital for this important clinical subject that becomes ever more prevalent as we see the difficulties with managing infections.
JASON WEBB: And so I want to briefly talk to you about biofilm biology and understanding it and why it then represents the clinical correlates of why periprosthetic joint infection is hard to manage, because these are the sort of cases that we get presented with in our PJI clinics. And if we understand why the biofilm acts as it does, then we've got a better chance of treating it. But more importantly, to prevent it as we're doing more and more operations, we've got to maintain good prevention.
JASON WEBB: So I'm going to take us back in time quite a long way. The Earth is 4.5 billion years old and for two thirds of that there have been bacteria and they are superbly evolved to their environment. We've only been around for about 300,000 years, so bacteria have been around 10,000 times longer than us and so not surprisingly, we don't really matter to them apart from representing a lovely host for which to colonize.
JASON WEBB: And that's exactly what they've done. But they've evolved not as regards interactions with us, but with other organisms that have been around a long time and probably chief amongst those would be fungi. They've been around for a sort of a billion and a half years and the evidence is in the evolutionary competition. Fungi produce antibiotics, I mean so do bacteria produce antibiotics, but fungi produce antibiotics. And bacteria respond to that with antibiotics resistance genes and existing in this all important biofilm.
JASON WEBB: Now, it isn't a sour relationship. We couldn't live without the bacteria. Our adaptive immune system relied on exposure to them to become functional, and the microbiome is in charge of, you know, digestion and many physiological and pathological responses are being found to have strong relations to that biofilm, to the microbiome. But evolution,
JASON WEBB: evolution went wrong, well human evolution went wrong because down one branch of the evolutionary tree, we got surgeons and then right at the end, it got even worse and we got orthopedic surgeons who thought they could improve the quality of life of their fellow humans who were middle aged and had slightly painful joints by putting in big bits of metal and plastic.
JASON WEBB: And suddenly they opened up a whole new area for bacteria to colonize because they set up this unique interaction. We're not dealing in these infections with just the pathogen and the host, but the interaction with the biomaterial that we place into the wound, which totally alters the overall behavior. Now, although biofilm had been understood for over 100 years, it was really the work of Bill Costerton, the microbiologist in the 70's that showed that sessile bacteria in the biofilm were really responsible for surgical infections.
JASON WEBB: And then Tom Gristina, an orthopedic surgeon from Florida, did a lot of early work with him. So for once, orthopedics was ahead of other surgical specialties in understanding the importance of this in surgical infections and understanding why it was so hard to manage them. And if you look at the key phrases or points in a definition of the biofilm, you won't go wrong if you remember that we are dealing obviously with bacteria that become intimately and irreversibly related to the substratum and the biomaterial with which they lie upon that.
JASON WEBB: Then they are then protected by this matrix or glycocalyx that we'll come on to discuss and it alters their phenotype so they behave entirely different to their planktonic versions. Now I wouldn't dare to go into the microbiology when I'm in such hallowed company but broad headlines, we deal predominantly with gram positives, of which the staphylococci are chief and they are much harder to kill than in our other interactions in medicine.
JASON WEBB: A brief audit from our PJI clinic looking at the prevalence of the organisms we deal with. This was some time back, but we see that over two thirds are staphylococci, over three quarters are gram positives, and then we've got some gram negatives and then a smattering of mycobacteria and fungi in the sort of immunocompromised hosts. So let me just take you through the biofilm biology. First of all, what's it made of? Well as most things on this planet it's predominantly water, but then it's got the bacteria, their breakdown products and this all important matrix.
JASON WEBB: And some scanning EMS and light microscopy from some of our research showing it really is this protective layer that lets the bacteria do their thing. So artificially, I mean, obviously it's a continuum, but artificially the biofilm life cycle is described as being in different phases. The attachment and adhesion phase, accumulation, maturation and then dispersal
JASON WEBB: so I'll deal with each of those. And it's often presented in a schematic such as this. My main point when I teach and/or talk to surgical audiences is that we must remember that every single one of our operations is contaminated and the whole point in what we do during the operation is preventative measures and in the first 24 hours or so afterwards is in making sure the inoculum is small enough or that we kill that small inoculum so it doesn't then become a clinical infection.
JASON WEBB: So let's talk with, I think, the most important phase, the adhesion and attachment phase and this is often described as forming two processes. You've got an initial reversible phase where physical factors are related, and then you move into a second phase, which is irreversible, where there are molecular and cellular interactions between the bacteria and the substratum and and you've really lost the battle already by that stage.
JASON WEBB: So every bit of biomaterial we put into the body gets coated in blood and in the blood you have got your plasma and you get this conditioning layer that makes it advantageous for the bacteria to land with all of their various surface alterations. Those early stages, it is the physical factors. It's things like the electrostatic forces, the surface morphology, the surface tension and the sort of relative hydrophilicity and febricity of the region.
JASON WEBB: Once there are enough bacteria, we then get some cellular interactions. And so into a bit more detail. First of all, in the plasma it is the Fibrinogen and Fibronectin that form the conditioning film that lets the bacteria land. But in that second phase of adhesion, you get these interactions with these bacterial surface adhesion proteins that are so important.
JASON WEBB: These have all been studied in Staphylococcus where these really start to bind to everything else and make them a really stable attachment of bacteria. The next phase is the accumulation and maturation really involve multiplication of the bacteria and production of the glycocalyx, the slimy layer that protects them and, you know, so-called the matrix. So what is the matrix? Well, it's exopolysaccharides, DNA and proteins,
JASON WEBB: and as this process moves forward, we get these sort of mature biofilms with these sort of mushroom type shapes where they're often polymicrobial. We have gaps or spaces where nutrients can diffuse in and waste products diffuse away. And we really are dealing with something that is now we've lost the battle. We're now dealing with treatment rather than prevention.
JASON WEBB: Even worse, there's a control of these colonies by the process of quorum sensing. Once there are enough bacteria, then the concentration of extracellular proteins, oligopeptides, things like that reach critical levels so that they alter the behavior and the phenotype of the bacteria sort of housed within. And then finally, once it reaches a critical population size, then the biofilm is going to disperse and detach.
JASON WEBB: Now, although some organisms can leave in a relatively vulnerable planktonic phase, for staphylococci they tend to be released with a clump of the matrix around them, thus protecting them as they spread elsewhere in the wound or further afield. And really, that's one of the reasons why gram staining is no longer really recognized as a useful investigation for potential PJI because the stain can't get into those rafts of bacteria even if they're sitting there.
JASON WEBB: So there we have it. We've got this continuum that goes from initial inoculum through to a prosthetic joint infection. Some of the, some other of the factors that are key in its virulence. The biofilm varies in size from 50 microns up to, in some cases a few millimeters. And as it gets bigger, you get variable access to nutrients and oxygen, which changes the cellular turnover of bacteria, making them harder to kill or target.
JASON WEBB: And then other factors that have been shown to be present. Calcium ions are in high concentration at the surface and that blocks the ingress of charged antibiotics such as aminoglycosides, surface bacteria can denature antibiotics and then the pH gradients that go down as you get deeper in prevent antibiotic access. So we've only really got rifampicin that is said to penetrate biofilm to any significant extent,
JASON WEBB: but this is because there are all these processes. There's increased expression of resistance genes within sessile bacteria in the biofilm compared to their planktonic phase. And as I say, their phenotype changes so that they turn over less rapidly, making them less vulnerable to sort of antibiotic attack. And then finally they disable the immune system locally because they attract in the glycocalyx attracts in the macrophages, they release their reactive oxygen species, but it doesn't really damage the glycocalyx that does, however, set up a cytokine cascade, which brings more macrophages in that similarly discharge their sort of killing mechanisms
JASON WEBB: but they don't actually kill off the biofilm. And then you're left with this sort of immuno-incompetent fibro, inflammatory zone that essentially allows the biofilm to flourish and spread further. And all of these factors together led Costerton to say that compared to their planktonic phase, the bacteria contained within the biofilm are probably about 1,000 times harder to kill. They really sort of represent a city where these bacteria are protected, both chemically, physically and immunologically.
JASON WEBB: And all of the in vitro work shows that there's a similar time frame where we've got about 24 to 48 hours to effectively prevent the development of a mature biofilm. So just to finish, what are some of the strategies that have applied science, the application of science to try and prevent them? Well, there are some strategies that we've used for a long time and we still rely on. If, however, we get an infection and need to treat it, then a cunning plan is required,
JASON WEBB: and that cunning plan has two very simple elements that must always be obeyed. You've got to remove the biofilm and therefore you need to remove the biomaterials on which is surface, it is adherent, and then you need to combine that with antibiotics of appropriate strength and sensitivities based on your microbiology interaction to kill off the stragglers. OK. But prevention, as we've said, has got to be our goal.
JASON WEBB: So strategies that are relevant towards that, well we know from registry data and from basic science data and clinical studies that if you give appropriate systemic antibiotics to reach bacteriocidal levels in the tissues as you operate on them, you reduce your infection rates and that's killing off those planktonic bacteria as they arrive. But as it's a surface phenomenon, if we make the surface toxic as well, then we can add to that benefit and prevention,
JASON WEBB: and that's also been shown and really the work of Bucholtz and Engelbrecht at the Endor clinic in 1970, adding antibiotics to bone cement was shown to be effective in treating and preventing. The reason it works is you get very high concentrations just where you need it and here Boucher's group in at in Groningen showed that those tiny gaps that you get between the bone and the cement and the cement and the implant, you can get incredibly high concentrations
JASON WEBB: and with standard antibiotic loaded bone cement with aminoglycosides in by 2 hours, you're getting concentrations that are up at about 1,000 times the MIC. Now, they don't spread further afield and cause toxicity, but they are probably why even with emerging bacterial resistance, they're still effective at reducing the growth of those newly landed bacteria. And what other strategies might be useful or relevant based on an understanding of the biofilm?
JASON WEBB: Well, first of all, vaccines to those components that of the biofilm that keeps the biofilm together. So those bacterial surface adhesion proteins targeting those have been studied in animal models, enzymes to physically disperse the biofilm sort of and then taking away the protection of the bacteria, interfering with the quorum sensing so that the sort of mature behavior is disrupted. And then finally, other strategies
JASON WEBB: as regards the surface. There have been many strategies looking at this. You can put antibiotics onto metal, you can use antiseptics or other metals and we know that antibiotic loaded bone cement and antibiotic loaded, um, titanium perform perfectly well. But I think the finally the nanoparticle type research where you're changing the surface topography and metallurgy of things like titanium where bacteria are killed
JASON WEBB: the moment they land is really useful. So in summary, I think biofilm does matter because it's so shows us what a sort of foe we're up against and how we need to be on top of our game in order to beat it. So thank you very much for listening.
DOMINIC MEEK: Thanks very much. I don't think there's any questions in the chat, but based on what you've described, that biofilm being very difficult to remove, do you think there is a place for DAIR still?
JASON WEBB: I absolutely do. You've just got to think. I mean, we know that biofilm well, DAIR's, are successful in depending on how quickly you do them and what the initial presentation and therefore origin of the infection is, they are successful and we would quote to our patients, you know, you got a three quarter chance, but you've got to catch them early.
JASON WEBB: And if there are sort of hematogenous spread, I think they're one of the best types because you know that they're invading into the joint, the surfaces that you will deal with in a DAIR, you're probably more likely to be successful. A repeat DAIR, no, I don't think that works and honestly, if we think our DAIR is going to work, we've got to remove all the bits that we can do and therefore maybe we need to be slightly more extreme with our DAIR's rather than, you know, the evidence from the world literature is the less good, the less sort of thoroughly you do your DAIR, the less likely it is to be successful.
DOMINIC MEEK: You do wonder if you just extend into a one stage revision though. That's. Yeah.
JASON WEBB: Well I mean DAIR's now are becoming a one stage. If you've got a polish taper stem, you've changed the stem. So yeah, realistically there are one point five or whatever we say in there.
IAN KENNEDY: Couple of questions coming through from the chat, just to follow on from that. Optimal duration of DAIR presumably meaning how long after duration of symptoms do you think is acceptable to still perform a DAIR?
JASON WEBB: So Ziemeli's group in Basel are probably the most robust on that and they on their algorithms say three to four weeks. What we do in the real world is we're pragmatic. We get told someone's been, you know, they come in on call and you go, well, the symptoms started at three weeks ago and then they had this funny wound and then they've been under the physicians for a while and now it is.
JASON WEBB: So we push the margins, but I think the quicker you do it from our experience, I think everyone's experience here, the quicker you do it, the better chance you have. And then it goes into all the co-morbidities and things like that and the bugs.
IAN KENNEDY: There's a lot of questions. Let's just ask one more before moving on. Is there any difference in biofilm between gram positive and negative organisms?
JASON WEBB: Yeah so some. Yeah so it's all to do with how well they're sort of good slime producers and staph epi is more presented in percentage of infection for sort of our type of jobs rather than say trauma because they are so good at producing slime and some subspecies produce it better, but then there are some real kickers in the gram negative world, the Pseudomonas and things like that.
JASON WEBB: They really can produce just fantastic biofilms and it is subtly different, but it's based on a theme and even things like TB produce a biofilm, but it's just not based on quite the same proteins. It's more of a, you know, it's called the pellicle. But yeah, so yeah, they all do and, and that makes them difficult to treat.
DOMINIC MEEK: Yeah so what conclusions coming and summarizing all that in a really fantastic lecture.
DOMINIC MEEK: [VIDEO ENDS]
Segment:0 .
IAN KENNEDY: In our series. I'm Ian Kennedy, I'm an orthopedic surgeon from Glasgow. I'll be helping deliver these quarterly webinars, each covering a different aspect of musculoskeletal infection. I would encourage you all to join BAJIS. It's currently free of charge and we'll keep you updated on all our other upcoming education events.
IAN KENNEDY: If you have any questions for the speakers throughout the webinar, please type these into the Q&A box at the bottom of your screen and I'll go through these at the end of each talk. So our first session today is going to focus on periprosthetic joint infection. And joining me as co-host is someone with a vast amount of experience in this area is current British Hip Society President, Professor Dominic Meek.
IAN KENNEDY: So over to yourself Prof.
DOMINIC MEEK: Thanks very much, Ian. So we've got fantastic speakers with a huge amount of experience tonight, and I'm going to start with introducing Mr Jason Webb, who's a consultant orthopedic surgeon based in Bristol. He's one of the leading, the country's leading hip surgeons, an international reputation for the prevention and treatment of prosthetic joint infection.
DOMINIC MEEK: And he's an interest in fundamental science research for infection, particularly in antibiotic bone, cement and biofilms. So it's a great pleasure to ask him to give us his talk in biofilm matters. Thanks very much.
JASON WEBB: Thank you very much, Dominic, for those kind words. And thank you for inviting me to take part in this. And so here we go.
JASON WEBB: I hope everyone can see that. So, yeah, if tonight is a dinner party and the menu, I think I'm a slightly odd, quirky, unusual starter that may suit everyone's taste, but I think we're going to have a very satisfying and tasty main course from Lizzie and Lee. I'm sure puddings are going to leave everyone extremely satisfied. So yeah, as Dominic said, I'm an orthopedic surgeon in Bristol.
JASON WEBB: These are my disclosures. And my background in this is though though, although my clinical practice is in prosthetic joint infection, my research background interest is in the sort of basic sciences and biofilm mediated techniques of management. I'm the surgical lead for our regional PJI clinic and Lizzie is the microbiology lead and the real lead so you'll hear from her next.
JASON WEBB: And because of my sort of research background in MI, I was invited at the consensus meeting to be in a rare group, the work group of the BIOFILM work group, which of over 800 inverted comma experts involved with that whole process, the BIOFILM group was only 28. Now, fortunately, the majority were basic scientists and microbiologists, so they knew what they were dealing with,
JASON WEBB: and then I think there were a couple of interested amateurs, such as myself, surgeons in that group. But from that, of vital importance is, you know, the group that came back started to the UK PJI Consensus Group, and then that's evolved into BAJIS, which is vital for this important clinical subject that becomes ever more prevalent as we see the difficulties with managing infections.
JASON WEBB: And so I want to briefly talk to you about biofilm biology and understanding it and why it then represents the clinical correlates of why periprosthetic joint infection is hard to manage, because these are the sort of cases that we get presented with in our PJI clinics. And if we understand why the biofilm acts as it does, then we've got a better chance of treating it. But more importantly, to prevent it as we're doing more and more operations, we've got to maintain good prevention.
JASON WEBB: So I'm going to take us back in time quite a long way. The Earth is 4.5 billion years old and for two thirds of that there have been bacteria and they are superbly evolved to their environment. We've only been around for about 300,000 years, so bacteria have been around 10,000 times longer than us and so not surprisingly, we don't really matter to them apart from representing a lovely host for which to colonize.
JASON WEBB: And that's exactly what they've done. But they've evolved not as regards interactions with us, but with other organisms that have been around a long time and probably chief amongst those would be fungi. They've been around for a sort of a billion and a half years and the evidence is in the evolutionary competition. Fungi produce antibiotics, I mean so do bacteria produce antibiotics, but fungi produce antibiotics. And bacteria respond to that with antibiotics resistance genes and existing in this all important biofilm.
JASON WEBB: Now, it isn't a sour relationship. We couldn't live without the bacteria. Our adaptive immune system relied on exposure to them to become functional, and the microbiome is in charge of, you know, digestion and many physiological and pathological responses are being found to have strong relations to that biofilm, to the microbiome. But evolution,
JASON WEBB: evolution went wrong, well human evolution went wrong because down one branch of the evolutionary tree, we got surgeons and then right at the end, it got even worse and we got orthopedic surgeons who thought they could improve the quality of life of their fellow humans who were middle aged and had slightly painful joints by putting in big bits of metal and plastic.
JASON WEBB: And suddenly they opened up a whole new area for bacteria to colonize because they set up this unique interaction. We're not dealing in these infections with just the pathogen and the host, but the interaction with the biomaterial that we place into the wound, which totally alters the overall behavior. Now, although biofilm had been understood for over 100 years, it was really the work of Bill Costerton, the microbiologist in the 70's that showed that sessile bacteria in the biofilm were really responsible for surgical infections.
JASON WEBB: And then Tom Gristina, an orthopedic surgeon from Florida, did a lot of early work with him. So for once, orthopedics was ahead of other surgical specialties in understanding the importance of this in surgical infections and understanding why it was so hard to manage them. And if you look at the key phrases or points in a definition of the biofilm, you won't go wrong if you remember that we are dealing obviously with bacteria that become intimately and irreversibly related to the substratum and the biomaterial with which they lie upon that.
JASON WEBB: Then they are then protected by this matrix or glycocalyx that we'll come on to discuss and it alters their phenotype so they behave entirely different to their planktonic versions. Now I wouldn't dare to go into the microbiology when I'm in such hallowed company but broad headlines, we deal predominantly with gram positives, of which the staphylococci are chief and they are much harder to kill than in our other interactions in medicine.
JASON WEBB: A brief audit from our PJI clinic looking at the prevalence of the organisms we deal with. This was some time back, but we see that over two thirds are staphylococci, over three quarters are gram positives, and then we've got some gram negatives and then a smattering of mycobacteria and fungi in the sort of immunocompromised hosts. So let me just take you through the biofilm biology. First of all, what's it made of? Well as most things on this planet it's predominantly water, but then it's got the bacteria, their breakdown products and this all important matrix.
JASON WEBB: And some scanning EMS and light microscopy from some of our research showing it really is this protective layer that lets the bacteria do their thing. So artificially, I mean, obviously it's a continuum, but artificially the biofilm life cycle is described as being in different phases. The attachment and adhesion phase, accumulation, maturation and then dispersal
JASON WEBB: so I'll deal with each of those. And it's often presented in a schematic such as this. My main point when I teach and/or talk to surgical audiences is that we must remember that every single one of our operations is contaminated and the whole point in what we do during the operation is preventative measures and in the first 24 hours or so afterwards is in making sure the inoculum is small enough or that we kill that small inoculum so it doesn't then become a clinical infection.
JASON WEBB: So let's talk with, I think, the most important phase, the adhesion and attachment phase and this is often described as forming two processes. You've got an initial reversible phase where physical factors are related, and then you move into a second phase, which is irreversible, where there are molecular and cellular interactions between the bacteria and the substratum and and you've really lost the battle already by that stage.
JASON WEBB: So every bit of biomaterial we put into the body gets coated in blood and in the blood you have got your plasma and you get this conditioning layer that makes it advantageous for the bacteria to land with all of their various surface alterations. Those early stages, it is the physical factors. It's things like the electrostatic forces, the surface morphology, the surface tension and the sort of relative hydrophilicity and febricity of the region.
JASON WEBB: Once there are enough bacteria, we then get some cellular interactions. And so into a bit more detail. First of all, in the plasma it is the Fibrinogen and Fibronectin that form the conditioning film that lets the bacteria land. But in that second phase of adhesion, you get these interactions with these bacterial surface adhesion proteins that are so important.
JASON WEBB: These have all been studied in Staphylococcus where these really start to bind to everything else and make them a really stable attachment of bacteria. The next phase is the accumulation and maturation really involve multiplication of the bacteria and production of the glycocalyx, the slimy layer that protects them and, you know, so-called the matrix. So what is the matrix? Well, it's exopolysaccharides, DNA and proteins,
JASON WEBB: and as this process moves forward, we get these sort of mature biofilms with these sort of mushroom type shapes where they're often polymicrobial. We have gaps or spaces where nutrients can diffuse in and waste products diffuse away. And we really are dealing with something that is now we've lost the battle. We're now dealing with treatment rather than prevention.
JASON WEBB: Even worse, there's a control of these colonies by the process of quorum sensing. Once there are enough bacteria, then the concentration of extracellular proteins, oligopeptides, things like that reach critical levels so that they alter the behavior and the phenotype of the bacteria sort of housed within. And then finally, once it reaches a critical population size, then the biofilm is going to disperse and detach.
JASON WEBB: Now, although some organisms can leave in a relatively vulnerable planktonic phase, for staphylococci they tend to be released with a clump of the matrix around them, thus protecting them as they spread elsewhere in the wound or further afield. And really, that's one of the reasons why gram staining is no longer really recognized as a useful investigation for potential PJI because the stain can't get into those rafts of bacteria even if they're sitting there.
JASON WEBB: So there we have it. We've got this continuum that goes from initial inoculum through to a prosthetic joint infection. Some of the, some other of the factors that are key in its virulence. The biofilm varies in size from 50 microns up to, in some cases a few millimeters. And as it gets bigger, you get variable access to nutrients and oxygen, which changes the cellular turnover of bacteria, making them harder to kill or target.
JASON WEBB: And then other factors that have been shown to be present. Calcium ions are in high concentration at the surface and that blocks the ingress of charged antibiotics such as aminoglycosides, surface bacteria can denature antibiotics and then the pH gradients that go down as you get deeper in prevent antibiotic access. So we've only really got rifampicin that is said to penetrate biofilm to any significant extent,
JASON WEBB: but this is because there are all these processes. There's increased expression of resistance genes within sessile bacteria in the biofilm compared to their planktonic phase. And as I say, their phenotype changes so that they turn over less rapidly, making them less vulnerable to sort of antibiotic attack. And then finally they disable the immune system locally because they attract in the glycocalyx attracts in the macrophages, they release their reactive oxygen species, but it doesn't really damage the glycocalyx that does, however, set up a cytokine cascade, which brings more macrophages in that similarly discharge their sort of killing mechanisms
JASON WEBB: but they don't actually kill off the biofilm. And then you're left with this sort of immuno-incompetent fibro, inflammatory zone that essentially allows the biofilm to flourish and spread further. And all of these factors together led Costerton to say that compared to their planktonic phase, the bacteria contained within the biofilm are probably about 1,000 times harder to kill. They really sort of represent a city where these bacteria are protected, both chemically, physically and immunologically.
JASON WEBB: And all of the in vitro work shows that there's a similar time frame where we've got about 24 to 48 hours to effectively prevent the development of a mature biofilm. So just to finish, what are some of the strategies that have applied science, the application of science to try and prevent them? Well, there are some strategies that we've used for a long time and we still rely on. If, however, we get an infection and need to treat it, then a cunning plan is required,
JASON WEBB: and that cunning plan has two very simple elements that must always be obeyed. You've got to remove the biofilm and therefore you need to remove the biomaterials on which is surface, it is adherent, and then you need to combine that with antibiotics of appropriate strength and sensitivities based on your microbiology interaction to kill off the stragglers. OK. But prevention, as we've said, has got to be our goal.
JASON WEBB: So strategies that are relevant towards that, well we know from registry data and from basic science data and clinical studies that if you give appropriate systemic antibiotics to reach bacteriocidal levels in the tissues as you operate on them, you reduce your infection rates and that's killing off those planktonic bacteria as they arrive. But as it's a surface phenomenon, if we make the surface toxic as well, then we can add to that benefit and prevention,
JASON WEBB: and that's also been shown and really the work of Bucholtz and Engelbrecht at the Endor clinic in 1970, adding antibiotics to bone cement was shown to be effective in treating and preventing. The reason it works is you get very high concentrations just where you need it and here Boucher's group in at in Groningen showed that those tiny gaps that you get between the bone and the cement and the cement and the implant, you can get incredibly high concentrations
JASON WEBB: and with standard antibiotic loaded bone cement with aminoglycosides in by 2 hours, you're getting concentrations that are up at about 1,000 times the MIC. Now, they don't spread further afield and cause toxicity, but they are probably why even with emerging bacterial resistance, they're still effective at reducing the growth of those newly landed bacteria. And what other strategies might be useful or relevant based on an understanding of the biofilm?
JASON WEBB: Well, first of all, vaccines to those components that of the biofilm that keeps the biofilm together. So those bacterial surface adhesion proteins targeting those have been studied in animal models, enzymes to physically disperse the biofilm sort of and then taking away the protection of the bacteria, interfering with the quorum sensing so that the sort of mature behavior is disrupted. And then finally, other strategies
JASON WEBB: as regards the surface. There have been many strategies looking at this. You can put antibiotics onto metal, you can use antiseptics or other metals and we know that antibiotic loaded bone cement and antibiotic loaded, um, titanium perform perfectly well. But I think the finally the nanoparticle type research where you're changing the surface topography and metallurgy of things like titanium where bacteria are killed
JASON WEBB: the moment they land is really useful. So in summary, I think biofilm does matter because it's so shows us what a sort of foe we're up against and how we need to be on top of our game in order to beat it. So thank you very much for listening.
DOMINIC MEEK: Thanks very much. I don't think there's any questions in the chat, but based on what you've described, that biofilm being very difficult to remove, do you think there is a place for DAIR still?
JASON WEBB: I absolutely do. You've just got to think. I mean, we know that biofilm well, DAIR's, are successful in depending on how quickly you do them and what the initial presentation and therefore origin of the infection is, they are successful and we would quote to our patients, you know, you got a three quarter chance, but you've got to catch them early.
JASON WEBB: And if there are sort of hematogenous spread, I think they're one of the best types because you know that they're invading into the joint, the surfaces that you will deal with in a DAIR, you're probably more likely to be successful. A repeat DAIR, no, I don't think that works and honestly, if we think our DAIR is going to work, we've got to remove all the bits that we can do and therefore maybe we need to be slightly more extreme with our DAIR's rather than, you know, the evidence from the world literature is the less good, the less sort of thoroughly you do your DAIR, the less likely it is to be successful.
DOMINIC MEEK: You do wonder if you just extend into a one stage revision though. That's. Yeah.
JASON WEBB: Well I mean DAIR's now are becoming a one stage. If you've got a polish taper stem, you've changed the stem. So yeah, realistically there are one point five or whatever we say in there.
IAN KENNEDY: Couple of questions coming through from the chat, just to follow on from that. Optimal duration of DAIR presumably meaning how long after duration of symptoms do you think is acceptable to still perform a DAIR?
JASON WEBB: So Ziemeli's group in Basel are probably the most robust on that and they on their algorithms say three to four weeks. What we do in the real world is we're pragmatic. We get told someone's been, you know, they come in on call and you go, well, the symptoms started at three weeks ago and then they had this funny wound and then they've been under the physicians for a while and now it is.
JASON WEBB: So we push the margins, but I think the quicker you do it from our experience, I think everyone's experience here, the quicker you do it, the better chance you have. And then it goes into all the co-morbidities and things like that and the bugs.
IAN KENNEDY: There's a lot of questions. Let's just ask one more before moving on. Is there any difference in biofilm between gram positive and negative organisms?
JASON WEBB: Yeah so some. Yeah so it's all to do with how well they're sort of good slime producers and staph epi is more presented in percentage of infection for sort of our type of jobs rather than say trauma because they are so good at producing slime and some subspecies produce it better, but then there are some real kickers in the gram negative world, the Pseudomonas and things like that.
JASON WEBB: They really can produce just fantastic biofilms and it is subtly different, but it's based on a theme and even things like TB produce a biofilm, but it's just not based on quite the same proteins. It's more of a, you know, it's called the pellicle. But yeah, so yeah, they all do and, and that makes them difficult to treat.
DOMINIC MEEK: Yeah so what conclusions coming and summarizing all that in a really fantastic lecture.
DOMINIC MEEK: [VIDEO ENDS]
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