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Selecting Oral Antibiotics for PJI
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Selecting Oral Antibiotics for PJI
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Segment:0 .
DOMINIC MEEK: She subsequently trained in infectious diseases and medical microbiology, took up her post in North Bristol NHS Trust, and she's the lead clinical doctor for Bone and Joint Infection. So it's a great privilege to ask her to give us a talk on selecting oral antibiotics for periprosthetic joint infection. I'm sure, given the recent MHRA advice on quinolones, there may be some topics of discussions afterwards.
DOMINIC MEEK: Thanks very much, Elizabeth.
ELIZABETH DARLEY: Lovely. Thank you and thank you for the invitation to come and present today. So as you've just heard, I'm one of the microbiologists at NBT. I work with Jason and the team of Orthopedic Surgeons and for about 20 years now, we've been doing the joint infection clinics together so knees and hips predominantly and a few other stragglers who join us.
ELIZABETH DARLEY: So I'm going to talk a little bit about oral antibiotic options and what we use and I'll just share my screen just now. OK is that? Is that clear for everybody? Yeah great. Thank you. OK so I think there's probably a lot that we could look at today in terms of oral antibiotic therapy.
ELIZABETH DARLEY: There are a lot of questions that still need to be answered and the ones that I thought of immediately were switch therapy. I think we all are probably very comfortable now with the idea of switching to oral therapy quite early on, but when exactly do we switch? What about combinations versus monotherapy and when would you use a combination and when is it better just to settle for a single agent?
ELIZABETH DARLEY: There's still a lot of active debate about when to add rifampicin into your therapy, particularly when there's metalwork in place and then how long would you continue to treat for? And is there a role for suppression therapy at the end of what we might consider a therapeutic course? And if so, do you use the same agent or a different one? For how long?
ELIZABETH DARLEY: When do you stop? And then finally prophylaxis and there's still a lot of ongoing discussion about what the optimal agents are. But I'm going to leave all of those alone and just focus on what antibiotics might you choose for your oral switch therapy and illustrate what we do at North Bristol Trust and why. So just a little bit of a foundation.
ELIZABETH DARLEY: So this is the IDSA guidance and it's quite clear that oral therapy has a role in treatment of these kinds of patients. However, it's not entirely clear about when you might switch, and it's not clear at all in some cases about whether or not you want to give suppression and how that might look and what you might choose. And you have to be on your toes about what procedure you're actually doing and what organisms you've got, because the advice varies, as you can see here, for whether or not you've got staphylococcal infection or anything else and whether there's metalwork in one stage or it's coming out.
ELIZABETH DARLEY: But as I said, I'm not really going to talk an awful lot about that today. I'm going to sort of hone in on what the antibiotics are. So Jason's already shown a nice slide of what the common culprits are and I think this will all be very familiar to you. So staphylococci are the big ones and then streptococci and then various proportions of miscellaneous other bacteria and gram negative organisms
ELIZABETH DARLEY: so things like gut flora, E-coli, pseudomonas klebsiella, that kind of thing are becoming certainly more of a problem now than they were maybe ten, fifteen years ago. And that probably reflects the kind of patients we're dealing with and their longevity and the co-morbidities they have and possibly how many antibiotic courses they're actually getting in their medical career now compared to ten and fifteen years ago.
ELIZABETH DARLEY: So how do you decide what you're going to give? So the way I look at it is what's the spectrum of activity? Is it, is it going to work? And that's not always as straightforward as just looking at a laboratory report which will have sensitive or resistant and sometimes slightly unhelpfully intermediate. But that's a very obvious starting point.
ELIZABETH DARLEY: How potent are the antibiotics? So not all the same, despite what the lab report might imply. Does it matter whether the antibiotic you're going to choose is bactericidal or just bacteriostatic? And can we even remember what that actually means? I suggest it probably doesn't matter if the surgery has got rid of most of the infection in the first place. It's probably more important if metalwork has to stay inside the tube and can't be removed for mechanical or other reasons.
ELIZABETH DARLEY: And then we talk a lot about bone penetration and bone penetration is really, really hard to understand because most studies look at single snapshots of bone penetration. If they're in humans, they're usually at the point of excision of bone, which may or may not be infected, and if there are animal studies, there's no long term follow up. There's one endpoint and that point is, well, there's nothing after that.
ELIZABETH DARLEY: So once the animal has reached the end of the study, then there's no how are they doing in a year's time or two years' time or after therapy stopped. Biofilm activity is very important, and Jason's just sort of given us a fantastic overview of what a difficult area of treatment that creates and how we really need to be mindful of that, I think, in our preventative measures. And then we think about oral bioavailability
ELIZABETH DARLEY: and I think this is very important because there are some antibiotics which are highly bioavailability highly bioavailable, and they're the ones that we'll be talking about. But there's others that look good, maybe, perhaps like flucloxacillin, but they're only 50% bioavailable when you take them orally. So you don't get a lot of it for your money and possibly would avoid those.
ELIZABETH DARLEY: And then there's the interactions and we're definitely going to talk about that. So this is a very simplified table of what we tend to do at North Bristol with our patients who've got prosthetic joint infection and it, and it fluctuates depending on what the organisms are sensitive to and also whether there's metal in or out and also what the long term surgical plan is for the patient. But this just gives you a sort of a very broad idea.
ELIZABETH DARLEY: So MSSA, staph aureus, equally probably would apply for culture negative infection as well. They start with their standard IVs through clots. Maybe we'll find some, maybe not at that stage. And then we like quinolones and rifampicin for oral switch therapy. That's my, that was my first line therapy for patients with bone and joint infection and it has served us very well. There's a good literature base for it, and the patients tend, in my experience, to tolerate it very well.
ELIZABETH DARLEY: That's our finding locally. But if that's not suitable for any reason or it's not susceptible, then clindamycin and rifampicin are a good second line choice. Quite well tolerated as well. And then third line doxycycline, which is really a very good drug in terms of bone penetration and spectrum of cover, but it's not so well tolerated. And then for MRSA, which I have to say, fortunately, we see very little of in our PJI patients in North Bristol.
ELIZABETH DARLEY: And start with vanc plus or minus rifampicin and then the options roughly in order are probably doxycycline, clindamycin, septrin, and then maybe delafloxacin, which is a newish quinolone and has anti MRSA activity and broad gram negative activity too. And then coagulase negative staphs, very similar, same sort of antibiotics. Again, if they can be treated with a quinolone and it's susceptible, that would be my first line.
ELIZABETH DARLEY: And I just made a note that here to advise you that flucloxacillin testing, standard disk testing that we do in the laboratories for most organisms is not reliable for coag-neg staph. So be very careful if you see a report that says fluclox sensitive. It's an unreliable result unless it's had further testing, which most labs don't do and quite reasonably don't do, it just means it's not necessarily one to pay attention to.
ELIZABETH DARLEY: And then if your axilo is fosfomycin and pristinamycin and I'll talk a bit about those in a moment. And they're not used so commonly. So moving down the list of organisms, enterococci, we see quite a lot of this. If they're sensitive to amoxicillin, then that's a great drug, both IV and orally. It's not brilliant at bone penetration, but it's reasonable.
ELIZABETH DARLEY: And unfortunately, enterococci tend to be very resistant organisms, so you don't have as much choice as you'd like and that often really direct what you're going to do next. So if they're sensitive to septrin co-trimoxazole, that's a useful drug. Linezolid is great, but as you're probably aware, it's limited to about 28 days and then after that, you're really every extra week of therapy is a gift because patients do develop side effects
ELIZABETH DARLEY: but I'll mention those in a moment. Pristinamycin, now this, this is a bit, um, a bit old fashioned and it's actually quite difficult to get hold of quite a lot of the time, but it's a very useful drug if the Enterococcus is an Enterococcus faecium and what that means is that it's going to be intrinsically resistant to amoxicillin and more resistant. So pristinamycin can be useful, but it's quite hard to get hold of and there's only really one supplier of it.
ELIZABETH DARLEY: And when they run out, we all have to wait. So that's, it sort of it takes and it gives back at the same time. Then streptococci. So these are things like the group A strep, also Viridans streptococci, maybe not quite so common group B streptococci. I think we're seeing those a little bit more now, maybe related to co-morbidities in the patient. So they are almost invariably sensitive to amoxicillin, which is great and often sensitive to clindamycin and septrin and generally sensitive to linezolid.
ELIZABETH DARLEY: But that's very much fourth line because of the side effects and the restrictions on duration, and there are other agents so sometimes you could use a novel quinolone such as moxifloxacin or levofloxacin if they test sensitive. And then coliforms and coliforms are generally very susceptible to ciprofloxacin so this has been a really valuable drug to date
ELIZABETH DARLEY: and you can give it pretty much from the outset because it's hugely bioavailable, it's almost 100% So as soon as somebody can eat their breakfast, lunch and tea post op, they can in my book move on to ciprofloxacin if you've got a susceptible gram negative. And then Pseudomonas. These are a little bit more tricky because they're intrinsically pretty resistant organisms. If they're susceptible to the quinolones orally, that's great.
ELIZABETH DARLEY: If they're not susceptible to the quinolones, then you have no oral option at all for these organisms so it's IV all the way. So we treat the quinolones with respect and we introduce them after a course of something else so that you debulk the infection effectively and get on top of the symptoms with something like prazosin ceftazidime. And then when you feel that you're tidying up, bringing the quinolones at a high dose to reduce the risk of resistance developing, which otherwise happens pretty frequently and pretty early.
ELIZABETH DARLEY: So I'm just going to go into a bit more detail now about the actual choices of antibiotic, because I think this is what is sometimes hard to understand if you're not a microbiologist and dealing with them every day. So, so until 48 hours ago, these slides were sort of standalone and I've now got an extra slide and we'll come to that. So quinolones are very good in that they have excellent bioavailability.
ELIZABETH DARLEY: They get into bone tissue very well. Generally patients, I was going to say tolerate them very well and our experience in the clinic at North Bristol from 20 years experience of using these first line and we've been using an early oral switch since the first days of this clinic and it was about 2004, 2005 when we very first started these clinics. And patients get on fine and we haven't bar a few patients, had problems with them, certainly no more than we have experienced with other classes of antibiotics.
ELIZABETH DARLEY: That may not be your experience and that may not be what the evidence is going to show us from the MHRA but that's our experience. They're not equal. They're not interchangeable. So levofloxacin is an oral quinolone, which is much more active against gram positives and cipro. So we recently switched over from cipro to levo for our gram positives and culture negative patients. Delafloxacin we haven't used yet in our clinic, but it's got more gram negative activity
ELIZABETH DARLEY: and it also covers MRSA. However, when we think about the kind of learnings, we have to remember the side effects and there have been various warnings that come out over recent years about tendinitis, Achilles tendinitis particularly, prolonged QTc intervals and the risk of moving into [?] if you do develop prolonged QTc. And there's also been a recent report of an increased risk of aortic aneurysm dissection, and I'll mention that in a moment.
ELIZABETH DARLEY: So the risk of prolonged QTC, I mean, it's a very real thing. It's much more likely to happen with moxifloxacin than it is with levo and more likely with levo than cipro. So cipro is low risk for prolonged QTC, moxifloxacin much higher risk. Moxifloxacin also had some alerts a year or two ago about liver failure, so we don't tend to use moxifloxacin even though it's got most anti gram positive activity.
ELIZABETH DARLEY: And so the advice was until Monday, don't use a fluoroquinolones if you can use anything else if it's mild to moderate infection, I'm not going to read all of this. You can read it. You may be familiar with it anyway. And if patients report any symptoms such as muscle pain, joint pain, et cetera, take note, stop the antibiotics promptly and investigate further.
ELIZABETH DARLEY: Now, this is a table from a paper and related to the quinolones, but just had a really nice table about the prolonged QTc interval. And for those of you who aren't cardiologists, we maybe don't think about it or recognize it too often in our patients, but essentially the risk is that the patient goes into a serious arrhythmia and what I wanted to show here was that when you look at the quinolones, roughly halfway down the table, they're actually much less likely to predispose to this prolonged QTc
ELIZABETH DARLEY: than the macrolides that we give very, very frequently for our patients with cap and pneumonia who come through the door. Linezolid also has a sort of modest profile there too. So I think that we have to be careful that we don't overcall the risk. If patients don't have an ECG in our clinic, then they get one. If we're going to start a quinolone and so long as that looks normal, then we will prescribe them a quinolone.
ELIZABETH DARLEY: If they have any predisposition to it, then we might give them cipro and just ask them to be mindful of any symptoms or we might withhold them completely. Um, but I just included that to sort of try and put it in context. And then there's the AAA anxiety. So this was a paper and some evidence which showed that there was a three-fold risk of either dissection or AAA in patients who had quinolones
ELIZABETH DARLEY: and therefore we should adopt a lot of caution in giving them to anybody who had any underlying risk. And the feeling was this was related to the collagen again. However, a recent paper in JAMA looking at over 3 million patients in a crossover study found that there was no increased risk once you remove the confounding factors that went with it and they compared it to other classes of antibiotics and said, anybody who's had antibiotics is more likely than not, then the naive patients to have an aortic aneurysm dissection.
ELIZABETH DARLEY: But the risk is still very, very small and it's not specific. So that was very reassuring and I was just feeling reasonably happy about that until.... Until we got the MHRA warning. I'm sorry. I don't know why this slide hasn't come out. I'll just tell you what it says.
ELIZABETH DARLEY: It essentially says that you may not use quinolones first line for anything unless the patient has had side effects to the existing therapy resistant dictates that you must use it and there's nothing else. And that's going to be a real problem, I think, for treating these types of deep seated infections because they are very good drugs and if they are removed from our sort of armamentarium of what we can have, then I think it's going to have a significant impact on patients morbidity and mortality
ELIZABETH DARLEY: down the line if we have to use other antibiotics. However, at this point in time it's an MHRA Warning. There have been no further comments on the evidence or what's behind it, and so I'm very keen that we get more information about this so that we can consider the implications of it and understand why we've moved away from a position of risk assess your patients before you give them quinolones, think about the risks of tendinitis.
ELIZABETH DARLEY: Are they on steroids? Are they diabetic? Do they have, are they transplant patients? Do they have risk factors for tendinitis to move into A you cannot give it unless it's your last antibiotic. We'll take questions about that later maybe.. So Rifampicin, a very good drug. I'm sure I don't need to sell this to you. It does reduce linezolid concentrations.
ELIZABETH DARLEY: Also probably, septrin and clindamycin concentrations. However, a very nice study looking at clindamycin rifampicin in treatment found that there was no clinical impact if the levels were reduced slightly. It's obviously contraindicated for some patients on anticoagulants, antiepileptics and the contraceptive pill. And there's an ongoing debate about when you would add it.
ELIZABETH DARLEY: So would you give it to somebody when the metalwork is freshly in? When it's been a while, only if it's taken out. You can't use it as monotherapy ever, because you get very rapid resistance and you need to monitor the LFTs. Clindamycin, another very good drug, I'd very fond of clindamycin. If the organisms are susceptible and that's gram positive organisms, then it's a good go to antibiotic.
ELIZABETH DARLEY: It's highly bioavailable, bioavailable, nearly 100% It's very good at getting to bone. It probably does get into biofilm as well. It's got a reputation of being C diffigenic, but not really, I don't think, in the way we use it now and be generous with the dosing. Doxycycline, a bit old fashioned, sort of went out of vogue some years ago, but it is a very good drug.
ELIZABETH DARLEY: Again, if the organisms are susceptible and they often are, very bioavailable and very good bone penetration. You can use it with rifampicin as well. It's not that well tolerated. You have to tell patients to have something in their stomach and stay upright for probably an hour after taking it otherwise they'll get gastritis and often feel quite nauseous and they have to stay out the sun, which is not generally a big problem in this country.
ELIZABETH DARLEY: But they do need to think about how they take it and it's not always very well tolerated. Septrin is also having a bit of a comeback in the last couple of decades. It's a good drug. It's active against staph aureus, coagulase-neg staph and some streptococci, but not all and some enterococci and also gram negative organisms.
ELIZABETH DARLEY: However, it did have its own MRHA warning some years ago regarding bone marrow failure so you must monitor the full blood count for patients who are going to take it. You also must monitor the U&E's and potassium because it may cause a rise in potassium and AKI and of course it has a bit of a reputation for causing rashes and Stevens-Johnson syndrome. Although in our practice I think we've seen rashes very rarely and even more rarely seen some Stevens-Johnson syndrome.
ELIZABETH DARLEY: However, for our patients, the Bone Joint infection patients, we have to remember you cannot give it with methotrexate, they can't overlap. You probably shouldn't give it to patients with an eGFR below about 35 because it entails reducing the doses, monitoring levels and higher risk of the side effects. But all that said, many patients get on very well with it. And then the other things that we use, so beta lactams and cephalosporins, there are some concerns about bone penetration, some more than others,
ELIZABETH DARLEY: and in oral formulation the bioavailability is very variable between and so I'd say take advice if you're going to go down that route. But they're not our first or second or even third line antibiotics for oral switch. Minocycline another tetracycline. It does cause skin staining. It can be irreversible,
ELIZABETH DARLEY: and that's particularly problematic if it's on the face and it has been associated with hepatotoxicity. So probably not your first line tetracycline. Linezolid. Also very good, very bio-available. But it's got its MAO-I interactions and it also does cause bone marrow suppression. Some patients never seem to experience this after months and months of therapy, other patients start to drop their platelets exactly on four weeks and you have to stop it at that point.
ELIZABETH DARLEY: You can use it again in due course once the bone marrow is recovered, but you should expect it to do the same thing again so it may be a very short term treatment. Pristinamycin I've mentioned, there are supply issues. Fusidic acid. Can be sometimes substituting rifampicin if rifampicin is resistant, but it's not that well tolerated. It makes patients feel pretty sick and I don't tend to ever use the macrolides.
ELIZABETH DARLEY: I don't think the bone penetration is great and there's usually better agents available. And then Fosfomycin, we occasionally use if we're backed into a corner in terms of resistance and no one's quite sure what the dose should be, probably something like three grams BD and it can be active against MRSA, enterococci, some gram negatives, and it does get into bone. So just to summarize, I think that early on switch is generally accepted now as a good idea.
ELIZABETH DARLEY: I think most patients can get on very well with it. I think it's preferable to having k-line therapy if they possibly can, no lines. You don't need to worry about staying at home for your infusions and injections and so on, which is a good quality of life. But you have to be selective about what antibiotics you use. Preferably find a funny microbiologist who can advise on all these nuts and bolts.
ELIZABETH DARLEY: And with the quinolones, I think we have to watch this space and am very interested to know exactly how hard line this MHRA advice is because as I said, they are a very good class of drug and I think I've probably spoken too long so I'm going to stop now.
DOMINIC MEEK: So thanks very much. I think, Elizabeth, maybe just with the time wise, if we could get you to interact with them on the chat and the question and answers.
DOMINIC MEEK: And then, Ian, is there one particular question?
IAN KENNEDY: Yeah, just one quick question. How quickly would you switch to oral antibiotics If there are oralable options?
ELIZABETH DARLEY: Usually within about five days.
DOMINIC MEEK: OK. Perfect. There's a lot of questions for you, Elizabeth, so I'll let you maybe deal with them. So we're now got Professor Lee Jeys.
DOMINIC MEEK: [VIDEO ENDS]
Segment:0 .
DOMINIC MEEK: She subsequently trained in infectious diseases and medical microbiology, took up her post in North Bristol NHS Trust, and she's the lead clinical doctor for Bone and Joint Infection. So it's a great privilege to ask her to give us a talk on selecting oral antibiotics for periprosthetic joint infection. I'm sure, given the recent MHRA advice on quinolones, there may be some topics of discussions afterwards.
DOMINIC MEEK: Thanks very much, Elizabeth.
ELIZABETH DARLEY: Lovely. Thank you and thank you for the invitation to come and present today. So as you've just heard, I'm one of the microbiologists at NBT. I work with Jason and the team of Orthopedic Surgeons and for about 20 years now, we've been doing the joint infection clinics together so knees and hips predominantly and a few other stragglers who join us.
ELIZABETH DARLEY: So I'm going to talk a little bit about oral antibiotic options and what we use and I'll just share my screen just now. OK is that? Is that clear for everybody? Yeah great. Thank you. OK so I think there's probably a lot that we could look at today in terms of oral antibiotic therapy.
ELIZABETH DARLEY: There are a lot of questions that still need to be answered and the ones that I thought of immediately were switch therapy. I think we all are probably very comfortable now with the idea of switching to oral therapy quite early on, but when exactly do we switch? What about combinations versus monotherapy and when would you use a combination and when is it better just to settle for a single agent?
ELIZABETH DARLEY: There's still a lot of active debate about when to add rifampicin into your therapy, particularly when there's metalwork in place and then how long would you continue to treat for? And is there a role for suppression therapy at the end of what we might consider a therapeutic course? And if so, do you use the same agent or a different one? For how long?
ELIZABETH DARLEY: When do you stop? And then finally prophylaxis and there's still a lot of ongoing discussion about what the optimal agents are. But I'm going to leave all of those alone and just focus on what antibiotics might you choose for your oral switch therapy and illustrate what we do at North Bristol Trust and why. So just a little bit of a foundation.
ELIZABETH DARLEY: So this is the IDSA guidance and it's quite clear that oral therapy has a role in treatment of these kinds of patients. However, it's not entirely clear about when you might switch, and it's not clear at all in some cases about whether or not you want to give suppression and how that might look and what you might choose. And you have to be on your toes about what procedure you're actually doing and what organisms you've got, because the advice varies, as you can see here, for whether or not you've got staphylococcal infection or anything else and whether there's metalwork in one stage or it's coming out.
ELIZABETH DARLEY: But as I said, I'm not really going to talk an awful lot about that today. I'm going to sort of hone in on what the antibiotics are. So Jason's already shown a nice slide of what the common culprits are and I think this will all be very familiar to you. So staphylococci are the big ones and then streptococci and then various proportions of miscellaneous other bacteria and gram negative organisms
ELIZABETH DARLEY: so things like gut flora, E-coli, pseudomonas klebsiella, that kind of thing are becoming certainly more of a problem now than they were maybe ten, fifteen years ago. And that probably reflects the kind of patients we're dealing with and their longevity and the co-morbidities they have and possibly how many antibiotic courses they're actually getting in their medical career now compared to ten and fifteen years ago.
ELIZABETH DARLEY: So how do you decide what you're going to give? So the way I look at it is what's the spectrum of activity? Is it, is it going to work? And that's not always as straightforward as just looking at a laboratory report which will have sensitive or resistant and sometimes slightly unhelpfully intermediate. But that's a very obvious starting point.
ELIZABETH DARLEY: How potent are the antibiotics? So not all the same, despite what the lab report might imply. Does it matter whether the antibiotic you're going to choose is bactericidal or just bacteriostatic? And can we even remember what that actually means? I suggest it probably doesn't matter if the surgery has got rid of most of the infection in the first place. It's probably more important if metalwork has to stay inside the tube and can't be removed for mechanical or other reasons.
ELIZABETH DARLEY: And then we talk a lot about bone penetration and bone penetration is really, really hard to understand because most studies look at single snapshots of bone penetration. If they're in humans, they're usually at the point of excision of bone, which may or may not be infected, and if there are animal studies, there's no long term follow up. There's one endpoint and that point is, well, there's nothing after that.
ELIZABETH DARLEY: So once the animal has reached the end of the study, then there's no how are they doing in a year's time or two years' time or after therapy stopped. Biofilm activity is very important, and Jason's just sort of given us a fantastic overview of what a difficult area of treatment that creates and how we really need to be mindful of that, I think, in our preventative measures. And then we think about oral bioavailability
ELIZABETH DARLEY: and I think this is very important because there are some antibiotics which are highly bioavailability highly bioavailable, and they're the ones that we'll be talking about. But there's others that look good, maybe, perhaps like flucloxacillin, but they're only 50% bioavailable when you take them orally. So you don't get a lot of it for your money and possibly would avoid those.
ELIZABETH DARLEY: And then there's the interactions and we're definitely going to talk about that. So this is a very simplified table of what we tend to do at North Bristol with our patients who've got prosthetic joint infection and it, and it fluctuates depending on what the organisms are sensitive to and also whether there's metal in or out and also what the long term surgical plan is for the patient. But this just gives you a sort of a very broad idea.
ELIZABETH DARLEY: So MSSA, staph aureus, equally probably would apply for culture negative infection as well. They start with their standard IVs through clots. Maybe we'll find some, maybe not at that stage. And then we like quinolones and rifampicin for oral switch therapy. That's my, that was my first line therapy for patients with bone and joint infection and it has served us very well. There's a good literature base for it, and the patients tend, in my experience, to tolerate it very well.
ELIZABETH DARLEY: That's our finding locally. But if that's not suitable for any reason or it's not susceptible, then clindamycin and rifampicin are a good second line choice. Quite well tolerated as well. And then third line doxycycline, which is really a very good drug in terms of bone penetration and spectrum of cover, but it's not so well tolerated. And then for MRSA, which I have to say, fortunately, we see very little of in our PJI patients in North Bristol.
ELIZABETH DARLEY: And start with vanc plus or minus rifampicin and then the options roughly in order are probably doxycycline, clindamycin, septrin, and then maybe delafloxacin, which is a newish quinolone and has anti MRSA activity and broad gram negative activity too. And then coagulase negative staphs, very similar, same sort of antibiotics. Again, if they can be treated with a quinolone and it's susceptible, that would be my first line.
ELIZABETH DARLEY: And I just made a note that here to advise you that flucloxacillin testing, standard disk testing that we do in the laboratories for most organisms is not reliable for coag-neg staph. So be very careful if you see a report that says fluclox sensitive. It's an unreliable result unless it's had further testing, which most labs don't do and quite reasonably don't do, it just means it's not necessarily one to pay attention to.
ELIZABETH DARLEY: And then if your axilo is fosfomycin and pristinamycin and I'll talk a bit about those in a moment. And they're not used so commonly. So moving down the list of organisms, enterococci, we see quite a lot of this. If they're sensitive to amoxicillin, then that's a great drug, both IV and orally. It's not brilliant at bone penetration, but it's reasonable.
ELIZABETH DARLEY: And unfortunately, enterococci tend to be very resistant organisms, so you don't have as much choice as you'd like and that often really direct what you're going to do next. So if they're sensitive to septrin co-trimoxazole, that's a useful drug. Linezolid is great, but as you're probably aware, it's limited to about 28 days and then after that, you're really every extra week of therapy is a gift because patients do develop side effects
ELIZABETH DARLEY: but I'll mention those in a moment. Pristinamycin, now this, this is a bit, um, a bit old fashioned and it's actually quite difficult to get hold of quite a lot of the time, but it's a very useful drug if the Enterococcus is an Enterococcus faecium and what that means is that it's going to be intrinsically resistant to amoxicillin and more resistant. So pristinamycin can be useful, but it's quite hard to get hold of and there's only really one supplier of it.
ELIZABETH DARLEY: And when they run out, we all have to wait. So that's, it sort of it takes and it gives back at the same time. Then streptococci. So these are things like the group A strep, also Viridans streptococci, maybe not quite so common group B streptococci. I think we're seeing those a little bit more now, maybe related to co-morbidities in the patient. So they are almost invariably sensitive to amoxicillin, which is great and often sensitive to clindamycin and septrin and generally sensitive to linezolid.
ELIZABETH DARLEY: But that's very much fourth line because of the side effects and the restrictions on duration, and there are other agents so sometimes you could use a novel quinolone such as moxifloxacin or levofloxacin if they test sensitive. And then coliforms and coliforms are generally very susceptible to ciprofloxacin so this has been a really valuable drug to date
ELIZABETH DARLEY: and you can give it pretty much from the outset because it's hugely bioavailable, it's almost 100% So as soon as somebody can eat their breakfast, lunch and tea post op, they can in my book move on to ciprofloxacin if you've got a susceptible gram negative. And then Pseudomonas. These are a little bit more tricky because they're intrinsically pretty resistant organisms. If they're susceptible to the quinolones orally, that's great.
ELIZABETH DARLEY: If they're not susceptible to the quinolones, then you have no oral option at all for these organisms so it's IV all the way. So we treat the quinolones with respect and we introduce them after a course of something else so that you debulk the infection effectively and get on top of the symptoms with something like prazosin ceftazidime. And then when you feel that you're tidying up, bringing the quinolones at a high dose to reduce the risk of resistance developing, which otherwise happens pretty frequently and pretty early.
ELIZABETH DARLEY: So I'm just going to go into a bit more detail now about the actual choices of antibiotic, because I think this is what is sometimes hard to understand if you're not a microbiologist and dealing with them every day. So, so until 48 hours ago, these slides were sort of standalone and I've now got an extra slide and we'll come to that. So quinolones are very good in that they have excellent bioavailability.
ELIZABETH DARLEY: They get into bone tissue very well. Generally patients, I was going to say tolerate them very well and our experience in the clinic at North Bristol from 20 years experience of using these first line and we've been using an early oral switch since the first days of this clinic and it was about 2004, 2005 when we very first started these clinics. And patients get on fine and we haven't bar a few patients, had problems with them, certainly no more than we have experienced with other classes of antibiotics.
ELIZABETH DARLEY: That may not be your experience and that may not be what the evidence is going to show us from the MHRA but that's our experience. They're not equal. They're not interchangeable. So levofloxacin is an oral quinolone, which is much more active against gram positives and cipro. So we recently switched over from cipro to levo for our gram positives and culture negative patients. Delafloxacin we haven't used yet in our clinic, but it's got more gram negative activity
ELIZABETH DARLEY: and it also covers MRSA. However, when we think about the kind of learnings, we have to remember the side effects and there have been various warnings that come out over recent years about tendinitis, Achilles tendinitis particularly, prolonged QTc intervals and the risk of moving into [?] if you do develop prolonged QTc. And there's also been a recent report of an increased risk of aortic aneurysm dissection, and I'll mention that in a moment.
ELIZABETH DARLEY: So the risk of prolonged QTC, I mean, it's a very real thing. It's much more likely to happen with moxifloxacin than it is with levo and more likely with levo than cipro. So cipro is low risk for prolonged QTC, moxifloxacin much higher risk. Moxifloxacin also had some alerts a year or two ago about liver failure, so we don't tend to use moxifloxacin even though it's got most anti gram positive activity.
ELIZABETH DARLEY: And so the advice was until Monday, don't use a fluoroquinolones if you can use anything else if it's mild to moderate infection, I'm not going to read all of this. You can read it. You may be familiar with it anyway. And if patients report any symptoms such as muscle pain, joint pain, et cetera, take note, stop the antibiotics promptly and investigate further.
ELIZABETH DARLEY: Now, this is a table from a paper and related to the quinolones, but just had a really nice table about the prolonged QTc interval. And for those of you who aren't cardiologists, we maybe don't think about it or recognize it too often in our patients, but essentially the risk is that the patient goes into a serious arrhythmia and what I wanted to show here was that when you look at the quinolones, roughly halfway down the table, they're actually much less likely to predispose to this prolonged QTc
ELIZABETH DARLEY: than the macrolides that we give very, very frequently for our patients with cap and pneumonia who come through the door. Linezolid also has a sort of modest profile there too. So I think that we have to be careful that we don't overcall the risk. If patients don't have an ECG in our clinic, then they get one. If we're going to start a quinolone and so long as that looks normal, then we will prescribe them a quinolone.
ELIZABETH DARLEY: If they have any predisposition to it, then we might give them cipro and just ask them to be mindful of any symptoms or we might withhold them completely. Um, but I just included that to sort of try and put it in context. And then there's the AAA anxiety. So this was a paper and some evidence which showed that there was a three-fold risk of either dissection or AAA in patients who had quinolones
ELIZABETH DARLEY: and therefore we should adopt a lot of caution in giving them to anybody who had any underlying risk. And the feeling was this was related to the collagen again. However, a recent paper in JAMA looking at over 3 million patients in a crossover study found that there was no increased risk once you remove the confounding factors that went with it and they compared it to other classes of antibiotics and said, anybody who's had antibiotics is more likely than not, then the naive patients to have an aortic aneurysm dissection.
ELIZABETH DARLEY: But the risk is still very, very small and it's not specific. So that was very reassuring and I was just feeling reasonably happy about that until.... Until we got the MHRA warning. I'm sorry. I don't know why this slide hasn't come out. I'll just tell you what it says.
ELIZABETH DARLEY: It essentially says that you may not use quinolones first line for anything unless the patient has had side effects to the existing therapy resistant dictates that you must use it and there's nothing else. And that's going to be a real problem, I think, for treating these types of deep seated infections because they are very good drugs and if they are removed from our sort of armamentarium of what we can have, then I think it's going to have a significant impact on patients morbidity and mortality
ELIZABETH DARLEY: down the line if we have to use other antibiotics. However, at this point in time it's an MHRA Warning. There have been no further comments on the evidence or what's behind it, and so I'm very keen that we get more information about this so that we can consider the implications of it and understand why we've moved away from a position of risk assess your patients before you give them quinolones, think about the risks of tendinitis.
ELIZABETH DARLEY: Are they on steroids? Are they diabetic? Do they have, are they transplant patients? Do they have risk factors for tendinitis to move into A you cannot give it unless it's your last antibiotic. We'll take questions about that later maybe.. So Rifampicin, a very good drug. I'm sure I don't need to sell this to you. It does reduce linezolid concentrations.
ELIZABETH DARLEY: Also probably, septrin and clindamycin concentrations. However, a very nice study looking at clindamycin rifampicin in treatment found that there was no clinical impact if the levels were reduced slightly. It's obviously contraindicated for some patients on anticoagulants, antiepileptics and the contraceptive pill. And there's an ongoing debate about when you would add it.
ELIZABETH DARLEY: So would you give it to somebody when the metalwork is freshly in? When it's been a while, only if it's taken out. You can't use it as monotherapy ever, because you get very rapid resistance and you need to monitor the LFTs. Clindamycin, another very good drug, I'd very fond of clindamycin. If the organisms are susceptible and that's gram positive organisms, then it's a good go to antibiotic.
ELIZABETH DARLEY: It's highly bioavailable, bioavailable, nearly 100% It's very good at getting to bone. It probably does get into biofilm as well. It's got a reputation of being C diffigenic, but not really, I don't think, in the way we use it now and be generous with the dosing. Doxycycline, a bit old fashioned, sort of went out of vogue some years ago, but it is a very good drug.
ELIZABETH DARLEY: Again, if the organisms are susceptible and they often are, very bioavailable and very good bone penetration. You can use it with rifampicin as well. It's not that well tolerated. You have to tell patients to have something in their stomach and stay upright for probably an hour after taking it otherwise they'll get gastritis and often feel quite nauseous and they have to stay out the sun, which is not generally a big problem in this country.
ELIZABETH DARLEY: But they do need to think about how they take it and it's not always very well tolerated. Septrin is also having a bit of a comeback in the last couple of decades. It's a good drug. It's active against staph aureus, coagulase-neg staph and some streptococci, but not all and some enterococci and also gram negative organisms.
ELIZABETH DARLEY: However, it did have its own MRHA warning some years ago regarding bone marrow failure so you must monitor the full blood count for patients who are going to take it. You also must monitor the U&E's and potassium because it may cause a rise in potassium and AKI and of course it has a bit of a reputation for causing rashes and Stevens-Johnson syndrome. Although in our practice I think we've seen rashes very rarely and even more rarely seen some Stevens-Johnson syndrome.
ELIZABETH DARLEY: However, for our patients, the Bone Joint infection patients, we have to remember you cannot give it with methotrexate, they can't overlap. You probably shouldn't give it to patients with an eGFR below about 35 because it entails reducing the doses, monitoring levels and higher risk of the side effects. But all that said, many patients get on very well with it. And then the other things that we use, so beta lactams and cephalosporins, there are some concerns about bone penetration, some more than others,
ELIZABETH DARLEY: and in oral formulation the bioavailability is very variable between and so I'd say take advice if you're going to go down that route. But they're not our first or second or even third line antibiotics for oral switch. Minocycline another tetracycline. It does cause skin staining. It can be irreversible,
ELIZABETH DARLEY: and that's particularly problematic if it's on the face and it has been associated with hepatotoxicity. So probably not your first line tetracycline. Linezolid. Also very good, very bio-available. But it's got its MAO-I interactions and it also does cause bone marrow suppression. Some patients never seem to experience this after months and months of therapy, other patients start to drop their platelets exactly on four weeks and you have to stop it at that point.
ELIZABETH DARLEY: You can use it again in due course once the bone marrow is recovered, but you should expect it to do the same thing again so it may be a very short term treatment. Pristinamycin I've mentioned, there are supply issues. Fusidic acid. Can be sometimes substituting rifampicin if rifampicin is resistant, but it's not that well tolerated. It makes patients feel pretty sick and I don't tend to ever use the macrolides.
ELIZABETH DARLEY: I don't think the bone penetration is great and there's usually better agents available. And then Fosfomycin, we occasionally use if we're backed into a corner in terms of resistance and no one's quite sure what the dose should be, probably something like three grams BD and it can be active against MRSA, enterococci, some gram negatives, and it does get into bone. So just to summarize, I think that early on switch is generally accepted now as a good idea.
ELIZABETH DARLEY: I think most patients can get on very well with it. I think it's preferable to having k-line therapy if they possibly can, no lines. You don't need to worry about staying at home for your infusions and injections and so on, which is a good quality of life. But you have to be selective about what antibiotics you use. Preferably find a funny microbiologist who can advise on all these nuts and bolts.
ELIZABETH DARLEY: And with the quinolones, I think we have to watch this space and am very interested to know exactly how hard line this MHRA advice is because as I said, they are a very good class of drug and I think I've probably spoken too long so I'm going to stop now.
DOMINIC MEEK: So thanks very much. I think, Elizabeth, maybe just with the time wise, if we could get you to interact with them on the chat and the question and answers.
DOMINIC MEEK: And then, Ian, is there one particular question?
IAN KENNEDY: Yeah, just one quick question. How quickly would you switch to oral antibiotics If there are oralable options?
ELIZABETH DARLEY: Usually within about five days.
DOMINIC MEEK: OK. Perfect. There's a lot of questions for you, Elizabeth, so I'll let you maybe deal with them. So we're now got Professor Lee Jeys.
DOMINIC MEEK: [VIDEO ENDS]
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