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[00:00:07] Emily: Hello and welcome back to Communicable the podcast, brought to you by CMI communications ESCMID's open access journal, covering infectious diseases and clinical microbiology. I'm Emily McDonald. I'm a physician in general internal medicine, an infectious disease trialist and scientist at McGill University in Montreal, Canada, and associate editor at CMI Communications.

[00:00:26] Emily: Today on the podcast, we're discussing the pros and cons of fluoroquinolones, and we're pleased to welcome two experts in the field. We'll be discussing the incredible versatility of fluoroquinolones and also some of the common and not so common harms and downsides to treating infections with the class.

[00:00:42] Emily: Of course, with excellent spectrum of activity and very good oral absorption, they're somewhat of a celebrity class of antibiotics, especially following landmark oral transition trials such as POET for endocarditis and Oviva for osteomyelitis, still clinicians may hesitate to prescribe them due to side effects such as prolonged qt.

[00:01:02] Emily: Drug interactions and effects on connective tissue, ranging from Achilles rupture to ocular lens dislocation. And because of their incredible utility, we also seek to protect them from overuse for syndrome such as bronchitis and UTI and they are meant to be stewarded. I'm really excited to be co-hosting this episode with Thomas Tangden, fellow editor at CMI Comms. Thomas is a professor and senior consultant of infectious diseases in Upsala Sweden, an expert in PKPD and a MR and president of the Swedish National Stewardship Organization, STRAMA

Hi everyone. I'm really happy to introduce our guests, Staffan Tevell and Bernadette Young.

[00:01:42] Thomas: Staffan Tevell is a senior consultant at the Department of Infectious Diseases at Karlstad Central Hospital in Sweden. He is linked to the Center for Clinical Research and Education in Region Värmland and affiliated researcher at Örebro University. Staffan Tevell's main research area is orthopedic infections, primarily prosthetic joint infections and staphylococcal infections.

[00:02:05] Thomas: He is coordinator of the Swedish Association for Infectious Diseases Treatment Guidelines Committee for Bone and Joint Infections. He is also a member of the ESCMID Study Group for implant associated infections and the European Bone and Joint Infection Society.

[00:02:19] Staffan: Thank you. Nice to be here.

[00:02:21] Thomas: Dr. Bernadette Young studied medicine and Arts at the University of Melbourne Australia.

[00:02:26] Thomas: She completed specialty training in infectious diseases and medical microbiology in the uk and a doctor of philosophy in clinical medicine at Wolfson College Oxford. She currently works as a consultant. Infection at Oxford University Hospitals where she is a part of the Oxford Bone Infection Unit.

She's also a researcher in the modernizing Medical Microbiology Unit at University of Oxford. Her research interest include the microbiology of orthopedic infection as well as studies of pathogen genomics. She has also worked as an investigator in clinical trials to improve the treatment of and diagnosis of serious infections.

She's the clinical tutor in medicine at Oriel College Oxford, welcome

[00:03:08] Bernadette: Thank you.

[00:03:08] Emily: So, as our regular listeners know, we always start the podcast with an icebreaker. Today's icebreaker has to do with an imaginary scenario. So you wake up tomorrow and you're a microbe.

[00:03:20] Emily: What microbe would you be and what would you spend your day doing? I think I would be staph aureus.

[00:03:26] Emily: I think that it's, kind of a famous bacteria at the moment getting a lot of attention with the SNAP trial. People have a lot of respect for it. And would be maybe hanging out with the SNAP trial group and, having a good debate about cefazolin versus Oxacillin with them.

[00:03:43] Emily: okay, Bernadette, you go next.

[00:03:45] Bernadette: I thought maybe I could go altruistic here. I could maybe be like a bacteria busting phage and be treating PJI or I could be like an attenuated virus and try and protect people against disease. But I might actually just go really hedonistic and be Saccharomyces cerevisiae, which is the yeast that makes bubbles in champagne.

[00:04:04] Bernadette: And I thought that actually sounds like a nice way to spend my day. I

[00:04:07] Emily: love that. Staffan, this is hard. Can you beat that choice?

[00:04:10] Staffan: Uh, it's difficult as you said, this is a very imaginary scenario, right? if we go back in time to 1950s, there was a jazz pianist in, the USA called Horace Silver. He, wrote a song called The Preacher that actually became a Swedish hit song with Swedish lyrics.

[00:04:26] Staffan: And in Sweden, it's called jazz bacillum,

[00:04:29] Staffan: , or the Jazz Bug. so that was a bug causing symptoms such as the head busting with music, a body pulsating with the rhythms and a longing to listen to music. And I think I'd like that actually.

[00:04:39] Bernadette: Staffan, you'd have to be worried about Leonard Cohen coming after you with the jazz police.

[00:04:44] Staffan: Yeah, most likely.

[00:04:45] Emily: Okay. Thomas, you get to go last.

[00:04:47] Thomas: Okay. So, first of all, I think I would like to be a bacterium because I think viruses are far too small and they're not independent, and I think fungi are too slow. So my first impulse was to go for a really cool multi-drug resistant gram-negative bacteria.

[00:05:01] Thomas: I'm a gram-negative guy. so for example, on MDM producing e coli. But then it's not very nice to cause untreatable infections. So, second choice. I thought about being some friendly bacteria in the gut that could help with digestion or the immune defense, but I figured that could be a very dark and anaerobic place to live in.

[00:05:19] Thomas: So I'm leaning towards either, an environmental bacteria living at some beautiful place, or a more positive cutibacterium living on the cheek of someone I like.

[00:05:29] Emily: Amazing choices. Okay, let's get down to business time to discuss a clinician's love-hate relationship with fluoroquinolones.

[00:05:36] Thomas: let's start with a refresher on quinolones Staffan. Can you take us through a brief history of the drug class and the different role?

[00:05:43] Staffan: I can try that. they've been around since, the early sixties.

it's a synthetic class of antibiotics and as we know, they inhibit the DNA synthesis, both through the DNA drugs and topoisomerase. the first one, that, emerged was nalidixic acid . It's quite difficult to pronounce for a swede, I think. it was used basically for gram-negative urinary tract infections, but as it achieved low serum levels, there was also rapid resistance development.

[00:06:10] Staffan: So, work kept continuing on this class of antibiotics. They added the fluorine in the seventies, which led to the fluoroquinolone, which is basically what we're talking about now. further development led to a Better activity against gram-positive bacteria better gram negative activity and also an improved PKPD, for these kind of drugs.

[00:06:30] Staffan: the next couple of drugs that emerged were, fluoro quinolones such as norafloxacin in and ciprofloxin, and also ofloxacin, further, evolution of these drugs, started to include also other gram-positive bacteria, apart from the staphylococci that we had to the pneumococci as well, the streptococcus pneumonia.

[00:06:48] Staffan: and there we had drugs such as Gatifloxacin, Temafloxacin and Grepafloxacin. But also the L isomer of  ofloxacin that is levofloxacin with that. I think we're all familiar with. and further work. You got even further gram-positive spectrum, with drugs like moxifloxacin, also delafloxacin. That is a quite recent, development there.

[00:07:07] Staffan: Also trovafloxacin comes around that time. but during this process there's also been some trouble since some of these drugs have been put on the market and then withdrawn as well. some examples of these are temafloxacin back in 1992 where there were, problems with hemolytic, anemia, also three deaths, and it was discussed whether this could be linked to some kind of immune complex formation.

[00:07:31] Staffan: Then came Grepafloxacin in 1999, where, interestingly, first of all, about a quarter of the patients experienced alterations in their taste. There was quite a lot of abnormal liver functions, but it was actually withdrawn in 1999 due to cardiac issues. next one, was trovafloxacin in 2000, where there were problems with hepatotoxicity.

There were, about 140 events, documented, five liver transplants, five deaths. and this was in about 2.5 million treatments. the last one that has been . Partially, withdrawn was gatifloxacin discontinued in the US and Canada back in 2006, at least when it comes to systemic treatment, it's still available as an ophthalmic solution for local treatment.

it's also available for systemic use in some countries still. when you look at all these different kind of fluoroquinolones, it's quite difficult to see which ones are available where, In Sweden, we have availability to Cyprofloxacin, levofloxacin, and moxifloxacin.

[00:08:31] Staffan: And, that's kind of it.

thank you, Staffan. I think that's very good summary, and I agree with you that it's very confusing and sometimes hard to understand why. Some countries have access to some drugs and other countries do not have access to the these drugs because we are treating in the end the same bacteria.

bernadette, can you give us a quick review of the spectrum of activity of the drug class? Some notable differences between the drugs within the class and some of the special properties.

I'll, focus mainly on the sort of three drugs which we covered in our review, and which also I think are the most commonly available.

[00:09:05] Bernadette: So thinking about ciprofloxacin, levofloxacin, and moxifloxacin, all three are very active against Enterobacterales, you know, really across that whole group of organisms. with the exception being that we often see acquired quinolone resistance, particularly in multi-drug resistant organisms. And they have activity against the aerobic gram-negative bacilli, thinking about legionella species, hemophilus species, and chlamydiophyla species within the group, there are some organisms, ciprofloxacin, is more recommended for, thinking about Shigella Yersinia Vibrio species. And then of the three, only ciprofloxacin and Levofloxacin show clinical activity against pseudomona species. Pseudomonas aeruginosa. Compared with the other two. the big difference really is, gram-positive activity. So ciprofloxacin is not really recommended as monotherapy for gram-positive organisms, either the staphylococci or streptococci.

[00:09:59] Bernadette: [00:10:00] whereas moxifloxacin, levofloxacin, often called respiratory fluoroquinolone, show much more gram-positive activity. So they're active as single agents against staphylococci, against streptococci, including streptococcus pneumonia, against enterococci, and even sub mycoplasma pneumonia.

and then to really round out, their respiratory qualifications, they also have activity against mycobacterium, tuberculosis, and they're really important parts of, treatment for multi-drug resistant tb or even more sensitive tb, where other agents haven't been tolerated. in general, the group don't have, cover for anaerobes, with the exception of some Pepto Streptococcal cover for Moxifloxacin Levofloxacin.

So that's quite a broad activity. And, you know, to add to that, if you're gonna make the positive case for Fluoroquinolone that you'd highlight as we have already, the very high bioavailability, meaning that oral dosing really gives you equivalent levels to iv. they have quite patient friendly dosing of once or twice a day.

And then as infection doctor, one of the things I like about them is they are active in biofilm. So this is a, a statement we use reflecting that the chemical property of being able to diffuse into the matter of a biofilm, and that they appear to be able to penetrate the polysaccharide component of a biofilm.

[00:11:17] Bernadette: And then due to their mechanism of action, they're also able to be, effective against non replicating bacteria. So penicillins, beta-lactams, they have their effect on the replication of the cell wall. fantastic for dividing bacteria, but not so good when your bacteria are sitting, chilling out in biofilm and not actively turning over.

[00:11:37] Bernadette: one of the less good features of the group is that we talk about them having what we call sort of a low barrier to resistance, and that again relates to their, mechanism of action and their target. So these drugs target either the DNA gyrase or topoisomerase which is a part of DNA replication.

[00:11:54] Bernadette: and resistance can relate either to efflux pump activity or outer membrane porins. But resistance of fluoroquinolones can also be acquired just from single point mutations arising by chance or under selection pressure in the gene target. even a single, point mutation, can be enough to turn your bacterium from being sensitive or susceptible to resistant.

[00:12:16] Bernadette: And if you think about the number of bacteria that can be, present when we have an infection and they're really rapid doubling time. It's just a numbers game for one of these, random mutations to potentially arise. And if you have the selective pressure of an antibiotic there as well, that resistance subpopulation will very quickly become dominant.

[00:12:35] Bernadette: And so you get the emergence of resistance on treatment. for that reason, it could be a problem to use agents like ciprofloxacin. if there's a large burden of infection, if they used early and resistance develops, same in the case of a pseudomonal infection, we can then lose our only oral option.

there is some vitro evidence to show that ciprofloxacin resistance is less likely to emerge in staphylococci if ciprofloxin given in partnership with Rifampicin. these two are sort of natural partners. Rifampicin is also active in biofilm, penetrates into biofilm. Rifampicin itself also has a very low genetic barrier to resistance because again, it's mechanism of action means, it's vulnerable to resistance emerging through single point mutations.

[00:13:16] Bernadette: but the two can be given together quite effectively to treat staph aureus infections, in vitro. There are some studies I think, showing that Levofloxacin and Rifampicin can actually be antagonistic. So it's not always fun games to add the two. but that synergy has led to us using ciprofloxacin-rifampicin, quite widely in treatment for staph aureus infections.

[00:13:37] Emily: Thanks, Bernadette. Can you tell us a little bit more about the anti pseudomonal effects of Cipro and Levofloxacin and the, differences.

[00:13:46] Bernadette: So, these are our only oral agents that have, clinical activity against Pseudomonas aeruginosa. And I think all of us involved in treating those, patients with those infections know the heart sink of not having any oral or kind of ambulatory option, for treating these patients.

[00:14:03] Bernadette: so we have ciprofloxacin, was traditionally thought to be the most active, quinolone against pseudomonas, and I think Levofloxacin was often accepted as being a little bit less active. but around 2019, I think was the CSLI break points for fluoroquinolone at least were revised on the basis of some updated PKPD data, to provide a guidance for break points where, giving, confidence for susceptibility with Levofloxacin, although it's slightly lower.

[00:14:32] Bernadette: Break points, and they'd previously published. And around the same time, the EUCAST updated break points had some major changes. And in particular, this was the introduction of the, new category of susceptible at increased exposure. these were new break points reflected that you could only treat, some organisms like pseudomonas, using much higher doses, of some antibiotics.

[00:14:53] Bernadette: So that means for ciprofloxacin as well as some of the beta lactams, like piperacillin-tazobactam or Ceftazidime , you'll never report a susceptible phenotype. You would only ever report resistant or susceptible at increased exposure because a high dose is always recommended for those organisms.

[00:15:10] Thomas: So Bernadette and Staffan, the two of you recently published a systematic review in CMI communications looking at the role of fluoroquinolones specifically in the treatment of prosthetic joint infection.

[00:15:21] Thomas: What made you want to do this review and can you tell us a bit what you found?

[00:15:26] Staffan: I can start there. I work, quite a lot clinically with both prosthetic joint infection and fracture related infections and other bone and joint infections. So in that setting, it's quite common to prescribe fluoroquinolones and both high doses and also prolonged treatment durations.

[00:15:42] Staffan: while doing so, we treat patients that are frail. We treat patients that we know are at risk for, side effects from the drugs that we give them. so basically managing adverse events from the medications we prescribe is part of the day-to-day clinical work in a way.

[00:15:58] Staffan: From this point of view, I think it's very important to try to, while working as a clinician, always do this kind of risk benefit analysis for the patient you have ahead of you. and to be able to do that, of course you need to have some basic knowledge about the medications that you are about to prescribe.

When we talk about the fluoroquinolone since the regulatory warnings emerged during the last 15 or 20 years, I mean, there've been a stream of publications on these topics. Then, in 2024, there came, an email for the, ICM 2025. the International Consensus meeting on infection?

It's a meeting on, orthopedic infections initiated by Javad Parvizi and Thorsten Gehrke back in 2013. a, huge number of, clinically relevant questions are distributed to multinational teams that are to provide some kind of mini review to respond to that question.

[00:16:49] Staffan: and there I. Got the opportunity to lead the team that would try to answer the question of the role of fluoroquinolones in the treatment of prosthetic joint infections. I was lucky enough to be in this team together with Bernadette, but also Craig Aboltins from Australia and Angela Hewlett from USA and Dolors Rodriguez-Pardo from Spain. But quite soon when we started to work on this, we realized that the format of the ICM review would, lead to us omitting quite a lot of data and a lot of discussion about, this complex and difficult topic.

so we, discussed with the executive committee of the ICM and decided that, once we had answered that question, we would move on and expand and keep working on this question to see if we could get a little broader discussion and actually, include, a lot more information than would be possible in the ICM format.

we had quite a small publication limit, didn't we? It needed to be just a few pages. Summary for all the thousand or so delegates to read and absorb and all the delegates were reading hundreds of questions. So quite good reason to concentrate it.

[00:17:53] Bernadette: But we found the nuance of everything in this topic we thought would benefit from a more wide, or a more fulsome discussion.

[00:18:00] Emily: And then what were some of the main findings of your study and, what type of evidence did you come across? were there randomized control trials? Was it mainly observational?

Well, first of all, when we started thinking about this, we have focused on the prosthetic joint infections. So we have, not been looking at other, osteoarticular infections in this, manuscript. we are also looking at implants as Bernadette was discussing earlier on the role of the fluoroquinolone as a biofilm active treatment here.

[00:18:27] Staffan: So it's, implant associated prosthetic joint infections. and when we came to the efficacy here, we were trying to find papers that were actually comparing the fluoroquinolone to other kind of treatments. so we can have. some picture on, the efficacy of these treatments. first of all, we started to look at the gram-negative prosthetic joint infections, and, we found seven studies. So not, that many papers, so no RCTs among these papers. one of the challenges here is that, I think all of these papers actually have mixed gram-negative pathogens. And I mean, when you talk about all these different gram-negative pathogens, is it really one size fits all that you can treat all of them the same way? With this limited amount of data, , most of these studies, reported superior outcomes when using fluoroquinolones, when compared to other oral options. and when we tried to pull the unadjusted data from these studies , we found an 83% success rate in, the Fluoroquinolone group, versus 57 for the other oral options.

there are a couple of other papers. There's one paper that compared the fluoroquinolones to the intravenous Beta lactam for the entire treatment duration, and they found no significant difference in that paper. there's also a paper from 2022 from the piano trial, where, You can in a table just find that, received ciprofloxin if gram negative actually was not a significant benefit, but I couldn't find any information on what was the comparators there. So in conclusion here, there is quite low level of evidence, few studies and quite small, populations.

but there seems to be a [00:20:00] benefit of using fluoroquinolones when comparing to other oral options. intravenous beta lactams seem to be an alternative, but I mean, we all know also that treating for intravenous for that kind of long time periods also are associated with, costs. With risks and with other kind of, problems,

[00:20:15] Emily: can you talk a little bit about why you focused on prosthetic joint infection with implant, retention? Do you think this is a scenario where we need to maybe convince clinicians that, fluoroquinolones and particularly an oral switch is effective and safe?

[00:20:31] Staffan: I think we're coming back a little bit to the Oviva and that maybe later on, but it's an interesting discussion and, during my entire training, for like the last 25 years, we have been working with early oral switch here in Sweden, so, when the OVIVA trial came, it really didn't change that much here. I think we usually do these couple of weeks of intravenous and then we switch to, oral, and we are quite confident with that. I think for me, when we, thought about this and discussed it, it's more, about the thought of, where do we have the greatest benefit of using fluoroquinolones, in these kinds of infections?

and actually using these, drugs, where they are, the most needed. it's a little bit about stewardship in that way, which I think we might come back to later on as well. and as we said we have, this biofilm activity, for the fluoroquinolones. When we come to, Staphylococci later on, it's the same thing there that we believe that we have this benefit from using the combination of fluoroquinolones and Rifampin when we have an implant in place, with a potential biofilm on it.

and that was also kind of the reason that we chose to not look into, other gram-positive pathogens. I mean, there are discussions as well about the use of, fluoroquinolones and Rifampin for cutibacteria or for enterococci and so on. But, as of now, I have not found any hard evidence that it actually works better to use fluoroquinolones-rifampin compared to other combinations.

[00:21:54] Staffan: so that's why we choose not to look into that indication. We, focused on the gram-negative bacteria and also the staphylococci, which are the two groups that we actually have most data and the strongest support for its use.

maybe Bernadette, can you at this point give us a little refresher on OVIVA?

[00:22:11] Emily: 'Cause we have mentioned it a couple of times now.

[00:22:13] Bernadette: Yes. So, OVIVA was a study of oral versus IV antibiotics for the treatment of orthopedic infections. So this was an international multicenter, open label, randomized controlled trial. and now I have to declare my interest here. I wasn't an investigator on OVIVA, but the current clinical lead of my department, Matt Scarborough, was and, the current lead of my research department, Philip Bejon, actually did the initial application and designed the study.

[00:22:38] Bernadette: So, like Staffan, it's never been controversial to me, so I'm having to. Put myself like my imaginative microbe into an imaginative space of being, an OVIVA skeptic to try to think about this. So the aim of the trial was to compare an early switch to oral antibiotics in patients where a prolonged course of IV antibiotics of say six weeks, was the usual standard of care for that infection.

[00:23:02] Bernadette: so it was quite a broad range of infections included. it included both prosthetic joint infections, osteomyelitis, fracture related infections, and some septic arthritis in native joints, as well as spinal infections. but the vast majority of patients included did undergo, a surgical treatment for their infection.

[00:23:20] Bernadette: About 85%. and the, primary endpoint was treatment failure at 12 months. So 1054 patients were randomized, and, 14.6% in the intravenous control group met that primary endpoint of failure at 12 months. But the rate of meeting, it was actually 13.2% in the oral group. So that was a slightly lower rate.

[00:23:42] Bernadette: And on the intention to treat analysis failure was in fact 1.2% lower in the oral group. So non-inferiority was very clearly met. so this represented a big change, I think, internationally to the tenants of practice and for a very long time. You know, the, Accepted practice was that these difficult infections needed prolonged courses of intravenous antibiotics.

[00:24:04] Bernadette: and although we had vast experience using those long courses, that treatment itself wasn't something that had really, derived from randomized control trial or, experimental evidence. It really began from the first principles of thinking, believing that these, deep seated difficult infections would benefit from that.

[00:24:21] Bernadette: in the center where I was training at the time, and am now working really were applying the results of OVIVA from 2017 when the results were first publicly discussed at ECCMID as it was then known. and I think it's important for the context to know that the patients included in OVIVA, not just their antibiotics that were part of their treatment. So they were all being recruited in centers where the surgeons were engaged in, this trial and therefore thinking about, the treatment. we would extrapolate from that, that most of these patients had good kind of integration between the surgical teams and the infection teams looking after their patients.

[00:24:56] Bernadette: and the vast majority did have, surgery to treat their infection as well. thinking about whether we can apply that to say patients undergoing a DAIR for a PJI, there were, I think a quarter nearly of the patients in OVIVA actually had a DAIR procedure. and the failure rates were almost identical in those, groups at 23.5% for the IV treated patients undergoing a dare and 23.3 for those having oral.

[00:25:22] Bernadette: I think we have to recognize there is a high failure rate in the treatment of debridement, implant and retention for PJI. But there's no good evidence for intravenous antibiotics, having an effect in lowering that risk. And I'd say there's quite high quality evidence for the use of oral antibiotics.

[00:25:38] Staffan: Yeah, I'm both impressed and grateful that you have performed these kinds of studies, actually. 'cause I think it, definitely benefits patients.

Well, the funding for this trial when it was done as a pilot was relatively easy to secure because it actually made it simpler to treat patients.

[00:25:54] Bernadette: It got patients out of hospital and it was, less costly in terms of treating with lines. So actually it was one of those studies, I think where everybody involved, could see a clear benefit. obviously it's difficult and expensive to run trials, but if the treatment that you're trialing is more cost effective than the standard of care, there's a bit more, momentum behind that trial.

[00:26:13] Bernadette: I think.

Thanks Bernadette for, refreshing us on OVIVA. I'm, actually jealous that, both of you have such high uptake of early role switch. it is still something that we're a little bit more behind on in North America. so it's always great to hear from centers that, were doing it even before the trial and that were early adopters and, hope that we all will get there over the next few years.

[00:26:37] Emily: So we talked a little bit about efficacy in gram-negatives. Why don't we switch gears and talk about efficacy in terms of staph aureus.

[00:26:44] Emily: Do you wanna take that Staffan?

Yeah, I can, move on to that. it's, actually a mixture we are talking about. It's both the staph aureus and the coagulase-negative staphylococci. So the same caveat here as in the gram-negative that we are mixing up pathogens that are quite different to each other in, terms of behavior.

[00:27:02] Staffan: but, here we had, 12 studies. we identified, none of them were RCTs either. when you talk about staphylococcal PJI, you think about Zimmerli and his study from from 1998, which is a randomized controlled trial, but, that contained both prosthetic joint infections and fracture related infections.

[00:27:18] Staffan: And what might be interesting in this setting is that they compared, ciprofloxacin as monotherapy to ciprofloxacin and Rifampin as a combination therapy and, found that ciprofloxacin and Rifampin as a combination therapy was, superior. it's out of the scope of, our review, but it's still interesting as a background.

[00:27:37] Staffan: So when we talk about, fluoroquinolones and, staphylococcal prosthetic joint infections, it's not for the independent benefit of, of fluoroquinolones. it's a co-administration of fluoroquinolone and Rifampin that, is interesting here, and to try to determine whether that combination is, beneficial compared to other, combinations.

here, it's a little bit more difficult to draw conclusion. And, most of these studies actually did not present any statistically significant differences in treatment. there were some studies, where you could find a benefit in the multivariate analysis. and when we started try to extract and pool data here as well, there was, a little difference between the two groups with, a higher, successful, outcome in the fluoroquinolone group, 87% compared to 75%. But, again, it's quite low level evidence. And the group is really heterogeneous. Further on there is actually a review article from, Cortes-Penfield in, 2022, where they did a meta analysis on 8 studies and tried to compare, the fluoroquinolone Rifampin combination to other combinations in prosthetic joint infections. And when you compared fluoroquinolones and RIF in that study to the other Rifampin combinations, there were actually a significant better outcome when you had Fluoroquinolone Rifampin combination compared to other combinations with Rifampin.

But when you compare the other rifampin combinations to regimens without Rifampin, they could not find any significant benefit. and that is, also quite, interesting discussion right now. So, uh. I would say that there seems to be a benefit from combining fluoroquinolones with, Rifampin compared to other combinations after DAIR for, staphylococcal prosthetic joint infections.

[00:29:17] Staffan: But when you start to think about these other, antibiotics that you combine with Rifampin, you have quite a lot of interaction trouble there, right? we have the, Pushkin study from 2016 with a combined rifampin and Fusidic acid for, prosthetic joint infections, and they had to terminate it early due to these interactions that you got.

[00:29:35] Staffan: Basically unmeasurable, concentrations of Fusidic acid. We have these sub studies from the POET. I mean, that's for endocarditis, but, when you look at PKPD, you can see that you have the substantial increase of linezoli clearance when you combine it with Rifampin as well. there you have the opportunity to actually follow the therapeutic drug monitoring and follow the concentrations to see that you actually have adequate concentrations.

[00:29:57] Staffan: But, you need to be aware of that. And also, there's [00:30:00] a paper from Zeller, I think in, in 2021, where they did a prospective study on the PKPD of, Clindamycin Rifampin combinations, and where you can also see increased first pass effects and, very much, lower bioavailability and, higher Clindamycin clearance.

actually, I think in that study they did not recommend that combination due to these, interaction problems. So, I mean, this is something that is. needed to look into even more in the future to try to see what are the optimal combinations when you're treating prosthetic joint infections.

and also I think one of the interesting points in the ICM, in Istanbul this spring was is there role for administration of rifampin for patients undergoing surgical treatment for implant associated infections? and the response recommendation starts with unknown.

[00:30:45] Staffan: I mean, we have very limited data here, and we are actually in a phase now where we need to do more research to actually find, when, and where do Rifampin and what kind of rifampin combinations, should we use for, implant associated infections.

thanks for providing the flip side of the gram positives to the gram negatives. it also gave me the idea that we could do a whole podcast on Rifampin because it's such an interesting drug. what I really loved about your review is that you also looked at the safety of the drug class. I'm gonna be honest, one approach that I take when I'm trying to convince my students and my colleagues to practice antibiotic stewardship with the quinolones is sometimes I try to scare them about the side effects.

[00:31:29] Emily: so I'll talk about tendinopathy lens dislocation, disglycemia, QT prolongation. Drug interactions, delirium, risk of c Difficile. And so I guess my question for you is, am I overdoing it? how common are some of these harms and is this a good reason to use this drug class sparingly?

[00:31:50] Staffan: So first I could start again with, how we thought when we started doing this review. We focused on these rare but serious adverse events that have actually led to restrictions in the use in, several regions. so we have not specifically looked at, for example, hepatotoxicity or nephrotoxicity.

[00:32:05] Staffan: We have not specifically been looking at, Clostridioides difficile infection, which is very troublesome. And we know we also have an elevated risk for fluoroquinolone compared to some other antibiotics. the stewardship issues when it comes to fluoroquinolones is also a very important part, but it's not been part of this review.

[00:32:22] Staffan: so first of all, I thought I could. Start up with one of the papers that we found that, was a small study where they actually looked specifically, at, patients, treated with DAIR for Staphylococcal prosthetic joint infections. It's a small cohort, 156 patients by Vollmer in 2021. first you think 156 patients, what can you actually find in that small cohort?

[00:32:43] Staffan: We're talking about adverse events, but in their study, they actually find that the unplanned drug discontinuation rate was 35% in the fluoroquinolone group compared to 3% in the non fluoroquinolone group. And I mean, these adverse events that were reported there was tendinopathy, myalgia, arthralgia, and nausea.

it's quite a lot of what we recognize from our clinical day-to-day job. still, it's quite interesting that you see that rate of, adverse events, even if it's not those, rare but serious adverse events that we may be focusing on here. But, there are challenges in treating, these infections for, quite a long time with these, high doses of antibiotics.

[00:33:21] Staffan: And I think that's quite apparent as well if you're trying to do a retrospective chart review of your patients that have received, treatment for prosthetic joint infections, that is very difficult to follow the antibiotic strategy over time as there are several switches during the treatment course.

Then when we look at these more, severe but rare events, large cohort studies, it case control studies, other types of epidemiological studies where you try to look at quite.

[00:33:46] Staffan: Large populations to, identify these adverse events and try to stratify the risk for it. there are a lot of potential confounders, that might not be easy to adjust for when you look at these large data sets. Not only the patient confounders, you can have confounders from the indications of the study drug and the comparator drug. when you have drugs, with different indications and different spectrums? another problem is in the decision making process in prescribing for these drugs when they have, gotten some attention, possibly from adverse events or from restrictions in prescribing that might, cause, altered prescriptions patterns, which might also, influence the results that you reach in the studies.

and, furthermore, of course, when you're trying to combine a drug prescription to, an unfavorable outcome, it's also necessary that this outcome is documented in some kind of way, in some kind of a chart system. So it requires the patient to actually seek the medical attention, to actually find that.

[00:34:44] Bernadette: There's lots of confounding by investigation too, isn't there? And confounding by indication. big population studies examining the risks of rare harms in fluoroquinolones versus other antibiotics, seem like a fantastic way to detect these rare events.

[00:34:59] Bernadette: But if the people getting fluoroquinolones are people who have intraabdominal infections, that group is much more likely to have investigations that will find an abdominal aortic aneurysm, than say the control group who are receiving amoxicillin who may have no particular indication for imaging.

[00:35:16] Bernadette: even the best constructed epidemiological observational study is still going to be subject to unmeasured confounding.

[00:35:23] Emily: Yeah, that's a great point. And There are, clinicians of course who are aware of the side effects and so may have a priori decided not to prescribe quinolones to people who are at risk of complications.

[00:35:33] Emily: So you might see underreporting as well,

[00:35:36] Bernadette: and we have to worry about that same confounding in the observational evidence for fluoroquinolones here, you mentioned scaring yourself or your colleagues about fluoroquinolone prescription. If I'm thinking about three months, six months of a medication that has lots of toxicity and my patient is very frail, I am less likely to prescribe it.

[00:35:54] Bernadette: And therefore, how comparable these groups are, in these observational studies is limited and we lack the randomized kind of high quality evidence, to truly understand the different impact they have.

I was just thinking about what, you said, for example, about these abdominal infections. That was one of the things that we saw when we started looking into, the aortic aneurysm and, aortic dissections. there was one study from 2020, for example, that, at first found this significant dissociation between the fluoroquinolones and the aortic aneurysms, and then we made the analysis after excluding the patients that did not have a baseline imaging of the abdomen, and then there were no longer a statistical significance. So, I mean, of course when you have an intraabdominal infections, you're more likely to do the x-ray than if you have a, upper respiratory tract infection, for example.

so that is one of the, traps you might fall into.

What did you find in the literature about these rare or uncommon side effects, Can you tell us a little bit about the numbers of the adverse events you saw? , We started really looking at the tendinopathy, which I think we are all aware of. and there we, definitely find an association. In most of the studies, we found 14 papers that looked specifically at tendinopathy, .

[00:37:01] Staffan: You can see that the risk for tendonitis is elevated early on in the treatment, but, there's no elevated risk. Six month after treatment. So that is basically during the treatment. And here, I think it's also important to be aware of the additional risk factors such as, corticosteroid use that further, increases the risk of, developing a tendinopathy while being on fluoroquinolone antibiotics.

then another collagen related adverse event, it's these aortic aneurysms or dissections as it is, really a serious potential adverse events. there were 18 studies that we found , and there were, quite mixed results most of these studies actually excluded patients with preexisting aortic disease. When we come to arrhythmia, then we have a potential, interaction with, cardiac potassium channels that might lead to this prolonged QT interval. and there we found eight studies where moxifloxacin seems to be the fluoroquinolone that has the strongest association there. again, it's important to, control for confounders, and there's a lot of discussion about that in the studies.

The neurological side effects might be quite troublesome, but there's very limited data.

[00:38:06] Staffan: We actually found, only three studies on peripheral neuropathy and only one study on central nervous system neuropathy here. for the peripheral neuropathy, you have an increased risk that actually persists up to 180 days of after the fluoroquinolone exposure.

finally about the dysglycemia. we found seven studies on, disglycemia focusing on, these, fluoroquinolones that we have been looking at in this review.

[00:38:29] Staffan: Most of the outcome definitions, they vary, but often it's, dysglycemia that causes hospitalization or, hospital contact. but there are studies that show that there is an increased , risk of dysglycemia, both hyper and hypoglycemia and then especially a diabetic patient.

[00:38:44] Staffan: So for this patient group, I think it's also important to inform that this drug actually may, cause alterations to their blood sugar levels.

[00:38:52] Emily: Bernadette, can you talk to us a little bit more about how a clinician should weigh the benefits and the potential harms? And maybe a little bit about, how do we avoid some of the harms in terms of, duration or types of infections we treat with this drug class?

[00:39:09] Bernadette: Yeah. So I think that's an incredibly important part of our role.

[00:39:12] Bernadette: and not easy to do. Well, stewardship's a really important part of our role because these are precious medications, partly because they do work so well for some important infections, and sometimes they're our only tablet option. the advice from, regulatory bodies that these antibiotics should not be used for minor illnesses, which may not even be bacterial infections.

[00:39:32] Bernadette: Thinking about asymptomatic bacteria or bronchitis is really important. These are top shelf or last resort sort of options. and we should be working, with other, options where we can in terms of balancing the harms and the possible benefits, I think. This is one of the reasons why having infection specialists, is very important, is that we can have this hopefully patient-centered discussion weighing those up.

and Emily, you mentioned the possibility of scaring your colleagues, but [00:40:00] there's also the real possibility of scaring our patients because do I inform you about rare but serious risks while still saying, but I do recommend this drug and that you should take it for the next few months.

[00:40:10] Bernadette: And it, it is a difficult balance. personally, my practice, I try to begin by sort of contextualizing that decision and saying, look, there is a lot of ways that we could treat this infection. I'm gonna suggest to you the way I think is most likely to give you a good outcome. But there are other options.

[00:40:26] Bernadette: There are some rare important downsides, and I'm about to talk to 'em in detail. But before I scare you with 10 possible side effects, I want you to know, I still think this. Is a good treatment for you. and then I try and talk about them sequentially and specifically contextualizing it with what, someone might experience or what actions they need to take.

[00:40:44] Bernadette: for example, I always talk about tendinopathy because we need patients to recognize the early symptoms. If you have new aches and pains, stop the medication, contact us straight away. others are more difficult to talk about risks of, significant psychological morbidity, like depression or suicidality.

[00:41:01] Bernadette: And there was a, a coroner's after death review in the uk, which, made the recommendation that we need to warn patients about the risk of depression and suicide with these drugs. so again, I don't wanna scare my patient literally, to death. And I'll usually frame that, alongside recognizing.

[00:41:17] Bernadette: How much psychological morbidity some of these serious infections can have. you know, you've just may have had major surgery, decreased mobility, not back to your regular life. And so look, you might feel quite rotten over the coming weeks and months, but if you find yourself feeling so rotten, you don't think it's worth going on, you need to remember that it could actually be the medications I'm giving you doing that.

[00:41:39] Bernadette: And so if you feel that way, please again, get in contact with us straight away. And having those, lines for patients to come back to us is really important. So we use emails and phone numbers as well as, clinic reviews. And finally, I think when having that kind of discussion and, talking through the possible side effects, I think if there is a, patient specific reason not to use the medicine that often comes out in that discussion.

even if it says something as, Common and non-life threatening as diarrhea. There will be patients who will say to me, actually, no, I can't bear that. I need an alternative medication. That's the only thing that I can, manage to take. I think if you follow that kind of process, by the time you're making your prescription, you have thought about the serious side effects.

[00:42:22] Bernadette: You've empowered your patient to recognize them and given them actions to take, if they begin to encounter them and you've come to a patient centered option, there.

[00:42:32] Staffan: I think that is very important and I think when you talk about these patients, the implant associated orthopedic infections, it's very easy that you end up looking at an antibiogramm and you see that you have this pathogen and you have this resistance pattern, so I should give this antibiotic, but I think the process should start even before that.

I think it's when you talk about these complex patients, it's good to have these, multidisciplinary teams from early on so you can actually start to. evaluate your options even before you perform the revision surgery, for example, because, resistance is not the only, reason for not being able to give a patient a drug.

[00:43:10] Staffan: I mean, you can have polypharmacy with interactions that makes it impossible. You can have patients with comorbidities that makes it impossible. You can have patients with frailty that makes it impossible. so you need to, from an early stage, start to think about what is the consequence of failure to eradicate the infection, for example, what is the of the potential adverse events you can run into during the treatment?

You need to think about if infection eradication always is the most beneficial to the patient. that might not always be the case. And the study endpoints. When you start to design a study, what are the important endpoints?

[00:43:43] Staffan: What is it that actually matters to the patient in the end? And that's not always the same thing that matters to the scientists that designs a trial.

This patient reported outcome measures rather than infection clearance. If you are at home miserable with diarrhea and feeling depressed, it's unlikely you feel you've had a good outcome.

so we've talked a lot about the risk benefit analysis, like you have to take a pros and cons and judge. based on your review do you think we have some more specific knowledge gap that need to be filled in before we can say that we really have the evidence to first convince the prescribers and then convey this message also to patients?

[00:44:22] Thomas: Anything in particular where you think there's maybe some misunderstanding or overestimations of risks or something like that?

[00:44:29] Staffan: I think there are definitely knowledge gaps that we need to fill in. We, have touched on one of them earlier on, and that is, for example, the role of Rifampin in the staphylococcal implant associated infections.

that is, a field that we need to know more about right now. definitely. another field of course is the treatment durations. how long do we need to treat these different infections? we had the DATIPO trial a couple of years ago. Bernard and, colleagues, that tried to see if it was possible to, shorten the duration after DAIR, and they did not succeed in, demonstrating that it was possible to shorten from 12 to six weeks.

But does that mean that 12 weeks is optimal? we really don't know that. if we could treat for shorter times and shorter durations, of course we use less antibiotics and we might also, incur less harm, less adverse events. you are running very exciting trial in, Oxford, the SOLARIO right now for local antibiotics.

the SOLARIO trial, led by, Dr. Maria Dudareva, as well as Dr. Matt Scarborough and Professor Martin McNally. And is a trial of using, long or short systemic antibiotics in patients treated for orthopedic infection, specifically where local antibiotics have been, used.

the patient population. is quite, specifically defined. These were all people who had had surgical treatment for an orthopedic infection, and that treatment had to be, expected to be definitive. So it wasn't a washout, we'll come back and look again. It did not include anyone having debridement and retention of prosthetic material.

[00:45:57] Bernadette: They all had definitive, surgical treatment and removal of all prosthetic material. the antibiotics placed locally was certainly not sprinkling vancomycin powder into the wound at the end of surgery. It needed to be, antibiotics in, an authorized carrier, where the elution characteristics of antibiotic from that carrier well known.

[00:46:15] Bernadette: And, those patients were randomized to either usual care with a course of treatment, usually four weeks or longer of antibiotics following on their surgery, or to stop systemic antibiotics within seven days. and those who were randomized to the short arm, uh, stopped at a mean of I think six days.

[00:46:35] Bernadette: And, then, endpoint was non-inferiority in terms of infection recurrence at one year. and the use of local antibiotics and short systemic, was indeed non-inferior to the longer courses of, systemic antibiotics, which is really kind of mind blowing if we think where we've come from. It must be six weeks IV to, you can give a couple of days of oral antibiotics and if you have local antibiotics in the right form, and you've had good surgical clearance, the job's done.

[00:47:02] Bernadette: I'm incredibly lucky to work in a setting where we have fantastic multidisciplinary working. treatment is planned between orthopedic surgery, but also plastic surgeons who ensure that the wound can be closed at operation, and make a nice environment for healing. and we get to see patients alongside our surgical colleagues.

[00:47:20] Bernadette: We see them before their operations. So the planning of treatment really begins before then, and that means that all those different expertise can come together to make up where a plan with the best, chance of treatment. And I think where you have those conditions, antibiotics are really mopping up just the last bit of infection and we can be more sparing with them, and that is, better for patient outcomes.

in the SOLARIO trial, those people who were in the short arm had significantly fewer antibiotic related side effects.

[00:47:50] Thomas: Yes. So obviously if you can do that, you can save side effects, but you can also prevent emergence of persistence. quinolones really stand out. if you look at studies on the gut microbiome, some studies reported that even after eight years you could still see which people in a cohort have been treated with quinolones.

[00:48:09] Thomas: And if you compare it even with IV broad spectrum drugs like meropenem or pip-tazo, oral ciprofloxacin in is far worse in terms of collateral damage on the gut microbiome. So that sort of brings us back to the pharmacokinetic perspective. you, discussed to switch early on to oral antibiotics in terms of side effects or in terms of, AMR.

[00:48:31] Thomas: Prevention, it might actually be worse. It is not always better to switch to an oral drug, but obviously there are some other benefits for patients in healthcare. Can you comment on that? Do you think there are other innovations?

[00:48:43] Bernadette: Yes. I guess I push back a little and think about if I'm using broad spectrum anti gram negative agents intravenously, that's going to have a profound effect on AMR selection in my patient and my center as well.

might have a different effect on the gut microbiome, but in terms of selecting out resistant organisms, we know from big studies that broad spectrum IV agents will also do that. So I think when it comes to treating something like say, pseudomonas aeruginosa. There's no option that won't profoundly have an impact on AMR I think our best options are those which well prevent infection, deal with the infection as definitively as possibly surgically, and narrow shorten, reduce as much as possible antibiotics. And yes, absolutely local antibiotics means less systemic exposure and, less selection for resistance.

[00:49:29] Staffan: the long-term, intravenous treatments also comes with other potential harms, such as, line thrombosis or, bacteremia or line infections. we have already discussed the problem with staphylococcus aureus, for example, and how troublesome may be with endocarditis, vertebral osteomyelitis and all other kind of complications that might come with that.

[00:49:49] Staffan: So, Always you have to just sit down and think about what are the potential risks and harms. You need to be aware of these different options that you have and try to see in which way may I benefit [00:50:00] this patient the best? what is the best option here? And now,

[00:50:04] Thomas: yeah.

[00:50:04] Thomas: Talking about treatment options, if we look into the future, I mean, would be even better to have a more narrow spectrum drug for staph aureus infections, for example. Do you think that there are new drugs in the R&D pipeline for antibiotics?

[00:50:18] Staffan: I thought about this question in two different ways. one way is, what's new on the horizon? And also when, listening at conferences, there are discussion about, trying to find other ways to target biofilm, other ways to get antibiotics, to get to the right point.

[00:50:33] Staffan: I mean, there are studies on monoclonal antibodies. There are studies on different kind of bone targeted antibiotics that you. Chemically link in some way or the other. But I mean, that's early on in research so far. that's one way to see it. How, do we move the frontiers on what we can do?

[00:50:48] Staffan: And the other way is, do we need to move forward? Maybe sometimes we should look backwards, like SNAP trial with Benzylpenicillin for penicillin susceptible staphylococci, for example, where it can go to a more narrow spectrum antibiotic and still treat these staphylococci, So that's, another way to look at it.

[00:51:05] Bernadette: I think the dream scenario would be to have actually some randomized controlled trial evidence to support any of these treatment decisions. and I know the Roadmap study is hoping to actually provide that kind of information around the role of rifampicin in these infections. but of course the challenges in such, variable patients is how do you construct solid trials, that compare patients meaningfully and the meaningful variance.

I'm interested, Emily, why you think OVIVA hasn't translated or what the barriers to accepting that result are?

[00:51:34] Emily: Yeah, that's a great question. I think it is the classic, it takes more than 10 years to get something into practice. And, you know, in North America, we were just, not in the habit and we really have.

[00:51:47] Emily: Always approached severe infection means treat more and more means intravenous and more is better. And so there is that kind of culture in our practice. we've done a lot of work on getting people to change the language that they use when they talk about early oral switch. so most people call it step down.

and it's seen as a removal of care. so I think it is, that culture change that's needed. so I'm, you know, very careful even just to say transition or switch as opposed to step down to try and convince people that this isn't necessarily a removal or lack of care to change to an oral antibiotic.

postoperatively we have you on very broad antibiotics. We now know what we're dealing with so we can target that therapy. so yes, as you say, it's not taking it away, it's actually making sure you're getting the right and just the right amount.

[00:52:38] Thomas: that's a very important communication strategy. And also I think sometimes patients misinterpret, like if you say they're switching to a narrow spectrum drug, they would tend to think that that's less effective. But as a matter of fact could be the opposite And also reduced risk of side effects. So, yes. is it colleagues or patients who are most concerned, do you think?

[00:53:00] Bernadette: about. Moving to oral therapy ?

[00:53:02] Emily: I would say it's primarily from colleagues in that most patients are open to switching to oral antibiotics, if they're doctor says it's safe to do so. But on occasion I will have patients who will say that they prefer the iv.

[00:53:19] Emily: you know, we are randomizing people to early oral switch in the SNAP trial in my center. And some patients do decline and say that they, want to have the intravenous and they want someone to come in and give them the IV antibiotic and that they, have been tolerating it, for example, and they haven't had any side effects and things have been going well.

[00:53:36] Emily: And so they might hesitate to change 'cause they don't wanna switch to something new or different. So I do think I hear it from patients as well, but maybe the, big bulk of it is from colleagues.

[00:53:46] Bernadette: we found, when we made a big move to primarily outpatient oral treatment for prosthetic joint infections, our, outpatient antimicrobial team sort of pivoted to become what we call the complex outpatient antimicrobial team.

they no longer only look after people having intravenous antibiotics outside of the hospital, but they also, monitor and, check in on patients having more complex or difficult oral antimicrobial therapy, kind of recognizing, that very high rate of people needing to change away from an antibiotic in terms of side effects and giving them, a close link to professionals who can help them manage that and dealing a little bit with that sadness in having the removal of the team looking after you that might come with being moved to tablet treatment.

thank you so much to Bernadette and Staffan and my co-host Thomas, for this fascinating discussion on fluoroquinolones. This drug class has a special role in infectious diseases, especially as more trials test out early oral switch strategies, making it all the more imperative to understand the potential harms and to protect them from being over-prescribed.

[00:54:51] Emily: Thank you for listening to communicable the CMI Comms podcast. This episode was hosted by Thomas Tangden and me, Emily McDonald, editors at CMI Comms ESCMID's Open Access Journal. It was edited by Katie Hostettler and peer reviewed by Dr. Ljiljana Lukić of University Hospital for Infectious Diseases in Zagreb, Croatia. Theme music was composed and conducted by Joseph McDade. The executive producer of Communicable is Angela Huttner. This episode will be citable with a written summary referenced by A DOI in the next eight weeks. Any published literature we've discussed today can be found in the show notes. You can subscribe to Communicable on Spotify, apple, or wherever you get your podcasts, or you can find it on ESCMID's website for the CMI COMMS Journal.

[00:55:37] Emily: Thanks for listening and helping CMI, comms and ESCMID move the conversation in ID and clinical microbiology. Further along