72. IDIOTS journal club: the SABATO trial

JOURNAL CLUB, YO, IT’S A SABATO!!!

Join Jame and Callum as we travel back in time to when we recorded this deep dive into the SABATO trial pre-print, now peer-reviewed and published in the Lancet ID!

In the next episode we'll give a little update as to how the final article differs from the preprint (not much).

We also talked about in our FIS Highlights Episode 3.

We loved this trial and we hope you’ll all give it a read, it’s well worth it!

Article here:
Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial, Kaasch, Achim J Valiente, Adoración et al. Lancet Infect Dis. 2024 Jan 17:S1473-3099(23)00756-9.
PMID: 38244557.
https://doi.org/10.1016/S1473-3099(23)00756-9

Transcript

Jame&Callum: 0:18

Callum what do you what do you tell a patient if they've got grandposterococca in their blood and you've determined that it's foot infection as the cause? They've got staph aureus. Bactremia from the toe. So I guess it's Sabato. Sabato, yeah. And what a coincidence is forced, man. That is so forced. Oh, I'm sorry I'm not up to the, you know, ludicrous standard of viewer puns normally. Well, you know, those are peer reviewed, so. That you think of femto seconds before we start recording. A femto second? A femto second. Well, I would say that Sabato is Italian for Saturday. Oh, I did not know that actually. Oh interesting. And there was a man called Ernesto Sabato who was an Argentinian novelist, essayist, painter and physicist. Are you going to leave all this in? I don't know. Yes, it's another Journal Club episode and today we're doing the Sabato trial, aren't we Callum? Yes, we are. So we've already talked about Staphylococcus aureus in episode one, so go back and have a listen to that. And I guess, why is this important? So Staphylococcus aureus is I guess one of the, maybe public enemy number one from bacteria, anyway, in general. It's so hard to pick a, hard to pick a public enemy. A few episodes ago I did state that Pseudomonas and Staph aureus were, I think are two greatest enemies in bacteriology. Certainly in terms of the. complexity of managing them and also the kind of the greatest evidence base for ID physician involvement resulting in superior outcomes are probably those two. But yeah, I think you know, if we're talking about what the greatest enemy You know, Nyserium meningitidis does kill a lot of people if it goes out of control. But you know, certainly in the gram positive space, I think Staph aureus is really it. Yeah, so go back and have a listen to that if not, or you don't know much about Staph aureus. And I guess, the context coming into the Sabato trial was that Staphylococcus aureus bacteremia. There's a lot of dogma in practice, so we've got these durations of therapy for an antibiotic treatment of a Staphylococcus aureus bacteremia or a SAB, where we say that, for an uncomplicated. So there's no deep source of infection, we give 14 days generally, and then for more complex infections you might give four or six weeks, but that's not really evidence based practice. Yeah, all IV as well isn't it Calum? Yeah, and it's historically You're currently quoting UK practice in general and Scottish practice in particular, because you're referring to the SAPG, the Scottish Antimicrobial Prescribing Group guideline, which gives us very kind of common standards. Yeah. To follow, but actually as we're about to come on, there's huge variation in practice all over Europe and in the US too. Yeah. So I guess, this is a common infection that has a significant morbidity mortality in which there is a sort of established practice, but that isn't really evidence based. And there's more recently been some larger trials looking at trying to, maybe challenge some of the dogmatic practice and say, actually, is this is this really the best treatment? And I think that sits also into the space of a general look at. We have a lot of dogma around IV therapy being necessary and challenging that in certain patient groups. So I guess the classic ones being like POET trial and OVIVA as a, as a two big recent ones. Yeah. And this trial is clearly, following on from those kind of, landmark studies, but let's say it's following on because it's actually following on because they started the trial. you know, in 2013. So it's, maybe that was, this is a forerunner and they've followed on. I don't know. True enough. It did take a while to get to completion. Yeah. So what we are particularly talking about today is early oral switch in low risk Staphylococcus aureus bloodstream infection by Cash et al. Was published as a preprint. So the, we're going by the MedArchive preprint here so that we can try and drop it as close to true publication date as possible. So there may be some minor changes between what we discuss and what actually comes out in whatever journal eventually comes out at. So They start with a little bit of background about what you've just discussed. Staph aureus bacteremia, a kind of well known clinical phenomenon, has an incidence of about 20 to 30 per 100, 000 patients, 100, 000 people per year, and mortality is about a quarter. Which seems a bit high, I think, until you take into account all the bacteremias that are related to, endocarditis and other deep seated infections. They have a definition here of uncomplicated SAB which would be the absence of deep seated infection, metastatic foci, or prolonged Bacteremia. Prolonged bacteremia is more than 72 hours, I think, or 48 hours. They define it further down in the study. And like you say, Cal, there's a general trend to two Constantine units or 14 days of therapy for uncomplicated and four Constantine units or 28 days after source control for complicated. Staph emia, but there's loads and loads of variation to that. And I've got a, in the show notes, which are a PowerPoint presentation, I've got A-A-D-O-I for a paper, that, that essentially just surveyed ID physicians and, and infection specialists and checked out the practice. All over the world. I mean, obviously there's some advantages to IV over oral, like there's a guaranteed amount of drug that's going to be hitting the plasma. Usually if you're trusting the individual who's administering it there's guaranteed administration of the drug, whereas the, the patient may not take the pill that you give them and you. Almost by default have to observe the patient closely, whereas if you're have the patient in a COPAT situation or they're just at home taking medication you won't be able to identify complications as quickly. Just to find COPAT for us there quickly. Sorry, complex oral patient antibiotic therapy. So OPAT with oral antibiotics. And then, but there are some disadvantages too. You need an IV line, obviously, and usually you need to either keep the patient as an inpatient or put them to an OPAT service. And a big part of ID consult work in Nados, Royal Infirmary North was surveying these staph aureus bacteremia patients to see if we could put them to OPAT and discharge them. And that depends on there being a, an option for, for one stele administration and, we were at the time the really three options, Keftraxone, Tycoplanin and Daptomycin. I mean, I think there's definitely some controversy about the effectiveness of Keftraxone for Staph aureus and and it's reflected in some of the breakpoints that are released now. Yes, absolutely. And, dapsomycin at the time was quite expensive too, and that limited its use. That's, that's changed. But yeah, you know, once you're thinking about OPATing somebody on IVs for once daily administration you very rapidly run out of options. And if it's stem RSA, there's fewer options still. The sort of paper surveying kind of variants of. Variants of care is from CID by West Geist et al. Again, I've got the DOI in the in the, in the notes. And essentially they, they had a different definition for uncomplicated SAB. It had to be community acquired. They had to be had to clear their blood within 48 hours of positive blood culture under appropriate antibiotics and no sign of metastatic infection and about 2, 000 respondents, mostly from America. And the US and to a lesser extent from Asia. And then the, the the variance was kind of clear. So America by far prefers 1st generation Keflavosporin, predominantly Keflazolin for treatment of these kind of infections for MSSA, whereas most of the rest of the world, we used an anti staph penicillin. So in the UK, that would be Fluclox. Other places, it would be kind of Ofloxacin and no, sorry. Other places it would be Gloxacillin or things like that. And then for MRSA almost everybody is choosing Vancomycin as their, as their first line, although now Daptomycin's off patent and a lot cheaper. I wonder if that might change. It was the second option, and of all the places in the world, that were, going to use it the most, Europe was where it would be used, and that was about 23%. Whereas in the US it was only 8 percent of first line choices. And then in terms of oral switch, it's interestingly, I thought most people would say would say never, but actually there's a reasonably interesting mix that there are some places that would say sometimes or frequently it's easier to see as an image, really, this sort of split, but the kind of very rough split would be something approaching 40 to 60 percent would never use oral therapy, and between 20 and 40 percent would sometimes do it. The remainder would would frequently do it, but the, the highest percentage was in African respondents, but there was only six respondents, so maybe reflecting low sample size in there. But yeah, so in, in North America, 8 percent would do it, use orals frequently and in Europe 16 percent would use them frequently. I must admit like before a few years ago, Callum, I've never considered doing it. And I would, I remember having these kind of tooth and nail fights with the clinical teams to keep the patient on IVs and you know, patient wanted to go home, the team wanted rid of them. But I was like, you have to keep them in. Yeah, which is difficult, particularly in the setting of someone who's very well and hasn't got any complications. And I'm interested by the oral switch in terms of what they meant by that. You know?'cause I guess there's a difference between, you know, oral switching before the two weeks is up. Or if it's complicated, oral switching between before your four weeks is up. But sometimes there might be a like uncomplicated, we'll give you two weeks of IV and then we'll give you two weeks of oral antibiotics just for the hell of it. Yeah. Yeah. Maybe. Yeah. So what is it? Is it like a bare, cause there's so much variance in practice. So that data, I think it needs to be a bit more granular to understand what that means or what it's meant historically. Because I think, if you, if you just start giving them the bare minimum IV. or what we've accepted as that, and then giving them an oral extra just in case, to mop anything else up. Yeah, I think that's a bit different than saying, we switch you to orals a few days in. Yeah, true. And then I've got on, on the next slide, some sort of the, the breakdown of duration of therapy for needs of valve endocarditis, arthritis, and spondylitis, but I'm not going to go through that. So coming back to this trial, the noted the outcomes of the POET trial, so the Partial Oral for Endocarditis Treatment trial, which was set up in Europe. It was 400 people, left sided endocarditis only, gram positive organisms only. And they noted that for both penicillin sensitive and methicillin sensitive Staph aureus. The, you know, the, there were treatment regimens that were kind of recommended. So for penicillin sensitive staph aureus, it was a MOX plus one of a fusidate or rifampicin. And the second line option was linezolid plus fusidate or rifampicin. And then for MSSA it was dicloxacillin because it was done in kind of Europe, mainland Europe and not the UK plus fusidate or rif. tHe second option was Laneslet plus either Fused Data or RIF. There was no MRSA in the study. But there were 87 Staph aureus cases. And they were given 10 days of IV and antibiotics and then switched to, one of those oral regimens. There were more regimens, used than those four described because, people just used random stuff, really. And so I've listed them as well. But, IV was non inferior. Sorry. Oral was non inferior to IV in the POET study and so that, that kind of contributed to the idea that maybe we don't need to use IVs certainly for the full duration. And it's worth pointing out in the POET trial, there was quite a lot of exclusion criteria and everybody got a TOE aortic root abscess. So, you know, it was a carefully selected patient cohort, but I think nobody would say that infective endocarditis is. is uncomplicated. That's a complicated staph aureus. And these patients, the diagnosis was made on blood cultures, so they're by definition bacteremic. So it is a really interesting thing to say, actually, this potentially has legs. Angus Yeah. Small numbers though, only about 87 people larger numbers seen in the Aviva trial which was published in 2019. This is oral versus IV. Antibiotics for bone and joint infection and was a parallel cohort, open label, non info trial about a thousand patients, 317 of which were staph aureus, 10 percent of which were MRSA, but importantly, none of them were bacteremic. That was an exclusion criteria for Aviva. And the intervention in comparator were either six weeks of oral or IV for bone and joint infection. And the orals were a mix of quinolones, penicillins, clindamycin slash macrolides or tetracyclines. And 17 percent got combination therapy of some of that, and the primary outcome was one year failure rates, and it was 15 percent in the IV group and 13 percent in the oral group. But there were, you know, IV therapy had longer hospital length of stay, increase in premature discontinuation of therapy, and line complications, all of which were significantly more than oral therapy. It's cheaper and there's. Cost saving associated with using orals and, in Nados South, in our bone infection unit, we. We were a heavy participant in the Aviva trial, and we do this as a matter of routine. I don't know that's really seeps out into all areas of UK or world. Of the NHS, yeah. Yeah, and I think it's quite hard. I think that this, the whole general theme here is that we are so used to saying You must use IVs, IVs are better and as a move towards we've got evidence that in select patient cohorts in these clinical syndromes that oral is non inferior and I guess it's just mounting on the evidence, which is. You know that in a lot of situations, orals are probably fine. And the other thing that went through my head, reading both of these papers, but particularly in OVIVA, and just in general, in trial settings, is that I think we really dichotomize patients into bataremic or not bataremic. bUt I, I think there's often that, there's a slight worry in my head a lot of the time when people aren't quote unquote battery remic. But when you go back to the initial presentation, they didn't have blood cultures pre antibiotics, or they only had one set of blood cultures, which we know the sensitivities in the 60 percents. For me, if we go back to back, go back to B to bacteremia, one of our episodes because I think it is really important to think about like. what diagnostics were done, and how confident are we that they were or are not batcheremic. And I think in these sort of real life trials, You know, who's to say that these, these patients weren't bacteremic? But maybe that's too controversial. You know, we only find bact It's not like we have this absolute empirical, absolute knowledge that people weren't bacteremic. All we can say is that in the blood culture sets that were taken, when they were taken, we didn't grow any organisms. But I think you really have to caveat that a lot of the time with the fact that, we're quite poor at sending enough blood cultures or putting enough blood in the blood culture bottles or taking the blood cultures before antibiotics are started. And there can be a tendency to just say they're not bacteremic. How confident are you in that recommendation? My point is that I think sometimes people are going to be included in trials that potentially were bacteremic and we're still seeing, but that's, I don't think I can really, I can't really support that with any evidence, but that's just something that's gone through my head. Yeah, but I mean, even in the bacteremia trials that we've got, there's, been the signal that you know with POET that the orals can be good. So the, the question arises, can Staph aureus bacteremia be treated with oral therapy? And that's what this trial the Sabato trial wanted to answer, at least for uncomplicated Staph aureus bacteremia. So let's talk about what they did. So it was a randomized parallel group open label non info trial. It ran from 2013 to 2019 in four European countries and 31 separate sites. The PICO here was uncomplicated Staph aureus bacteremia, which they defined as we've said above, and the, just to, just for PICO is population, intervention, comparator and outcome. sO the intervention was oral therapy from either day five, six or seven, all 14. So day 14 was the end point for uncomplicated SAD. And the comparator was IV therapy throughout. So both groups got five. To seven days of IV therapy is a lead in and then in terms of the outcome, in terms of the outcome I'll talk about that in a moment the inclusion criteria were age more than 18 treatment with five to seven days of IV therapy and treatment starting within 72 hours of positive blood culture. And then follow up blood cultures were negative one to four days after IV antibiotics were started. So you had to have evidence of clearance of the staph aureus from the blood, or rather an absence of persisting bacteremia, which would imply an endocarditis. Exclusion criteria were a complicated SAB, defined as deep seated focus, bacteremia more than 72 hours after antibiotics were started, and septic shock. 96 hours prior to randomization. Other exclusions were fever on two separate days 48 hours prior to randomization, or in other words, three days into IV treatment, if you see what I mean, because you were randomized at day five. Got it? I'm understanding that, yeah. So on treatments, you started IVs, and you were main febrile, which seems quite a, quite a strict exclusion criteria. Isn't it just? Yeah, but they wanted to make sure that whatever your initial antibiotics were had sort of licked the problem. And note that you were on, you know, substandard treatment that wasn't doing the trick, but you're right, it's kind of a bit of an odd exclusion criteria. IV catheter not removed 96 hours after first positive blood culture. And patients at high risk of complications of staph aureus bacteremia. So that's previous SAB in the past three months. Injecting drug users. immunosuppressed patients and prosthetic heart valve or vascular graft patients. So if you had those, then you were excluded too. They were randomized to a couple of treatments. The first was for MSSA or MRSA you could get cotrimoxazole 960 milligrams twice daily. For MSSA, you could also receive clindamycin 600 milligrams three times a day. But for MRSA, you wouldn't receive clindamycin, but you could receive linezolid. 600 milligrams BD. And this is a bit of an odd one, Calum. I was going to ask you about this because I, I don't know why MSSA or IMRSA, you couldn't receive all three of those medications. Do you have any idea of why that is? I guess it depends on local epidemiology. I imagine it's, including the caveat if sensitive on susceptibility. But if, if it's SUS testing and it's an MSSA and if it's sensitive to lenesolid, which most of them will be, I don't know why you wouldn't just go and use that. Yeah, I guess Lonezolid is a reserve antibiotic on our WHO classifications, so we should be using clindamycin preferentially. Yeah I, yeah. Maybe you're right, maybe it's that MRSA has earned the right to be treated with a reserve antibiotic. The other thing I guess to say is that, everybody, you know, so I think in Scotland the And our, our MRSA are generally susceptible to co oxone clindamycin, not universally, but the majority of them will be and Gentamycin for that matter. And in other parts of the world, I think you see more higher rates of multi-drug resistance in MRSA. Yeah, true, true. And then in terms of IV options for MSSE, you could either get Flucloxacillin or Oxacillin in France and Spain or Kein. Two grams, three times a day. anD then for MRSA you could receive daptomycin 6 to 10 milligrams per kilogram per day, although I wouldn't go less than 10 for an MRSA infection, even if it was uncomplicated. And then both MSSA and MRSA could receive vancomycin one gram BD. That's, that's interesting as well, because I think we know quite clearly that vancomycin is inferior to antistatic local penicillins and cafezolin for staph aureus, so it is, Calum, but if you've got a penicillin allergic patient You should de label them. You should de label them. But if they're truly allergic, you could probably use Kefazolam because this is an aseptomedical side chain that doesn't cross react with anything else. But that's relatively recent knowledge. And so Yes, that's true. Relatively recently widespread. Yeah. It's easy to look back and retrospect and be like, how did they not know? Well, exactly. It was 2013 to 2019. Yeah. You know, you're talking about a time when, not even you nor I. Callum, you've got the kefazole and zygium thing. It's it's very easy to look at a trial and criticize it. But I would not be able to have done this. So I'll pipe down. And then it was run in four sites four, four countries, as I said. So Germany contributed 73 patients, France, 69, Spain, 64. And then the Netherlands had had seven. In terms of what the outcomes were, the primary outcome was SAB complications at 90 days. So that's relapse, deep seated infection, or death related to bacteremia. And then secondary were length of stay between the first positive blood culture to discharge, complications of IV therapy, C. diff incidence, and mortality at 14, 30, and 90 days. In terms of the sort of stats, they used a non inferiority margin of about 10%, a one side of alpha of 0. 05, and a beta of 0. 2, as in a power of 80%. So some might say that that's a little bit low. I think they were probably had one eye on the numbers that they were expecting to get. anD they studied both the Per protocol and ITT populations note here that. The lawyer listener may be used to analyzing superiority studies where you want to use the ITT population because, if your treatment is effective at, curing the person, but they can't tolerate it because of side effects. Sometimes pair protocol will miss that, whereas ITT intention to treat. Yeah on some stats which we prefer pair protocol analysis when you're doing non inferiority studies, as ITT tends to favor producing a null result because those sort of side effects are working in the opposite direction to compared to answering the question that you really want which is non inferiority, yes or no and then the for the pair protocol the Analyzed they didn't analyze the strict pair protocol population. They analyzed the clinically evaluable population, which is people that were treated pair protocol observed until the end of follow up or reach the primary endpoint and didn't receive antibiotics during follow up that could mask the primary endpoint. So it's a subset of the pair protocol population to meet all those criteria, the clinically valuable population. So we ended up with 86 and 79 patients. Respectively in the clinically valuable population so 86 in the oral and 79 in the IV. In the IV. Yeah, that's right. And then in the ITT, there were 105 and 101 respectively. So the groups are losing about 20 patients each moving from ITT to clinically valuable population. There were a couple of imbalances between the groups. The oral group had more moderate to severe liver disease and diabetes, but I mean, they should argue, be detractors. For demonstrating non inferiority, so that's, it's not a good thing, it's better than it being in the IV group because then you don't really know where you are. There was running a mean of about six days and the most commonly used drugs were cotrimoxazole for 58 percent and clindamycin at 32%. And then for the IV group, it was 44 percent cafezole and 43%. Either flucloxacillin or cloxacillin. aNd non inferiority was achieved in both the clinically valuable population and the ITT groups. And the only difference between the two was length of stay. So 12 days for the oral therapy versus 16 days for IV and no significant difference in terms of adverse events. As well. A resounding success, I feel, resounding success. Obviously a lot of work, a really complicated trial, lots of sites, it must have been a huge amount of coordination required, and they've done, I guess it's maybe like a starting off point? Yeah, because how many patients did they screen again? Over 5, 000 people were assessed for eligibility. And of those they excluded 4, 850. Majority was because they didn't meet the inclusion or exclusion criteria, which is hardly surprising because they were very strict. I was particularly surprised about the fact that people would, weren't allowed to remain febrile for a couple of days. Yes. Well, the two incidences of fever and you've it out. Yeah. So, I mean, that was you, you're right, that, that does end up excluding a lot of people. I just need to know which inclusion exclusion criteria got rid of people. I don't know if it goes into that much detail. No, it doesn't. No. So yeah, I guess in a carefully selected cohort of patients with uncomplicated staph aureus bacteremia, this study is suggesting that oral therapy is non inferior to IV. Yeah. And they, they then sort of hacked out their data to see if there were. sort of any differences between you know, older people and younger people, male, female, MSSA, MRSA cran and clearance whether or not the patient had an echo and the country that it was done in. And there was nothing that was getting close to favoring IV, versus all, it was kind of all over the place, but Nothing was hitting the non inferiority margin particularly. You know, that's good to know as well, though, once you get into those individual groups, you're getting real small numbers. so I'll, I'll state the conclusion here in this multi center randomized trial of patients with low risk SAB, early oral switch antimicrobial therapy was non inferior to IV standard therapy with regard to the primary endpoint. And I've also included a link here to a Twitter infographic that was published. Sabato has been actually presented at a couple of conferences. I think it was presented at a NESC ECMID. Yeah, it was at a NESC that one. Yeah, and it's been presented at ID Week as well. It's been buzzing around for, a year and a bit now. Everybody's been desperate to see it published and to, maybe to implement it. Down the line and, you after I found out I was, it was one of my the things that I wanted to see published too. Yeah. So, what's the, what are the advantages of this trial? So it's, it, I think it was fairly pragmatic. All the options, oral options are off brand, off patent. You know, you can get them cheaply. I put as a strength here, the definition of low risk SAB was quite strict, but I think that sort of works in its favor. We've both expressed concerns about that fever exclusion criteria, but I think, that This trial was always going to be limited in its applicability and at least now, who this, really can be used for. And there was a SAV specific primary endpoint, which I really, liked. If you're going to use a combination out point, which is basically what they've done here, you might as well make it three things which kind of really matter. And as a reminder that they are relapse, deep seated infection or death. Now, I don't like combination endpoints where they include death because usually it's say in cardiovascular trials, it would be like a heart attack, repeat heart attack, need for, bypass grafting and death. And obviously death is much more important than those two things. That reminds me of something that we talked about recently, which I don't know what episode it was on, or even if we recorded it. But it was that as an infection specialist, you can sometimes be fixated on the fact that the patient does or doesn't have an infection as the primary goal, and you always have to remind yourself that's not the goal. It's about patient more, survival and also quality of life. So sometimes actually, if you have microbiological failure, have you an ongoing infection? Not maybe in this context, but that can be fine. If the patient's asymptomatic, like an osteomyelitis or something. Yeah. Yeah. But yeah, getting rid of the infection is not the. It's not the primary goal. It's looking after the people. Yeah, that's true. That SAB specific primary endpoint I think makes sense to me. I think so, yeah. In terms of, weaknesses, the you know, the screening exclusion ratio was 25 to 1. And that's, that's a lot. If you'd ask me to Gauge how many sabs I saw were because of uncomplicated staph aureus bacteremia, like an IV catheter has gone in and, it's introduced staph into the bloodstream and then it gets pulled out and maybe there's localized infection and you deal with it. I would have said that was maybe about like 10%, 15%. Something like that. I wouldn't have thought it was, 5% or, or 4%. bUt this is apparently comparable to other uncomplicated ssab trials that recruitment and the exclusion ratios are kinda about that. so Maybe it is more complicated than we thought. I mean, there are patients that are meeting the definition, so it's not like a Yeah, I can think people do. It's not a unicorn. But yeah, there was obviously there was no blinding, which is an issue. As obviously, if the patient stay in hospital on IVs, they'll know about it. I would say, though, that that's makes it all the more pragmatic. And I think since the. People have been participating in the recovery trial, which was all unblinded. I think people have made their peace with the idea that blinding is ideal, but in a non ideal trial it's, you know, in a pragmatic trial, it's probably the first thing to go. And comparing IV therapy to oral therapy, blinding it by giving people sham IV treatments would just jack the price up so high that those trials are, almost impossible to do. They terminated the trial early because of the slow recruitment. Their target sample size they didn't meet. And then one last thing to note is that of the deaths attributed to SAB, both were in the oral group. So 1 participant was disheartened and declined readmission when her condition deteriorated and the. Said that the, they think that this mean, they make the point that you, on these patients, if you're going to discharge them, you have to monitor them closely to make sure that they're not developing complications. OnE thing that goes through my head when I'm, when I'm reading all this, right, and again, maybe this is a bit controversial, is that when we get Staphylococcus aureus growing in a bud culture, We get very concerned and we say this is important and it must be treated and then you go see the patient and they've got normal inflammatory markers and they don't really have any suggestion of Staphylococcus aureus disease and they're pretty well some of the time. And in the back of your mind you're thinking is this a contaminant? Because Staphylococcus aureus is an organism that we know can be part of the skin flora. And I think it's, I can think of one case I've been involved with where we've ended up doing lots of body cultures, the patient remained very well, and we ended up calling it a contaminant, and we didn't do anything further with it. And that was pretty controversial, I think, within the department. And, yeah, so I wonder One, one concern I guess I have is that if we take out anybody with any sort of hint of a complication or fever, are we left with a group of patients that potentially actually had a contaminant? I mean, I suppose those patients would fall into the, to the inclusion criteria group. I don't know. Do you think that's a reasonable thought or do you think that's, I don't know, it doesn't seem very often, but then I guess it's so hard to say is this a true maturina or is this a contaminant? It's quite hard to say. I don't know if there's that. Quite a lot of the patients had an origin point. So they would be either there are a peripheral cannula, a central cannula that had to be removed or skin and soft tissue infection. That was what most of the patients were presenting with. And they they say this in supplemental data. And there's also a in subgroup analysis, which is the analyzed by. Presumed origin of the battery media. And was there anything that is true? Is there unknowns or is there? There must've been, but like they've not stated it here. I don't know. I think. Like you say, Calum, it's controversial to do it because the, the risks of missing a true bactremia and delaying, therapy, because if you're going to sit back and do loads of blood cultures, you better have them off antibiotics when you do it. Otherwise it will be negative. And to be honest if it doesn't really matter, does it? Because even if they were. Some people with contaminants in this it's still useful data because what we've been doing at the moment is We get a blood culture staph aureus as one blood culture. We never find it again The patient's completely well, and we inter them in hospital for two weeks or send them to OPAP for two weeks for IVs Which seems extremely restrictive and sometimes seems a bit Overkill. And actually, maybe this is really helpful to say, actually, we don't need to do that. Yeah. Yeah. And all the more reason to evolve an ID physician in all your staff or his battery media so that decision could be made because no other specialty is going to do this and be involved with enough staff or his battery means that. They're going to be able to kind of maintain this kind of knowledge of the evidence base. Well, I think all the specialists, if you don't have any ID physicians in your center, it might fall to someone else in the public. No, but then an infection specialist is in an ID physician or a microbiologist. Everybody's got access to a microbiologist. Yeah, so anyway, that was the saboteur trial and it's getting presented at FIS in November. By the lead author, Dr. Cash himself is coming over from, I think, Germany is where he's from. To present the Sabato trial, hopefully once it's been published but who knows? Great thanks for, for walking us through that, James. I think an important trial. Glad that we've managed to see the sort of pre print and looking forward to the peer reviewed publication and hearing about it at Fizz. Thanks. Bye. Yeah, I think it's adding wood to the fire, which is. Oral is the new IV. Indeed it is.