CEimpact Podcast

The ACORN Study: Nephrotoxoicity in Antibiotics

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Piperacillin/tazobactam and vancomycin have been reported in numerous clinical trials to be associated with acute kidney injury. Comparatively, cefepime with vancomycin may increase neurotoxic effects. Join host, Geoff Wall, as he evaluates a new randomized controlled trial evaluating the safety of these medications.
 
The GameChanger
Vancomycin, even at appropriate doses, can cause nephrotoxicity. Piperacillin/tazobactam does not seem to increase the risk of adverse kidney outcomes. However, cefepime is associated with an increased risk of neurologic toxicity.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Tong SYC, Venkatesh B, McCreary EK. Acute Kidney Injury With Empirical Antibiotics for Sepsis. JAMA. 2023;330(16):1531–1533. doi:10.1001/jama.2023.18591

https://jamanetwork.com/journals/jama/fullarticle/2810593
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Describe the risk of nephrotoxicity with piperacillin/tazobactam
2. Discuss the factors that exacerbate neurologic adverse effects with cefepime

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-353-H01-P
Initial release date: 11/13/2023
Expiration date: 11/13/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Welcome to Game Changers clinical conversations. I am Jeff Wall, your host. I'm a professor of pharmacy practice at Drake University and internal medicine clinical pharmacist at Methodist Hospital here in Des Moines. Welcome to our show, welcome to the pod where we really try to give you guys the latest pharmacotherapy information. Whether it's a study, whether it's a new guideline, whatever it is, we're hoping to break it down, make it easy for you guys to utilize right at the bedside as soon as you possibly can. And part of that, of course, it requires us to kind of keep an ear to the ground when it comes to some of the big organizational meetings, and in fact just finished for us is ID week, which is the big week meeting for the infectious disease Society of America. There was a number of terrific studies announced and guidelines for diabetic foot infection were released. So my guess is we'll be hitting a couple of those things big in the next several months. But the one that, for inpatient pharmacists in particular, I think generated a lot of buzz, especially in social media, was the acorn study, and that's what we're going to talk about today. As I said, the acorn study generated a lot of buzz and still is, and it purports the answer kind of once and for all, something that has kind of raised its head and again for the 100,000 time, you know, shows that correlation is not causation. The acorn study revolves around the potential nephrotoxicity of Piper Cilenteza backgam I'm just going to call it Piptazo for the rest of the pod and is thought to increase the nephrotoxicity of Banco, which, of course, everybody knows is a nephrotoxic drug and so you know this around 2011,. Kind of look at the history of this.

Speaker 2:

There are several kind of retrospective studies that were published almost simultaneously that looked at patients who had received the combination of vancomycin plus Piptazo. If you work in any hospital of any large size, that is a very, very common combination that you're going to see used in patients who might have some sort of nosocomial infection whether it's nosocomial pneumonia or things along those lines or someone who's just super sick, who's not doing well on the ICU, on pressers or we're not exactly sure what's going on. The combo of Piptazo and Banco is very, very commonly used. Now I'm not saying I endorse that in most of the infectious disease physicians, I know, you know, hate that combo and they call it vocin or something along those lines, and so you know I'm not saying that that's necessarily a good thing, which is it's one of the most common things you're going to see done in big hospitals across the country and several studies looking at this had suggested that in retrospective studies, when you took a look at a lot of other factors, pippercilin added to vancomycin seemed to increase the rate of nephrotoxicity. So nephrotoxicity was worse with the combination of and Banco versus Banco itself, and the reason for that was really never clearly established. Animal studies had never really figured that out.

Speaker 2:

You know several retrospective studies you know found that and of course it's a relatively easy study to do. I mean, you're really just you know, pull everybody in your database who got the combination versus those who just receive Ancomycin by themselves and maybe stratify for certain confounders, but then just take a look at them and look at the numbers. So basically we had a few of these retrospective studies, then a few more, then a few more, then a few more. Then all of a sudden we had enough, I think, of a significant mass of retrospective data that it entered kind of the general medical subconscious or unconscious, and I still believe that exists, where rumor has it sort of thing and kind of goes around and more and more people read what literature there is and makes the decision.

Speaker 2:

Well, I'm going to do this, basically. And so it basically just reached this general mass where yeah, I heard that too. I heard Sosin is defertoxylethanco but we're just gonna start using Cephapim Now. Again, I have nothing against Cephapim as an anti-pseudomortal agent. I would argue that it has its own set of problems and certainly we and others have seen cases of it causing confusion, mental status changes, delirium. There's even been case reports of it causing seizures and stuff because of its high level of penetration into the CSF.

Speaker 2:

So I mean, of course, no drug is completely free of adverse effects, but the whole notion of well, okay, well, we're just going to abandon Sosin and go to Cephapim was made, I think, in a lot of hospitals, largely based on this mass of retrospective data. Now, really, one of the things I always tell my students is that if you're gonna look at a study, the very first thing you have to ask yourself is is there a biologic plausibility for what they're claiming is happening in the trial? Right, you know you could do a study that suggests that gargling peanut butter treats cancer. Okay, and you may even be able to pull off a study that's large enough and weird enough that you actually find a statistically significant increase in survival in the people who gargle peanut butter three times a week. But again, what is the biological plausibility of that? There's no real biological reason why that would happen. It's really probably not a good study, and so that's a bit of an extreme example. But several authors that pointed out that there was no laboratory or animal data suggesting that Pippezzo was in fact a nephrotoxin, and so it didn't make any sense that that went added to another nephrotoxic drug. You would increase the overall risk.

Speaker 2:

Now it is known that because Pippezzo inhibits OAT1 and OAT3, these are organic anion transporters that does really lead to a reduced secretion of creatinine in the urine, and so you can see a slight increase in serum creatinine. But like someedidine and like metformin and like bacterium and a couple of other drugs, which all do this, you see a slight increase in creatinine without actual kidney damage or any of the negative clinical outcomes associated with it, and in almost cases it all goes back to normal. So many have termed Pippezzo as a pseudo nephrotoxin. Okay, and so that if that's the case, then the logical conclusion is maybe what they found was that Pippezzo does in fact increase adverse kidney outcomes, but in fact this basically causes the numbers to go up a little bit. And if that was your outcome in your retrospective study then, yeah, you would have probably found a difference or an additive increase in creatinine when adding Pippezzo to Vankel.

Speaker 2:

But that was really it. And again, it's worth noting that, if anything, there's some evidence suggesting an animal models that blocking OAT1 and OAT3 may actually be nephrotective and not damaging to the kidneys. But the bottom line was there never really was any biologic plausibility whereby Pippezzo would actually act as a nephrotoxin, and again only in the face of Vankel myosin. And so, because of all that, even though most some of these studies would come out, there really wasn't a lot of hard battle looking at hard kidney outcomes and there were always people who kind of felt like this just doesn't make any sense to me. I'm not really sure that's what we're gonna do, but, as I said, just this critical mass of information caused a lot of clinicians to say, well, I could use either one of them, it doesn't really matter. So why don't we just pick cephalopathy? And again, there's nothing inherently wrong with that strategy if you're trying for a broad gram negative approach to impaired treatment. But it isn't a safe regimen either, and there are times when using three drugs let's say you had somebody who you needed to cover anorhubes with, and now you're stuck with cephapine, flagell and a vankel myosin that you're adding a level of complexity that you probably don't need to add.

Speaker 2:

And so, to try and answer this question, the Vanderbilt University did a study called the Acorn Study, and the study was heralded, not necessarily only for its outcomes and the way it was designed, but that it may show people who don't have the money or the staff to pull off large randomized controlled trial data, a path forward, especially in academic medical centers to do this kind of prospective randomized study. And so we'll talk about that in just a second. But the authors know in the beginning of the Acorn Study everything we just basically talked about, that cephapine and pitpaiso have similar activity against gram-negative bacteria. Yes, your mileage may vary in your antibiogram, but on the whole that's usually the case that some observational studies have reported in association with pitpaiso and acute kidney injury, particularly with concurrent recede of vankel myosin. And so they really just wanted to answer once and for all does cephapine which is gonna be kind of the control arm here versus pitpaiso, increase the risk of actual serious adverse kidney outcomes? And while they were there, they also wanted to take a look at the risk of delirium and confusion in patients in the study too. So also they were kind of, I think, looking at the same time at adverse CNS events with Cephipeme. So study itself was done over about a year.

Speaker 2:

Again, this was done primarily at Vanderbilt Medical Center. It was a pragmatic, open-label parallel group randomized comparative safety study of Cephipeme and Peptazone on adult patients with suspected infection in the emergency department or the ICU. It was approved by all the people that needed to approve it, including IRB. They included patients over age 18 in the emergency department or the medical ICU from a clinician initiated order for Cephipeme or Peptazone within 12 hours of the presentation to the hospital. They were excluded if they had an allergy makes sense. If they had already received one or more doses of an anti-sutimonal, cephalosemore or penicillin within the last seven days, they were incarcerated or they had the treating clinician determined that there would be a better treatment option. So basically, they allowed the treating physician to say no, I'm not gonna enroll this patient because I think there's a better choice for this patient. I would, yes, that would be things like all this patient is a history of ESBL.

Speaker 2:

So we better pick a carbopanem or something along those lines. We'll talk about how these patients were enrolled here in just a little while, but basically that was their inclusion exclusion criteria. Then they basically used the electronic medical record to just follow these patients over time and what they did was, when an order came through, the pharmacy would review the order for appropriateness and then, if the patient did not meet any exclusion criteria, the physician or the physician would be contacted and say hey, would you be interested in enrolling in this study or enrolling this patient in this study? And if so, all we ask is that you put the patient on, based on what they decide with the randomization scheme, if you use a PIP-Tazor or if you use a Cephipene in this patient. And the vast majority of physicians who understand about the studies said, yeah, sure, why not? So that's kind of what happened. And again, as long as you have good agreement from your on the ground physicians, that is an incredibly easy way to do that. So for the protocol, the standard admission of Cephipene was two grams Q8 and they gave my intravenous push and then PIP-Tazor was given as a 3.3 to 75 gram bolts over 30 minutes initially, followed by 3.3 75 grams Q8 over four hours, which almost all American hospitals are doing, partially to take advantage of the PKPD of Zosin, but mostly to save money, because you basically eliminate one dose of Zosin a day in those patients, which is kind of nice.

Speaker 2:

Everything else was determined by the clinicians. So treatment duration, adjustment of antibiotics, all that other stuff. So that's nothing else except this kind of selection of antibiotics in these patients and then again they would just go downstream and look at their outcome. So all of this was extracted from the electronic medical record by the investigators. That's pretty impressive. They had their electronic medical record calculate things like the Sulfascore and the Richmond agitation sedation scale and the KAMIC scale for looking for delirium, et cetera, et cetera. So I mean they have a pretty sophisticated electronic medical record that would system that would basically calculate all that stuff for them and they would just kind of mark that down and see what was going on. They also use the electronic medical record to pull demographic data et cetera, et cetera.

Speaker 2:

The primary outcome again was not just a increase in CRAT and the primary outcome was a hard adverse kidney outcome, which is the highest age of AKI or death arising between randomization and day 14. And this was measured on a four level ordinal scale and the stages of AKI were defined by the Cadiago criteria. So basically, the Cadiago criteria for AKI starts at zero, which is fine, nobody has any problems. One is an increase of CRAT and of 1.5, 1.9 times the level of baseline, and then two was 2.2 to 2.9 times baseline, and on and on, and on and on. You got to a level of three, which is AKI greater, a crime, greater than three.

Speaker 2:

Level four was AKI that required dialysis or any sort of new renal replacement therapy, and if someone died, so that they didn't have the competing risk of death, they counted them as a four as well. So as they did look at secondary outcomes, there was the proportion of patients who experienced any major adverse kidney event, and including the composite of death, new renal replacement therapy or persistent kidney dysfunction. But they also took a look at the incidents of delirium and confusion, and again they use this using the RAS scoring or the CAMICU scoring and these patients to determine the incidence of a hospital acquired confusion or delirium.

Speaker 2:

So, and again, I think that was more to try and compare the other way around and take a look at Cepherpene versus Zocin. The statistics were pretty straightforward. They had originally figured that they needed 2050 patients but they ended up looking at their data and deciding that at the interim analysis they wouldn't have enough patients. So then they went to 2,500 patients and that adjusted their statistics a little bit. But I don't think anything really big and indifferent done there.

Speaker 2:

The statistical test all made sense. They did have a number of covariance in their model that they did a logistic regression analysis on. The one, of course, I was most interested in was the in that concomitant receipt of vancomycin. But they looked at a wide variety of things including age, gender, what their baseline credit was, if they had previously been on renal replacement therapy, if they were on mechanical ventilation, et cetera. So again, their model I thought would get quite a good job of trying to account for some of these compounders and taking a look to see if any of them played a role, the trial population they had about 3,800 patients who met criteria.

Speaker 2:

They had 2,600 patients actually enrolled.

Speaker 2:

So again pretty impressive for one year and one large medical center and I get Vanderbilt's, a gigantic hospital, but again 2,300 patients that they enrolled. So that's pretty impressive, I think. So in the end the median age was 58 years old. The majority were white. Those significant number were black or other races. The vast, vast majority of them were enrolled in the emergency department, about 95% of them.

Speaker 2:

As far as suspected source of infection, it's the three big ones you would expect, generally urinary, interabdominal or lung, and that would kind of make sense why you would do that. Three quarters of them did receive at least one dose of vancomycin on the initial day of treatment and about half of them had no kidney injury walking into the study, with a median creatinine of 0.7 in the, except for P Marmin, 0.8 in the Zosanar. So essentially the over half of these patients had zero kidney problems walking into the study. So that's worth noting and it's the patients you would expect to see. So what did they find in this study? What were the outcomes and how does this give us a guidance to how we can maybe do studies like this in the future? We're gonna answer all this once we hear from our sponsor, ce Impact.

Speaker 1:

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Speaker 2:

So we are back talking about the Acorn study, a study that has generated a lot of buzz, especially among inpatient pharmacists, and we, taking a look at the study that it's comparing PIP-PASO versus Cephapine, really with an eye to safety, in particular adverse kidney outcomes, again assuming that that Zocin may be nephrotoxic and Cephapine is almost to control that they're not. So what did they find? Well, for the primary outcome, which again was this highest stage of AKR death, but day 14. On that ordinal scale, it did not significantly difference between the cephapine group and the epiptazo group and in fact the epi-value was 0.56, and the overall numbers were virtually identical to each other. And so 75% in the cephapine group versus 73% in the epiptazo group did not experience any adverse kidney event or die at day 14. And again, the overall numbers were 7.1 versus 7.4%. There was no difference in the individual stages of acute kidney injury. There was no difference in the patients who went on to receive renal replacement therapy or died between the two groups. So basically, in this primary outcome, they did not show a statistically significant decrease or adverse effect, I should say, of bad at kidney outcomes in the epiptazo group compared to the zoosin group. And again, since we think that this is.

Speaker 2:

The thought has always been that this may be related to concomitant ancomycin use. That was one of the confounders they used and they found big surprise again, there was no difference whether or not these people had received ancomycin. How long they'd received ancomycin, it just in this study did not make any difference across the board. So in this study, epiptazo not only in and of itself was not nephrotoxic, but did not seem to potentiate or cause more nephrotoxicity in patients who were receiving concomitant ancomycin. So I think again, that's one of the key pieces that I think is worth noting because that's the thought that has been propagated Again. Even some of my own colleagues have really steered away from using epiptazo vancoe and have kind of switched over to using cephopene vancoe. And you may say to yourself well, so what Price is about the same, the coverage is about the same.

Speaker 2:

It is worth noting that in this same study, when they took a look at the incidence of delirium between enrollment, they actually found that there was a difference in the amount of patients who received either Comer or developed either Comer delirium between enrollment in day 14. It occurred in 20% of patients who received cephopene versus 17% of patients who received epiptazo. That was statistically significant. They also did a post-talk analysis where they looked at days alive and free of delirium Comer within 14 days and again they found that there was a 22% relative increased risk of developing that in the cephopene group compared to the epiptazo group. It just reached a statistical significance, but it was there and that, as you might imagine, patients who have baseline delirium or Comer were ones that were at increased risk and I don't think that's a particular surprise. So while the effect size wasn't gigantic, they did find a statistically significant increase in the development of delirium or Coma in patients by day 14 and the patients in the scuca received cephopene preferentially to epiptazo.

Speaker 2:

There are several exploratory outcomes which, again, are probably beyond the scope of talking about in this pod. I think again suffice it to say that while they were looking at some sort of possible exploratory outcome they could turn around and do another study on. They just really didn't find one. When it came to kidney outcomes, epiptazo and cephopene, whether or not the patient received Ancomycin, were virtually identical to each other. So, again proven.

Speaker 2:

How many times has this happened in medicine, where a whole bunch of retrospective studies show one thing and then we finally get around to doing a decent randomized control trial and find that no, we were just getting on that, and so again, this generated a lot of interest on social media.

Speaker 2:

I still have friends who have felt like they've seen this, that in real time they've seen this happen, and again, I have no doubt that they've seen this. But it is the question that these are patients who are just developing Ancomycin-induced nephropoxicity, which we are well aware causes nephropoxicity. And in the increasing sizes of patients that we've been treating with Ancomycin, we know that obesity is a risk factor for acute kidney injury and almost all hospitals in the United States, the pharmacy departments, have gone to AUC dosing of Ancomycin, which has been shown in a couple of studies, to decrease the risk of nephropoxicity. But the bottom line is, someone who's on Vanco, a lot, is gonna be at risk for nephropoxicity just one of a million reasons why it's a good idea to not use Vanco unless you have to. For many, many years we've used Amuris anasal swabs and if those are negative, almost all of these we stopped the vancomycin of these patients.

Speaker 1:

So you know so that's you know.

Speaker 2:

So when they go into the discussion they feel like there's some strong pieces of the study, but they note that there are some limitations, that this was just a single academic center, even though it was a fairly large one. They did note that a number of patients did receive an assigned antibiotic within the first 14 days of the study and again, given that these patients were sick and in the ICU, that doesn't really surprise me. The other piece that has been discussed, I think, a lot more online, is that, given giving cephapine by IV push may and again this is, I think, kind of theoretical may increase the risk of adverse CNS outcomes. We really don't know, in places that use intermittent piggybacks in these patients instead of IV pushes, if you would see the same adverse effect in these patients. But they note that as well and they note that obviously they can't really speak to that as well either. So their conclusion and I think it's a decent study and the conclusion makes sense is that we can basically stop worrying about PIP-TASO and Banco increasing the risk of A-K or death, but we need to start worrying a little bit more about cephapine resulting in more neurologic dysfunction. Again, I'm not saying the patient should completely stop using or physicians stop using cephapine or zoosin. But I think defaulting to cephapine just because you think it's safer than Zocin this study really kind of disproves that, and I have no issue using cephapine in appropriate patients. But I think basically withholding Zocin with the only reason being that you think it may increase adverse kidney outcomes, is not only not helpful, but then you're kind of leaning on cephapine, which we do know is associated with increased risk of FCNS side effects. So that's kind of the study in itself, but even as interesting to that is, several experts in the field have noted that this is a very interesting way to do randomized perspective studies.

Speaker 2:

The problem with these studies, of course, is that they're very time dependent. You have to have an army of people who will help with consent and get the study going, up and going and monitor the results, data, data safety monitor board and all this other stuff, and it becomes really especially if you're not an academic physician you really just don't have the time to pull it off, and unless you're able to get a lot of money, usually from a drug company, you're not gonna have the money to pull this off, and so it's the reason why, in my world. As a pharmacist, the overwhelming number of studies I've done in my career have been retrospective cohort studies, because I literally cannot afford the time or the people or the money to pull off a prospective study. And the way that electronic medical records have allowed us to do a lot of that work and help streamline a lot of the process is really what's kind of talking about here, and that in this study they did not get a whole bunch of positions together and say, okay, well, we're gonna start the study and let's everyone sit down and go through the slide set and if you think your patient's a candidate, you can call us and we'll get the study coordinator down there and they'll sign a consent and then we'll start collecting data and all that stuff. The power of the electronic medical record basically allows them to a lot of that information right there and then when the pharmacist is assessing the data, which is exactly kind of what happened here. So if you read blog posts and other experts in this field, they feel that the real advantage of the Acorn study was that you eliminated a lot of that stuff to make referrals, enrollment and infection and form consent as easy as possible.

Speaker 2:

In this study, after the doctor ordered either Cephepema or Ptazone. In the medical center, the investigators used the electronic medical record. They screened automatically for exclusion criteria. If those weren't found, then that order automatically triggered a prompt for the doctor to consider a rolling the patient in the trial. And again they found that the vast majority of patients or physicians said yeah, sure, why not? Because again, they never really felt like. They didn't feel like that.

Speaker 2:

From a clinical or efficacy perspective, there may necessarily be a big difference between them, right? So I mean, it radically simplifies and makes a lot less expensive since you don't have to have an army of trial personnel the ability to do these kind of studies. Now again, you're not gonna be able to do every randomized study this way, but I think there are, to my knowledge, and if I just sat here and thought about it and thought about my head, there's gotta be at least a dozen clinical questions that I could think of that we could answer with this kind of pragmatic study, where you've got two treatments that are kind of an equipoise with each other and you're trying to figure out if one treatment's better than another, that the standard of care allows you to pick either treatment, and so then really it's just a matter of contacting your reposition, taking 30 seconds and explaining it and saying would you mind if we included your patient with this drug, which the standard of care says is just as good as that drug? And while you're not gonna get 100% enrollment that way, you're gonna really increase the number of people who do this. And so, again, it makes things a lot simpler.

Speaker 2:

The other piece is the informed consent piece and having done enough of these studies, I can tell you that if there's a time consuming and frustrating part of doing these kind of prospective studies, it's obviously finding the family member, finding the patient, to try and take some time, sit down and really explain what's going on, because that's our duty. We need to really explain what's going on to them and let them know Well how do they handle conformance at this study. They note that that for consent to a study can be waived if the study is deemed minimal risk and the interventions and emergency. So in their IRB interpretation, empiric antibiotics for acutely ill, hospital febrile adults meets the standard of emergency and would be considered standard of care, which means it's minimal risk. And so that was again. I'm not sure every IRB is gonna go for that, but I think you can actually make an argument that we're just comparing two standards of care. This is an emergency, because these people are really sick and we need to give them antibiotics as quickly as possible. So, again, I suspect that in the realm of medical ethics and the realms of IRBs, this study will also be discussed and we'll be interested to see what rules, if any, are kind of allowed them.

Speaker 2:

But again, a very pragmatic way to answer the question about two treatments that are standard of care, to try and piece the other of ones necessarily better than another, and I can certainly think of a lot of studies that we could do this. So, again, you'll probably hear some social media buzz about this, but I'm gonna take this to the bedside right away. I'm gonna start talking to my docs about it. I'm not a huge fan of Zosin Banco in the first place, but if I'm going to use an anti-sutimonal drug with vancomycin, I'm not going to let that decision be placed on whether one would be additively nephrotoxic or not. So that's it for this week's game Changers. Hope you like what you heard. We will see you next week, but until then, remember time flies. I don't know where it's going, but the most important day is today.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one-stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.