Hi, everyone. Thank you for having me here today. So like Corinne said, my name is Julie Farah. I'm currently an assistant professor at the University of Tennessee College of Pharmacy. I'm also a clinical specialist in the trauma ICU and around with the nutrition support service at Regional One Health in Memphis, Tennessee. Today I'm going to be discussing updates in critical care nephrology. I also heard that I have Paul Reynolds to thank for the title of this presentation. And if you know Paul at all, you know he loves a good dad joke. So here we go with urine good hands. I have no disclosures for this presentation. And so while we are going to be discussing nephrology, we're actually going to have a little bit of an ID flavor as well. So our objectives today are going to be to discuss the nephrotoxic potential of zinc and piperacillin-tazobactam in combination. And we're also going to analyze recent study data evaluating the risk of acute kidney injury or AKI conferred by this drug combo. And we're going to start off by contextualizing this question with a patient case. So ES is a 45-year-old male presenting to the surgical ICU with various injuries, including a type 3 open femur fracture, and is initiated on piperacillin-tazobactam or pip-tazo, as I'll refer to it during this presentation, for open fracture prophylaxis. So 18 hours later, the right thigh is erythematous and hot to the touch. And you can see on the CT scan, there's subcutaneous gas that is concerning for necrotizing fasciitis. So the primary team also initiates vancomycin and clindamycin in addition to pip-tazo. I've also included a basic metabolic panel here for you to see. K is on the higher end of the normal range, and serum creatinine is also slightly elevated. So I want to start off again with a little bit of an audience response question. Maybe everybody can raise your hand for the answer that you'd like to select. Would you recommend a change in antimicrobial therapy for this patient due to the risk of AKI associated with the drug combo? So maybe raise your hand if you think yes. All right. Any takers for no? And how about maybe? All right. So it does seem like there's an overwhelming consensus, but a little bit of divergence and answers amongst the group. So hopefully that leads to a good discussion today. So I want to provide a little bit of background on this sort of hot topic for everyone. The majority of data for this drug combination and the risk of AKI is retrospective or observational in nature. So you can see from these graphs, when we look at a lot of the retrospective data dating back to 2016, for all AKI, whether that be KDGO, Rifle, or AKIN criteria, you do see that overwhelmingly, the majority of data indicates that there is an increased risk with vancomycin and pip-tazo. So when you further parse that out into higher stages of AKI, a more severe presentation, again, overwhelmingly, we see that there's a higher incidence of risk with vanc and pip-tazo. Now, the other thing I will say about all of this data is that it varies pretty substantially in terms of duration of antibiotic use. The one study I'll specifically pull out from the stage 2 and 3 AKI is Schreier and colleagues from 2019. They looked at a smaller or shorter duration of time, 24 to 72 hours specifically, and did not see any significant increase in the risk of more severe AKI. So this brings us to the current controversy, which is this idea of pseudotoxicity or pseudonephrotoxicity. Creatinine is secreted through this receptor in the proximal convoluted tubule, the OAT-1 and OAT-3 receptor. And so pip-tazo actually operates as a competitive inhibitor for creatinine with this transporter. And also, vancomycin operates as an actual transporter suppressant. So in combination, you can see a decreased ability of this transporter to move creatinine from the serum out and to be secreted, or excreted, rather. And so what we then result with is an elevation in our serum concentrations of creatinine with an unchanged GFR. So you do see accumulation of creatinine, but kidney function, in theory, remains just fine. So that brings us to the discussion of our first study today, which is the association of vancomycin plus pip-tazo with early changes in creatinine versus cystatin C from Miano and colleagues. This was a large single-center observational study that included patients with severe sepsis or septic shock. Patients in the two groups received either pip-tazo and vancomycin or cefepime and vancomycin for at least 48 hours. And patients were excluded if they had significant renal dysfunction. The primary outcome here was kidney function biomarker concentrations. And again, that's relatively shorter duration of time, anywhere from 48 to 72 hours after drug combo initiation. You can see the secondary outcomes here. What was novel about this study is that they not only looked at serum creatinine as their biomarker of choice, they also expanded that to look at BUN as well as had a cystatin C subgroup within this study to further elucidate whether this was true nephrotoxicity or pseudotoxicity. So you can see the results of the entire cohort here on the right. But what I want to draw your attention to is the cystatin C subgroup. So you can see here for those patients who experienced at least a 50% increase in cystatin C, that was not statistically significant. This study did adjust their outcomes based on inverse probability of weights based on propensity scores. So that's what the adjusted analysis looks like. So again, no statistically significant difference here. And also, when we look at creatinine in this subgroup, while there is a difference in the overall crude numbers, again, when we adjust this, it is not statistically significant. And that also holds true for BUN. When we look at some of their secondary outcomes, the only statistically significant number here would be the incidence of KDGO AKI at 14 days. Again, that seems to hold true for many of the other retrospective studies that have been published. All of their other secondary outcomes, however, were not statistically significant on adjusted analyses. That included, again, the more severe presentations of AKI, AKI requiring kidney replacement therapy, and then mortality at 30 days. So what can we conclude from this study? The combination of vancomyptazo did result in a significant increase in creatinine, but not cystatin C or BUN, which further supports the idea that creatinine is flawed, and therefore, there might be some pseudotoxicity that's associated with this drug combination. We are limited by a smaller cohort of patients that had cystatin C biomarker concentrations, and also the shorter duration. Although I listed this as a limitation, I would argue that clinically, we often don't see a lot of patients that receive these drug combinations for much longer than 48 hours as we start to narrow our antibiotics from empiric coverage down to more definitive coverage with culture results. And then this leads me into the second study that we'll talk about today, which hopefully everyone has seen this trial published, has been discussing it with your clinical teams and your ICUs. But this is the ACORN randomized clinical trial published earlier in 2023. It was a single-center, open-label randomized clinical trial. So this is the first randomized data that we have to date looking at this sort of question. It included adult patients enrolled in either the ED or the medical ICU, and patients were initiated in the two study groups on either piptazo or cefepime. Of notes, over 75% of the patients in both study groups were also initiated on concomitant vancomycin. For their primary outcome, they did look at highest stage of AKI or death in a sort of ordinal scale approach. And for secondary outcomes, they did look at major adverse kidney events and also number of days alive and free of delirium or coma, which is a totally separate discussion that I won't get into today. But the groups were well-matched at baseline. All right, so for their primary outcome, there was no statistically significant difference in their overall ordinal scale. The majority of patients did survive, so they were in this sort of no-stage group. What I will point out is that in the stage 2 AKI, there were numerically higher number of patients with AKI in the piptazo group, but this did not hold true for the other stages that were studied. And again, overall, a non-statistically significant difference. For their secondary and exploratory outcomes, the only significant difference that they really found here was in the incidence of new kidney replacement therapy in their patients looking out to 28 days. Now, the interesting thing here is that there was actually a higher incidence of new KRT in not the piptazo group, but the cefepime group. And so again, I think this further supports the idea of our pseudonephrotoxicity, which also is consistent with this increase in serum creatinine that we saw in the piptazo group. So we did see a higher incidence of final creatinine level greater than two times the baseline, similarly to other studies that we have seen. So this, like I said, is the first randomized data for this question of whether or not piptazo and vancomycin is nephrotoxic. There was no difference in AKI. And this was for a median duration of three days. There were high proportions of patients in both groups that did receive that concurrent vancomycin, and that was, again, for a median of two days. So we still have that shorter duration of period of time. But as I stated before, I just want to reemphasize that clinically, this seems like probably something we would more often see in our actual practice in our ICUs. So this is data that's in opposition to a lot of the retrospective data that we've seen to date. So I have one more audience response question, if you'll bear with me. Do you consider the combination of vancomycin and piptazo to be nephrotoxic? Raise your hand for yes, for no, and for maybe. All right, wonderful. So again, a large group of people we have consensus with, but still some divergence in opinions. And so I'd love to hear some discussion about that a little bit later when we get to the end. So just overall, in summary, data on the nephrotoxic potential of this drug combo has been historically mixed. But we do have some new data to support the fact that this may not necessarily be as clinically significant as we initially thought, especially with the use of novel biomarkers like cystatin C, where we have a little bit more reliable understanding of what it's demonstrating to us in terms of kidney function as opposed to serum creatinine. And short courses of the drug combination were proven safe even when looking at serum creatinine without increased incidence of AKI or death in the ACORN trial. And with that, I'd love to acknowledge my mentors for this presentation, Aaron Broto and Anna Simone Saad. They spent a lot of time with me and imparted a lot of knowledge, so I really appreciate their expertise. And with that, we will, again, hold questions until the end. Thank you so much. Thank you.

critical care nephrology

piperacillin-tazobactam

vancomycin

acute kidney injury

cystatin C