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Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
Communicable E60: Quarterly catch-up, August 2026
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Angela: [00:00:00] Hello, Communicable listeners. I'm Angela Huttner, editor-in-chief of CMI Communications and clinical trial enthusiast. I've got a couple fellow enthusiasts with me Josh Davis and Steve Tong to tell you about a post-graduate education course we've planned for this November in Malta.
Josh: This is a two and a half days, so Thursday, Friday and half day Saturday, The content is aimed at anyone who wants to do clinical trials. And it really answers the question: How do I do a clinical trial? How do you generate an idea?
how do you take that idea and turn it into a protocol? How do you then operationalize that into a trial? And then right at the other end, how do you turn that into a paper and get it published? so in the mornings we'll have, talks, and in the afternoons it will be workshops where you can bring along your own trial ideas, and the faculty can help you develop them.
Angela: Steve, who are some of the faculty who will be teaching at this course?
Steve: There's great faculty, yourselves, Angela, and Josh.
as well, [00:01:00] David Paterson of Merino Tom Holland of DOTS and Eradicate. Henry Van Jerkoven to talk about the basics of frequentist analysis, and Sarah Walker on the basics of Bayesian analysis.
And those topics are becoming increasingly important as we conduct more and more trials with a Bayesian focus. Josh, what are some of your highlights?
Josh: for me there's a, talk on AI in clinical trials and what role it might play in helping to design trials, but also trials of assessing the role of AI. And I'm also really looking forward to just hearing, people's proposals for new trials Cause we all have different ways of thinking about things and different ways we would approach things.
The course, is a CLARITY initiative, but it's got some great support from various organizations. it's being organized by CMI Communications and ESCMID.
And the sponsors are Advance ID, based in s- in Singapore and Southeast Asia, the US-based Antibacterial Resistance Leadership Group, ARLG, the Australasian Society for Infectious [00:02:00] Diseases, that's ASID, ECRAID, the European Clinical Research Alliance on Infectious Diseases, and, SIDP, the Society of ID Pharmacists from the US.
Josh: So come and be with us in Malta. Apparently it has direct flights from roughly 100 cities across 36 countries, so it's not hard to get to.
. you can sign up for the course at ESCMID's website for postgraduate education courses. -
Steve: We hope to see you all there, so snap to it and get registered.
thanks for listening.
Don't turn off your radio.
Angela: say. Your actual show is starting now.
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 MacDonald, general internist and infectious disease trialist, coming to you from Montreal, McGill University in Canada, and I am an associate editor at CMI Communications.
Today's episode is the second in a [00:03:00] recurring series that we call Quarterly Catch-Up. As a reminder, here's what you can expect for Quarterly Catch-Up episodes. Every three to four months, we'll have CMI Comms editors pick one to two articles that have been published in the last three months. We will give you our take on the studies and catch you up because we know everyone has very busy schedules, and it's hard to keep track of all the science being published.
We'll aim to keep these episodes short, so you can hop on the treadmill or get ready for your commute. We've got you covered with a rapid-fire update on the latest research. Unlike some of our other summary episodes, such as the annual Top 10 or our post-ESCMID episodes, we may not always focus on clinical trials, so you'll get a variety.
Emily: Depending on which editors are hosting, we'll pick topics that we find personally interesting, so you can look forward to a bit of different science that we'll be presenting on the Quarterly Catch-Up. Today, my co-host is the never dreary Erin McCreery, fellow editor at CMI Comms.
Erin: Oh, , Emily, it's a joy to be here with you, and even more so because I [00:04:00] went back and re-listened to first quarterly catch-up episode, which I'd encourage our listeners to do so. to prepare for this, I not only got to read new articles, but also hear your beautiful voice. So what a joy.
Thanks, Erin. we won't have an icebreaker today because most listeners already know both of us, and we wanna, be speedy on this episode for busy folks, so we'll actually really get right into it.
Erin: I realize we're not doing an icebreaker, but I should probably say I am in Pittsburgh, Pennsylvania.
I am an infectious diseases pharmacist, working for the University of Pittsburgh Medical Center for those of you who might, be your first Communicable episode. Okay, Emily, so I'm really excited to go through our four articles that we chose, but before that, I thought we should just honor some pretty massive things that happened in science in the last quarter, but that we've talked about quite a bit already.
So the, the first thing I want to mention is that the SNAP trial, the largest adaptive platform trial in the world, studying patients with staph aureus bacteremia, the first two major released results from that trial and subsequent publications have officially been published as [00:05:00] of June 17th, 2026. And so cefazolin for methicillin-susceptible staph aureus bacteremia was published in The New England Journal of Medicine, and then benzylpenicillin versus flucloxacillin or cloxacillin for the treatment of penicillin-susceptible staph aureus bacteremia was published in The Lancet on the same day.
And this is cool. Listeners should know that the final peer-reviewed publications are available, but I wanted to just comment that this took over a year from when the trial was stopped, and then the initial preliminary results were announced at ESCMID Global 2025. We actually did a podcast episode back then called Snap Out of It: Rethinking Antistaphylococcal Penicillins.
Erin: That was published on Communicable and another sister podcast called Breakpoints. And for, like, a year, that's been the only thing we could cite was our pod conversation because- Yeah ... these publications took a long time. So Em, I mean, obviously amazing that the final publications are out, but what do you think about the fact that it took [00:06:00] oh, so long?
you know, behind the scenes, so we recruited, quite a lot to SNAP in Canada. I was privy to the extensive efforts it takes to coordinate, clean, and share data around the world. so even just within Canada, collecting and cleaning the data, answering all of the different queries, making sure that there was no missing follow-up data, and then transferring our data, you know, to combine it with, not just Australia, but several other countries, is really something, that I hope...
Emily: Well, it depends if you would like to experience that or not. You, may if you'd like to join a global trial
Erin: it's your cup of tea or not, you know? Yeah.
Emily: We really like that. but wow, like what an effort and, thanks so much to our team in Canada. Shout out to Lena Petrella, our national coordinator.
So I saw, you know, what that took in our country, and then imagine that being duplicated in several countries over with different rules, people going on holidays at different [00:07:00] times. and the statistics as well, quite complex, and getting more complex for a Bayesian adaptive trial.
Some of the analyses when you run them can take several hours. Some of them can take days on the computer system because there's so much data and it is a complicated analysis. So you know, all of that together, I have to say it's not a big surprise that-- I think that it took that time. but very exciting also to have coordinated with two major journals, right?
To have them come out on the same day. Like, don't underestimate that element of coordination. To have a trial come out in the New England and in The Lancet at the same time, all of that big, big efforts behind the scenes. huge global team effort, so congratulations.
For sure. And that is a great point.
Erin: We wanna thank the journals for that. That is always really cool when we can coordinate like that. I would rather, I think, coordinate data across the global footprint than get on the treadmill, for what it's worth. So- Sounds-
Emily: Fair.
Erin: You s- for people listening on the treadmill, I admire you. I am not a runner.
Yes. I am many things.
Emily: Good job treadmillers.
Erin: Yes, we're proud of you. [00:08:00] I am many things. I am not a runner. but okay, okay, moving on. Other important things are new drugs and what a quarter it has been in the antibiotic development space.
I mean, I was preparing for this and I was Wow, there's four drugs at a minimum and several that are very close in the pipeline." So in the last quarter, first tebipenem, the first oral carbapenem-- second oral carbapenem, my bad. We have sulbactam approved. But tebipenem was FDA approved on June 17th, 2026.
The EMA has not yet granted marketing authorization or listed this on its list of centrally authorized medicines, but in the United States this is, I think, going to be quite a game changer for, you know, avoiding pipelines in patients with ESBL bacteremia in particular. Cefepime-sulbactam received approval in India on May 27th, 2026, and in the FDA on June 1st, 2026, and is under EMA review with an accelerated assessment.
This is a very interesting [00:09:00] beta-lactamase inhibitor that has kind of a dual mechanism, and we're gonna talk about a similar compound in one of our trials today. But this I think will be very, very important in our Metallo beta-lactamase and complex non-fermenter treatment space IV fosfomycin finally made its way to the United States, so all my European colleagues listening are laughing 'cause you've been using IV fosfomycin for years and years and years, but it finally got FDA approval.
And then incitrovir, so a antiviral for COVID-19, has been used in Japan for quite some time, received FDA approval on May 29th. Nothing yet from the EMA, but the FDA approval is for post-exposure prophylaxis for COVID-19, which I think is really important and fills this void that monoclonal antibody therapy had, and then when monoclonal antibody therapy went away, we felt this deeply, particularly in, high concentrated patient volume areas like prisons, you know, shared housing, nursing homes or skilled facilities, long-term care facilities.
I think there is meaning to post-exposure prophylaxis in these patient populations during [00:10:00] viral outbreaks, so we'll be interested to see if that gets positioned now that it's available.
Emily: Yeah, that'll be all about the timing, of course. You gotta get those drugs in, super quickly for them to be most effective.
and citrovire, am I saying it right?
Erin: I think so. Okay. I think that's how it's said. If not, just say it quickly and confidently.
Emily: Sounds great. Yes. It could be also, like, a very nice, addition to, like, a citrusy summer spritz type of cocktail.
Erin: Yes. It does sound like that. With your side of zidebactam.
Emily: Okay. yeah, let's dive into our studies. I'll go first. so these are the two studies that I picked. The first one, for listeners who have heard me on here before, I have an interest in pneumocystis pneumonia. We're running, a platform trial in pneumocystis out of Canada and actually have gotten, quite a bit of global interest in sites joining the pneumocystis platform.
So I thought I would talk about this study by the French RECIF Study Group. I hope I pronounced that right. pneumocystis [00:11:00] jirovecii pneumonia in solid organ transplant recipients. So this was a prospective observational cohort study by Alanio et al. The background for this, PCP, obviously very important, very serious fungal infection, does affect our solid organ transplant recipients.
and it not only affects how we manage the organ, if I can put it that way, in terms of, you know, perhaps having to reduce your immune suppression, but it also increases mortality for our recipients. So very important to try and prevent PCP, which is why we put patients on prophylaxis after a solid organ transplant.
Our mainstay of prophylaxis is trimethoprim-sulfamethoxazole or Septra or TMP-SMX. I'll use those synonymously. However, we lack evidence for how long to prescribe prophylaxis for in solid organ transplant patients. So we often give it for six or maybe 12 months. not usually longer, although sometimes patients will get secondary prophylaxis.
[00:12:00] And at times when it looks like they might be heavily immune suppressed, like they're undergoing, treatment for an episode of rejection, or they've got very bad lymphopenia, you might consider giving them, prophylaxis for PCP. It works extremely well, so we do have some, cohort studies that have shown that when you're on Septra for PCP prophylaxis, it works incredibly well.
but it does have some toxicity. People can have allergy. It's another pill for people to take, you know, on a daily or thrice weekly basis. So you do have people who may not take it for one reason or another. and we do see breakthroughs, and we see people, develop infection, when they're not on prophylaxis.
So in this sectional study that was nested within a nationwide laboratory surveillance network for invasive fungal infections, we saw adults with solid organ transplant, with PCP included, over a 10-year period. So they had five hundred and seventeen cases of PCP, which is a very large PCP cohort because although it is common, it is [00:13:00] rare.
Emily: so common in our transplant patients, but overall rare. this was from twenty-five centers, and about seventy percent of the cases were in kidney transplants. So I guess that's one of the first take-home points. we do do a lot of kidneys. Kidney is one of the most commonly transplanted organs, and so you are gonna see more cases because there are more kidney transplants.
and then the cases were most common in liver, heart, and lung at about ten percent each. So the predominant, cases are in kidney. The ages of people with PCP, nice to see this because I've been sort of arguing this of late. It's older adults. So it's people between the ages of fifty-five and seventy-five years old when we're looking at transplant cases.
Emily: And, you know, these are patients who are more at risk of dying from the disease, so age is a modifier that increases your mortality from PCP, increases toxicity from the treatment. So, you know, if you can prevent the PCP, that's probably ideal. one other thing they found from the cohort is that the number of cases have remained steady over time, not increasing, not decreasing.
It [00:14:00] does seem to affect men more than women, so sixty-five percent of the cases were men but many cases among women. And if we look at all of the old data for treatment of PCP, all of the old data is exclusively in men because it was predominantly, treated in trials in men in the '80s, and most of the patients in the original trials have HIV.
So we don't have a lot of data in transplant patients, in older adults, in women. cases occurred a median of two years after the transplant. So I think this is really key because we're giving prophylaxis for six to 12 months. Now, part of that is, of course, during that six to 12 months when you're on prophylaxis, you're not gonna see as many cases of PCP.
And so yes, the cases you observe are going to be later, but I think it was quite interesting just how late they occurred. So if you looked at kidneys, actually the median time for them to develop PCP was four years. That's the median time. So that means people are developing PCP quite late after their kidney transplant.
another couple of interesting things that I'll mention is [00:15:00] that, you know, we use, PCR now for diagnosis, and the CQ values, differed. So it differed on the timing of your PCP, it differed on the organ. for example, CQ values were higher in PCP cases that occurred later, or put another way, PCP that occurred in the first two years had a higher fungal load.
Fungal loads were higher in kidney compared to liver. So, you know, I think we have a lot to learn about PCP, and PCR. Mortality didn't differ, between cases that occurred near your transplant or further away from your transplant. So whether you got PCP two years after or six years after, you had the same risk of dying, which was quite high, about 20%.
That said, they found that if you went to the ICU, double. So mortality shoots up to 40% if your PCP requires ICU care So, my question for us to discuss, Erin, is are we giving way too short a duration of PCP prophylaxis?
Erin: Well, I laughed when I [00:16:00] read this because if you come to Pittsburgh and you get a solid organ transplant, you will get Bactrim or Septra or TMP-SMX for the rest of your existence.
So we actually are a universal prophylaxis for life center, and I will admit, I have always argued that that is not maybe ideal. So I have tried with many, many, many, a transplant pharmacy resident that has done a transplant ID rotation with me to work with our transplant teams, work with our infectious diseases providers, all of whom are amazing, and try to pull this back a little.
And actually, right before the pandemic, I think we almost convinced everyone to agree to do a year in lower-risk patients, which I honestly consider kidneys to be lower risk. I mean, you can get a kidney transplant and be out of the hospital the next day practically, right? These patients tend to do quite well.
They're not as immunosuppressed or as environmentally at risk as a lung, right? and we tried to pull this back to a year in some patients, lifetime for lungs and [00:17:00] hearts, abdominal cases we tried. And we have kind of gone back to , life for everyone, and perhaps there's utility to that, right?
Perhaps there's value if we're seeing such late cases and the mortality is as high as it is. i- ... So I don't know the right answer, and there is no data-driven answer but I will say at least some centers, cough mine, have been doing prophylaxis for life for this reason, for the fact that we saw some late cases and if you get PCP, you do poorly.
But my question back to you, Emily, the pharmacist in me has to ask is, do you think the mortality is the disease or the treatment? Because giving high-dose trimethoprim-sulfamethoxazole is extremely challenging for patients to tolerate and it can cause, you know, neutropenia, which is very bad when you're trying to fight a fungal infection.
Your cell lines are actually quite so important and Bactrim will effectively hurt those a lot. And it can cause a lot of other toxicities If you're giving it IV, you're giving an unbelievable amount of fluid. And I, I actually think sometimes the drug might, might make patients worse. And [00:18:00] as you said, the data are all from the '80s treating PCP pneumonia in men with AIDS, and we're giving these just insanely high doses- Astronomical
Emily: high doses
Erin: 20 mgs per kg per day. I'm so happy you're doing a trial because what we really need to know is what's the right dose, and it's probably a lot less. And if you give less, would you do better? I don't know
Okay. Well, I did not ask Erin ahead of time to bring up this question- She didn't
Emily: but I'm really glad that you did. Honestly, I did not. But I love it because, it's such an interesting point that a, big component of the toxicity could be in the treatment. And so maybe we're giving too much, and so yeah, it'll be really interesting to see the results of the low TMP trial.
We've started recruitment already. I think we have, a few patients, like maybe just under 10 that we've recruited to date, so very cool We'll have to see how that turns out to see if we actually hypothesized that giving less, so 10 milligrams per kilogram would be superior. So a pretty, pretty bold hypothesis but [00:19:00] really along your, line of thought that, you know, that 15 to 20 milligrams per kilogram can be really, really toxic and you end up having to stop the treatment even though I think it is the best treatment.
but people get switched off of it due to toxicity. The other, question that I have is, if we're gonna give prophylaxis could we give a low-dose prophylaxis? So could we be giving like a single strength three times a week? maybe we don't also know the lowest effective prophylaxis dose that we could be giving.
that's something to think about. That could be a trial as well. And finally, you know, what are the downsides? Resistance to Septra is not super well-described in PCP. It does happen but of course you always have to think if you're gonna put everybody on prophylaxis at large scale maybe you're gonna increase that possibility.
Emily: yeah ...
Erin: the, the prophylaxis dose we could probably do an entire podcast on 'cause I see anything and everything under the sun and renal dose adjusting prophylaxis has never made sense to me ever in my life. and then I do wonder from a patient perspective is it easier to take the same thing every single day?
So a single strength daily is that a more patient-centric regimen [00:20:00] or a double strength three times a week, is that better? I, I don't know the answer. I'd be curious what patients think and I'd like to involve them in the discussions and yes, that's a whole nother thing which I mean you'd have to have funding to follow patients for like 20 years, right to see if there's- Yep
a difference in prophylaxis regimens but that would be so interesting. But anyway Emily we could talk about this all day. Do you wanna go onto your next trial?
Emily: I will go onto my second one. So the second study I picked was procalcitonin to guide seven versus 14 days of antibiotics in bloodstream infections a secondary analance- analysis of the Balance trial by Ramendra et al.
So the idea behind this reanalysis of the Balance trial which, to remind people was seven versus 14 days of antibiotics for bacteremia. Most of those bacteremias were gram-negative. A lot of it was urinary. but you know many thousands of patients were randomized in this trial and it included all types of bacteremia other than for example staph aureus which was excluded.
and found that seven days was non-inferior to 14 and, perhaps even suggested that seven days might be superior, might be [00:21:00] better in some secondary analyses. And so this was looking at patients, who in some centers in Canada on day seven had a procalcitonin collected. it was not shown to the investigators but it was stored and then processed later and the, investigators looked to see if it was prognostic, at day seven to have a higher procalcitonin if you did worse and, linked to that if you had a higher procalcitonin at day seven and you were randomized to seven versus 14 days, you know did the Finding that seven, days was non-inferior to 14 days hold up in that group of what would be considered perhaps higher risk patients.
So this really was a much smaller number of patients who had this, procalcitonin collected, 125 patients. Median age was 63. about, 65 of 125 participants, so about half the participants, had a low procalcitonin level at day seven. So investigators defined that as less than 250, or depending on your [00:22:00] unit, less than .25.
And then the other half of patients, had a high procalcitonin, so balanced, between the two groups. 90-day mortality was higher in the high procalcitonin group. So 90-day mortality if your procalcitonin was high on day seven was about, 21.6%, and if your procalcitonin was low on day seven, less than .25 or less than 250, mortality was 6.2%.
So quite a striking difference in, mortality. If your procalcitonin was high on day seven, you really were much more likely to die by day 90. Now, among patients who had the high procalcitonin level, 90-day mortality was 10% for participants with seven days of antibiotics, so, lower, and 30% for those that got 14 days of antibiotics, so higher.
actually that corresponds to a rather large absolute risk reduction in favor of seven days. so about a 20%, [00:23:00] risk reduction, in mortality if you were randomized to the seven days and you had a high procalcitonin level. albeit it's quite a large confidence interval because it's a small number of patients.
What I thought would be interesting to discuss here is this notion, that procalcitonin circulating, if you will, in the blood at day seven seems to be bad. but it's possible that giving more antibiotics doesn't help this problem. And this aligns with many systematic reviews and meta-analysis now that show that a low procal- procalcitonin helps reassure us as clinicians about stopping antibiotics.
Emily: but it's maybe not the best marker to use to argue to continue antibiotics. we do know that procalcitonin is induced by a host inflammatory pattern, recognition receptor ligation via bacterial antigen. , And so yeah, th- this might just be a host marker that you're going to do poorly that isn't going to get better with [00:24:00] antibiotics.
yeah, let's discuss
Erin: I did not know Emily was picking this study, but this is a topic that is also so near and dear to my heart, so I'm so thrilled that we get to talk about this. A couple things here to unpack. One, I acknowledge my bias that I am anti-calcitonin, and I actually just published an editorial in CID with colleagues at the Mayo Clinic called Anti-Calcitonin in commentary to a recent publication.
That is a wonderful study. Again, these investigators did an amazing job. I am not anti-people who do good science or try to do antimicrobial stewardship. I love you all. I know we're all trying to do the best we can for our patients and find ways to use the just right Goldilocks amount of antibiotics. I just don't think procalcitonin helps with that, and I arguably think it hurts because I think as we see here, if they're high patients do not want more antibiotics.
If the procal is high, providers give more antibiotics and that is not-- the positive predictive value is terrible and it was never meant to guide, "Okay, I need to keep giving antibiotics if the procal's high," and I think patients do worse [00:25:00] as we kind of saw here, right? Like having a high procal potentially means something's going on with you that your risk of mortality is higher, but giving more antibiotics doesn't help.
And yes, a negative procal makes people feel good about stopping antibiotics, but that's also not universally true. We see consistently in the literature that it's essentially a coin flip, that about half of negative procals get antibiotics and about half of positive procals do not get antibiotics.
Erin: And providers' clinical gestalt continues to trump any kind of algorithm we try to come up with, and these just continually fail. the Mayo Clinic team published a really beautiful, case across their entire infrastructure of systems showing that patients that got procal-guided therapy actually had longer length of stays and more antibiotics because I think we're treating the positives and we're not always acting on the negatives.
And then I will say at UPMC, at my health system in the United States, we actually removed procalcitonin in September of twenty twenty-five and I'm in the midst of pulling those data and trying to publish this showing [00:26:00] that, you know, the removal did not impact our antibiotic use and looking forward to that.
Erin: But we only have procalcitonin available for the treatment of a febrile infant. It is an, you know, American Academy of Pediatrics very data-validated pathway to use procal, and I think in that kind of setting, that's appropriate. So we only have it at our hospitals that admit babies less than or equal to 60 days, and otherwise we don't allow it.
You cannot order it in my health system anymore. So those are my thoughts on procalcitonin.
Emily: Procalcitonin, the D-dimer of the infectious disease world- ... should only be used to rule out . yeah, I often, am confronted by someone showing me a D-dimer that they did and said, "Now we have to do a pulmonary embolism scan."
And I say, "But I didn't think that that person had a pulmonary embolism." And they say, "But yes, the D-dimer is positive." I say, "But that's not what the D-dimer is for. The D-dimer is when you don't think they have a pulmonary embolism, and then it's negative, and you're like, 'I'm right. They don't have a pulmonary embolism.'"
So yeah, very, very tricky. A fickle test. there's a great, commentary that [00:27:00] accompanies this article by Brad Spellberg that talks about the negative procalcitonin being a nice anxiolytic, for providers, so that if we have a low pretest probability that the patient needs antibiotics and it comes back negative, that is, lovely and reassuring to us, and we feel a little bit more confident about stopping antibiotics.
but as he so nicely puts it, we give so many antibiotics that the pretest probability that we're giving too many antibiotics is quite high. And so a negative procalcitonin can, be helpful in that respect. But as we shorten and shorten durations, the pretest probability that we're giving too much antibiotic becomes smaller.
And so this test is gonna change even further and possibly become less useful, as we just truncate treatment times. You know, as we move from 14 to seven days, that's a, big jump down. now, at Balance, we're gonna be looking at randomizing patients to stopping at four days. and so, the pretest probability that you're giving too much, at day five, six is much lower, [00:28:00] making that test even a little bit murkier in that situation.
So we'll really have to see how things evolve.
Erin: For sure. I think that's part of the problem too is we don't just send one procalcitonin to patients, we send several, and then it's how many tests are you sending to do what you were going to do anyway, All right. The first study I want to talk about is a PK/PD study.
No surprise as a pharmacist . But I love this one. It's called Challenging Weight-Tiered Antibiotic Prophylaxis in Obese Patients Undergoing Colorectal Surgery Using CT-Derived Body Composition. This was published in CID on June 20th by Amit Pai and colleagues from the University of Michigan. And I love this study 'cause it has a lot of things, right?
Surgical prophylaxis to me remains like this mythical voodoo that I don't think any of us completely understand . So, you know, surgical prophylaxis and SSIs I think are such a complicated space and then this concept of do we increase doses in obesity with beta-lactams in particular, and then this novel aspect of using, you know, imaging and technology to mirror in with our antibiotic choices, so I [00:29:00] love it So the background of this study is we know obesity is an independent risk factor for SSI due to, several things: impaired tissue perfusion, prolonged operative duration, and then reduced antibiotic penetration in general for most antibiotics, beta-lactams for sure, as they're mostly water-loving antibiotics into adipose tissue.
So we have, at least at my center, I think very commonly around the world, you get two grams of cefazolin if you're a baseline patient, and then if you're greater than or equal to 120 kilos, some centers will give three grams based on mostly feels. So that is also making assumptions that your body weight alone is completely representative of your physiological determinants of antibiotic distribution into fat tissue, and that this kind of uniform interval for redosing, which we use four hours and they used four hours of redosing in this study, that that is appropriate for every single patient, and that weight is the only variable that would impact that.
And that [00:30:00] is probably wrong. We know from living in the world that patients with the very same weight can have very different distributions of adipose tissue. And if you don't understand this concept in humans, I actually liken this to dogs. So I have a 70-pound golden retriever, and she is huge. Like, she is this big, fluffy dog.
And then my friend has a 70-pound lab that is short and stocky, and they weigh the exact same, and they are-- the lab is probably half the actual, like, area size of my golden retriever, right? So this makes sense. Like, muscle weighs more than fat. We get it. You can have the exact same weight and be a totally different composition.
Okay, so I think this is really interesting that they explored this. Other stuff they used as background, which just was good learning for me as I read through that, is that, there are actual data in the surgical literature, and I think in ID we forget this, but reading surgical journals is very helpful, right?
publishing our stuff in surgical journals is also very important. I mean, this is published in an ID journal, but, but there's surgical data saying that local adipose tissue at the actual surgical site is [00:31:00] much more informative of SSI or not than your total global measure of your body size.
Erin: And any increased subcutaneous fat at your actual incision site, that's what's actually independently associated with SSI and a stronger predictor of a postoperative infection than just simply your BMI. So your body composition is better capturing all these biological factors that subsequently influence your wound healing and your infection risk.
Okay, the other thing I learned when reading this is that there have been a lot of advances in medical imaging that can actually characterize your body composition in just a routine scan. So at first I was like, "Oh, they use these fancy CT scanners that no one will ever pay for in any healthcare system in the world."
That's actually not true. They only included patients that had just a standard pre-op CT, and then they were able to use those data alone to do what they call analytic morphomics, which is again, a pre-procedure routine care scan, but then they can use this medical imaging and then apply these specific [00:32:00] biomarkers of body composition to provide more precise data.
So that was neat. To be in this study, you had to be 18 years of age or older, have this preoperative abdominal CT that was per routine care within 90 days of surgery, a BMI greater than or equal to 25, and an estimated creatinine clearance greater than or equal to 55. They did this study in two sequential phases.
In the first one, they enrolled patients to develop the PKPD model, and in the second one, they prospectively enrolled patients to essentially apply the morphomic-derived predictors and the model The surgeons agreed to participate in the study, so that's cool too. Yay, collaboration. The surgeons provided plasma, subcutaneous adipose tissue, and colorectal tissue samples during the procedure.
They did measure total rather than unbound concentrations for this. Cefazolin is heavily protein-bound, so just kind of a mental note, although again, in routine care, if you're lucky enough to have, the ability to do drug concentrations, it's almost always total. They redosed cefazolin every four [00:33:00] hours if the procedure was extended, like I already said.
And then the target-- So whenever you're trying to do a study that says, "Do I give enough drug to achieve a goal?" You have to have a goal. And I'll be honest, we don't really know what that goal is, so we pick something that seems good. And they picked two milligrams per mil at the site based on the staph aureus and E.
coli systemic breakpoint, which is as reasonable as you're gonna get. And then they set two thresholds, beta-lactams, of course, being time over MIC agents. They set an eighty percent time above two as kind of a pragmatic prophylaxis benchmark, and then a hundred percent time over two as their more stringent benchmark.
And then for clinical interpretation of the data, they said they would consider going from two grams to three grams when the probability of target attainment was below ninety percent and if by simulating giving a three-gram dose, it would improve that by at least ten percentage points, which again, that all seems very reasonable.
So they screened one thousand and fifteen patients [00:34:00] to enroll a hundred and fifty-three patients, fifty-eight in phase one, ninety-five in phase two.
And what they found is using our current standard of two gram if you're less than a hundred and twenty kilos and three grams if you're greater than a hundred and twenty kilos, the probability of target attainment was eighty-four percent for that eighty percent threshold and seventy-eight percent for the hundred percent threshold.
They found that almost half of the patients that had a weight of ninety to a hundred and nineteen kilos, so patients that we would give two grams, that they were likely to have a subcutaneous fat area greater than or equal to three hundred centimeters squared. And that three hundred centimeters squared was significantly associated with needing higher doses.
Erin: And so they said relying on weight alone is really not optimal And their recommendation from this is that you should give three grams of cefazolin to patients that have a subcutaneous fat area greater than or equal to 500 centimeters squared independent of their renal function, or if they [00:35:00] have a greater than or equal to 300 centimeter square area and they have a creatinine clearance greater than or equal to 90.
So that enhanced clearance of drug also played a role here. If you apply those criteria, there would be an additional 22 patients that would need a 3-gram dose, and there was only 153 patients in the study, so it's not an insignificant number of the population. And then they had a direct quote in their discussion that I'm going to read exactly 'cause I love how they wrote this.
They said, "Existing dosing strategies remain anchored to body weight despite consistent evidence that both tissue penetration and clearance are poorly captured by patient's weight alone and this creates a structural mismatch between guideline simplicity and the underlying pharmacology." So I love that.
I have, like, actual chill. Like, because that's life, right? Like, clinical data is so important in the science that we do and this pure patient data is so important, but actually operationalizing it out in the wild for the millions of colorectal procedures that get done around the globe is really [00:36:00] challenging.
And on that note, the authors did say, and I'm-- honestly, I imagine a peer reviewer made them put this line in there. They said, "- This study should not be interpreted as a recommendation to obtain a new CT image solely for the purpose of cefazolin dosing." I'm like some pharmacist peer reviewer made them put that in there or some, like, operations person or some health system executive, right?
Because that's gonna be the key, right? Is we can't be just doing CTs 'cause we wanna improve our beta-lactam dosing. But this whole marriage of it is actually really cool. So yeah. Em, what do you think?
I think it's really interesting and I really do appreciate the high-value care nature of the study, which is using existing investigations, to get more, and better care out of them.
Emily: we have a cardiologist, Jonathan Afolalo, who uses CT scans that have been done routinely for TAVI, so aortic valve, replacement. and he's able to use the CT [00:37:00] to determine people's frailty, by a similar mechanism. So I think, you know, taking existing information that we have and then using it to individualize care is very nice.
Yeah. It's excellent. And, it really does show that quite a few patients in that study, more than 20 out of a sample of, you know, just over 100, were being underdosed. so that's significant findings that would change practice, especially as you said, on a global basis if we look at the number of procedures, that are being done annually.
Erin: Couple things to point out. This is in the United States, so BMI and body composition, take it for what you will and how that compares to populations of other countries. Amit Pai is the first author of this study. He's absolutely brilliant. He's done a lot of work in the obesity space.
And then the last thing I'll leave our stewards with is the University of Michigan is apparently giving cefazolin for colorectal surgery, which is mind-blowing to me because we use ceftriaxone, metronidazole, and that was like a compromise over them wanting to use ertapenem. [00:38:00] And I think there's, you know, the constant carbapenem data in the colorectal surgery space.
So again, what is surgical prophylaxis? Do any of us know what we're doing? So kudos to the University of Michigan. Okay. And to wrap us up today, I'll end with my last study, which actually is a randomized trial. We said, you know, these quarterly catch-ups don't always have to be trials. But this one was published on May 16th, by Takahashi and colleagues, The Efficacy and Safety of Cefepime-nacubactam and Aztreonam-nacubactam Compared With Imipenem for Complicated Urinary Tract Infection.
This was published in The Lancet. So I love this 'cause I am very interested in the gram-negative resistance space, and we talked at the beginning of the episode about cefepime-zidebactam. Well, nacubactam is a very similar beta-lactamase inhibitor where it is a novel DBO and inhibits class A, C mostly, some class D but really not the OXAs we think of like the, the scary ones in Acinetobacter.
But the cool thing with nacubactam and, zidebactam is they both have intrinsic antibacterial activity through PBP2 inhibition. So they have this dual mechanism [00:39:00] of they block beta-lactamases and they also intrinsically act against the organism And the reason this was brought forward with aztreonam and cefepime was some in vitro early modeling and some early studies showing that that significantly reduced MICs for these complex gram-negative pathogens.
Erin: It was actually also explored with meropenem, but meropenem didn't have that, you know, potent synergy effect that you see with cefepime and aztreonam, particularly for Metallo beta-lactamases. And so they kind of abandoned the meropenem, nacumbam and moved forward with cefepime and aztreonam. So this was the INTEGRAL 1 study.
It was a global phase III randomized double-blind clinical trial of adults enrolling at 79 sites, mostly in Eastern Europe, some China, some Japan, and they had to have complicated UTI or pyelo So Maji Sika Pharma designed this trial, and they did have complete control over the data analysis and publication.
So this is very much an industry-funded study for their drug. Patients were randomized two to one to one to [00:40:00] receive cefepime/nacubactam, aztreonam/nacubactam, or imipenem/cilastatin every eight hours for five to 14 days. So you had to require at least five days of therapy. They stratified randomization by diagnosis and geography, and they administered every dose of antibiotic over one hour.
It was a double-blinded, and imipenem isn't stable over, you know, extended or prolonged infusions, and so that's why the one-hour infusion. And then these antibiotics are all renal dose adjusted. This trial took place from May 2023 to November 2024. Patients had to weigh 140 kilos or less. They had to get at least five days of therapy, like I already said.
And then they had to stay in the hospital for the entire study duration, because they did not allow oral step-down therapy. So the entire course was completed with study drug. They also did not allow patients to receive any antibacterials prior to enrollment, which I kinda love. You know, it really takes away that empiric, oh, the first 48 hours are the most important.
The only exception to this was just for feasibility. They allowed [00:41:00] 15% of patients to get a single dose of a short-acting antibacterial that was in vitro active or not prior to enrollment. So if you got a dose of ceftriaxone, you were out. But if you got like one dose of pip-tazo, 15% of patients or less were allowed to still be enrolled.
They excluded patients that had Acinetobacter, that had complete obstruction of the urinary tract, that had a creatinine clearance less than 30 or greater than 240, and then we talked about this, you know, pre-antibiotic before enrollment. So trials like this, I totally understand it, and it makes it very pure for the actual antibiotics being studied.
But it essentially says Canada, the US, and Western Europe are out because you're not gonna keep patients in the hospital just to stay on IV therapy. So as with many, many, many trials, you'll see no patients from the United States and none from Canada in this setting, in this trial. They did randomize 614 patients, and 431 were included in the primary efficacy analysis.
patients were allowed to be enrolled before the urine culture was back. And so if patients ended up with a negative urine [00:42:00] culture, it was enroller's discretion whether or not to continue, and those patients were included in the safety analysis but not in the microbiological intention-to-treat analysis.
Patients were about 65 years old. Just over half were male, 85% white, and a mean BMI of 27.6. 34% had pyelonephritis, 8% also had secondary bacteremia, and only about 10% received that one dose of active drug before enrollment. 25% had ESBL positive isolates. 76% of patients had E. coli, which tracks with urinary tract infection studies.
Erin: 14% had Klebsiella, and all the rest of the pathogens were less than 3% prevalent. The primary endpoint was a composite of clinical and micro success, again, very common for UTI studies. This was achieved in 82% of patients that got cefepime-nacubactam, 72% of patients aztreonam-nacubactam, and then 61% with imipenem.
And so based on their pre-specified statistics, they declared [00:43:00] that cefepime-nacubactam met criteria for both non-inferiority and superiority, and aztreonam-nacubactam met criteria for non-inferiority. But importantly, it wasn't powered for aztreonam to show superiority because it was that two to one to one.
Among the patients with secondary bacteremia, which is a population of great interest, success rates for clinical and micro eradication were 80% for cefepime, 89% for aztreonam, and 60% for imipenem. And then amongst patients with ESBL-producing infections, success rates were 75% cefepime-nacubactam, 68% aztreonam-nacubactam, and 56% imipenem.
Treatment emergent adverse events were very rare. Study drug was only discontinued in a handful of patients, and it was headache, diarrhea, nausea, nothing, life-threatening or critical. I do wanna point out because I, I think sometimes in studies we see things less than 5% and we just move on, but then later with more and more use, they become more common and we're like, "Oh, there was that little signal."
Erin: So I don't know if this [00:44:00] is a thing or not, but 4% of patients receiving cefepime-nacubactam and 3% of patients receiving aztreonam-nacubactam experienced what they called, quote, "vascular disorders," and they noted hypertension was what they classified in there. but there were zero patients in imipenem, and that was the only thing that had, you know, nothing in one arm and showed up with nacubactam.
So just to note the strengths of this are obviously, you know, it's a double-blinded RCT. They used actually a pretty stringent definition of micro-eradication, more strict than what is required in registry trials and more strict than what we've seen for some of the other novel drugs, 'cause every single one of these drugs is studied in a UTI trial 'cause that's how you get it done.
The limitations were there were no carbapenem-resistant isolates. It was a UTI trial, so we still don't know how this behaves in complex infections. We couldn't do oral step-down, so it's not really how we would treat patients in the real world. And we could talk about global applicability 'cause, you know, they mostly enrolled only in Eastern Europe.
But I don't love this as a critique. Like, people do the best they can to enroll in trials. Like, it is what it is, [00:45:00] right? We know patients are different, but we have to enroll where we can enroll. They did characterize the resistance mechanisms of the isolates in this study, but they're working on that as a separate publication.
So we don't have a genomic analysis at this point in time. And based on this, they actually submitted for approval of this drug in Japan in late 2025. They haven't submitted to the FDA or the EMA yet. It is available via an expanded compassionate use program. And I think the most important thing, though, is that the INTEGRAL 2 trial is currently under review.
I believe the study is complete, and I think they've submitted it for publication. This is a Phase 3 trial as well of these two drugs compared to best available therapy for patients with CRE, any infection source. So that's like-- that's what we're really waiting for. that's the patient population we'd use these drugs in.
But yeah, yet another novel antibiotic, which is exciting
Emily: Yes, very exciting. do we know what the median time to enrollment is? I'm very curious about this criteria of, receiving only one dose of a short-acting [00:46:00] antibiotic. I think that is something where we might not have been able to enroll patients in North America for that either.
that would be something to look into to see if there was some kind of delay but, you know, it was still randomized between the three different antibiotics. I am curious about the imipenem as a comparator. I wonder why not meropenem. So is this a win for, cefepime/nacubactam or a loss for imipenem?
Emily: something I'll let you guys think about and, always good to have another antibiotic, in the pipeline
Erin: It is an excellent question, and I'm looking at the publication right now because I also was like, "Wow, they enrolled fast," which is fantastic. it doesn't declare a time to enrollment. It just does have the caveat, which I kind of glossed through, but that you could randomize and enroll the patient before any data was back essentially.
And then if it came back with an isolate that wasn't like gram-positive, polymicrobial, or negative, then they let the investigators say [00:47:00] if you wanna continue study drug or not, and then they just removed them from the MITT, which was the evaluable population. So it is kind of a, somewhat different approach to this, and I think it's, you know, probably so they could increase their enrollment.
cause they screened 678 patients in total. Sixty-four were ineligible right off the bat, probably from a creatinine clearance standpoint. And then they enrolled 614, but only the 400 or so were actually evaluated, so.
Emily: Yeah. Very interesting.
Erin: Yeah. It is an interesting approach. It's kind of the, uh, Vanderbilt ACORN approach, you know.
Which I-- not here 'cause you're trying a totally new drug, but I think in order to evaluate patients earlier, I mean, that is the most strong criticism and most valid of all of our ESBL treatment trials is that patients are enrolled on day three. And if you survive to day three, you're probably okay, right?
the, the definitive therapy really matter, so.
Emily: Yeah. Continuation of treatment versus, initiation of treatment makes a big difference. Or maybe we [00:48:00] hypothesize that it could. All right, folks. that's a wrap for us for this quarterly catch-up. Thank you so much to my co-host Erin for joining me for this second iteration.
we hope you liked it. Look out for episodes like these to come out every three to four months to help keep you in the loop on some of the latest infectious diseases and microbiology science. Thank you for listening to Communicable, the CMI Comms podcast. This episode was hosted by Erin McCreery and me, Emily McDonald, editors at CMI Comms, ESCMID's open access journal.
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