Thanks for joining us again at the Canadian Breakpoint, a Canadian infectious diseases
podcast by Canadian infectious diseases physicians.
I'm Summer Stewart, back again with Dr. Rupeena Purewal, pediatric infectious diseases physician
from Saskatoon.
We're delighted to be welcoming you to the start of season three.
Thank you so much for your support over the past two seasons.
The response has been wonderfully positive.
We have so much planned for 2024.
In the first episode of this season, the Canadian Breakpoint welcomes back Dr. George Zhanel,
medical microbiologist in Winnipeg and research director for CARA to expand on the clear registry
and spotlight clear results for IV ceftobipral.
Dr. Purewal.
Hi, everyone. Welcome to another episode of our podcast, the Canadian Breakpoint.
Today we are joined by Dr. George Zannell, as a microbiologist and pharmacologist who
received his PhD in the Department of Medical Microbiology and Infectious Diseases at the
Faculty of Medicine, University of Manitoba, and a doctor of clinical pharmacy at the University
of Minnesota.
He is presently professor and associate head in the Department of Medical Microbiology
and Infectious Diseases, Max Reidy College of Medicine, and research director of the
Canadian Antimicrobial Resistance Alliance.
Dr. Zannell is the founding and chief editor of the Canadian Antimicrobial Resistance Alliance
website www.can-r.com.
Dr. Zannell has published over 1200 papers, chapters, and abstracts in the area of treatment
and prevention of infectious diseases.
He has presented over 1300 lectures as an invited speaker at international, national,
and local meetings, speaking on the topics of antimicrobial resistance infections, as
well as treatment and prevention of infectious diseases in Canada, United States, Central
and Southern America, Western and Eastern Europe, including Russia, Australia, Southern
and Northern Africa, the Middle East, and Asia.
He has been extensively involved in the treatment guidelines for a variety of infections in
Canada, the U.S., and internationally.
Dr. Zannell has received or been nominated for more than 100 teaching awards, including
the Canadian Association for Medical Education Merit Teaching Award in 2020.
Congratulations, Dr. Zannell.
Dr. Zannell is a member of the Who's Who in Medical Sciences Education.
In 2022, he was elected as a fellow of the Canadian Academy of Health Sciences in recognition
of sustained excellence in research and teaching within the health sciences.
In 2023, Web of Science identified Dr. Zannell as one of the world's most influential researchers,
selected among an elite group recognized for exceptional research influence, demonstrated
by the production of multiple highly cited papers that rank in the top 1% by citations
for field and year.
Also, in 2022, Dr. Zannell received the Dr. Fred Ioki Career Achievement Award in recognition
of a career of dedication and excellence in multiple domains of medical microbiology and
infectious diseases, including research, education, clinical practice, service, and administration.
All right, thank you, Dr. Zannell, for coming on another episode of our podcast, The Canadian
Breakpoint.
I think a lot of our listeners have heard you from our previous season in episode 6
and then episode 10 as well, talking to us a little bit about the CLEAR registry.
And so just to remind our listeners, this is the Canadian Leadership on Antimicrobial
Real-Life Usage Registry.
And so without further ado, I do want Dr. Zannell to kind of introduce the CLEAR registry
again, just give our listeners, and maybe we have some new listeners too this season,
but it would be nice to see kind of, you know, what's changed, what's the ultimate purpose
of this registry.
Dr. Ipita, I'm delighted to be back and I thank you so much for the invitation.
I've had lots of feedback from the prior podcast we've done.
Colleagues across the country have been emailing me how when I start talking, they have a
wonderful sleep.
So they enjoy the podcast because George Zannell is teaching and they're sleeping.
So I'm delighted to come back.
You know, thank you to everyone who's part of CLEAR.
We're going to be talking a lot about CLEAR.
What is it?
In brief, this is a national across Canada registry that really serves to capture data
and then share data on how new IV antimicrobials are being used by clinicians in the Canadian
setting across Canada.
And the real purpose is to inform clinicians about why new IV antimicrobials are being
used, how they're being used, are they working, what are the side effects in the Canadian
context by Canadian clinicians.
Yes.
We've talked about this multiple times, but I'm just so grateful that this data exists.
Today specifically, we're going to be talking about IV septobiprote.
So we've done previous episodes on kind of the introduction of CLEAR registry when we
had episode six in season two.
So our listeners can tune into that if they just want to have the basics of the CLEAR
registry, what medications are we looking at and what data we're collecting.
And then our last episode of last season, we also went through IVOSFO, so IV fosfomycin,
and really went through the indications and what the data was showing across the nation.
So today we'll be focusing on IV septobiprote.
And so specifically for septobiprote, Dr. Zanel, what specific data have you collected
within the registry and what are our experiences?
So thank you for that.
As you've said, CLEAR has data on IV septobiprote, that's our focus today.
But as a quick reminder to listeners, CLEAR is collecting data on intravenous fosfomycin,
intravenous ceftolzentezo-bactam, and intravenous dalbovansin.
So we've got a lot of good data out there.
But specifically for IV septobiprote, in a nutshell, an overall summary, what clinicians
are telling us in Canada is that they use this drug to treat on-label indications, meaning
indications that are Health Canada approved, and there are only two, community-acquired
bacterial pneumonia and hospital-acquired bacterial pneumonia.
But they're using it a lot also off-label.
And we'll talk about the indications that they're using it for.
It is mostly being used as directed therapy.
So we actually have a pathogen that we have grown.
So we'll talk about it's being used to treat a variety of infections, but almost all the
time they are documented MRSA infections.
So infections due to MRSA, usually we'll talk about that clinicians have regimens, they're
using daptomycin or vancomycin, or potentially both, to treat documented MRSA infections.
And patients are doing poorly.
They're clinically failing.
So clinicians are typically adding septobiprote to the daptomycin.
They're adding septobiprote to the vanco, or they're adding septobiprote to dapto and
vancomycin.
And what we've seen is we have surprisingly very high microbiological eradication rates,
high clinical cure rates.
And then lastly, no surprise, it's a cephalosporin.
It's a beta-lactam, typically very safe drugs.
And this is a safe cephalosporin with very few side effects.
Essentially, the only thing we've seen are a few episodes of hypersensitivity.
No surprise, it has the beta-lactam nucleus.
So all in all, some really great news for septobiprote in Canada.
Okay.
Yeah, and actually I've seen it recently on a lot of our susceptibility reporting come
up because here where I'm practicing in Saskatchewan, we do have high MRSA rates.
And a lot of times we're running into issues with higher MICs with vancomycin and other
medications.
And also practicing in the pediatric world, we don't have too much data on linesalid and
daptomycin in terms of dothing and indications.
And so it's nice to see that there is a beta-lactam because for us, pediatricians, beta-lactams
are, and I think for prescribers in general, but beta-lactams are kind of our go-to drugs.
And so it's nice to see that there's something else on the market for us in terms of MRSA
management.
And so you mentioned that most people are using it as combination therapy.
Are there indications or have people had real life usage experience with using it as monotherapy
in any states?
Yes.
So excellent points.
And a quick thing you brought up was the pediatric side.
I will say that the indications for this drug are in adults.
However, clinicians in Canada, risk versus benefit, we've had several submissions of
septobipril being used in children and it's showing that it was safe and effective.
So the power of the clear registry is not what we think people are doing, but we actually
find out what they're really doing.
These are experts like you who are saying, look, in this case, risk versus benefit, I'm
going to use the agent and it's working.
What we've seen in Canada is the patients who are being treated are 94% of them are
bacteremic.
So the vast majority of them are bacteremic with MRSA, 30% of them are in the ICU.
The other 70% are on the ward.
The most common indication is endocarditis, but patients also being treated for hospital
acquired bacterial pneumonia, community acquired pneumonia.
A lot of patients with bone and joint infections, device related infections, central nervous
system infections, complicated intra abdominal infections, complicated skin soft tissue infections.
So a variety of infections, but virtually everyone is bacteremic and we've grown MRSA.
So we have actually directed therapy against MRSA.
And if we look at in terms of the combination therapy, so 25% of the time it's being used
alone.
Patients are saying, okay, look, I've got MRSA, I'm treating endocarditis, I'm treating
a pneumonia, treating a bone and joint.
The vanco, the Daptomycin that the patients are on is not working.
That's the most likely indication for ceftobiprol.
The other agents are clinically failing.
They'll stop vanco Dapto and use ceftobiprol alone.
And the outcomes that we'll talk about are very, very, very good.
But the majority of the time, 75% of the time they're saying, no, no, no, no, no.
Yes I'm failing Dapto, yes I'm failing vanco, but I'm going to add on ceftobiprol because
I'm worried, I'm clinically doing poorly.
I've got bacteremia, I got endocarditis, I got a pneumonia, I got bone.
I'm going to add on ceftobiprol and the drug is working.
And interestingly now this is the Canadian experience, but then we reviewed the world
literature.
This is actually quite common of what is happening throughout European countries who've published
a lot in Italy, in Spain, and in other countries.
The same experience, ceftobiprol can be used alone and it works well, but frequently clinicians
are adding it to vanco and Dapto when they have a documented MRSA infection.
Okay, and so what dosage has been kind of reported in the clear registry in terms of
all of those infections or does it vary based on the infection that we're treating?
So it does vary, but I will say, and this is the great thing about the clear registry,
you know, half of the data submitters are clinical pharmacists, half of the data submitters
are infectious disease medical microbiologists.
And what we've seen is that in every patient treated with intravenous ceftobiprol in Canada,
it is clear that ID, micro and pharmacy are working together, customizing that dose based
on renal function, but also the vast majority of patients actually get the pharmacodynamically
optimized dose that's in the product monograph that is infusing it over two hours or more
to maximize the time above the MIC.
So the majority of clinicians are saying, okay, first of all, what's my renal function?
And they'll customize it to the renal function, but then they're optimizing the pharmacodynamics
by prolonging the infusion.
So the most common dose is 500 milligrams every eight hours, and I'm talking in adults.
However, we've seen a lot of dosing of 500 Q12 to 50 Q12 to 50 Q24.
So depending on the renal function, but the majority of the time it's being optimized
pharmacodynamically with prolonged infusion.
That's good to know.
Yeah.
And so I think most of our listeners, if they're not pharmacists themselves, can reach out
to their pharmacists and really get some support in terms of for this clinical indication,
for this patient, what would be the best dose and regimen is what I'm hearing from that.
So in terms of kind of switching gears to the micro data, do we have specific break
points for septobipral that can be reported and what type of antimicrobial susceptibility
testing our labs doing?
So we do have break points.
I will say that septobipral is not available in United States.
They have seftarilene available, which is similar.
We do not have seftarilene in Canada, but septobipral is available in the majority of
European countries.
And so we have UCAS break points.
Health Canada has adopted break points typically of one, two, four, less than or equal to one,
S greater than or equal to four being R. But what we've seen in Canada, and I think this
is because of our Can Ward study, Dr. We have a national surveillance study that we have
been running since 2007.
We partner with Health Canada, our friends in Winnipeg here across the street.
And we have been testing septobipral for a very long time.
We have never found an MRSA that's been resistant to septobipral in Canada.
We've actually never found a staph aureus that's been resistant to septobipral in Canada.
So I think clinicians are aware of that data.
And with clear 70% of the time when clinicians are using septobipral in Canada to treat a
documented MRSA infection, they do not even do susceptibility testing.
You know, but a third of the time they do and they're using everything from e-test or
discs and they're showing susceptibility.
But the majority of the time clinicians are saying, look, I know that this staph aureus,
I know that this MRSA will be susceptible.
So they just started without doing susceptibility testing.
And they're also adding it to Vanco or Dapto.
So very rarely are clinicians using septobipral because there's actually documented resistance
to Vanco or Dapto.
Typically, you know, the MIC is one or maybe two or 0.5 to these agents, but they're clinically
failing Vanco or Dapto.
So they are adding the septobipral and there's good data that septobipral because it's a
beta-lactam and inhibits penicillin binding proteins focusing on 1A1B3, but it actually
interacts synergistically with vancomycin, which is more of a glycosylation inhibitor
or Dapto, which is a membrane insertion inhibitor.
So there's synergy.
So they're saying, you know what, I don't need to do MIC testing.
I know it'll be susceptible.
Plus I'm using it as part of a combination regimen and I know I'm going to get synergy
and it's working.
And with it being a beta-lactam and us having so much experience with other beta-lactams,
I think it makes it easier to kind of trust the penetration into certain tissues, especially
with us, you know, like I deal with a lot of bone and joint infections with MRSA and
including bacteremias.
And oftentimes in the pediatric population we'll have low vanco troughs and I, you know,
I'm not seeing clinical cure in that context.
And so that's kind of when I resort to an agent like septobipral.
You know, I'll say a couple of things there and this is, you know, a different podcast.
Vancomycin as you know, is not a great drug.
This was one of my first publications back in the mid 80s to show you how old I am.
We reviewed the literature on Mississippi mud, which was isolated in 1956.
It's not a great agent.
We've lumped it as being bactericidal, but it is not nearly as bactericidal as adaptomycin
or a penicillin or a cephalosporin or a carbapenem.
This is a weekly bactericidal drug and we've kind of continued to use it.
Why?
It's cheap.
We much rather use something that is more rapidly bactericidal like adaptomycin or a
beta-lactam like septobipral.
Well, we've literally used it just because it's cheap, but the synergy part is something
that is important in terms of the beta-lactam.
You know, the great thing about cephalosporin, septobipral being one is clinicians like you
consider it to be one of the safest drugs in the world, right?
If you're not going to be one of the ones who drops dead anaphylaxis, one in 80,000
that drops dead of anaphylaxis, these are the safest drugs in the world, whether it's
in pregnancy, whether it's in lactation, whether it's in the very young, whether it's in the
very old, the critically ill, these are proven safe drugs and so clinicians like you like
to use them.
Yeah.
And that being said, I guess like in the registry, have people mentioned any side effects like
outside of I would say like beta-lactam induced neutropenia?
That would probably be probably the most common thing that I would see clinically when I use
beta-lactams, but are there any side effects that have been reported?
So they have reported side effects and I want to go back to talking about the types of patients,
the majority are bacteremic, you know, a third are in the ICU so they're critically ill.
In terms of is it working, we've shown 94% microbiological success, which is really astonishing
considering these patients have documented MRSA, a lot of endocarditis, their bacteremic,
their failing vanco and dapto, clinically 85% success rates, you know, patients getting
better, which is what you're really interested in.
And in that setting, the vast majority have had no side effects whatsoever.
So really sick people, bacteremic, endocarditis, bone and joint, pneumonia, MRSA, failing vanco
dapto, clinically they're doing well, and the vast majority no side effects whatsoever.
We have seen a little bit of hypersensitivity, you know, this is typically our rashes, et
cetera.
In only one of those cases have Canadian clinicians told us the drug had to be discontinued.
We had one patient who had hypersensitivity and had blisters and the clinician said we're
going to have to stop the drug and go to a different therapeutic category.
But you know, we're getting close to 100 patients here and clinicians are telling us this is
an unbelievably safe drug.
The only thing they've seen is a little bit of hypersensitivity, but in only one patient
did it lead to stopping the drug.
You know, I always focus on, okay, you've got a side effect, but was it bad enough to
stop?
No, the majority of the time, even if there's a side effect like hypersensitivity, they
continue.
So a lot of good news here, the drug is working and despite treating really sick people, very,
very few side effects, which is what you would expect with a cephalospora.
I agree.
And then being part of the beta-lactam, we already know that they're good drugs, they
work well and you know, rarely we run into severe side effects.
So that's fantastic.
And so in terms of, we already mentioned kind of the outcomes for our patients, which is
fantastic for this drug, which I'm actually grateful to hear because you know, there's
a lot of times when you're, as a clinician, it's very stressful when there's MRSA and
you don't have your patients not doing very well because we know that MRSA causes serious
infections or patients are very, very sick.
They can have very poor outcomes.
And so to know that we have another drug on the market that's available to us is fantastic.
So in terms of accessibility, so I know like this probably very center by center, but is
septobiprl on formulary in a lot of provinces or is this a health Canada approved drug that
we have to get special access for?
Health Canada approved and the majority of hospitals have it on the formulary.
It's available for you to use.
You know, I talk to clinicians a lot about special access drugs.
I'm delighted to say this is not a special access drug.
Special access drugs work well in Canada for these chronic conditions that you're going
to have for weeks, months, years.
Special access clinicians have told us over and over is a disaster for clinicians like
you who are treating a patient with an acute infectious disease, where ideally if you choose
to use the drug, you want to use it within an hour or two, not wait five days or 10 days.
So I'm delighted to say this is health Canada approved is on the majority of hospital formularies
and it's available to be used right off the shelf, which is very, very good.
Okay.
That's great to hear.
And so for our listeners, you know, in the past we've talked a little bit about the data
that you've presented and where to find this data.
And so for septobiprl specifically, I think you mentioned that there's more than a hundred
experiences that you've looked at.
And so where can some of our listeners reach out to see some of the resources or some of
this published data?
Our general clear vision has been that every IV antimicrobial, every new one that comes
onto the clear registry, we will define its use and share the data with all clinicians
in Canada who are clear participants for septobiprl no different.
My vision is that it's on the clear registry for maximum two to three years.
And then three years later, clinicians know all about the drug.
It moves off the registry and we move on now and you drugs.
So our typical plan is, and this is what we've done with septobiprl is once we hit about
20 ish or 30 patients, we present an amy poster.
And we did that with septobiprl in 2022.
Once we hit 50 patients, we published a paper in the journal of global antimicrobial resistance
in 2022.
And then once we hit more than that 50, 60, we had a second amy poster, which we presented
in 2022.
Now that we're approaching a hundred patients, I would like people to continue to hit that
clear link and get us over a hundred.
We've committed to writing our third and final amy poster for this December of 2023.
We'll present that poster in the new year in Vancouver.
And then once we get over a hundred, we will write the final paper and that'll be the final
chapter of how is septobiprl being used in Canada.
And so I'm hoping perhaps by mid 2024, we will wrap up septobiprl and clear with the
poster at amy in 2024 and then the publication in mid 2024.
And then we'll move on to another agent, but please keep hitting that link, whether it's
septobiprl, you know, whether it's a subtols, ain't taso, Dalva Vance and or IV phospho.
We really need all your help.
Thank you so much for doing that.
Fantastic.
And I think, I mean, all of us, I mean, the more submitters we have, the more data we
have, the easier it is for us clinicians as well, because we then have more and more real
life experience.
So thank you so much, Dr. Zanell.
It's always a pleasure having you on the podcast and especially talking about some of these
newer agents that we don't have that much information about, and we don't have Canadian
based information outside of clear registry.
So it's fantastic that we have a resource like this and it's fantastic that, you know,
our listeners can reach out to your registry.
They could submit cases, they can be involved in this and like we've mentioned previously.
And so we really, really appreciate all the support that you've given to our podcast.
And thank you so much again for such an educational conversation.
Dr. Rupia, two quick thank yous first to the clear participants and for the podcast listeners
who don't know, you can just Google George Zanell and you'll find my email, send me an
email, say I want to be a clear participant and it's free.
What do you get for that every two, three months?
I send all the clear participants, all of the slides of the new agents, how they're
being used.
So you keep up with your colleagues knowing how these agents are being used, but we also
send you the links.
And if you are motivated and you've treated a patient or have treated or will treat a
patient with one of the drugs on the registry, just hit that link and in three minutes, point,
click, point, click, and you are done entering the data.
So we've got 400 participants, half of them are AMI members, half are CSHP members, half
ID, micro, half clinical pharmacy.
And I'm very thankful for everything that they do, all clear participants.
And lastly, thank you to you.
For me, it's an honor to be part of your podcast.
I know people, I see them running down the street.
They've got earbuds in, I know what they're listening to, they're listening to what they
are podcasting.
Let's hope so.
I think we've had a lot of support and success based on the last few seasons that we've done.
And so we hope to continue to provide more educational information.
And I always like to tell everybody that the podcast is really designed for informational
and educational purposes and it's never to endorse a product or an idea or an agent.
And really, I think it's important for us to get together in our community of learners
and to continue learning through interfaces such as the podcast.
So it's fantastic.
It's honestly a lot of support from our listeners and a lot of support from our guests.
So we really appreciate it.
Thank you so much.
Thanks.
Take care.
Thank you, Dr. Rapina and Dr. Zanel for this valuable review.
To join the CLEAR registry, email drzanel at ggzanel, z-h-a-n-e-l, at pcsinternet.ca.
Links are in the episode description.
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