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.
In this episode, we welcome 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 fosfomycin.
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 US 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.
Hi Dr. Zannell.
Thank you so much for joining us again.
We really appreciate you being here today and offering your advice.
So we had, you had actually initially come on the podcast this season for episode 6.
So some of our listeners are probably familiar with what we talked about then, which was
the CLEAR registry.
We introduced the CLEAR registry.
And so for our listeners, just so they recall, that's the Canadian Leadership on Antimicrobial
Real Life Usage Registry.
And basically during that episode, we gave a lot of information, a lot of resources,
but today we're actually going to dive in deeper and talk about some of the data on
the registry.
And so we're going to talk about IV Fosamycin or IV Vosso and we'll go into that in a second
here.
So Dr. Zannell, if you want to just remind some of our listeners a little bit about the
CLEAR registry.
Has there been any updates and really what does it encompass and what's the ultimate
purpose of this registry?
Well, Dr. Uppina, thanks for inviting me again.
You know, we had so much fun last time talking about CLEAR, I thought, well, let's just go
more clear.
As a reminder to all your listeners, CLEAR is a national Canadian voluntary registry that
captures data and then shares information with all clinicians across Canada about how
new intravenous antimicrobials are being used across Canada.
And the whole purpose of this is to inform Canadians how clinically these new IV antimicrobials
are being used in Canada.
Why are clinicians using them?
How are they using them?
Are they working clinically?
Are there adverse effects?
So in the clinical context, how are we using them across Canada?
And it's been very exciting to be part of it.
Yeah.
So like you just said, it's about the IV antibiotics, some of the newer antimicrobials that we have
on the market.
And so I became familiar with IVOS a few years back when we started thinking about what are
we going to use for some of the antimicrobial resistance organisms that we are facing now
and the patterns that we're facing here in Canada.
So why don't we talk a little bit about, because I know our listeners are excited to probably
hear about the data that you've collected in the registry about IVOS.
So what is some of the shared experiences by providers for this drug across Canada?
So just as a quick reminder, the CLEAR registry captures data on intravenous phosphomycin,
and that's our focus today.
But we also capture data on intravenous cephtovipral, intravenous ceftozanthazobactam, and intravenous
dalbovansin, and I've committed to Canadian clinicians that for every new IV antimicrobial
that comes onto the market, we will get it into CLEAR and we will share the data.
But today in terms of IV phosphomycin, top line summary, and we'll go into this deeper,
this drug is used in Canada to treat a variety of infections, both on label, Health Canada
indication approved, and also off label.
It is used to treat a variety of multi-drug resistant gram negative infections, but also
some gram positive infections.
It is almost always used in combination treatment with other agents, and we'll talk about that.
Surprisingly, even though it's frequently used late in the game due to resistance, due
to clinical failure of other agents, we have relatively high microbiological efficacy and
clinical efficacy rates, and it's turning out to be a pretty safe drug.
We'll talk about hypocholemia, which is important to know about.
All in all, quite a success story for IV phosphomycin in Canada.
It's fantastic.
And so what are some of the indications when you've collected this data and prescribers
are using nationally?
So what are colleagues using it for, like you mentioned, overall multi-drug resistant
organisms?
Are there certain clinical conditions where IV phosphomycin has done superior?
So let me first talk about what are the Health Canada approved indications, and then we'll
talk about what clinicians are actually using it for in Canada.
So according to Health Canada, intravenous phosphomycin can be used in adults and children,
including neonates.
And this is because there's so much data internationally that's been available on the drug, but it's
indicated in Canada for bacterial meningitis, bone and joint infections, complicated intraabdominal
infections, complicated skin soft tissue, complicated urinary tract infections, hospital
acquired pneumonia, including ventilatory associated pneumonia, infective endocarditis,
and also bacteremia that occurs in association with or suspected to be a part of any of those
infections.
Those are the Health Canada indications.
What are Canadian clinicians actually using it for?
All of those, believe it or not, except skin soft tissue.
We have yet to see anyone use it for skin soft tissue, but clinicians using it for every
one of the indications I talked about.
And in addition, they've also used it to treat community acquired bacterial pneumonia.
So a real wide variety of infections that are being treated with intravenous phosphomycin
by Canadian clinicians.
Okay.
And so in terms of what dose are they using this at?
And then you mentioned that this is frequently used in combination therapy.
And so do you want to discuss maybe a little bit about what real life usage looks like
in terms of combination therapy?
Which other antibiotics are we combining it with?
Yeah.
So number one, why are they using it?
70% of the time clinicians are choosing intravenous phosphomycin because of resistance to other
agents.
And that's important to know.
They've got resistance to other drugs, so they're pulling it out.
Sometimes it's due to clinical failure of prior therapy or intolerance or adverse effects,
but the vast majority of the time clinicians are using it due to resistance of other antibiotics.
Then when it comes down to dosing, the dosing is actually very interesting because by far
the most common doses that are being used are eight grams every 12 hours, six grams
every eight hours, eight grams every eight hours, four grams every eight hours.
So we have a complete mishmash of dosing, a whole variety of dosing.
And the reason is 100% of the time when intravenous phosphomycin is being used in Canada, it is
infectious disease, microbiology, and clinical pharmacy working together to customize that
dose based on renal function, severity of illness, where that infection is.
So we have a whole range of dosing that is being used.
And then when we get to the types of infections we talked about, it's all types of infections.
But the interesting part is the pathogens treated.
The pathogens that are treated, what we found is that they can be multi-drug resistant gram
positives or gram negatives.
But what we have seen is that the vast majority of the time intravenous phosphomycin has become
the agent of choice to treat carbapenem resistant entero bacterialis infection.
So when clinicians have a CRE infection, we do not have some of these newer agents like
indipendum rilobactam, meropenem baborbactam, ceftazidymabibactam, cefideracol yet.
So what are we doing?
We are using combination treatment for CRE and it's involving intravenous phosphomycin.
So carbapenem resistant E. coli, carbapenem resistant clebsiella.
But we've also seen multi-drug resistant pseudomonas.
Clinicians are using intravenous phospho as part of a combination regimen to treat multi-drug
resistant pseudomonal infections.
And then you asked me in terms of the combination therapy, it is almost always used as part
of combination.
The only time we've seen IV phospho used alone has been in complicated urinary tract infection.
And that's because of the Zeus study that was published in the US using it alone compared
to Piptazole for complicated UTI.
But in the other indications, it's used in combination.
What is it used in combination with?
A lot of meropenem.
It's being used to treat CRE with meropenem.
It's being used to treat CRE with meropenem and tigecycline, meropenem and an aminoglycoside
to treat CRE.
The intravenous phosphomycin with a carbapenem with inhaled colistin, inhaled aminoglycoside.
So it's really being used a lot as a CRE regimen where clinicians are choosing meropenem and
intravenous phosphomycin, maybe in adding in tigecycline, maybe adding an aminoglycoside
or inhaled colistin.
But for the most part, this is a big CRE treatment as part of combination therapy.
Okay.
And like you mentioned, I mean, we don't have too many drugs on the market that can help
us in those situations.
So that's really important for us clinicians.
And in terms of, I think when we talked about the indications, we can see that penetration
into multiple spaces, you know, so it can be widely used, which is actually a really
important property, I think, of IV phosphomycin.
In terms of the antimicrobial susceptibility, so do most like across the country, or you
can speak specifically at your center, do most of us have this on formulary, first of
all, and then the second thing about antimicrobial susceptibility is, do we have breakpoints
that we're looking at?
And will this be reported by the labs?
So now we're on to a really touchy subject and it's our listeners are going to get all
upset.
I know phosphomycin is an interesting drug because yes, we have health counter approvals
for a whole range of indications.
It's on many and most hospital formularies.
It is being used quite ubiquitously in some centers, less often in other centers.
It's being used by infectious diseases, medical microbiology, and clinical pharmacy working
together.
We know that over half of the patients who get intravenous phosphomycin are bacteremic.
We know that more than half of the patients who are treated with IV phosphor are in the
ICU.
So it's being used in really, really, really sick people.
The vast majority of the time it's being used as directed therapy, meaning we actually have
a pathogen.
So we have a clinical diagnosis and we have a bacteriological diagnosis and now IV phosphors
being used in combination.
But then comes the rub, the susceptibility testing.
Susceptibility testing with intravenous phosphomycin is a real dog's breakfast and the reason is
auger dilution is the world standard.
And we do auger dilution in Winnipeg, you know, in our lab.
The labs don't want to do that and they don't do auger dilution.
So what do they do?
They've been trying other things predominantly e-test.
And what we have seen is in 70% of the cases when intravenous phosphomycin is used, the
lab has used some sort of antimicrobial susceptibility testing.
It could be disc diffusion, but usually it's e-test.
And that's what they've done to try and guide susceptibility testing.
The problem is breakpoints.
You know, if you look at the CLSI breakpoints, we only have urinary breakpoints for E. coli
and enterococcus.
And this is because there's an oral phosphomycin indicated for acute uncomplicated cystitis.
So the breakpoints are for UTI pathogens only, E. coli and enterococcus, UCAS, because intravenous
phospho is available in Europe.
It is not available in the U.S.
We have UCAS breakpoints for IV phosphomycin.
And I think some Canadian clinicians look at the UCAS breakpoints in order to guide
them.
But it's a real dog's breakfast.
No one wants to really do auger dilution susceptibility testing.
They're asking us what to do.
Many people send us the isolates to do auger because we have a national IV phosphomycin
susceptibility testing service.
But of the times it's used, clinicians are trying to do some sort of testing.
They're either sending the isolate test to do auger dilution, or they're doing some sort
of in-house testing with disc testing or E-test to try and get an idea of susceptibility testing.
But then I go back to how they're using it.
They're using it as combination therapy.
They're almost never using it alone.
So when you're treating a CRE and you're using optimized doses and pharmacodynamics of Meropenem,
you're adding in tigecycline, maybe even an amino glycoside like amicacin, and adding
IV phosphomycin.
I'm not sure that they know or we know what really that MIC value really means because
you're adding it for the purposes of synergy to try and optimize bacterial eradication.
So yeah, like you said, so more importantly, I think is what our microbiological cure rates
and our clinical cure rates.
I think that's what we can focus on because for us clinicians, obviously, if we're using
combination therapy like that, like you mentioned, sometimes it is to overcome some resistance
patterns.
And so, and if we don't have reliable break points, then really we're looking at how well
did our patients do.
And so in the clear registry, you guys look at outcomes and I believe both at micro and
clinical cure rates.
And so what type of information has been inputted?
So I'm very thankful to our clinicians who are participating in clear.
I'm giving you data right now and about 76 patients who've been treated with intravenous
phosphomycin and the clinicians who are submitting the data in Canada, it's about half infectious
disease medical microbiology, half of clinical pharmacists who are specializing in ID or
antimicrobial stewardship.
So I'm very thankful to them.
And what they're telling us is that in their hands coast to coast, even though they're
using the drug, typically when there's resistance to other agents, patients are bacteremic frequently,
frequently in the ICU, they're quite ill.
They've showed us that the microbiological eradication or success is in the range of
78%.
So 78% of the time from a microbiological perspective, the organism is either eradicated
or what we call presumed eradicated, meaning you're using it for hospital acquired pneumonia
and the pneumonia is improved.
You don't even have any sputum or tracheal aspirate fluid to submit.
So it's presumed eradicated.
So surprisingly quite high eradication rates despite the types of patients and the types
of infections that are being treated.
And then clinically that's obviously correlating because clinically their patients are improving.
And like you mentioned, whether that's very sick, ill patients in the ICU versus even
an uncomplicated cystitis type of picture.
So definitely a wide range of patients that they're seeing it used in.
Rapina, I will say that, you know, one of the differences between you and me is I'm
interested in killing bugs.
You know, I'm a microbiologist at a pharmacologist.
I like to kill bugs.
So I'm delighted that phospho is very rapidly bactericidal and in combination is killing
these organisms and the microbiological success rates are high.
However, you know, clinicians like you're interested in clinical success, right?
I'm not killing the pathogen.
I want to see how my patients are doing.
So patients are doing quite well.
You know, our clinical successes are in the mid sixties.
As you know, patients get better for a whole and worse for a whole variety of reasons,
including the heart failure that they have and the MI that they've had and the stroke
that they've had.
So clinical success is much more complicated, but surprisingly the clinical success rates
have been in the mid sixties, which is quite high again, considering these patients are
very sick, will back to make in the ICU and complicated infection.
So the drug is doing well on the eradication side and clinically it's doing quite well
on the clinical success side as well.
That's fantastic.
And so what are some of the side effects?
Cause I know an earlier on in the podcast episode, you mentioned that there might be
some side effects that we have to worry about.
Maybe we can just touch on that.
Cause I'm sure listeners are curious about that as well.
So no surprise.
This is a very safe drug and we thought this would occur because we have 25 years of experience
from Europe.
It's been used extensively in places like Germany and Austria and Spain and France and
many European countries.
So the vast majority of patients have no side effects, but the one side effect that has
come up is hypocholemia and it's important that clinicians monitor potassium levels and
potentially supplement potassium.
There's a sodium load that comes with the drug because it comes with a sodium, there's
sodium in the formulation.
We had three patients with hypernatremia.
So it's important to monitor sodium cause there's a sodium load, but the big deal really
is hypocholemia monitoring potassium levels, knowing where they are and potentially supplementing.
But interestingly enough, in no case was the drug discontinued.
You know, I always look at serious adverse effects and did the clinicians stop using
the drug as a result of adverse effects?
And the answer is no, but they've documented hypocholemia and in some cases have been supplementing
with potassium.
And did clinicians mention at like what stage?
So is this early on in the course?
Is it kind of very?
It's a great question.
They did not.
They did not ask him that the balancing act I have with clear is that clinicians have
been very clear to me about clear.
And they said, look, if this thing takes me any more than three minutes to enter a patient
case on my iPhone, my iPad, my desktop, no way.
So we have 17 drop down questions, point, click, point, click, point, click.
So there's virtually no writing.
It's all point, click.
And it's what is the infection?
What's the pathogen?
What dose are using or using in combination clinically, microbiologically is a working
side effect.
So all I have is, you know, was there a side effect?
Yes, no.
What was it?
Click hypocholemia.
So I don't know when, and I don't know at which point they intervene.
So those are the limitations of clear, but the whole goal of it is if a clinician wants
to submit data and we're delighted they do, it's quick.
Yeah, exactly.
And really we're looking at like, what's the indication?
And there's a lot of case by case, right?
So assessments and that, like when we're using any other drug and probably similarly, I don't
know if they comment on duration.
Have they commented on duration of use?
Yes, they have.
And you know, no surprise, close to half of the patients have received greater than 10
days of therapy.
And the other quarter has been seven to 10 days.
And the other quarter has been less than seven days.
And it's not that surprising that a lot of patients get longer therapy.
And the reason is if we look at our top indications, the most common reason it's being used is
bacteremia and sepsis, ventilatory associated bacterial pneumonia, hospital associated bacterial
pneumonia, endocarditis.
And these are due to multi-drug resistant pathogens where clinicians may want to treat
a little bit longer when you've got a CRE or a multi-drug resistant pseudomonas.
So treatment duration is frequently quite long, despite that it's a pretty safe drug.
And so for our prescribers and our listeners out there who are pharmacists, who are physicians,
medical students and training residents, are there any specific resources that they can
look in terms of for this drug?
So obviously, I mean, this would be one of the resources listening to the podcast episode,
but are there other brochures, posters, publications that they can search and get more information?
Yes.
Thank you for asking that.
So Dr. Rupina, my vision with CLEAR has been that a new intravenous antimicrobial comes
to Canada, is Health Canada approved, comes onto the shelf so clinicians can use it.
And it's maximally on the CLEAR registry for two to three years.
After that, two, three years later, we've educated clinicians on how and why they're
using these drugs and now they're just routine drugs in practice.
They come off the registry and new ones come onto the registry.
So it's a rolling model.
So what we've tried to do successfully, and we've done that with IV FOSFO, is once we
hit somewhere around 20 to 30 patients treated, submit an AMI poster, and we present the data
at the National AMI CACMED meeting, which is, you know, typically in March or April.
So clinicians can see how it's going.
Typically once we hit around 50 patients, we write up a publication.
So once we were about 20, we had an AMI poster in 2022.
We hit 50 patients.
We published a paper in the Journal of Global Antimicrobial Resistance in 2023.
Then typically once we get to higher 60, 70, we put together a second AMI poster.
So we had an AMI poster in 2023.
And then once we hit 100, and I'm hoping to get to 100 patients soon, we will write the
final, you know, it's the final story, how are Canadian physicians using IV FOSFO.
So we've committed to a third AMI poster.
We're writing up the abstract right now, and we'll submit that to AMI before Christmas.
And then I'm hoping that by the time we put that poster together in March of 2024, then
we'll write up the final publication of how clinicians are using intravenous FOSFO mice.
And my goal is really to hit 100 patients.
So I'm encouraging all your listeners, you know, please hit those links.
If you're not a participant of CLEAR, you just send George Zanell an email, Google me,
and you'll see my email address and it's free.
I just send you all the links.
And then you also get all the data.
What I do is we crunch the data and I send all of the PowerPoint slides of how these
drugs are being used to all CLEAR participants.
We're up to 400.
Rupina, I'm delighted to say.
That's great.
Half are kind of AMI members, you know, pediatric, adult infectious disease specialists, microbiologists.
The other half are clinical pharmacists and stewardship infectious diseases, coast to
coast.
So if you're a CLEAR member, you know, it's free.
You get all the data.
And if you're willing to be one of the submitters, you just hit one of those links.
We always send you the links every two, three months and you enter the data and here we
go.
So please continue to submit the IV FOSFO mice and treatment experiences.
If you have treated or will treat, hit the link three minutes and you're done.
Easy peasy.
That sounds fantastic.
And with that, I think you've answered my all my questions that I had for IV FOSFO mice
in and we're so grateful.
And I speak for probably all clinicians out there and prescribers that there is available
data within Canada about this real life usage, because I think it's really difficult sometimes
looking at data from, you know, international data that maybe you cannot correlate with
your patient population, but this is really real life, real time data that's being submitted.
And we all look forward to seeing the posters and the publications and the data submitted
at AMI next year.
So Rupina, two quick things before we sign off.
One is a big thank you to you.
You know, I think the goal is that every Canadian, if they're going for a walk or hiking, they
need to have Dr. Rupina podcast in their ear because these are fantastic podcasts.
That's what I do.
And secondly, a big thank you to every clinician in Canada who is willing to press that link
and then three minutes entering the data on one of these drugs, FOSFO, Dalbal Vansin,
Ceftovipros of Tulzaintazo.
So a huge thank you to Canadians for making this successful.
And a shout out to my colleague, an ID doc in Vancouver, Dr. Ted Steiner, who was really
instrumental in getting me to get this going.
So thank you, Ted.
Yeah, no, that's fantastic.
And we want to thank you as well because first of all, for supporting the podcast and coming
on for a second episode.
And I know we have some future episodes on other medications such as Ceftovipro coming
up in the next season.
So I think all of our listeners will be very excited to hear more about all the data that's
been collected and clear.
So thank you so much.
Thank you.
Thank you, Dr. Rapina and Dr. Zanel for the valuable review.
To join the clear registry, email Dr. Zanel at ggzanel, z-h-a-n-e-l, at pcsinternet.ca.
Links are in the episode description.
This concludes season two of the Canadian Breakpoint.
We'd like to thank all of our listeners, all of our fabulous guests, as well as Bayou Mérillou
and Verity Pharmaceuticals for their support with the podcast.
Have a wonderful holiday season and a festive new year.
And we'll see you again in 2024 at the Canadian Breakpoint.