00:00 – E. faecalis, candida, fungal species, they are no swimmers.
00:04 – They are attached to the catheter or attached to the walls.
00:07 – Yeah.
00:07 – So we’re not even analyzing them as we should.
00:25 – The work you’ve been doing with the fibrinogen has led you to developing a vaccine in antibody therapy.
00:30 – So can you tell us more about how that works and what pathogens they’re effective against?
00:35 – Yeah. So one of the vaccines – that was really early on when we’re trying to understand
00:40 – what are these pathogens do not cause an infection.
00:43 – But as soon as you put a catheter, now they are able to cause infection.
00:47 – So we found that, for example, E. faecalis, enterococcus faecalis, they have this adhesin that was binding to fibrinogen.
00:56 – And that was the key idea, right? Like, is this fibrinogen that important? Do you block that? Can now we reduce infection?
01:04 – And we found that, yes. It was really amazing.
01:08 – It was the first time that we have an idea how the system was working, right?
01:11 – What was the main mechanisms for the pathogens to interact? So, we developed a vaccine against enterococci.
01:21 – Basically, all that group that is a really big group causing those infections.
01:27 – And one of the things also we developed with this vaccine is monoclonal antibodies. Like, what will happen?
01:34 – To have a vaccine means that you’re already thinking that you’re going to have an infection in the future, right?
01:42 – Like, you’re going to have a urinary catheter. What we need is something to protect, right?
01:46 – So you need to have the vaccine before even you have the catheter.
01:50 – Okay.
01:51 – And what will happen if you’re already in the hospital,
01:53 – you have an infection with a multidrug resistant enterococci.
01:57 – Vancomycin resistant enterococci, they actually is a major problem in uro. Can we use a dose?
02:06 – And even if you have a pre-existing infection, can we give you a dose of these antibodies and reduce infection?
02:11 – And we found that, yes. We were able to reduce that against multiple enterococci strains,
02:17 – really virulent strains that have been isolated from patients that have died from that infection
02:23 – and things like that. So we developed this too. However, this is the problem.
02:31 – Even with COVID, people didn’t want to have a vaccine for something that was killing many of us.
02:38 – So also, you don’t want to have a vaccine if you don’t even know if enterococci is going to cause the infection.
02:48 – Monoclonal antibody therapy is really costly. Because you need to produce that all the time because it has a shelf life.
02:59 – So, for example, antibody therapy for inflammation, like IL-6 blockers, TNFi blockers, is extremely expensive.
03:08 – It could be 20k US dollars. So it’s not feasible. So we were rethinking the situation.
03:17 – If this interaction, if looking at this interaction, first of all, that was with enterococci when we started dissecting the system.
03:23 – But then we found that even E. coli, candida albicans, and Pseudomonas aeruginosa, Acinetobacter baumannii
03:31 – and many of the different pathogens that cause infection, they were using fibrinogen for that, to form biofilms.
03:37 – So we say, okay, what about if we – if this is 40% of the infections in the hospital, in the United States and Europe,
03:49 – can you imagine the incidence of these infections in places where we don’t have the sanitation protocols?
03:55 – Either because there is not really good medical system or there is no even resources.
04:02 – And I have people that have come and said that, yeah, my dad died of those infections. They put complications, right?
04:09 – Yeah, it was a complication, but at the end it was that infection that come from the bladder, go to the bloodstream.
04:15 – So we were thinking, how can we develop something that would be feasible to use?
04:21 – Thinking, doesn’t have a shelf life and anybody can have access to it. And you will use it only when you need it, right?
04:30 – And it’s when we developed a modification of urinary catheters by actually understanding the system.
04:37 – So we developed a catheter that prevents protein deposition, not only fibrinogen, because then we were so scared,
04:43 – like, what about you remove fibrinogen and then any other protein will attach with the same function.
04:48 – And then we go back to zero.
04:50 – So with Dr. Caitlin Howell in the University of Maine, we got together and we developed this catheter that would basically
04:58 – prevent, it’s a slippery catheter. It prevents protein to attach and also prevents the pathogen attachment, both of them.
05:08 – And this is perfect because you’re reducing the main problem. However, the other issue that we have is inflammation, right?
05:19 – None of these catheters that have any coatings and the microbial coatings will reduce inflammation.
05:26 – So something that we saw and let me explain why these were so successful and none of the other coatings were not.
05:34 – So some of the catheters that you have, they have the antimicrobial attach or they have a release system.
05:43 – But if you have all these proteins, they attach on top of the catheter, that will hinder the release of the antimicrobial.
05:50 – It will hinder the interaction of the antimicrobial with the bacteria because you have this layer in between.
05:56 – So that may explain the conflicting data that we have in hospitals, in clinical studies, right?
06:06 – So by having these catheters, we’re not using any antimicrobial.
06:11 – We’re not using anything that’s killing the pathogen. So basically we’re making blind.
06:16 – Like if they don’t know what they are, they float away with the urine, we’re happy.
06:19 – Everybody’s happy. We don’t want to develop more multidrug resistant pathogens, right?
06:24 – So that was the idea that we thought it would be functional in our studies.
06:31 – So where are you at with this surface technology now?
06:35 – So we’re working really hard to get it out, to get it out, to start with clinical trials to see if it’s true.
06:44 – Because again, one of the things that we have found is that the mouse model really mimics what happened in the urinary,
06:55 – like in the human infection. But we need to prove it.
07:00 – So right now we’re in the phase that we’re trying to actually test that.
07:07 – Do you think those trials might be in the near future?
07:10 – I hope so. I really hope so.
07:14 – You should let us know if it happens.
07:15 – Everything is about funding, remember?
07:17 – Yeah, it is.
07:18 – So that’s the thing. That’s the key point. So we’re really excited.
07:22 – And something that I didn’t mention before, we’re talking about this inflammation.
07:29 – These catheters reduce the damage because they are so slippery.
07:32 – So it’s like they are not actually causing friction in the bladder.
07:36 – And we have shown that they’ve reduced tons of inflammation markers in the bladder and actually could be a solution.
07:43 – Right? Remember, the main problem is that we have something that causes damage.
07:47 – Catheters do not cause the damage and prevents protein –
07:51 – even if we have a little bit of damage because something is inside of you, the bladder will react.
07:57 – But even if we have a little bit of damage and we have these proteins coming through, they’re not going to stick.
08:04 – And then pathogen won’t stick either because it’s so slippery.
08:08 – It sounds really promising. And I think there will be people in our community
08:11 – who are interested in participating in that trial when it happens. So if you want to share the information when it does happen.
08:17 – Yes, yes, yes. Yeah, definitely.
08:20 – Yeah, it’s really great to hear that this type of thing has been worked on.
08:24 – We also got a bunch of questions about what people can do in the meantime.
08:28 – So we often get questions about whether medications for recurrent and chronic UTI will work for people with catheters.
08:34 – And that’s something that we just don’t see enough research on. But we did get some specific questions about things
08:40 – like long-term low-dose antibiotic prophylaxis and whether that’s a good idea given the antimicrobial resistance problem.
08:50 – So the problem that we have in the bladder is that sometimes it works.
08:57 – But one of the problems that we see is that even with candida auris, oh, something that I forgot to mention before,
09:05 – these catheters are really good even against candida auris that is super sticky, super sticky.
09:10 – Like, please, please, like it works. That was great because again, it’s a nightmare.
09:15 – But one of the problems that we have in the, and again, I have to validate with this with clinic data.
09:25 – Most of the time we don’t reach a concentration that we really want in the bladder because it’s constantly flushing.
09:33 – It’s not like other organs that the antibiotic will stay there.
09:37 – Here is a system that is highly dynamic and is constantly flushing.
09:41 – It has been through some data, clinical data, that has shown that low dose of
09:47 – antimicrobial prophylactic therapy have worked for some patients.
09:52 – But again, we don’t understand all the patient population. So I cannot speak about it because we have not tested on that.
09:59 – And the problem that we have with the majority of the pathogens that
10:03 – cause an infection in the bladder is that they are highly resistant to antimicrobial.
10:07 – So we’re thinking that they are, we may allow them to evolve.
10:12 – But remember, for E. coli to infect, they have to go inside of the cell and seed and create these communities inside of the cell.
10:21 – So they are protected from the immune response and from the antimicrobials.
10:26 – And then they get released and they look like worms and they go and they attach to the next one, the next cell.
10:33 – In this case, when we look at the biofilms that they form, they have tons of proteins, including fibrinogen.
10:41 – We don’t know how those proteins protect them against antimicrobials
10:44 – and even against the immune response, like something I didn’t mention is that we see tons of immune cells
10:51 – in the catheterized bladder, but it seems that they don’t do anything.
10:54 – The question is, we don’t know whether they don’t see the path again or the conflicted signal
11:00 – is inflammation is hindering the antimicrobial activity. So I don’t know whether that may work.
11:07 – And I don’t know if that had been tested. In my knowledge, I don’t think it has been tested in patients with a urinary catheter.
11:18 – Okay, is it the same case that we just don’t know enough about
11:21 – non-antibiotic approaches like D-mannose and Hiprex and probiotics?
11:24 – For D-mannose, so there was an experiment done where they use
11:30 – an analog of D-mannose that is called mannoside that my previous mentor
11:34 – developed and they were able to see reduction of infection with E. coli.
11:41 – But it’s because E. coli binds to sugars. So that’s why when you have D-mannose,
11:46 – it’s a sugar, they bind and it’s like a decoy molecule, they flush away.
11:50 – So this is the situation. D-mannose may work with those pathogens that bind to sugar, protein interaction.
11:58 – However, so we have found that pseudomonas, E. coli, Klebsiella,
12:04 – and acinetobacter baumannii binds to sugars in fibrinogen. Fibrinogen has tons of sugars.
12:10 – Okay.
12:11 – It’s highly like oscillated. It has mannose, it has everything that you want is right there.
12:17 – So they bind through that interaction. However, gram-positive bacteria like enterococcus,
12:23 – staphylococcus aureus, they bind protein-protein interaction.
12:27 – So that won’t work. And candida albicans, we found that they use a protein that’s called ALS1.
12:35 – It’s like a little honey, it’s an adhesin, they allow them to attach. So suggesting that gram-positive and
12:42 – fungal pathogens, they won’t respond to D-mannose because they bind through different mechanisms,
12:47 – protein-protein interaction, not sugar protein interaction. So D-mannose may work for
12:52 – those patients that have an E. coli infection. But remember, most of these infections are polymicrobial.
13:00 – You may remove one of them, but some of the other may take advantage of that.
13:05 – Okay. A lot of these like probiotics and saccharomyces boulardii, gut health supplements, so people
13:12 – are familiar with them for that. And that question comes up a lot about the interactions between the gut microbiome
13:17 – and the urinary microbiome. Have you seen these types of documented these interactions in your work?
13:23 – No. So again, like everything is really new. This is most of the people that are worse with these infections,
13:31 – they focus on the pathogen. But what I believe is that we need to focus on the whole thing, right?
13:39 – The response of the host, the pathogen and in the immune response.
13:43 – Because for some reason the immune response is not working. So I don’t know if adding a probiotic in the bladder.
13:53 – I don’t know if the changes in the bladder and the inflammation may allow
14:00 – these microbes to take advantage and also increase in numbers.
14:07 – Right? Because again, E. coli, E. faecalis, candida albicans, they are perfectly fine in our gut, but as soon as you remove it in this
14:17 – really rich environment with tons of proteins and places where they can attach, then cause a bit trouble.
14:23 – Right.
14:24 – I don’t know. I need to test that. I need to put these microbes in the bladder with a catheter and see whether –
14:35 – we need to test that. We don’t have information about it. We have tons of information
14:38 – about uncomplicated UTIs, but not about CAUTIs.
14:42 – It is an interesting point. It’s not as simple as looking at uncomplicated and catheter-associated UTIs in the same way.
14:48 – And that validates the questions that patients send us about catheter-associated UTI and whether they can use
14:54 – the same supplements. On the surface, it seems like you should be able to, but it’s really not that simple.
14:59 – It really depends. I always say it depends. Like again, D-mannose may work, but also D-mannose is in the-
15:10 – there is a lot of contradictory data that they say that they work and sometimes they don’t work.
15:15 – And I guess it’s just the concentration in the bladder. Again, if you’re increasing volume, you’re reducing the concentration.
15:22 – Yeah.
15:23 – And then if you work, you remove the D-mannose completely. Right? So I think that the mannoside
15:28 – this molecule that I just mentioned, that has been really good, at least in the mouse model. I think it’s in clinical trials right now.
15:36 – Not sure. But it really, the D-mannose have this interaction that they can bind and release from
15:45 – the pathogen, but these mannosides attach and they don’t release anymore.
15:50 – Yeah.
15:51 – So even one molecule will target one pathogen. So and it seems that they – I’m not sure.
15:57 – I don’t remember correctly, but I think that they were really good in staying in the bladder for a long time.
16:05 – But I need to go back and check. Yeah.
16:09 – Yeah. I want to go back to the inflammation piece of this. You mentioned in your work and I mentioned in the
16:14 – introduction that this long term catheter use and inflammation that’s associated with that can be a risk factor for bladder cancer.
16:20 – Can you explain that connection and what your research has found in that respect?
16:25 – Yeah. So one of the main things and again, nobody – I think it’s only us that we’re studying this point, but if
16:33 – you ask many people, they have urine like they have family or they have the urinary catheter for a long time.
16:41 – Definitely people that have paraplegia, they are paraplegia, they need that. Right? So they have – there is a huge link or is –
16:52 – this is an increased data that shows a link of prolonged catheterization with bladder cancer development.
17:00 – So when we were looking at inflammation, we say, okay, what are the factors that are being induced? We found that many –
17:09 – we look at bladder cancer markers, we look at inflammation markers, immune response, everything.
17:16 – And we see that many cancer markers, they have poor prognosis in other cancer systems
17:27 – in other parts of the body that would be inactivated in the bladder, in the catheter.
17:34 – By seven days, we can see a huge increase of these bladder cancer markers and that keeps going up to 28 days.
17:42 – The question is that we don’t know as soon as you remove the catheter,
17:46 – does that go back to normal and then nothing happens again?
17:49 – And you just need to have this constant inflammation to actually develop these abnormalities and these carcinomas, right?
17:59 – Which is normally – we have seen that like gut inflammation may result in colon cancer, right?
18:05 – So we have many examples where the inflammation plays a role. You don’t have to have genetic factors
18:12 – that predispose you to develop cancer. We can see the development of cancer due to inflammation.
18:18 – So we saw that even at 28 days that these bladder cancer markers were highly elevated, right?
18:27 – But now we need to test. If we remove the catheter, do they go back to normal or this proliferative behavior stays there?
18:37 – So when is the point of no return? Is seven days good? 2 to 4 weeks is good and then you remove
18:44 – the catheter and you go back to normal? Do you need to have it for three months?
18:49 – So then remember, cancer is a silent disease. You don’t notice something is really bad.
18:56 – Yeah.
18:57 – So right now we’re doing research on that.
19:00 – We’re identifying the markers that are more exacerbated when you put the catheter.
19:07 – But the cool thing that we have found is that now we’re testing the liquid-infused catheters that reduce inflammation
19:14 – and the majority of those bladder cancer markers totally are reduced.
19:18 – That’s an amazing outcome because removing the catheter is not an option for a lot of people so you can’t.
19:23 – Exactly. Exactly. So now if we can have something that is
19:28 – really gentle to not cause damage but provides all the benefits, that could be something a solution for many people.
19:35 – And actually we also saw, we tested with mono-microbial infections, polymicrobial infections,
19:42 – and we found the E. coli exacerbate the increase of bladder cancer markers.
19:49 – Right.
19:50 – E. faecalis, they didn’t do much, candida, little bit, but E. coli was the one they induced the most.
19:59 – Okay.
20:00 – With the liquid-infused, we were able to turn all of them down even with E. coli.
20:05 – So you said that bladder cancer or cancer in general is a silent disease,
20:09 – but what are the symptoms when it gets to that point and how could you differentiate them from UTI symptoms?
20:16 – There is no studies. We don’t have anything. And I remember that I received a call and it was really sad.
20:24 – We got a funding like three years ago. Can I say the funding agency?
20:32 – If you’re allowed to, it’s fine for us.
20:34 – Yeah. Open philanthropy. They were really believing what we were doing.
20:40 – And the idea was to understand, yeah, like how this, like, first of all, do we have bladder cancer markers?
20:47 – Which ones are they? And how can we dissect the whole mechanism? So that was in the news.
20:54 – It came out in different platforms that we got the funding. And then somebody called me and I said, you’re 30 years late.
20:59 – I’m like, sorry, I was 10 years old at that point. And I said, my brother was in the army. He had an accident.
21:12 – He became paraplegic. He had a catheter. He has tons of infections. He almost died in some of them.
21:19 – Now he developed bladder cancer. Now they need to remove the bladder and then basically put him in dialysis.
21:25 – And the outcome, like people with dialysis has really poor outcomes.
21:31 – Because now the infections go directly to the kidneys. So we want to understand that.
21:35 – We want to understand for these people, they are silent. We don’t know.
21:40 – You get these and people telling you the stories, but we don’t have studies.
21:45 – We don’t have anything. How can you differentiate that?
21:48 – If your bladder is not working, how do you feel pain? How do you feel that something is wrong?
21:54 – So I think that we have a lot of work to do.
21:57 – It sounds like it.
21:59 – I feel like sometimes limited because I received this call from this patient.
22:03 – Believe me, we’re doing everything we can. But we need to pay attention.
22:09 – I agree. And with the data that we do have, do we know what the instances
22:15 – of catheterization leading to bladder cancer?
22:17 – It really is a poorly studied. We have many people that have focused like a spinal bifida that
22:25 – right that they need a urinary catheter and they see the outcome. But this really is like a silos in a specific population.
22:33 – Right.
22:34 – And but we don’t have anything that basically does the analysis.
22:38 – Like, yeah, we don’t have like a widespread analysis.
22:42 – So one of the things that we want to do is that we’re able to work with like at the veterans affairs or any other agency that
22:52 – has tons of data over time is to understand like it has been really well documented with AI.
22:59 – If a patient like for, for example, like somebody in the army, they develop this,
23:05 – they have all these infections, then they have the bladder cancer.
23:08 – Do they have comorbidities? We still don’t know whether comorbidities plays a role – plays a role in this situation.
23:14 – Can we start actually analyzing like tons of data that can indicate
23:20 – what could be the relationship between the different things. Right.
23:25 – The type of pathogen as I mentioned, right, E. coli seems to be promoting more cancer markers than others.
23:34 – So we see the person that has more E. coli develop this type of infections. I’m sorry, this type of outcome. So we don’t know.
23:44 – And the problem also that we have is with diagnosis.
23:48 – Previously, we have just your analysis that they just take urine culture,
23:54 – they look for the one that is more abundant. Everything else is contamination. But now we see that that’s not the case.
24:02 – Yeah.
24:02 – And one of the things that we have, one of the major problems that we have is that with urine, we’re just
24:09 – counting those microbes that like to swim like E. coli, pseudomonas, things like that.
24:15 – But E. faecalis, candida, fungal species, they are no swimmers.
24:20 – Staphylococcus aureus, they are no swimmers. They are attached to the catheter or attached to the walls.
24:24 – Yeah.
24:25 – So we’re not even analyzing them as we should.
24:30 – Like we really don’t know. We’re like just fragmenting, just picking up whatever is in the urine.
24:36 – This is a big problem in chronic UTI as well. And patients are very well aware of it.
24:41 – But the work that you’re doing in this space is giving me hope for the future.
24:45 – What do you think is the most hopeful? What gives you hope in terms of solving this problem of catheter associated infection?
24:53 – So what I really think is the inflammation is the one that is affecting the whole system.
25:00 – If we’re able to target inflammation, we will be able to develop better systems.
25:05 – Like, I don’t know. What about if we found that, just saying, I’m not saying people have to use it.
25:13 – Let’s say that we develop these catheters and they are commercially available.
25:20 – What about if we combine that with ibuprofen?
25:24 – And that totally really reduced tons of inflammation. So if we don’t have inflammation,
25:30 – we don’t have protein being coming from the bloodstream to the bladder.
25:34 – We don’t have enough nutrients from the pathogens to attach.
25:40 – And then we have a win-win situation. I think that by understanding and actually doing really critical research,
25:47 – like we need to do a really well documented research to say, yes, this is working. We should move there.
25:53 – And again, targeting inflammation, that could be the key,
25:57 – which the majority of the people what it does is targeting the pathogen.
26:02 – And I think that we have targeted pathogens so much that we have developed all these multi drug resistance.
26:09 – And also it’s not healthy for the patient because they are taking all these into microbials.
26:14 – Like, if my hypothesis is correct, they are taking all these anti-microbials,
26:19 – they are increasing the amount of E. coli, candida, E. faecalis in the gut, the bad microbes.
26:27 – And then they are able to translocate to the bloodstream. We’re seeding them.
26:34 – So we’re affecting our whole system. And we know now that our microflora is
26:40 – critical for mental health, for our metabolism, everything.
26:45 – Yeah.
26:46 – Yeah.
26:47 – Yeah, well, it seems like the solutions might be more simple than we thought they were originally.
26:51 – It would be great if that’s the direction it goes in. It will be much easier for patients to recover.
26:58 – I know and just to point out something else.
27:01 – We don’t know how these antimicrobials are affecting the bladder urobiome.
27:05 – Yeah.
27:07 – We don’t have any idea.
27:09 – A lot of unknowns.
27:10 – Yes.
27:11 – So you have to keep doing the work you’re doing.
27:13 – Yes. Yeah, no, we’re really excited. We’re really, I really, like, I hear all these people that calls me right.
27:22 – And there is no – we’re trying to do our best. I really am – I’m really passionate about what we do.
27:28 – And I think that we can have better treatments if we understand the system better.
27:34 – I agree. And I’ll let you get back to all that really important work. But I want to thank you so much again for
27:39 – joining us and sharing your research and I’d love to talk to you again in the future about developments in that space.
27:45 – Oh, it’s my pleasure. Thank you so much for inviting me and
27:48 – giving me this opportunity to share what we have done and to hear also the patient population.
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