Philippe Zimmern: Thank you, Alan. That was a very generous introduction from you. Yes, bladder fulguration has been part of my life for a quarter of a century now, if not plus. So I've been thinking and reflecting on all this for a long time, so I'm very, very happy that you gave me this opportunity to present where we stand right now to your audience. The title is Bladder fulguration in women with recurrent UTIs. Sorry, men, we don't have you in our radar for the moment because UTIs are way more common in women than they are in men, but there will be some work done in men in the future as well. Briefly, I have no disclosure. And what I'd like to do today is cover my thoughts, how I got to that fulguration, which is powered by the mouse UTI model, how we can affirm that up with human findings, how cystoscopy became a big part of my approach to this condition to recognize the chronic cystitis and staging these women with these recurrent infections. And then we'll talk about fulguration itself, our long-term data, and where we're going right now where they just started NIH multicentric randomized controlled trial. So Alan asked me before, and I think that's a question that I'm often asked, how did I come to this? I came to this because I was seeing older women in my practice post-menopausal, like you probably all do. And I was thinking, "Why do they keep having a recurrent infection?"
They're no longer sexually active. I examine them. I see nothing abnormal. They have no prolapse. I do post-void residual, they empty the bladder properly. I check the upper tracts with renal scan or CT, whatever you prefer, and I see nothing wrong with upper tracts. And I study the bladder, even went as far as doing a bladder X-ray, avoiding cystogram, and I see no diverticulum, no reflex, no bladder dampening, no reason really for infection. And so I said, "Where is these infections coming from?" And so at that time, I probably had the chance to read the literature on that and stumbled into this really wonderful work from Scott Hultgren from St. Louis, who's an expert microbiologist who had worked on trying to understand more about bladder infection in a mouse model. Now, his model came from a special bacteria called UTI89, and that's an acute infection model. It was a bacteria from a student, not my older patient, obviously. So I don't know how many UTI89 my patients have. Probably not much, but that aside, he was able to use that model to understand better how bacteria attach the surface of the urothelium, get internalized, and then start to grow into bacterial communities and ultimately into quiescent reservoirs. And I said to myself, if it's right in the animal model, what would be the human equivalent? So looking in the bladder of my patients carefully, I started to notice more and more what they had on the trigone with oftentimes referred as trigonitis, which is an inflammation of the trigone. And the trigone is an ideal spot for infection because the bacteria obviously is sent up the urethra, kind of anchor the cells on the trigone. It's embryologically different.
It does not have a lot of flux of urine like the rest of the bladder wall that move more. It's a very welcoming, enfolding urothelium, so it's ideal for bacteria to attach. And you typically see them between each of these orifices and the bladder neck. And here are some obvious classic example of some that have pus pockets, chronic infected stones, and a lot of cystitis cystica, as we call it. And then I said to myself, "Well, that's maybe what these infections are." And so the next step was to convince a team of people at my institution to study those patients. And back then I was really blessed in meeting Nicole De Nisco, who was finishing her post doc at the time in a very well known lab by UT Southwestern led by Kim Orth. And then Nicole took that on as her lifetime passion now and developed a special FISH technology, which is a two-day preparation, to try to fluoresce the bacteria in tissue. This had never been done before and that was published in JO. And so on the right here, what you see in green in the center here are the first slide that we saw one day when she had finished her preparation and we were kind of jumping for joy because we had finally seen bacteria in tissues.
Not necessarily in the cells because we don't know exactly if they're in the cells or just in the tissues, but they were clearly now just on the urothelium. They had invaded the wall of my patient's bladder and they were basically residing there and very likely causing those recurrences. And so that was the first big publication. It involved six centers. The university was about two or three years of work and it was published in the Journal of Molecular Biology. That was really our first big turning point to support what we knew by then was effective, which was fulguration, but at least there was some now science to support it, referring to the hypothesis that Alan mentioned earlier in his introduction of my work. Now, if you look carefully in these images, you'll see on the left side the classic image of we call trigonitis with some reactive cystitis cystica around this obvious pus bucket. They're not always present, but they're obviously very typical, but I want you to pay attention to the center image here. This is not the trigone. This is a lateral wall, but if you cauterize on the surface and you remove that kind of biofilm on the surface, just below the surface, you see those white little pods, as we call them, or little abscesses in the wall and that's where the bacteria are located. And as long as they're there and covered by biofilm, none of your antibiotics, in my opinion, will work because they won't penetrate through that.
Once you burn that off and it's gone, this area will heal nicely, as we've proven as well, that they do heal well and the infection never recurs in that same location because the surface ligands changed. There's no longer Uroplakin 3A here for the bacteria to attach. So that's on the side, but that's important to realize that once you cauterize, the area that you cauterize will not have infection ever again in that spot. Now, here on the right side is how the trigone looks like after you've cauterized. This is done on an outpatient basis, light anesthesia, MAC or simple LMA. I use a very fine tip Bugbee electrode just on the surface. It's a surface procedure. I'm not really pushing for laser or resection loop. I think they provide too much deep current that could damage the bladder wall. It's just a surface procedure. Very much like if you had pimples on the surface of your face, you don't want to damage anything below the surface. That procedure takes about 30 minutes on average or less. Patients go home. After that, you have to manage sometime the reaction of that burning, which can cause some emergency and some frequency and almost a feeling of having an infection. If it's intense, we recommend to limit their fluid intake to rest their bladder. Don't go home and drink five gallons of water. That doesn't work well for you after these types of procedure. The usual thing that we use, Azo and Cystex and whatever else you want to use is fine. Bleeding is rare. It's primarily in patient that are on anticoagulation.
We do put them on low-dose daily antibiotics for the first four to six weeks because the symptom they have are similar to cystitis. And we will not continue if they have another infection or if it's just the effect of the fulguration. So this is a simple prevention for a few weeks after which we can discontinue if they're doing well. And the classic problem we run into is that if they go to an emergency room for whatever reason during that timeframe, people will get a urine analysis like they do in every ER in the world and they'll find red cells and white cell and they'll tell the patient you have an infection. No, you don't have an infection. Just had a recent fulguration. That's why it looks full of white cells and red cells. Now, at the bottom is how it looks six months later. And why six months? Because we've studied that. That's the time it takes for the fulguration to heal in the bladder. The bladder is lined with urine all the time. The healing is slow. The scab forms around two or three months after the procedure and the new tissue that starts growing takes that time to allow the healing to be complete.
So don't look before. It's not going to be used to your patient, but do look at six months. And the reason you look at six months is just to make sure that way you've cauterized is healed and, very importantly, to make sure there are no new lesions that have appeared during that timeline because bacteria can be already attached to the bladder wall. As we've shown in this first GMB paper, at the time we had biopsied some normal appearing areas which already contained bacteria. So the bacteria could still be there, you don't see them and sometimes you look back at six months and now you see some new spot that you're not seeing at the time of your fulguration. So before you declare that patient "cured", go back endoscopically if you don't mind. And then use your flexible scope to look back from top down because the trigone is very easy to look at from a top-down view, not always easy to really fully evaluate from a straight-on view. Now, when I start to look at my outcomes, I realized that there was apples and oranges and the first papers did not really sort that out very well. We had women with just trigone involvement, some where the infection had traveled a little bit more toward the bladder base, not just the trigone. So there was some local progression and then some where clearly the lateral walls were involved, lateral to the urethral orifices. And then the very difficult one to treat, in my opinion, is when the whole bladder is involved. We use the term pan, PN, pan studies, so those very invasive form of bladder infection. And obviously, if you have a confined area of infection versus the whole bladder being involved, those are totally different diseases in term of success with the fulguration.
Now that it cannot be done as we have published, but the outcome will not be as good, obviously, and repeat fulguration may be needed in those situation or the form of treatment that we can talk about if people are interested by that topic. So this is simple. Everybody can relate to that. It's not complicated. It's not a TNM classification. It's just a visual classification, but it might help people in how they report their outcome if they start to do this in their own practices. As far as publication, I could not list all of them. We have a lot in this field, but the first one were really in the order of time. The 2019, where we showed some solid cure and improvement at a minimum five-years follow-up. The outcome definition there was based on the definition of recurrent UTI, which is two in six months or three in a year. So the cure was zero in a year, improvement was one to two, and failure was three and above, following just the definition we had. We had recurrences, as I mentioned, and we showed that we can go back and win out some of these patients by repeating the fulguration in the areas of recurrences.
We had clearly better outcomes in women who had just stage one, the chronic trigonitis, a less favorable outcome, but still better than having your bladder removed in those with very involved pancystitis who are at that stage. Recalcitrant, as Alan said, to a lot of antibiotics comes sometime to us with PICC line and several hospital admission and IV antibiotic courses. And more recently in general urology we had a very long-term outcome paper, which provided the best result that we have in this field with follow-up up to 10 years, following which the editor of the Journal of Urology invited me to write a JU forum. And in that forum, which many of you may have read, we had three sections. The first one asking the group, if you have a woman who's recurrent UTI whose treatment has been antibiotic therapy and now she has antibiotic recalcitrance, she has a lot of allergies to antibiotics of resistance, what do you do? What happens when this fails? And what if these recurrences were due to persistent bacteria in the bladder wall, which is what we've been thinking is the real role of fulguration. And is that fulguration really the best treatment for those people at that stage?
And the title of that JU forum concluded that time for trials, which I was fortunate to at that time submit an NIH grant, which was very well reviewed. It was a very excellent score and just got funded this year. So we're starting a multicentric trial which I think will need that level-one evidence for really a change in opinion about fulguration. And I totally respect people that are on the fence about it because we don't have level-one evidence yet. We have some good clinical report, but not the level of science I would like to see to get out and for sure this is a way to go. Now to conclude briefly, when I see someone coming to me with bladder infection, I put them into three simple categories. The one that have good response to antibiotics do well on cell therapy or critical treatment or a large array of non-antibiotic alternative that we have, including D-Mannose, hippurate, et cetera.
You all know those very well. I have some patients clearly tell me as soon as I stop the antibiotic infection restarts. Those are clear recurrent people and their option, they are very limited. I will scope those patients to see if fulguration is an option sometimes. In fact, they're coming to me to scope them because nobody did so far to see if there's an area that could be cauterized in their bladder. And if so, that's what we will do. And the people that have a very, very advanced form of bladder infection, especially those where the whole bladder is involved, where we have only a few sometimes just IV treatment left to treat them. They've had urosepsis before, the infections arise very quickly. It can totally control their lives because they can't go anywhere by fear of having another infection and those have really very little option at that point. We have extensive fulguration, cystectomy as the last resort. We published our experience with that as well and right now we're working into intravesical instillation to see if there is an in between alternative to help them or maybe a combination of fulguration and intravesical treatments. So Alan, this is where we are. Thank you so much for me to give this overview.
Alan Wein: Terrific. Thank you. So I think one thing that should be a lesson to young investigators is basically how to get an idea and how to develop it from really its inception to clinical trials and culminating in an NIH grant, which I'm delighted that you got. So when you initially start out with these people, do you render them infection-free before you cysto and fulgerate them?
Philippe Zimmern: Yes, because you can't do a cystoscopy on someone infected, so they obviously have to be on antibiotic prophylaxis at the time. And if the decision is to go for fulguration or now we can offer them to be part of a randomized trial, very few of them want to take the risk of another infection between the time they see me and the time of the fulguration. So they tend to come in to the operating room on daily prophylaxis at that time and then we continue the daily prophylaxis for about six weeks after the procedure until I see them back in the office.
Alan Wein: Right. What do you use after the procedure? You said low dose antibody ...
Philippe Zimmern: Typically, the one we use most, which is nitrofurantoin, which is low cost, been around for a long time, specific of bladder. Does not use for any other antibiotic treatment in the body, has a low resistance profile as we published. And in fact, in this multicentric trial that we have, we have studied our bacterial profile against nitrofurantoin to make sure that it was a good choice for our patient in this randomized trial.
Alan Wein: Right. What's the other arm of the trial?
Philippe Zimmern: So one trial is just a standard of care, which is six months of daily nitrofurantoin, which is what the long-term antibiotic prophylaxis is right now. And the other arm is the same, same basically as the other arm, six months for everybody, but we have the fulguration. And then after six months, the hypothesis that those who had the fulguration will have a lesser chance of recurrence than those who stop their antibiotics and just get observed. So the trial goes for two years, but we'll have one year and two years follow-up so that people that would say, "Well, maybe people did great for one-year, but it's not durable," will not have this argument against doing the fulguration. But that's how we have to follow standard of care for NIH trial and standard of care is long-term low-dose antibiotic treatment. So everybody has to get that.
Alan Wein: When you see these people back, let's say it's six months and you look in and even if they have had no issues, but you see what you think are reservoirs, do you tell them that they need another fulguration?
Philippe Zimmern: That's a great question. There are obviously different shades of gray here, correct? So if I see a couple of spot, I'm not going to worry about that because this will not manufacture enough bacteria to make them sick. It's only if I see several areas that I'm concerned about. Sometime we just open up for six months of our observation to see which way things are going. I think the immune systems can kick in and help them fight this infection better when the volume of infection is less. But right now we're looking at immune changes in the bladder wall with our microbiology team. We're looking at lymphocytes and the lymphoid tissue to see how people respond. Why are this bacteria not eliminated by your body? Where are they still there in the tissue? So there are obviously unanswered question there. So in the future, we may be able to work on local immunotherapy to get to those sites. I think fulguration, at some point, I hope will become obsolete when we have the ideal intravesical treatment to take care of these people because it's a surface disease like you treat bladder cancer with BCG. I hope one day I can have my BCG equivalent for bladder infection or having to spend time doing the fulguration. But as we speak, that's the best option I have to fight and eliminate this large volume of infection in some of these people.
Alan Wein: What's the most number of times you've refulgurated someone?
Philippe Zimmern: I think we've gone up to three or four times. When people have no other option than that or a cystectomy, well, as long as I see areas I can fulgurate that clearly show recurrences, I will be happy to do that. This is a very low-risk operation, as we discussed. So if it's really a few spots, I've done them in the office under local. Some patients are at that, some not that great, but that we've developed that with a very small pediatric scope. And I'll report on that next year probably as we're building up our experience with that, but it's really for very small areas. If I see enough to have them asleep, I'll put them asleep because once they're under anesthesia, I have more time to really look carefully at the surface to survey everything in the office. As you know, you're limited, so you really have to go after a specific area, but not a large volume of disease.
Alan Wein: And the small Bugbee electrode that you refer to, that's commercially available?
Philippe Zimmern: Absolutely. It's very commercially available. There are some fine teeth, there are some round shape. Yeah, every OR can have that. I've been asked about laser, but I don't think laser or resection loop can really tell you the depths of penetration of the current, and I don't want to really alter the detrusor muscles, so I want to stay right on the surface. So the Bugbee allows you to just very gently ... And I have movies on that that you may have had the chance to review to show how we do it.
Alan Wein: Do you use a special wattage?
Philippe Zimmern: Yes, we do. We do typically 15 to 20.
Alan Wein: Right, so really low.
Philippe Zimmern: Yeah, it's a low setting. We use water, low setting. And outpatient, I usually put Lidocaine gel at the end of the procedure before they wake up so they're comfortable waking up. And I'm, again, very careful to stay away from the ureteral orifices. We don't burn the ureteral orifices and we don't burn the bladder necks. We don't get a secondary bladder neck contracture.
Alan Wein: Right. Congratulations on really developing this. And well, I think it's a great body of work and thanks so much for being with us.
Philippe Zimmern: I appreciate the invitation, Alan.
Alan Wein: Absolutely. Take care.
Philippe Zimmern: Thank you.