Janelle Hart

J. Curtis Nickel, MD, FRCSC, discusses the antibiotic stigma associated with recurrent UTIs in a recent interview. Along with dissecting the issue, he gives advice to practicing urologists about prescribing treatment and highlights research that could potentially transform recurrent UTI treatment for good. Nickel is a professor of urology at Queen’s University, and a research chair in urologic pain and inflammation at Kingston Health Sciences Centre, Kingston, Ontario, Canada.

What is the scope of the problems surrounding recurrent UTIs?

We have all come to understand that recurrent urinary tract infection in women is a major health care problem. 

Depending on what literature you read, between 40% and 60% of women suffer from urinary tract infection sometime in their lifetime. Many of these women have recurrences, and these recurrences can occur within 6 months in about 20% of patients who have an incidental urinary tract infection. 

One in 5 women overall suffer recurrent urinary tract infections that is defined as greater or equal to 3 UTIs per year. However, many of these women suffer much more, with the average being 6 UTIs per year in this population of women with recurrent urinary tract infection. 

To summarize, in the course of any year, 11% of women will suffer a urinary tract infection while 3 out of 100 will suffer from recurrent urinary tract infections. So, this really is a major health care issue.

How is the personal burden surrounding recurrent UTIs a problem for patients?

We usually think of recurrent urinary tract infections as uncomplicated, simple infections that will resolve with our standard antibiotic therapy. However, in reality, recurrent urinary tract infections can cause severe debilitating health consequences. 

Patients suffer recurrent bladder and urinary pain and bothersome urinary symptoms each time they get an infection. These women suffer from disability, and by disability, I mean problems doing life activities, including employment. 

Studies have shown that women with recurrent urinary tract infections have significantly worse mental health compared to a normal population. And it's even more significant in some aspects of physical health, but particularly physical sexual health. We also note that as part of this, patients have trouble with their overall social well-being. This translates into a very poor quality of life for women suffering from recurrent urinary tract infections.

And then we look at the impact of the treatment they have to endure. There are multiple short- and long-term side effects from antibiotics including serious, irreversible side effects that many of these women end up having. They can develop intolerances or allergies to the standard antibiotics prescribed, and this can make it more difficult to treat subsequent infections. 

Many of these women, because of the long-term accumulation of antibiotics from either multiple episodic or prophylactic dosing that can be prescribed for 3 months or as long as 12 months, develop a personal reservoir of resistant uropathogens in their gut that can make treatment of subsequent urinary tract infections very difficult, sometimes requiring parental or intravenous antibiotics for simple recurrent uncomplicated UTIs. 

And then again, there's the problem—rare, but it does occur—that patients can transition or develop complicated urinary tract infections, serious episodes of pyelonephritis and even urosepsis. Some of these consequences are associated with the threat of hospitalization, and in rare cases, even death.

And finally, frequent use of episodic antibiotics or longterm prophylactic antibiotics to treat or prevent urinary tract infection, change the patient's personal microbiome to an unhealthy state. 

Our gut microbiome is important to keep us healthy. It impacts our reaction to stress, anxiety, sleep, and well-being, and changing that to a dysbiotic or somewhat polluted gut microbiome with less diversity caused by antibiotics, can be a very unhealthy state for these women. It also impacts the microbiome of the vagina, leading to increased yeast overgrowth and yeast vaginitis. In addition, it can impact the microbiome of the bladder, leading to less diversity, sensitization, and even chronic pain states between episodes of recurrent urinary tract infections. 

So, as you can see, there is a huge personal burden associated with a diagnosis of recurrent urinary tract infections, despite the fact that it appears we have effective therapy with the use of antibiotics.

Are there any stigmas related to this condition?

Yes, there is, and it's becoming more obvious with our knowledge about the increasing importance of overall anti-microbial resistance that is evolving in this patient population and in society as a whole.

Antibiotic treatment and prophylaxisis the only guideline-recommended therapy in North America. It does work, but it comes with all sorts of problems. We talked about the mild, moderate, severe, and even irreversible adverse events associated with antibiotic use. But overall, the 1 major issue that we see from a population perspective is the fact that it promotes anti-microbial resistance. 

So, the stigma is that the massive use of antibiotics in this population is helping to drive the overall cost, the difficulty in treating infection, and the transition to serious UTIs and even mortality, in not only these patients but other patients because of this massive use of antibiotics in this population. 

That's really the only stigma and it's not the fault of the patients with recurrent urinary tract infection, and most of us in the medical profession realize that this stigma is more the result of our only treatment we have for this condition.

What can urologists do about this stigma?

We can do something about it for our patient population and for this stigma of promoting antibiotic resistance in our community. The most important thing is antibiotic stewardship. We have to be very careful of what antibiotics we prescribe for UTIs, try and stick to the first-line anti-microbial therapy that's recommended by guidelines, try and keep the course of anti-microbial therapy as short as possible, but long enough to treat and eradicate the bacteria, and be careful how we use prophylaxis. Perhaps a stewardship program of post-coital antibiotics will achieve the same results in sexually active young women compared to long-term, 3-to-12-month prophylaxis. 

Alternate day prophylactic therapy works in many patients. Keep the dose and duration as low as possible with planned drug holidays. And then we can recommend conservative measures. We've always done that, including post-bowel hygiene, the non-use of douches, baths versus showers, and the type of clothing patients wear, but none of these really benefit the patient. They actually can cause self-guilt and personal anxiety. 

The only conservative measure that's really proven is to increase water intake. If patients increase their water intake to 2 liters per day, yes, they'll void a little bit more often, but that dilution of the lower urinary tract keeps the uropathogenic bacteria at bay and we do reduce urinary tract infections.

For postmenopausal patients, evidence-based use of intravaginal estrogen reduces UTIs in this population. It's not the panacea and it doesn't work for everybody, but it certainly reduces the recurrent UTIs in the susceptible patients. 

We can use various supplements, like cranberry extract, but it's important that we use those with a described dose of proanthocyanidins (PACS). We can use D-mannose, particularly in patients with 

 recurrent urinary tract infections. Probiotics might help to improve or regenerate the microbiome of the gut and the vagina. 

And prebiotics, trying to feed the good bacteria in our microbiome can be accomplished by a good, healthy diet. A number of dietary improvements can be made in many of our patients that will help their microbiome fight infection.

Finally, I believe that science is going to help. I recently presented, in the late-breaking abstract session at the 2021 American Urological Association Annual Meeting, the exciting potential of a new, very safe sublingual vaccine, MV140, which significantly reduces recurrent urinary tract infections in this population of women; in fact, preventing it in almost 60% of women who once had a median of 6 UTIs going to a median of 0 UTIs in a 9-month efficacy period. This particular vaccine is being used in special access or compassionate drug programs in Europe, Australia, New Zealand, and the UK. 

And to date, over 40,000 patients have received this vaccine and it has shown safety and appears, in observational studies and this most recent pivotal trial, to be efficacious. So, I do believe that there's something that physicians will be able to offer beyond these conservative measures and antibiotic stewardship in the future. I think our goal is to reduce antibiotic use in this population, while reducing the issue of recurrent urinary tract infections in our female population.

Is there anything else you feel our audience should know about this topic?

I think it's important to address the issue of the burden that these patients are carrying. We have to address the fact that overuse of antibiotics in this population is a major healthcare problem, and see what we can do through antibiotic stewardship. We have to explore all the conservative measures we can in this population to reduce overall antibiotic usage. 

The perceived stigma that this population is promoting antibiotic resistance is not the patient’s fault. It's our responsibility as physicians and urologists to find the answers for our patients. And I do think the evolving science, as I mentioned, is going to help us help our patients. Any burden or stigma associated with this condition will gradually improve as we get better at addressing the underlying issue by reducing the risk of developing recurrent UTIs.

This article was originally published on Urology Times®. 

Articles

Recurrent urinary tract infections (UTIs) place a large burden on women as they struggle to find the right remedies for this problem. According to guidelines, there is only 1 temporary cure for this condition and that is antibiotics. As more antibiotics are taken by this susceptible population, however, the bacteria can adapt and make recurrent UTI treatment in the future much more difficult.

The stigma around antibiotics for recurrent UTIs

In a recent study, “A novel sublingual vaccine will dramatically alter the clinical management of recurrent urinary tract infections in women,” presented at the 2021 AUA annual meeting, J. Curtis Nickel, MD, and a team of investigators found that the novel MV140 vaccine is a safe and effective strategy for treating rUTI in women.1 Nickel is a professor in the department of urology at Queen’s University and a urologist at Kingston and Hotel Dieu General Hospitals, Kingston, Ontario, Canada.

According to Nickel and his coinvestigators, MV140 is a polybacterial sublingual vaccine, consisting of E. coli, K. pneumoniae, E. faecalis and P. vulgaris, which induces a T-cell specific adaptive and an immune response at the genitourinary tract.

The findings shared at the AUA meeting included results from early uncontrolled studies, the first phase 3 multicenter, double-blind, placebo-controlled randomized controlled trial (RCT), ongoing safety monitoring from special access programs (SAP; 2014-2020), and the first North America (NA) clinical experience evaluating MV140 (Uromune) for the prevention of rUTI in women.

Across 5 uncontrolled studies, results found that 1408 women treated with MV140 had significantly higher UTI-free rates (35% to 90%) compared to 499 women treated with antibiotics (0% to 9%). Additionally, the RCT revealed UTI-free rates of 55.7% at 3 months and 58.0% at 6 months, while the placebo group exhibited a rate of 25%. The median number of UTIs in MV140-treated patients within this study were 0.0 (IQR, 0.0-1.0), compared to 3.0 for placebo patients (IQR, 0.5-6.0).

As for the ongoing SAP study, only 1.7% of over 20,500 patients reported adverse reactions. And in the NA study, patients experienced a 48% UTI-free rate with an overall 82% reduction in UTI episodes. Only 1 patient had 2 mild vaccine-related adverse reactions in this study.

Taken as a whole, these findings suggest a potential, evidence-based alternative to standard antibiotic regimens in treating patients with rUTI.

Further discussion with study investigator J. Curtis Nickel, MD

Please provide the background for this study.

Recurrent urinary tract infections in women are a major health care issue. It's not really associated with mortality; it's associated with a lot of morbidity. With more than half of women having a UTI sometime in their life, about 40% of them will be classified as having recurrent urinary tract infections. That's more than 3 per year, and for many that can be, on average, about 6 a year. So, 3 out of 100 women every year are classified of having recurrent urinary tract infections.

The way we manage those are using things like cranberry extract, probiotics, and certainly intervaginal estrogen for perimenopausal and postmenopausal women. But the only treatment that's really effective is antibiotics—either episodic antibiotics or long-term prophylactic antibiotics that are taken for weeks and months. The antibiotics themselves are problematic. There is cost to patient and society, there is the detrimental effect of antibiotics on the patient with adverse events or effects, sometimes being quite serious and even irreversible. Antibiotics only work as long as the patient is taking the antibiotic. And then we have the rising spectra of national and international antibiotic resistance, which is becoming a huge international medical issue.

In the abstract, the vaccine is described as “game changing.” Can you explain why that’s the case?

Right now, there is a huge unmet need in women's health for some way to prevent recurrent urinary tract infections. I mentioned the methods that we have, and the only one that really works well is intervaginal estrogen in peri- and postmenopausal women, but it doesn't work in all. We discussed the problems associated with antibiotics. So, what we're looking for is some safe and effective intervention that will completely change the way we manage recurrent urinary tract infections in women. I and others have always believed that the answer would be a vaccine. Over the last 20 years we've looked at vaccines, and there are vaccines available with some efficacy, but not enough to change the game from antibiotics to something safer and more effective. That's why I think this vaccine, with its effectiveness and safety, will be a major game changer.

What were some of the notable findings from this study? Were any of them surprising to you and your co-authors?

I am always surprised when a large, well-planned, randomized, placebo-controlled trial is positive or even more positive than we thought with early observational, uncontrolled studies. And we do have evidence from at least 5 studies that this sublingual vaccine is effective and safe. I have the only early clinical experience in North America, having had over 65 patients vaccinated and having followed them, some for over a year. So, I know the vaccine works. But we're always wondering whether or not it would show in a randomized, placebo-controlled study and this study met and exceeded the endpoint in reducing the risk and preventing urinary tract infections.

What is the next step? What will future research on MV140 focus on?

In this particular study, we were able to show that there was a very clinically significant decrease in the rate of UTIs in the vaccinated group, preventing UTIs in almost 60% of vaccinated patients. We found that if patients did get a UTI, and there was a significant median time to UTI that was many times greater in the vaccinated group, it was usually mild and self-limited. The study went for 9 months. Based on real world experience with this vaccine in special access programs outside North America, we believe that the vaccine efficacy may wear out after a year or 2. So, future studies are going to have to look at re-vaccinating patients who revert back to their recurrent urinary tract infection state.

Further, there is some evidence in observational studies that's effective and complicated, showing outcomes for UTIs in the frail elderly, in children and in men, we're going to have to look at all those groups. This could be a game-changer for recurrent urinary tract infections in children who rely on antibiotics. It could be a game changer in the frail elderly, particularly those in long-term care homes, where UTIs are a significant problem, even causing mortality and antibiotic over utilization. We'd also like to see it used in complicated UTIs in men. All these are going to have to be studied, and that's why it's so exciting. This vaccine has legs to run on.

What is the take-home message for the practicing urologist?

The take-home message for international urologists is that this vaccine is available on named patient programs or special access programs. Unfortunately, that's not the case for North America. Health Canada realizes the huge unmet need and is going to be looking at regulatory approval on an expedited basis based on the observation studies, the special access program safety audit on over 20,000 patients have already received this, the Canadian early experienced trial that we're doing and the RCT. We may have approval in Canada for this vaccine for Canadian women with recurrent UTIs sometime next year. The FDA is going to probably look at this data and advise whether or not further studies will be required in the United States before it's widely available in the United States either under special access programs, or across the board. It'll take a little time in the United States. Vaccines are a little more problematic in United States compared to the rest of the world.

Is there anything else you feel our audience should know about the research?

It's exciting research. The randomized, placebo-controlled study has replicated all the previous studies, looking at recurrent urinary tract infections and this vaccine. The other thing they should realize is that it is a vaccine that is self-administered by the patient sublingual over 3 months. That is why it appears to be so safe. It's not an injected vaccine. The immunity builds up very slowly over 3 months, and it persists for 9 months. We'll see how long that durability effect is over the long term, but keep your eyes and ears open because, like I said, this vaccine will be a game changer for women's health in the future.

1. Nickel JC, Lorenzo-Gómez MF, Foley S, Saz-Leal P. A novel sublingual vaccine will dramatically alter the clinical management of recurrent urinary tract infections in women. Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PLLBA-02.

This article was originally published on Urology Times®.

Women who suffer from recurrent urinary tract infections (rUTIs) are typically treated with antibiotics. These treatment regimens, however, are associated with high rates of morbidity as the world faces rising antibiotic resistance.

Novel vaccine for recurrent UTIs

Nitya E. Abraham, MD, Christina Shin, BA,

 and their team of researchers conducted a cross-sectional, survey-based study of female pelvic medicine and reconstructive surgery (FPMRS) patients to assess the satisfaction and savings of televisits, using their findings to draw conclusions and predictions regarding the future of telemedicine. Abraham is an associate professor and residency director of the department of urology at Montefiore Medical Center, and Shin is a medical student at the Albert Einstein College of Medicine, Bronx, New York.

Could you discuss the background for this study?

Abraham: Our practice switched to telemedicine completely in 2020 during the COVID-19 pandemic, and now we realize that telemedicine is here to stay. So, we wanted to look back at all the telemedicine visits we conducted specifically in FPMRS and we wanted to look at whether patients were satisfied with their telemedicine visits, what kind of savings they experienced, whether it be financial savings or time savings, and then also what happened after those telemedicine visits and if the outcome of the visit differed based on what the patient presented with. So, based on the diagnosis or chief complaint they presented with, were certain chief complaints more amenable to telemedicine than others?

What were some of the notable findings? Were any of them surprising to you and your co-authors?

As the COVID-19 pandemic prevails, many clinicians and patients question whether telemedicine will be the new mainstream form of health care.

Shin: The most surprising thing we found is that the majority of patients with televisits were satisfied, with many saying it was easy to schedule, easy to comfortably share sensitive information with their doctor, and with the most surprising finding being 80% saying they would choose it again over an in-person visit.This makes sense given our other findings. Forty-eight percent were able to save 1 hour on travel, 29% were able to save $25 on transportation, 23% have a health condition that makes it difficult to go to in-person visits, 20% say transportation is a barrier for in-person visits, and 22% say that they or a family member were able to avoid taking time off from work by doing a televisit instead of an in-person visit.

Another part of our study was outcome-based. We found that 53% of televisits required an in-person exam or an in-person procedure being scheduled, with certain patient diagnoses and characteristics as significant predictors, like Dr Abraham said. We found that patients presenting with chief complaints of prolapse as well as those presenting as new patient visits rather than follow-ups were more likely to need a face-to-face visit. The other way to interpret these findings is that 47% of televisits didn't require another face-to-face visit being scheduled, so this suggests that some televisits could reasonably substitute an in-person visit.

Abraham: It makes sense that when a patient is presenting with prolapse, you would want to do a physical exam to look at the severity of it. Whereas other conditions, like perhaps urinary incontinence or recurrent urinary tract infections, there's a lot of patient counseling involved. Those kinds of chief complaints would be more amenable to a telemedicine visit.

How do these findings compare with previous research and/or anecdotal evidence regarding telemedicine visits with an FPMRS specialist?

Shin: One thing to keep in mind with our patient population is that the New York City comptroller executive study found that 48% of Bronx households, which is the patient population we serve, are without broadband Internet access. So, video visits are not that feasible for our patient population. In light of this, as well as our patient population being underserved, our study strongly suggests that telemedicine can become the mainstay of treatment within FPMRS even after the COVID-19 pandemic has ended. This validates the anecdotes of patients who come in for face-to-face visits, saying that they have time and cost constraints, so this is a great study of the benefits of televisits.

Shin: Televisits are a valuable form of health care, and I think it could be better reimbursed even after the pandemic ends, especially for telephone visits. A lot of our patients actually preferred that. Fourteen percent of our total visits were video visits, so the majority were telephone visits. In addition, our research is unique in identifying patient characteristics that are less amenable or more amenable for televisits. This is important for televisit providers in terms of optimizing their practice as well as how best to balance in-person visits vs televisits. Patients with prolapse need to be better assessed on physical exam as well as new patient. They may require additional lab testing or a procedure being done, so maybe it's better to offer them an initial face-to-face visit.

Abraham: I would add that patients are happy with telemedicine visits, even if they’re telephone visits. In half of those visits, the issues are adequately addressed with telemedicine, meaning that they don't need a subsequent face-to-face visit within 30 days. This is an important form of providing health care, especially for people who have a lot of limitations in coming for in-person visits.

Is there anything else you feel our audience should know about the findings?

Shin: With the ever increasing use of telemedicine, more research could be done to better define what a successful televisit is. In our study, we used not requiring a face-to-face visit or a face-to-face procedure within 30 days as a proxy for success, but there are more nuances to televisits. I think that this will become a mainstay of treatment and more research needs to be done in identifying patient characteristics that are more amenable or ways to optimize televisits for the future, as well as developing a better understanding of patient barriers with televisits or in-person care and to address them as needed.

Abraham: I hope health care insurers will see this kind of research and whatever research comes down the pipeline to justify reimbursing telemedicine visits as an equivalent, or at least a really great option in addition to in-person visits. Reimbursement for these visits is key.

What are some tips you would give providers for conducting a successful telehealth visit?

Abraham: The most important thing is appropriate patient selection. I have patients in my practice who are wheelchair-bound, who need to take an ambulance or an ambulette to come in. So, it's a big production to come to an in-person visit. Those would be ideal patients to follow up with a telemedicine visit if it's just patient counseling that you're providing. On the other hand, patients who need to be physically examined; for example, a patient with prolapse or other physical complaint like a vaginal mass, bleeding, drainage, should be seen in person. So, I think appropriately selecting your patients will result in a successful telehealth visit.

This article was originally posted on Urology Times®. 

Janelle Hart

Articles

The stigma around antibiotics for recurrent UTIs

Novel vaccine for recurrent UTIs

FMPRS patients happy with virtual visits