new research uti

Research reveals potential new strategy to combat urinary tract infections

Identifying the dynamic events occurring during urinary tract infections (UTI) has revealed a new potential strategy to combat this condition, considered the most common type of infection. Researchers at Baylor College of Medicine and Washington University School of Medicine have discovered that the sequence of events taking place during UTI sustains a delicate balance between the responses directed at eliminating the bacteria and those minimizing tissue damage that may occur in the process.

The NRF2 pathway stood out as a key contributor to this balance, by regulating both the potential damage to tissues and the elimination of bacteria. Treating an animal model of UTI with the FDA-approved, anti-inflammatory drug dimethyl fumarate (DMF), a known NRF2 activator, reduced tissue damage and bacterial burden, opening the possibility that DMF could be used to manage this condition in the future. The study appears in the journal Cell Reports.

"Urinary tract infections are not only common, but typically recurrent and tend to give rise to antibiotic-resistant bacteria, a serious medical concern," said corresponding author Dr. Indira Mysorekar, E. L. Wagner Endowed Professor of Medicine- infectious diseases at Baylor, previously at Washington University School of Medicine.

"More than 85% of UTI are caused by uropathogenic E. coli (UPEC), bacteria that can attach to the surface of the epithelial cells lining the inside of the bladder, called urothelial cells," said first author Dr. Chetanchandra S. Joshi, a postdoctoral associate in the Mysorekar lab. "Attached UPEC can then enter the urothelial cells, where they reproduce. In the current study, we looked at how urothelial cells fight back UPEC invasion and proliferation while preserving their integrity, which is essential for proper bladder function."

A dynamic balance of responses

Working with urothelial cells grown in the lab, Mysorekar, Joshi and their colleagues discovered that a precise sequence of events followed UPEC invasion of urothelial cells. First, in the early hours after their infection, urothelial cells defended themselves by producing reactive oxygen species (ROS), highly active compounds that kill bacteria. However, if sustained, ROS also can damage urothelial cells, which would be detrimental for the bladder.

"We found that accumulation of ROS activated an anti-ROS response in urothelial cells, called the NRF2 pathway, that minimized the damage excess ROS could cause to the urothelial cells," Joshi said.

The NRF2 protein is located in the cytoplasm of the cells bound to another protein called KEAP1. "When ROS reaches a certain level, NRF2 separates from KEAP1 and goes into the nucleus of the cell, where it activates a series of genes. Some of these genes produce proteins that block ROS, and some that limit inflammation," Joshi said.

"Interestingly, one of the genes NRF2 activates is Rab27b, which promotes the elimination of UPEC from urothelial cells," Joshi said. "Together, these coordinated events mediate the elimination of UPEC while preserving the integrity of the cells attacked by the bacteria."

A potential new way to combat UPEC

Understanding the process that follows a UPEC infection revealed a potential new strategy to combat the condition. "We learned that active NRF2 was involved in both neutralizing ROS, which helped protect urothelial cells, and eliminating UPEC," Joshi said. "These findings suggested that a drug that activated NRF2, such as DMF, might help clear UPEC infections."

DMF is FDA-approved to treat inflammatory conditions such as multiple sclerosis by dampening the inflammatory response.

"Working with an animal model of UTI, we showed that treatment with DMF activated NRF2, dampened the immune response, limited the level of damage the bacteria caused to urothelial cells, and promoted activation of RAB27B, which removed bacteria from the bladder," Mysorekar said. "Our findings support further exploration of this approach as a potential treatment for UTI."

Women tend to have recurrent UTI, which can lead to chronic inflammation, extensive bladder mucosal damage and chronic infection. Continued antibiotic treatment also negatively affects the microbiome, the 'good bacteria' of the body, and promotes the development of antibiotic-resistant bacteria.

"The most exciting part about this work was identifying a non-antibiotic-based therapy that contained the infection and reduced inflammation," said Mysorekar, who also is professor of molecular virology and microbiology at Baylor. "Although much work is needed before it reaches the clinic, treatment with DMF has the potential of helping millions of women affected by this condition."

Other contributors to this work include Amy Mora and Paul A. Felder, formerly at Washington University School of Medicine.

This work was supported in part by NIH grants R01AG052494, R01DK100644 and P20 DK119840.

• Bladder Disorders
• Immune System
• Bladder Cancer
• Infectious Diseases
• Healthy Aging
• Kidney Disease
• Pharmacology
• Urinary tract infection
• Upper respiratory tract infection
• Sexually transmitted disease
• Gastroenteritis
• Human parainfluenza viruses
• HPV vaccine

Story Source:

Materials provided by Baylor College of Medicine . Note: Content may be edited for style and length.

Journal Reference :

• Chetanchandra S. Joshi, Amy Mora, Paul A. Felder, Indira U. Mysorekar. NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression . Cell Reports , 2021; 37 (3): 109856 DOI: 10.1016/j.celrep.2021.109856

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Strange & offbeat.

New UTI vaccine wards off infection for years, early studies suggest

More than 50% of the patients who used a new mouth-spray-based vaccine didn't have a UTI for up to nine years.

A new mouth-spray vaccine reportedly stops urinary tract infections (UTIs) from coming back again and again, as can happen in many people prone to the condition.

The pineapple-flavored vaccine, called Uromune, has so far been tested in one study without a placebo group and one completed gold-standard clinical trial. Both studies suggest that, for more than half of the participants, the vaccine helped ward off recurrent UTIs for months. It will need more testing to be fully approved but shows promise.    

"Vaccines would be a game changer for a huge number of people who are, at the moment, stuck with long-term UTIs and there's nothing that can help them," Jennifer Rohn , a researcher who specializes in renal medicine at University College London and was not involved in the studies, told Live Science. 

A new way to prevent UTIs?

UTIs can cause debilitating pain ; abdominal cramping; and an urge to urinate when you don't need to. Approximately 50% of women will have a UTI at least once in their life ; of those, 22% will experience recurrent infections. 

Women are about 30 times more likely to get UTIs than men .

Related: Dangerous 'superbugs' are a growing threat, and antibiotics can't stop their rise. What can?

Many patients who develop UTIs repeatedly are prescribed preventive antibiotics to help reduce their risk of future infections. Yet research shows that heavy reliance on antibiotics has led to the emergence of multidrug-resistant bacteria . Plus, antibiotics can wipe out helpful bacteria in the body along with the disease-causing kind. 

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UTI vaccines could offer an alternative approach, and Uromune is one such vaccine. The spray contains a mixture of the four bacteria most commonly responsible for recurrent UTIs: Escherichia coli , Klebsiella pneumoniae , Enterococcus faecalis and Proteus vulgaris .

"Together, they make up about 88% of urinary tract infections," Dr. Glenn Werneburg , a physician-scientist at the Cleveland Clinic who was not involved in the studies, told Live Science. For the vaccine, these bacteria are inactivated by heat so that the proteins on their surface are still intact and thus can be identified by the immune system.

The vaccine is sprayed under the tongue because exposing the base of the tongue, the tonsils and the roof of the mouth is thought to trigger a strong immune response in "mucosal" tissues. These include the lining of the urinary tract and bladder, Werneburg said.

Scientists first tested the vaccine in a U.K.-based trial of 75 female participants; there was no comparison group that didn't use the spray. In that study , 59% of the women who used the spray daily for three months had no subsequent UTIs for the following year. These participants had experienced three or more UTIs in the year prior to receiving the vaccine. 

In a second phase of the study, the scientists followed up with nearly 40 of the original participants, and they also added 17 men to the trial. In that group they found that, for 48 of them, the vaccine was still very protective nine years after its initial administration. These participants had remained UTI-free over that period and had no adverse effects. 

On average across the whole group, all the patients remained UTI-free for about 55 months, or about 4.5 years.

The findings of this study were presented at the European Association of Urology Congress in Paris on April 6. Uromune has also been tested in one gold-standard clinical trial with a placebo group. In that trial, 56% and 58% of women who used the spray for three and six months, respectively, remained free of UTIs for up to nine months, compared to only 25% of the placebo group. 

"I'm excited about these findings because it's more evidence that this vaccine may be an excellent alternative for these patients," Werneburg said.

Both the trials had limitations. For instance, the vaccine has only been tested for uncomplicated UTIs, meaning infections that don't involve catheters , fever, the kidneys or other complicating factors, for example.

"Some of the people who are most prone to infection are people with neurogenic lower urinary tract dysfunction and people with chronic indwelling catheters," Werneburg said. "I really look forward to trials that assess the vaccine's safety and efficacy in these populations."

Not everyone responded to the vaccine in these initial trials. But "given how complicated UTI is and how every patient has something different going on — different bugs, different immune systems — half of the people responding is actually really good," Rohn said.

One possible reason some patients did not respond could be that they were infected by types of bacteria not included in the vaccine. Bacteria can also hide from the immune system and antibiotics by sticking to the bladder wall and coating themselves with a slimy shield . Other UTI vaccines being tested in mice could potentially target these germs.

— Pain can linger even after a UTI is gone — haywire nerve growth may explain it

— Bacteria from meat may cause a half-million UTIs a year

— Fatal 'brain-eating' amoeba successfully treated with repurposed UTI drug

Uromune has not yet been approved by the Food and Drug Administration for any use in the U.S. However, currently, it's available for compassionate use in 26 countries, meaning it's available to people who aren't enrolled in a formal trial but who haven't responded to other treatments. Time will tell if it will earn full approval for UTI prevention.

This article is for informational purposes only and is not meant to offer medical advice.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun ? Send us your questions about how the human body works to [email protected] with the subject line "Health Desk Q," and you may see your question answered on the website!

Sahana Sitaraman is a science writer based in Lausanne, Switzerland, specializing in biology. She particularly enjoys writing about unusual animal behaviours and the neuroscience behind them, mental health and women in STEM. She also dabbles in illustrating cool findings that pique her interest. In her free time, Sahana can be found out on a hike, acting it up with the local improv group or painting. She holds a bachelor's degree in microbiology from the University of Delhi, India and a master's and PhD in life sciences from the National Centre for Biological Sciences in Bangalore, India.

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• Clinical Trials

Scientists Find New Ways to Tackle Urinary Tract Infections (UTIs)

As the threat of antibiotic resistance grows, researchers are developing ways to prevent recurrent and chronic urinary tract infections (UTIs) without using antibiotics, wrote Carissa Wong on May 2, 2024.

An article published in the journal Nature says the latest approaches include an oral spray vaccine.

In clinical trials, the pineapple-flavored Uromune™  (MV140) prevented recurrent UTIs in participants for up to nine years. The polyvalent bacterial whole-cell-based sublingual vaccine is sprayed under the tongue daily for three months.

Unfortunately, Uromune is currently unavailable in Canada or the United States. But it is offered in various countries.

Furthermore, scientists are also testing safer ways to treat UTI infections with antibiotics, which often cause side effects.

The anti-infective candidate RECCE® 327  (R327) was recently added to the World Health Organization's report on Antibacterial Agents in Clinical Development and Preclinical Development.

The U.S. CDC says UTIs are common infections caused by bacteria, often from the skin or rectum, entering the urethra and infecting the urinary tract.

UTIs are more common in females because their urethras are shorter and closer to the rectum. This makes it easier for bacteria to enter the urinary tract, says the CDC.

However, about 10% of men will also experience a UTI during their life. 

Younger children may not be able to tell you about their UTI symptoms. While fever is the most common sign of a UTI in infants and toddlers, most children with fever do not have a UTI.

Access to the complete Nature article is at this link .

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Science News

Here’s why pain might last after persistent urinary tract infections.

The immune response spurs nerve growth in mice, possibly explaining the unending pain

The reason behind the lingering pain from some urinary tract infections has long eluded researchers. New research ties it to nerve growth triggered by immune responses.

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By Helen Bradshaw

March 1, 2024 at 2:00 pm

Urinary tract infections are painful, inconvenient and incredibly common. For decades, doctors haven’t had any leads on why, even after several rounds of antibiotics, UTI pain can linger. Now they do.

Nerve growth from immune responses to the infection might be to blame , researchers report March 1 in Science Immunology. Understanding immune and nerve responses to persistent UTIs, the team says, could possibly lead to new, antibiotic-free forms of treatment. 

Over half of women will have a UTI in their life, and around a quarter of infections come back within six months . The pain from these infections can be quite difficult to treat, says Marcus Drake, a neurological urologist at Imperial College London. “It’s a ‘ heartsink situation ’ for the patients, and it’s a heartsink situation for the doctors, because there isn’t much that you can do.”

Puzzled by why pain persisted after UTI-related bacteria were wiped out, immunologist Soman Abraham of Duke University and colleagues collected urine samples from women with recurring infections. Compared with samples of women without recurring UTIs, these showed signs of nerve activation.

To better understand what was happening at the tissue level, the team induced multiple UTIs in mice. Compared with uninfected mice, “we saw a tremendous growth of nerves,” Abraham says. But that only confirmed what the team suspected about humans. The researchers still wanted to know what spurred the nerves to grow. 

Abraham knew that when the urinary tract is infected, one of the bladder’s first defenses is to shed a tissue layer to remove bacteria. But in this process, nerves are sloughed off, which jolts nerve-growing immune cells into action. A close look at the bladder tissue of the mice with repeat UTIs revealed an abundance of two kinds of immune cells.

Specifically, there were high levels of mast cells , which are stored in bladder tissue and produce a substance called nerve growth factor ( SN: 9/5/07 ). And there were monocytes , blood-based immune cells that rush to the site of infection to produce even more nerve growth factor ( SN: 7/30/09 ). Similar to respiratory infections, the more often the body has to fight off bladder infections, the better it gets at it; monocytes and mast cells get faster at their job with each UTI. “The unfortunate part is [it becomes] an overzealous response,” Abraham says.

Pain continues because nerve growth factor doesn’t just generate nerve growth; it also lowers the threshold at which nerve pain and pressure receptors activate. Even after no infection-related bacteria remained, the mice in the study had frequent urination and showed signs of lingering pain. “The slightest, innocuous volume of urine was enough to trigger the voiding response,” Abraham says. But with antihistamines and blockers of nerve growth factor, the mice were able to feel some relief.

Right now, persistent pain in UTIs in humans is usually treated with anti-inflammatory or other pain-reducing drugs, including antihistamines, but all of these are a bit unsatisfactory, Drake says. The researchers hope that understanding how nerves grow with recurrent UTIs can lead to more effective pain relief treatments in the future.

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The Persistent Confusion Around the U.T.I.

Much of the advice about urinary tract infections isn’t rooted in science. Here are four misunderstood facts about this very common affliction.

By Alisha Haridasani Gupta

Over half of women in the United States will get a urinary tract infection in their lifetime. (This is compared to an estimated 14 percent of men.) Despite being common, it is often an experience layered with frustration and stigma , said Dr. Kalpana Gupta, a professor at Boston University Chobanian & Avedisian School of Medicine who does research on U.T.I.s. Patients “feel some personal responsibility,” she said. “Like, ‘I’m doing something wrong.’”

In most cases U.T.I.s — known as bacterial cystitis — are only loosely correlated with personal behavior, she said. The main reason U.T.I.s are more common in women is that they have shorter urethras than men, which makes it easy for bacteria to reach the urinary tract; a U.T.I. in a man is often part of a larger health issue, Dr. Gupta said.

A vast majority of U.T.I. cases are caused by E. coli bacteria , which lives in the gut and sometimes hangs out on the perineum. How and in what circumstances the bacteria migrates into the urethra and infects the urinary tract is “not 100 percent worked out,” she said.

A lot of the misconceptions around U.T.I.s crop up because there is very little quality research into the issue, said Dr. Ja-Hong Kim, a urologist at UCLA Health. Here are some of the most common questions experts get from patients.

Is it a U.T.I. if there’s no burning sensation?

It can be. A U.T.I. can occur anywhere along the urinary tract, which includes the urethra, bladder, the kidneys and, in men, the prostate, Dr. Kim said. For an issue to be considered a U.T.I., a patient must show some symptoms and have confirmed bacteria in their urine.

A lot of the widely known symptoms, like burning and the constant sensation of needing to go to the bathroom, “come from studies that are done in young, college-aged, otherwise healthy adult women,” Dr. Gupta said. But, in fact, symptoms can vary.

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Unraveling a hidden cause of UTIs — plus how to prevent them

Allison Aubrey

Some urinary tract infections may be caused by food-borne E. coli bacteria, research finds. Getty Images/Westend61 hide caption

Some urinary tract infections may be caused by food-borne E. coli bacteria, research finds.

If you've had a urinary tract infection, you're in good company. About 60% of women will develop one in their lifetime. UTIs lead to more than a million emergency room visits each year and more than $2 billion in medical costs.

Many of these infections are caused by common strains of E. coli bacteria that humans have lived with for millennia. But now researchers are investigating an unsettling source of some of the illness: the meat supply.

UTIs make urinating painful or difficult and can interfere with sex, sleep and exercise . Sometimes they can cause fever or chills. But since they can be treated with antibiotics, they've been considered more of a nuisance than a public health problem. Recently though, multi-drug resistance to some of the bacteria, including strains of E. coli, that cause UTIs has become an increasing worry.

But many of the more than 700 known strains of Escherichia coli are harmless. So the authors of a new study set out to solve a mystery: Which strains cause infections, and where do they come from?

They had a hunch that the U.S. animal agriculture system could be a likely culprit.

Goats and Soda

Why do some people get utis over and over a new report holds clues.

Both farm animals and humans have some strains of E. coli bacteria in their guts. When farm animals are slaughtered, the bacteria from their guts can contaminate raw meat, which can in turn contaminate kitchen surfaces during cooking.

A team of researchers spent one year collecting samples of raw meat in Flagstaff, Ariz., to find out if there's an overlap between the strains of E. coli in the meat supply and the strains that can make people sick.

"We sampled all the chicken, turkey and pork from every grocery store in the city twice per month," explains Lance Price , a professor at George Washington University Milken School of Public Health and the founding co-director of the Antibiotic Resistance Action Center.

They also collected urine samples from the Flagstaff Medical Center from people who were hospitalized with UTIs.

In their study , published in the scientific journal One Health , the researchers found that about 8% of UTIs in Flagstaff could be attributed to bacteria from meat. Nationwide, they estimate as many as 640,000 infections each year are caused by foodborne E. coli strains from animals.

"Our study provides compelling evidence that dangerous E. coli strains are making their way from food animals to people through the food supply and making people sick," Price says.

Genomic sleuthing clarifies the link with livestock

To pin down the connection, the researchers brought both the meat and urine samples back to their laboratory and cultured for E. coli , explains co-author Paul Keim , the executive director of the Pathogen and Microbiome Institute at Northern Arizona University. They performed genomic sequencing to inspect the microbes' DNA.

This helped them identify segments of DNA from the bacteria that are specific to strains from animals, and others that are specific to strains in people. "We started recognizing that, hey, here's these little packages of DNA that are really strongly associated with chicken," Price explains. Others can be strongly associated with pork, and others with people.

"The genomic analysis allowed us to match up a number of different strains," explains Keim.

The degree of overlap between the E. coli strains from meat and those found in samples from patients with UTIs was striking, says Tim Johnson , a professor at the College of Veterinary Medicine at the University of Minnesota who studies poultry diseases and genomics.

"When I first saw the data, I was pretty overwhelmed at the connectivity," Johnson says, though he says the study falls short of proving that the UTIs were caused by E.coli from meat. He points to the other ways the bacteria can contaminate the food supply. For instance, they can get into irrigation water and contaminate crops.

Big picture, Keim, says, the study shows "there's lots of E. coli strains out there that cause UTIs and you can get them through the food supply."

Stopping human disease may start on the farm

The researchers plan to continue to trace the connection between the food supply and human UTIs. The study allowed them to create a data platform to which they hope to build on. It's similar to how the FBI developed a database of criminal's DNA fingerprints that they can search to solve crimes, explains Keim. "We didn't have that for E. coli ," or for UTIs until doing this study, he says.

This kind of knowledge could lead to new strategies to prevent the spread of bacteria that cause UTIs.

For instance, the study points to two E. coli strains that have particularly high virulence, including the ST131- H 22 strain, which has been found in poultry operations. A previous study showed this strain may be a vehicle for human infection.

It turns out this strain is also causing disease in birds in poultry operations, so Johnson says some farmers vaccinate their flocks against it. "They use what's called an autogenous vaccine ," Johnson explains. Those are customized for the flock from strains of bacteria isolated from animals in the flock. He says a better understanding of the overlap between human disease and animal disease, can help farmers take proactive prevention steps.

"If you're finding a problematic strain that's killing chickens or turkey, that could also be a food safety threat, they can make vaccines against those strains to try to eliminate them from the barns," Johnson says.

Be careful with how you handle raw meat, to prevent infection by foodborne E. coli . Matthew Ashmore/Getty Images/EyeEm hide caption

Be careful with how you handle raw meat, to prevent infection by foodborne E. coli .

Ways to prevent UTIs

UTIs involve a complex interplay of bacteria, our microbiomes, immune systems and anatomy, says Dr. Michelle E. Van Kuiken , a urologist who specializes in female pelvic medicine, at the University of California, San Francisco. And Van Kuiken says patients need to understand they may get sick because of factors beyond their personal control.

"We're seeing this connection and we need to be cognizant about how large-scale animal agriculture could be impacting human health," Van Kuiken says. "To some extent, women have been done a disservice by them thinking it's something they're doing wrong or things that they can modify," she adds.

Though some of what's causing them may be out of your control, there are evidence-based tips worth trying to prevent recurrent UTIs.

1. Understand your anatomy

People born with female anatomy are more prone to urinary tract infections, explains Elodi Joy Dielubanza , a urologist at Brigham and Women's Hospital. The urethra, which carries urine from the bladder outside the body, is typically shorter in women and it's in very close proximity to the anus.

The way the E. coli ends up invading the urinary tract is kind of gross, but the bottom line is that the bacteria comes out in our poop. And, if you don't wipe right (from front to back), it can end up in the urethra where it can invade the urinary tract.

Sex can play a role too. During penis in vagina sex, the bacteria – which can live in the tissue near the anus – can travel along the penis toward the entrance of the urethra. That's why it's smart to urinate after sex to flush out some of the bacteria.

2. Stay hydrated

It's important to consume enough fluids to maintain adequate urine production, says Dielubanza. "Our body's best defense against invading bacteria is to flush it away," she says. "I like to advise my patients to maintain at least a daily intake of six cups of water."

3. Be careful with kitchen hygiene

E. coli can not survive high temperatures, so if you cook your meat to recommended minimum temperatures , you will kill off the bacteria.

The bigger risk may be poor kitchen hygiene, says University of Minnesota's Tim Johnson. "It's a common misperception that most of the transmission from chicken to human occurs by eating undercooked meat. And the fact is that the vast majority of people fully cook [it], especially poultry," he says.

Pay attention to utensils that have touched raw meat, like the cutting board, knife and spatula. "Even though you think you may have washed them thoroughly, maybe you didn't," Johnson warns. Raw meat liquid can also get on the counter surfaces, so pay attention to where it seeps out and clean it up.

The USDA has tips on how to prevent cross-contamination in the kitchen and when you're outdoors on the grill.

4. Supplements may help prevent recurrent infections

Several studies show that cranberry supplements can help reduce the risk of recurrent UTIs, according to a review by the American Urological Association . Compounds in cranberries, known as proanthocyanidins, may help prevent bacteria from adhering to the lining of the urinary tract. But Dielubanza says the evidence is mixed, and she points out there's usually not enough concentration of the compounds in many of the sweetened cranberry juices sold in grocery stores to make a difference. So if you want to try it, some doctors suggest cranberry supplements instead.

Though there's less research to date, there's growing data supporting the use of another supplement, D-Mannose , a type of polysaccharide . Van Kuiken explains that D-Mannose gets rapidly excreted in urine. When bacteria bind to the polysaccharide, it can help flush them out of the urinary tract. "It's a safe supplement that's available over the counter," Van Kuiken says.

5. Approaching menopause and after, use vaginal estrogen cream

As the female body starts producing less estrogen during the years leading up to menopause, risk for UTIs can go up, says Dielubanza. "The loss of estrogen can change our vaginal microenvironment and make us more prone to developing UTIs," she says. "The good bacteria that colonize our vaginas may be less likely to survive after menopausal changes."

For women in perimenopause or later dealing with recurrent UTIs, some physicians advise starting some patients on topical vaginal estrogen.

"It amazes me how many women that I see that fall into this age category who have not heard of vaginal estrogen," says Van Kuiken. "Probably one of the single most important things that we can do to help prevent recurrent urinary tract infections is [prescribe] topical estrogen."

Editing and visuals research by Carmel Wroth. Audio editing by Jane Greenhalgh.

• urinary tract infection
• antibiotic resistant bacteria

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Relief for millions of UTI sufferers with new medicine breakthrough

Experts are calling gepotidacin a massive step forwards in the fight against resistance to antibiotics, article bookmarked.

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Louise Thomas

People in the UK who suffer from recurring bladder infections may soon be treated with a new antibiotic that isn’t yet anywhere else in the world .

Experts are calling gepotidacin a massive step forwards in the fight against resistance to antibiotics .

This is because bugs have not yet had the chance to become resistant to its attacks.

It means gepotidacin will be able to fight aggressive urinary tract infections (UTIs) that aren’t responding to the current antibiotics that are available.

It comes as new research has found some patients are waiting up to 12 years for a chronic UTI infection diagnosis, according to the i paper .

Expert doctors and scientists who treat these infections have shared battles patients face to get diagnosed, which sees some of them suffer symptom for more than a decade.

If it gets approved, gepotidacin will be the first new class of antibiotics produced in around 40 years, reports the Mail .

And researchers believe the treatment could be effective for as long as half a century.

Up to 1.7 million people in Britain suffer chronice UTIs, which is when you get three or more infections a year.

Symptoms of UTIs include a burning feeling when you go to the toilet, feeling like you need to go when you have nothing in your bladder and needing the toilet more than usual.

There is a risk of developing sepsis, which causes around 50,000 deaths a year.

Older people can also develop a condition almost like dementia, called delirium if they have a UTI.

Gepotidacin will also be used to treat a number of other infections.

This includes the sexually transfmitted infection (STI) gonorrhoea, which is one of the most drug-resistant bacterial infections that currently exists worldwide.

British multinational pharmaceutical company GSK, the company behind the new antibiotic, is likely to get approval from the NHS within the next two years, experts say.

GSK is also hoping to apply for approval in the US by spring this year.

Gepotidacin works by breaking down microscopic parts of the bacteria’s DNA. Experts say this is what may enable it to be effective for over half a century.

The antibiotic has been in development stages for over ten years.

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Conclusions, supplementary data.

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Definitions of Urinary Tract Infection in Current Research: A Systematic Review

M. P. B. and R. M. H. J. contributed equally to this work.

Potential conflicts of interest. All authors: No reported conflicts.

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Manu P Bilsen, Rosa M H Jongeneel, Caroline Schneeberger, Tamara N Platteel, Cees van Nieuwkoop, Lona Mody, Jeffrey M Caterino, Suzanne E Geerlings, Bela Köves, Florian Wagenlehner, Simon P Conroy, Leo G Visser, Merel M C Lambregts, Definitions of Urinary Tract Infection in Current Research: A Systematic Review, Open Forum Infectious Diseases , Volume 10, Issue 7, July 2023, ofad332, https://doi.org/10.1093/ofid/ofad332

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Defining urinary tract infection (UTI) is complex, as numerous clinical and diagnostic parameters are involved. In this systematic review, we aimed to gain insight into how UTI is defined across current studies. We included 47 studies, published between January 2019 and May 2022, investigating therapeutic or prophylactic interventions in adult patients with UTI. Signs and symptoms, pyuria, and a positive urine culture were required in 85%, 28%, and 55% of study definitions, respectively. Five studies (11%) required all 3 categories for the diagnosis of UTI. Thresholds for significant bacteriuria varied from 10 3 to 10 5 colony-forming units/mL. None of the 12 studies including acute cystitis and 2 of 12 (17%) defining acute pyelonephritis used identical definitions. Complicated UTI was defined by both host factors and systemic involvement in 9 of 14 (64%) studies. In conclusion, UTI definitions are heterogeneous across recent studies, highlighting the need for a consensus-based, research reference standard for UTI.

Urinary tract infection (UTI) refers to a plethora of clinical phenotypes, including cystitis, pyelonephritis, prostatitis, urosepsis, and catheter-associated UTI (CA-UTI) [ 1 , 2 ]. In both clinical practice and in research, the diagnosis of UTI is based on a multitude of clinical signs and symptoms and diagnostic tests. Signs and symptoms can be further subdivided into (1) lower urinary tract symptoms, such as dysuria, frequency, and urgency; (2) systemic signs and symptoms, such as fever; and (3) nonspecific signs and symptoms, such as nausea and malaise. Commonly used diagnostic tests include urine dipstick for determining the presence of leukocyte esterase and nitrites, microscopy or flow cytometry for quantification of pyuria, and urine and blood cultures.

When defining and diagnosing UTI, numerous combinations of signs, symptoms, and outcomes of diagnostic tests are possible, and this diversity is reflected in various research guidelines. For drug development and approval purposes, the European Medicines Agency (EMA) [ 3 ] and US Food and Drug Administration (FDA) [ 4 , 5 ] have developed guidelines for clinical trials evaluating antimicrobials for the treatment of UTI, summarized in Table 1 . These guidelines provide definitions for uncomplicated UTI, complicated UTI, and acute pyelonephritis. McGeer et al [ 6 ] have developed research guidelines for studies in long-term care facilities (LTCFs). Clinical practice guidelines include the Infectious Diseases Society of America (currently being updated) [ 7 ] and European Association of Urology [ 8 ] guidelines. It is important to distinguish between research guidelines and clinical practice guidelines as the latter are meant for treatment recommendations, and the definitions in these clinical guidelines are generally based on often limited diagnostic information available when assessing a patient in the clinical, near-patient setting.

European Medicines Agency and US Food and Drug Administration Definitions of Uncomplicated and Complicated Urinary Tract Infection

In the EMA guidelines, bacteriuria definitions were mentioned in the description of the microbiological intention-to-treat population. In the FDA guidelines, they were also mentioned separately, under clinical microbiology considerations.

Abbreviations: AP, acute pyelonephritis; BPH, benign prostatic hyperplasia; CFU, colony-forming units; cUTI, complicated urinary tract infection; CVA, costovertebral angle; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; uUTI, uncomplicated urinary tract infection.

While the aforementioned research guidelines overlap in the sense that they all include a combination of symptoms and evidence of pyuria and/or bacteriuria in the definition of UTI, they also differ. For instance, none of these guidelines include the same set (or minimum number) of symptoms for the diagnosis of UTI. Moreover, the definition of complicated UTI is variable and based on either systemic signs and symptoms or the presence of host factors predisposing the patient to a complicated clinical course (eg, functional or anatomical abnormalities of the urinary tract).

It is probable that this wide range of possible definitions and different research guidelines pose problems for researchers conducting studies with patients with UTI. A uniform research definition increases homogeneity between studies, which is important for the interpretation, synthesis, and comparability of results, and mitigates the risk of misclassification bias. This is especially relevant in an era of rising antimicrobial resistance, in which novel antimicrobials are being investigated in large randomized controlled trials. The aim of this systematic review is to evaluate how UTI is defined in current studies, and to which extent these definitions differ between studies.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines [ 9 ].

Eligibility Criteria

Studies published between January 2019 and May 2022, investigating any therapeutic or prophylactic intervention in adults with (recurrent) UTI, were eligible for inclusion. Given the fact that definitions tend to change over time, this time frame was chosen to reflect the most recent consensus. In addition, updated FDA and EMA guidelines were published in 2019. We excluded studies concerning only prostatitis, CA-UTI, pericatheter or perioperative prophylaxis, or asymptomatic bacteriuria. Studies investigating patients with spinal cord injury or neurogenic bladder were also excluded, because separate UTI definitions are mostly used for patients who are unable to experience (or have altered perception of) lower urinary tract symptoms. Finally, we excluded systematic reviews, meta-analyses, and studies published in non-English-language journals

Search Strategy

Multiple electronic databases (PubMed, Embase, Web of Science, and the Cochrane library) were searched on 16 May 2022. Our search strategy was constructed by a research librarian and was based on a population, intervention, comparison, outcome (PICO)–style approach. We applied language and publication year filters as described above and used an “article” type filter for clinical trials. The complete search strategy is provided in Supplementary Material 1 .

Data Extraction and Analysis

Covidence software was used for screening and data extraction. References were imported and duplicates were removed. Title and abstract screening, full-text screening and data extraction were performed by 2 independent reviewers (M. P. B. and R. M. H. J.). In case of disagreement, a third researcher was consulted (M. M. C. L.) and a final decision was based on consensus.

For each study, the following data were collected: study design, setting, population, intervention, and the type of UTI under investigation. Criteria for the definition of UTI were subdivided into 3 categories: signs and symptoms, urinalysis, and urine culture. For each of these categories, we assessed whether they were required or conditionally required (ie, dependent on the presence of other categories) for the diagnosis of UTI. If categories were not mentioned, or if they were only required for a secondary outcome or definition, they were considered as not required. Definitions were derived from eligibility criteria unless definitions were explicitly stated elsewhere. For signs and symptoms, additional data were collected on minimum number of symptoms and symptom specification (eg, if fever and frequency were further defined). Moreover, we recorded which symptoms were part of the definition of acute cystitis, acute pyelonephritis, and UTI if a clinical phenotype was not mentioned (henceforth described as UTI–phenotype not specified). For the urinalysis category, we extracted which methods were used for determining pyuria, which cutoff values were applied, and whether nitrites were part of the UTI definition. Regarding the urine culture category, we recorded the cutoff value for colony-forming units (CFU)/mL and the maximum number of uropathogens. For all 3 categories, we assessed whether study definitions met FDA and EMA guideline requirements. Concerning complicated UTI, we collected the same components of the definition as described above, but we also assessed whether the definition was based on host factors, systemic involvement, or a combination of both. Finally, we compared definitions between studies, stratified per UTI type. No risk of bias assessment was performed as we studied definitions instead of outcomes. Data are summarized as proportions.

Study Selection and Study Characteristics

The study selection process is summarized in a PRISMA flowchart ( Figure 1 ). We screened 348 reports published between January 2019 and May 2022. Studies that were excluded during title and abstract screening (n = 290) mainly involved patients with CA-UTI or conditions other than UTI (eg, interstitial cystitis), or investigated pericatheter or perioperative prophylaxis. During full-text screening, 7 non-English articles and secondary analyses of articles already included in the study using our search criteria were excluded. A total of 47 randomized controlled trials and cohort studies with a median of 145 participants were included [ 2–56 ].

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of the study selection process. Abbreviation: UTI, urinary tract infection.

Thirty-one studies (66%) investigated antimicrobials for the treatment of UTI, and 15 (32%) evaluated antimicrobial prophylaxis for recurrent UTI. Sixteen studies (34%) only included women, 4 studies (9%) only included men, and 27 studies (57%) included both. Participants were hospitalized in 25 studies (53%) and treated through an outpatient or primary care clinic in 22 studies (47%). None of the included studies were conducted in LTCFs. Twelve studies (26%) included acute cystitis, 16 (34%) included acute pyelonephritis, and 13 (28%) included UTI–phenotype not specified. A table containing details of all included studies is provided in Supplementary Material 2 .

UTI Definition and Heterogeneity

Table 2 shows how UTI was defined across the included studies. In 11 studies (23%) the definition consisted of only signs and symptoms, in 16 studies (34%) the definition consisted of both signs and symptoms and a positive urine culture, and in 5 studies (11%) all 3 components (signs and symptoms, the presence of pyuria, and a positive urine culture) were required for the diagnosis of UTI. None of the studies investigating acute cystitis (n = 12) or UTI–phenotype not specified (n = 13) included the same set of symptoms and diagnostic criteria in their definition. Of the studies defining acute pyelonephritis, 2 (17%) used identical definitions.

Categories of Urinary Tract Infection Definition

If categories were not mentioned, they were considered as not required. Definitions were derived from eligibility criteria unless definitions were explicitly stated elsewhere. Percentages may not add up to 100 due to rounding.

Abbreviations: CFU, colony-forming units; HPF, high-power field; UTI, urinary tract infection.

Signs and Symptoms

Signs and symptoms were required for the diagnosis of UTI in 40 studies (85%). Of these, 34 (85%) specified signs and symptoms in the definition. The different signs and symptoms that were included in the definition of acute cystitis, acute pyelonephritis, and UTI–phenotype not specified are highlighted in Table 3 . FDA guidelines [ 4 ] require a minimum of 2 of the following symptoms for patients with uncomplicated UTI: dysuria, urgency, frequency, and suprapubic pain. Two of 12 studies (17%) met these criteria. Flank pain and/or costovertebral angle tenderness, fever, nausea and/or vomiting, and dysuria were most often included in the definition of acute pyelonephritis. Frequency was not further specified in any study. Perineal and/or prostate pain was part of the definition in 3 of 31 (10%) studies involving men. A specific temperature cutoff for fever was defined in 7 of 17 (65%) studies that included fever in the definition of UTI.

Symptoms and Signs in Different Types of Urinary Tract Infections

All symptoms and signs are shown as No. (%). Other symptoms mentioned in studies focusing on acute cystitis or UTI–phenotype not specified were vesical tenesmus (n = 1), malodorous and/or cloudy urine (n = 1), hypogastric pain (n = 1), and nocturia (n = 1). Additional criteria for the definition of acute pyelonephritis not mentioned in the table: elevated serum inflammatory parameters (n = 1), signs of pyelonephritis on ultrasound or computed tomography (n = 1), and hypotension (n = 1).

Abbreviations: CVA, costovertebral angle; UTI, urinary tract infection.

This included all studies investigating acute pyelonephritis, either alone or in conjunction with other types of UTI.

Urinalysis and Urine Culture

The presence of pyuria was required for the diagnosis of UTI in 13 of 47 (28%) studies, while both FDA and EMA guidelines [ 3–5 ] require pyuria in their definition of UTI. A cutoff for pyuria was specified in 12 studies, of which 10 (83%) applied a cutoff value of >10 leukocytes/µL or >10 leukocytes per high-power field (HPF). None of the included studies required the presence of nitrites for the diagnosis of UTI, although they were conditionally required in 3 studies (6%). A positive urine culture was mandatory for UTI diagnosis in 26 of 47 (55%) studies, of which 12 (55%) were conducted in the primary care or outpatient setting and 14 (56%) involved hospitalized patients. Of the 19 studies that mentioned a cutoff value for CFU/mL, 8 (42%) used a cutoff of 10 3  CFU/mL. Among all studies, 7 (15%) required a positive urine culture with at least 10 5 CFU/mL, complying with EMA and FDA guidelines [ 3–5 ].

Complicated UTI

We included 14 studies that defined complicated UTI. Three (21%) based their definition on complicating host factors only, 1 (7%) on systemic involvement only, and 9 (64%) on both host factors and systemic involvement. The various host factors included in the definition are provided in Table 4 . Male sex was considered a complicating factor in 2 studies (17%).

Definition of Complicated Urinary Tract Infection

For the purpose of this table, systemic involvement was defined as the presence of fever and/or rigors in the criteria for diagnosis of complicated UTI.

Abbreviations: BPH, benign prostatic hyperplasia; UTI, urinary tract infection.

Host factors were specified in 12 studies; this was used as the denominator for the proportions.

In this systematic review, we demonstrate that UTI definitions used in current research studies are highly heterogeneous in terms of clinical signs and diagnostic tests. In addition, few studies met symptom, pyuria, and urine culture criteria mentioned in existing research guidelines.

The presence of signs and symptoms was required in the majority of UTI definitions used in the included studies. As symptoms and signs remain the cornerstone of UTI diagnosis, it is noteworthy that 15% of studies did not require signs and symptoms for the diagnosis of UTI and an even greater number of studies did not specify which symptoms and signs needed to be present. Defining specific symptoms may help to mitigate the risk of misclassification. Symptom specification is especially relevant in studies involving older patients with UTI, given the high background prevalence of asymptomatic bacteriuria and pyuria [ 57–59 ]. Most of the studies that did clarify which symptoms were part of the UTI definition included classic UTI-associated symptoms such as dysuria, frequency, and urgency. However, we also found a broad variety of nonspecific manifestations, particularly in studies that did not define the UTI phenotype under investigation. Regardless of the unclear clinical relevance of nonspecific symptoms in UTI, this diversity of symptoms contributes to heterogeneity between studies, which is supported by our finding that few of the included studies used the same set of symptoms to define UTI. Furthermore, in over a third of the included reports, a minimum number of symptoms (for diagnosis) was not mentioned. Given the fact that even classic lower urinary tract symptoms are not 100% specific for UTI, and probability of UTI increases when a combination of symptoms is present, a minimum number of symptoms should be specified [ 60 ].

Pyuria and Bacteriuria

Interestingly, less than a third of included studies required the presence of pyuria in the definition of UTI. With the exception of patients with absolute neutropenia and complete obstructive uropathy, pyuria is present in virtually all symptomatic patients with bacteriuria, and its absence has a high negative predictive value for UTI [ 61–63 ]. In the included studies, pyuria was rarely quantified and thresholds for significant pyuria were low. A recent study has shown that low pyuria cutoffs should be avoided in older women, as the specificity for UTI is very low in this population [ 64 ]. Moreover, studies used different units of measurement interchangeably (ie, identical thresholds were applied for cells/µL and HPF), while results are influenced by different (pre)analytical procedures and previous studies have shown a µL-to-HPF ratio of 5:1 [ 65 ]. Be that as it may, quantification of pyuria in UTI studies should be encouraged, and pyuria should be included in the definition of UTI to reduce the risk of misclassification.

As growth of a uropathogen supports the diagnosis of UTI in a symptomatic patient, it is surprising that a positive urine culture was not part of the UTI definition in approximately half of the included studies. Even though urine cultures are not always required in a clinical setting (eg, in primary care), we believe that culture confirmation should at least be encouraged in a research setting. Furthermore, we found that studies used varying cutoffs for significant bacteriuria, ranging from 10 3 to 10 5  CFU/mL, while EMA and FDA guidelines both recommend a threshold of 10 5  CFU/mL. The question remains whether this is the optimal cutoff [ 66 ]; colony counts as low as 10 2  CFU/mL in midstream urine have been found in symptomatic premenopausal woman with Escherichia coli bacteriuria [ 61 , 62 ].

Studies differed widely in their definition of complicated UTI. Since the majority of studies defined complicated UTI based on both complicating host factors and systemic involvement, different clinical phenotypes were included in each study. This not only contributes further to disparities between studies, it also affects the applicability of study results. Moreover, the aforementioned heterogeneity is compounded by the fact that host factors are very diverse in themselves and there is no consensus about which host factors should be included in the definition of complicated UTI. As astutely phrased by James Johnson [ 67 ], “it may be time to find a different term than complicated UTI for UTIs that occur in patients with underlying predisposing factors, since this term seems hopelessly mired in ambiguity.” Johansen et al [ 68 ]. have proposed a UTI classification system for clinical and research purposes based on clinical phenotype, severity, host factors, and pathogen susceptibility. However, this classification system was not used by any of the included studies in our review. In the Netherlands, the primary care guidelines for UTI have already made a distinction between a UTI in a complicated host versus UTI with systemic involvement [ 69 ].

Existing Research Guidelines

We found that few studies met symptom, pyuria, and urine culture criteria mentioned in FDA and EMA guidelines [ 3–5 ]. In addition, we identified that studies more frequently based UTI definitions on clinical practice guidelines. The use of clinical practice guidelines in the place of research guidelines seems inappropriate, as clinical guidelines are less stringent than research guidelines and base empirical treatment recommendations on limited diagnostic information. Taken together, our findings imply that a widely accepted, consensus-based gold standard for the diagnosis of UTI is lacking and is much needed in the field of UTI research.

Strengths and Limitations

Strengths of this systematic review include our comprehensive search strategy, including multiple electronic databases, and extracting data from supplemental material , as UTI definitions were frequently only mentioned in a supplemental protocol. Our study has several limitations. For some of the included therapeutic studies, eligibility criteria served as a proxy for the UTI definition, if a definition was not mentioned separately. This might have contributed to additional heterogeneity. For instance, prophylactic studies including patients with recurrent UTI had more frequently provided separate UTI definitions, since these often served as outcome measures. Also, some heterogeneity might be explained by the fact that we included studies that investigated different UTI phenotypes. However, this effect was mitigated by evaluating different UTI phenotypes separately. Another limitation is that we filtered our search strategy on publication date and study type. While expanding the time period would have provided more data, it would not reflect the most recent consensus and would likely have contributed to further heterogeneity, as these studies were published before the FDA and EMA guidance documents. Furthermore, including more observational studies most likely would not have reduced heterogeneity, as these are presumably less likely to follow FDA and EMA guidelines for drug approval. Since we did not find any recent studies that were conducted in LTCFs, and we excluded studies regarding CA-UTI and UTI in spinal cord injury patients, it is unclear how heterogeneous definitions are in these areas. Defining UTI might be even more challenging for these populations and settings.

UTI definitions differ widely across recent therapeutic and interventional studies. An international consensus-based reference standard is needed to reduce misclassification bias within studies and heterogeneity between studies. To avoid ambiguity, such a reference standard should veer away from the term “complicated UTI” and instead categorize UTI based on systemic involvement, as these are different entities with different treatments. Based on results of this systematic review, our group has initiated an international consensus study to construct a UTI reference standard for research purposes.

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Author contributions. Conceptualization and methodology: M. P. B., R. M. H. J., S. P. C., L. G. V., and M. M. C. L. Screening and data extraction: M. P. B. and R. M. H. J. Data analysis: M. P. B. Writing–original draft preparation: M. P. B. and R. M. H. J. Writing–review and editing: M. P. B., R. M. H. J., C. S., T. N. P., C. N., L. M., J. M. C., S. E. G., B. K., F. W., S. P. C., L. G. V., and M. M. C. L. Supervision: M. M. C. L., S. P. C., and L. G. V. All authors have read and agreed to the final version of the manuscript.

Acknowledgments. The authors thank J. W. Schoones for his contribution to the search strategy.

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• urinary tract infections
• heterogeneity
• urine culture
• urinary tract infection, acute

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October 19, 2021

Research reveals potential new strategy to combat urinary tract infections

by Baylor College of Medicine

Identifying the dynamic events occurring during urinary tract infections (UTI) has revealed a new potential strategy to combat this condition, considered the most common type of infection. Researchers at Baylor College of Medicine and Washington University School of Medicine have discovered that the sequence of events taking place during UTI sustains a delicate balance between the responses directed at eliminating the bacteria and those minimizing tissue damage that may occur in the process.

The NRF2 pathway stood out as a key contributor to this balance, by regulating both the potential damage to tissues and the elimination of bacteria . Treating an animal model of UTI with the FDA-approved, anti-inflammatory drug dimethyl fumarate (DMF), a known NRF2 activator, reduced tissue damage and bacterial burden, opening the possibility that DMF could be used to manage this condition in the future. The study appears in the journal Cell Reports.

"Urinary tract infections are not only common, but typically recurrent and tend to give rise to antibiotic-resistant bacteria, a serious medical concern," said corresponding author Dr. Indira Mysorekar, E. L. Wagner Endowed Professor of Medicine- infectious diseases at Baylor, previously at Washington University School of Medicine.

"More than 85% of UTI are caused by uropathogenic E. coli (UPEC), bacteria that can attach to the surface of the epithelial cells lining the inside of the bladder, called urothelial cells," said first author Dr. Chetanchandra S. Joshi, a postdoctoral associate in the Mysorekar lab. "Attached UPEC can then enter the urothelial cells, where they reproduce. In the current study, we looked at how urothelial cells fight back UPEC invasion and proliferation while preserving their integrity, which is essential for proper bladder function."

A dynamic balance of responses

Working with urothelial cells grown in the lab, Mysorekar, Joshi and their colleagues discovered that a precise sequence of events followed UPEC invasion of urothelial cells. First, in the early hours after their infection, urothelial cells defended themselves by producing reactive oxygen species (ROS), highly active compounds that kill bacteria. However, if sustained, ROS also can damage urothelial cells, which would be detrimental for the bladder.

"We found that accumulation of ROS activated an anti-ROS response in urothelial cells, called the NRF2 pathway, that minimized the damage excess ROS could cause to the urothelial cells," Joshi said.

The NRF2 protein is located in the cytoplasm of the cells bound to another protein called KEAP1. "When ROS reaches a certain level, NRF2 separates from KEAP1 and goes into the nucleus of the cell, where it activates a series of genes. Some of these genes produce proteins that block ROS, and some that limit inflammation," Joshi said.

"Interestingly, one of the genes NRF2 activates is Rab27b, which promotes the elimination of UPEC from urothelial cells," Joshi said. "Together, these coordinated events mediate the elimination of UPEC while preserving the integrity of the cells attacked by the bacteria."

A potential new way to combat UPEC

Understanding the process that follows a UPEC infection revealed a potential new strategy to combat the condition. "We learned that active NRF2 was involved in both neutralizing ROS, which helped protect urothelial cells, and eliminating UPEC," Joshi said. "These findings suggested that a drug that activated NRF2, such as DMF, might help clear UPEC infections."

DMF is FDA-approved to treat inflammatory conditions such as multiple sclerosis by dampening the inflammatory response.

"Working with an animal model of UTI, we showed that treatment with DMF activated NRF2, dampened the immune response, limited the level of damage the bacteria caused to urothelial cells , and promoted activation of RAB27B, which removed bacteria from the bladder," Mysorekar said. "Our findings support further exploration of this approach as a potential treatment for UTI."

Women tend to have recurrent UTI, which can lead to chronic inflammation, extensive bladder mucosal damage and chronic infection. Continued antibiotic treatment also negatively affects the microbiome, the 'good bacteria' of the body, and promotes the development of antibiotic-resistant bacteria .

"The most exciting part about this work was identifying a non-antibiotic-based therapy that contained the infection and reduced inflammation," said Mysorekar, who also is professor of molecular virology and microbiology at Baylor. "Although much work is needed before it reaches the clinic, treatment with DMF has the potential of helping millions of women affected by this condition."

Other contributors to this work include Amy Mora and Paul A. Felder, formerly at Washington University School of Medicine.

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Recent Research into Urinary Tract Infections (UTIs)

• Download PDF Copy

Introduction Bacterial behavior over the infection cycle of UTIs revealed Scientists develop vaccine strategy for urinary tract infections Scientists develop new AI that can identify UTIs References  

Urinary tract infections (UTIs) are very common and can be detrimental to health and quality of life. Recent figures estimate that more than half of women will suffer a UTI at some point in their life, and almost one in three will develop a UTI before they reach the age of 24.

Nearly all UTIs (80%) are caused by uropathogenic E. coli (UPEC). Data shows that this pathogen is becoming increasingly resistant to currently available antibiotics. This is worrisome as it reduces the efficacy of antibiotics. Antimicrobial resistance is now the leading cause of death due to bacteria worldwide.

Therefore, new research is vital to combatting antimicrobial resistance and developing new treatments and preventative strategies to protect people, particularly those most at risk, from UTIs.

Image Credit: ivector/Shutterstock.com

Bacterial behavior over the infection cycle of UTIs revealed

Scientists at the University of Technology Sydney (UTS) recently published results from their work in Nature Communications detailing how they used state-of-the-art microscopy to reveal how UPEC bacteria spread and multiply .

The research, carried out at the Australian Institute for Microbiology and Infection at UTS, took a close look at the shapeshifting behavior of UPEC. The team found that during a UTI infection cycle, UPEC bacteria develop spaghetti-like filaments that measure hundreds of times their original length before returning to their original rod-like shape. To discover this, the scientists used a human bladder cell infection model to watch the bacteria throughout its cycle.

It is still not fully understood why the bacteria make this transformation; however, the research showed that it was vital for the bacteria to return to their original form before reinfection could occur.

The study leveraged advanced microscopy to visualize the two cell division proteins and observe their localization dynamics during the reversal process. From watching these dynamics, the team established that filaments do not follow the rules for regulating cell division in bacteria. By revealing initial clues about the regulation of the reversal of filamentation during infection, the team at UTS paved the way for establishing novel approaches to tackling UTIs. The research will likely lead to the discovery of new treatment options.

Scientists develop vaccine strategy for urinary tract infections

Several vaccines against UTIs have been studied in clinical trials; however, they have been unsuccessful, and currently, no effective UTI vaccines are available. Researchers at Duke University have developed a new vaccination strategy to overcome this. Published in the Proceedings of the National Academy of Sciences , the researchers deserve their new vaccination strategy that has the potential to eradicate bacteria and prevent future infections.

The team had previously observed that the immune system did not respond sufficiently to resolve bladder infections. They saw that while the immune system released repair cells, it did not dispatch many barrier cells to fight off the bacteria, allowing the pathogen to live on and attack the bladder again.

Related Stories

• Gut bacteria and urinary infections linked, offering new angles for treatment
• Study reveals nerve changes linked to pain and urinary frequency in recurrent UTI sufferers

The new strategy involves ‘teaching’ the bladder to fight off invading bacteria, overcoming this insufficient immune system activation. The vaccine the team developed is administered directly to the bladder. Their highly effective vaccine antigen was combined with an adjuvant capable of enhancing the recruitment of bacterial clearing cells. Their study showed that the vaccine was more effective than a traditional intramuscular vaccination.

The research describes the development of a potentially highly effective bladder vaccine that could both clear up residual bacteria as well a prevent the risk of future infections.

Image Credit: Blue Planet Studio/Shutterstock.com

Scientists develop new AI that can identify UTIs

As artificial intelligence (AI) technology begins to mature, applications are being established in a wide range of sectors. Healthcare is one such sector that significantly benefits from advancing this technology. Recently, scientists at the University of Surrey, England, developed new AI technology capable of identifying urinary tract infections (UTI).

In a paper published in PLOS ONE , the team described how they leveraged a technique known as Non-negative Matrix Factorisation to identify markers of UTIs. The technique was then coupled with novel machine learning algorithms to establish a platform capable of detecting the early symptoms of UTIs.

The study was part of the TIHM (Technology Integrated Health Management) for dementia project, overseen by the Surrey and Borders Partnership NHS Foundation Trust in partnership with the University of Surrey and industry collaborators. It was conducted with patients with dementia, for which UTIs present one of the top causes of hospitalization. The new AI technology could significantly reduce the prevalence of UTIs in this cohort, thus reducing hospitalization, improving the quality of care and quality of life for this with dementia, and reducing the economic burden of the group of diseases.

Given the urgency of developing new and effective methods to prevent and treat UTIs, it is likely that more research will emerge in the coming years that will bring us closer to novel therapeutics and detection platforms.

References:

• Enshaeifar, S., Zoha, A., Skillman, S., Markides, A., Acton, S., Elsaleh, T., Kenny, M., Rostill, H., Nilforooshan, R. and Barnaghi, P., 2019. Machine learning methods for detecting urinary tract infection and analysing daily living activities in people with dementia. PLOS ONE , 14(1), p.e0209909. https://www.sciencedaily.com/releases/2019/01/190116115531.htm
• Söderström, B., Pittorino, M., Daley, D. and Duggin, I., 2022. Assembly dynamics of FtsZ and DamX during infection-related filamentation and division in uropathogenic E. coli. Nature Communications , 13(1) 3648. https://www.nature.com/articles/s41467-022-31378-1
• Wu, J., Bao, C., Reinhardt, R. and Abraham, S., 2021. Local induction of bladder Th1 responses to combat urinary tract infections. Proceedings of the National Academy of Sciences , 118(10). https://www.pnas.org/doi/full/10.1073/pnas.2026461118

[Furthering reading: Urinary Tract Infection]

Last Updated: Aug 30, 2022

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• Published: 07 April 2020

UTIGA: a new society for UTI professionals, researchers and patients

• Hans G. Pohl 1 ,
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Nature Reviews Urology volume  17 ,  pages 309–310 ( 2020 ) Cite this article

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The Urinary Tract Infection Global Alliance (UTIGA) — a new society in the field of urinary tract infection — has been established to promote cross-disciplinary interactions, provide access to new information, identify research needs and standardize patient management. UTIGA will also provide mentorship opportunities and patient advocacy.

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Acknowledgements

The authors acknowledge D. Hunstad for thoughtful critiques and discussion.

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Hans G. Pohl

Department of Medicine, Division of Infectious Diseases, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

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Genome Institute of Singapore, Singapore, Singapore

Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

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Pohl, H.G., Chen, S., Ching, C.B. et al. UTIGA: a new society for UTI professionals, researchers and patients. Nat Rev Urol 17 , 309–310 (2020). https://doi.org/10.1038/s41585-020-0313-0

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FDA Approves New Treatment for Uncomplicated Urinary Tract Infections

FDA News Release

Today, the U.S. Food and Drug Administration approved Pivya (pivmecillinam) tablets for the treatment of female adults with uncomplicated urinary tract infections (UTIs) caused by susceptible isolates of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus . 

“Uncomplicated UTIs are a very common condition impacting women and one of the most frequent reasons for antibiotic use,” said Peter Kim, M.D., M.S., director of the Division of Anti-Infectives in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to fostering new antibiotic availability when they prove to be safe and effective, and Pivya will provide an additional treatment option for uncomplicated UTIs. ” 

Uncomplicated UTIs are bacterial infections of the bladder in females with no structural abnormalities of their urinary tract. Approximately one-half of all women experience at least one UTI in their lifetime.  

Pivya’s efficacy in treating females 18 years of age or older with uncomplicated UTIs was assessed in three controlled clinical trials comparing different Pivya dosing regimens to placebo, to another oral antibacterial drug and to ibuprofen (an anti-inflammatory drug). The primary measure of efficacy for the three trials was the composite response rate, which included clinical cure (resolution of the symptoms of the uncomplicated UTI that were present in patients at trial entry and no new symptoms) and microbiological response (demonstration that the bacteria cultured from patients’ urine at trial entry was reduced). The composite response rate was assessed approximately 8 to 14 days after patients were enrolled into the studies. In the clinical trial comparing Pivya to placebo, 62% of the 137 subjects who received Pivya achieved the composite response compared to 10% of the 134 who received placebo. In the clinical trial comparing Pivya to another oral antibacterial drug, 72% of the 127 subjects who received Pivya achieved composite response compared to 76% of the 132 who received the comparator drug. In the clinical trial comparing Pivya to ibuprofen, 66% of the 105 subjects who received Pivya achieved composite response compared to 22% of the 119 who received ibuprofen. 

The most common side effects of Pivya included nausea and diarrhea.

Patients should not use Pivya if they have a known history of severe hypersensitivity to Pivya or other beta-lactam antibacterial drugs. Patients should also not use Pivya if they have primary or secondary carnitine deficiency resulting from inherited disorders of mitochondrial fatty acid oxidation and carnitine metabolism, or if they are suffering from porphyria.

Pivya comes with certain warnings and precautions such as hypersensitivity reactions, severe cutaneous adverse reactions, carnitine depletion, Clostridioides difficile -associated diarrhea and interference with a newborn screening test for isovaleric acidemia, a rare metabolic disorder. 

Pivya was granted Priority Review and Qualified Infectious Disease Product designations for this indication. 

The FDA granted the approval of Pivya to UTILITY therapeutics Ltd. 

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• v.29(3); Jul-Sep 2017

Recent advances in recurrent urinary tract infection from pathogenesis and biomarkers to prevention

Jia-fong jhang.

Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan

Hann-Chorng Kuo

Recurrent urinary tract infection (UTI) might be one of the most common problems in urological clinics. Recent research has revealed novel evidence about recurrent UTI and it should be considered a different disease from the first infection. The pathogenesis of recurrent UTI might include two mechanisms, bacterial factors and deficiencies in host defense. Bacterial survival in the urinary bladder after antibiotic treatment and progression to form intracellular bacterial communities might be the most important bacterial factors. In host defense deficiency, a defect in pathogen recognition and urothelial barrier function impairment play the most important roles. Immunodeficiency and urogenital tract anatomical abnormalities have been considered the essential risk factors for recurrent UTI. In healthy women, voiding dysfunction and behavioral factors also increase the risk of recurrent UTI. Sexual intercourse and estrogen deficiency in postmenopausal women might have the strongest association with recurrent UTI. Traditional lifestyle factors such as fluid intake and diet are not considered independent risk factors now. Serum and urine biomarkers to predict recurrent UTI from the first infection have also attracted a wide attention recently. Current clinical evidence suggests that serum macrophage colony-stimulating factor and urinary nerve growth factor have potential predictive value for recurrent UTI. Clinical trials have proven the efficacy of the oral immunoactive agent OM-89 for the prevention of UTI. Vaccines for recurrent UTI are recommended by the latest guidelines and are available on the market.

I NTRODUCTION

Urinary tract infections (UTIs) were first documented in Egypt in 1550 BC, and are still among the most common bacterial infections in the world [ 1 ]. The prevalence of UTI seems to be a J-shaped distribution, with higher frequency among very young children which gradually increases with age [ 2 ]. It is estimated to affect 150 million people each year worldwide, with an annual incidence of 12.6% in women and 3% in men [ 2 , 3 ]. Although most UTIs can be effectively treated by antibiotics, UTI recurrence is a common problem and sometimes may be very troublesome. Recurrent UTIs, which include relapses and reinfection, are traditionally defined as ≥2 uncomplicated UTIs in the past 6 months, or ≥3 infections within the preceding year [ 4 ]. UTI can recur easily in young immunocompetent women with anatomically normal urinary tracts. In one study, 27% of young college-age women with their first UTI experienced at least one recurrence within the following 6 months, and in another study, 53% of women over 55 years old reported UTI recurrence [ 5 , 6 ]. Although recurrent UTIs usually are not life-threatening, the high incidence significantly increases health-care costs and has a negative impact on patients' life quality [ 7 , 8 ].

The risk factors, pathogenesis, and prophylaxis of UTI have been well investigated since the early 20 th century. In the recent years, research on UTI recurrence has also attracted a wide attention. Rather than treating recurrent UTI with antibiotics alone, if symptoms relapse, the current guidelines suggest aggressive management, such as avoidance of risk factors or medical prophylaxis [ 9 , 10 ]. Although most clinical and laboratory studies have focused on the first UTI, new evidence suggests a distinct pathogenesis in recurrent UTI. Thus, the aim of the current review is to update clinicians on the latest evidence on recurrent UTI, including the pathogenesis, risk factors, biomarkers and prevention, and present recent advances in research.

P ATHOGENESIS

There are two possible pathways in the pathogenesis of recurrent UTI; frequent repeat ascending infections and chronic/persistent infections in the bladder. Each pathway also might result from two possible mechanisms; bacterial factors and deficiencies in host defense.

B ACTERIAL FACTORS

UTIs might be caused by Gram-negative or Gram-positive bacteria, and the most common causative pathogen is Escherichia coli [ 11 ]. In studies using pulsed-field gel electrophoresis, 52%–77% of recurrent UTIs were caused by an E. coli strain which was identical to the primary infecting strain [ 12 , 13 ]. Since the 1960s, several specific strains of E. coli had been found to be significantly increased in recurrent UTIs [ 14 , 15 ]. Adherence of vaginal isolates in different E. coli strains was associated with recurrent UTI [ 16 ]. E. coli with DNA papG coding for a P-fimbriae was also significantly associated with recurrent UTIs [ 17 ]. In a prospective study, 148 women with a total of 558 recurrent UTIs were recruited, and the E. coli isolated from urine culture was routinely serologically classified for 131 O groups [ 18 ]. The ten most common O-serogroups accounted for 76% of recurrent UTIs, and nearly 50% of recurrent UTIs were caused by the three most common groups (O4, O6, and O75). In the genetic aspect, phylogenetic classification was also associated with recurrent UTIs [ 19 ]. Virulence factor genes KpsM II K2 and agn43a were independently associated with persistence or relapse of UTIs. Patients with frequent recurrent UTIs might just be infected by a special strain of E. coli .

Another possible mechanism for frequent recurrent UTIs is the survival of bacteria in the bladder through progression of intracellular bacterial communities (IBCs). Early studies showed that E. coli could replicate intracellularly, form a loose collection of bacteria, and then escape into the bladder lumen [ 20 , 21 ]. In 2004, Justice et al . used time-lapse fluorescence videomicroscopy and discovered that E. coli could form a complex of IBCs within the superficial umbrella cells of the bladders in mice [ 22 ]. IBCs in the bladder could form 4–16 h after bacterial infection, and then develop a persistent quiescent intracellular reservoir 2 weeks later [ 23 ]. These IBCs could be quiescent for extended periods despite antibacterial therapy, and then re-emerge to cause recurrent UTI. These IBCs are difficult to detect in urine specimens, but immunofluorescence evidence showed 18% of women with acute uncomplicated cystitis presented IBCs in the bladder [ 24 ]. In an animal study, higher numbers of IBCs were also predictive of persistent bacteriuria after acute cystitis [ 25 ]. In addition, a recent study revealed that bacteria in the IBCs had highly upregulated lacZ and yeaR genes, which contributed to utilizing a galactoside for metabolism and oxidative stress resistance, respectively [ 26 ]. Since studies propose that most recurrent UTIs are caused by E. coli strains which are identical to the primary infection, IBCs and a quiescent intracellular reservoir might play important roles in the pathogenesis of recurrent UTIs.

D EFICIENCIES IN HOST DEFENSE

It is well known that patients with immunodeficiency tend to have frequent, recurrent, and severe UTIs [ 27 ]. However, recurrent UTIs in some immunocompetent patients might also be caused by host defense deficiencies. The host defense in lower UTI consists of two main mechanisms; innate immune responses and urothelium barrier function [ 28 ]. The innate immune response in the bladder comprises different inflammatory cells and cells with recognition receptors, such as toll-like receptors (TLRs), which can recognize pathogens and induce a robust inflammatory immune response. TLRs are essential for the activation of immune responses and may be associated with recurrent UTI. In a cross-sectional study, genotyped polymorphisms were investigated in women with a history of recurrent UTIs [ 29 ]. Polymorphism of TLR2 G2258A, a variant associated with decreased lipopeptide-induced signaling, was associated with an increased risk of bacteriuria. TLR5 C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of recurrent UTI in adult women [ 30 ]. On the contrary, TLR polymorphism including TLR4 A896G and TLR1 G1805T might have potential roles in protection from recurrent UTI [ 30 ]. Patients with specific TLR polymorphisms may have deficiency of pathogen recognition in the bladder, which then leads to higher prevalence of recurrent UTIs.

The urothelium in the urinary tract is the first-line barrier against pathogens and toxic substances. The urothelium can secrete pro-inflammatory cytokines and protective glycoprotein plaques such as uroplakin and Tamm–Horsfall protein (THP) on the bladder surface as anatomical barriers [ 28 , 31 ]. The urothelium's antibacterial adherence mechanism is fundamental in host defense, and it had been proven to be less potent in patients with recurrent UTI [ 32 ]. Uroplakins are the essential structural components of the urothelium and a deficiency compromises the urothelial permeability barrier [ 31 ]. Uroplakins also serve as the urothelium receptor for Type 1-fimbriated E. coli and play a role in bacterial adhesion [ 31 , 33 ]. Decreased or entirely absent uroplakin expression in the urothelium has been found in patients with recurrent UTI [ 34 ]. On the other hand, animal studies showed that urinary THP has the potential to prevent bacteria from interacting or aggregating in the urothelium [ 35 , 36 ]. However, clinical evidence is still lacking. The levels of urinary THP in patients with recurrent UTI were not significantly different from healthy controls in previous studies [ 37 , 38 , 39 ]. In our recent immunofluorescence study, we found increased mast cell and apoptotic activity, and decreased E-cadherin expression in the urothelium of patients with recurrent UTI [ 40 ]. Current evidence supports the idea that urothelial dysfunction impacts the pathogenesis of recurrent UTI. Further clinical and laboratory studies are necessary to elucidate the mechanism.

R ISK FACTORS

Patients with recurrent UTI should undergo a comprehensive investigation to identify the possible risk factors [ 9 , 10 , 41 ]. The evaluations should include a history review and a physical examination to rule out urogenital anatomical anomalies, immunodeficiency, voiding dysfunction, and health behavioral problems [ 9 , 10 , 41 ]. Urinary tract abnormalities, including obstruction and calculi, are well-known causative factors in UTI [ 10 ]. A high residual urinary volume (RU) was significantly associated with recurrent UTI in male patients, even in the patients without lower urinary tract symptoms [ 42 , 43 ]. An RU of 180 mL or greater had the best specificity and sensitivity in predicting bacteriuria in asymptomatic adult men [ 42 ]. In women, the role of large RU in recurrent UTI is controversial. Postmenopausal women with recurrent UTI had a significantly increased RU and reduced urine flow compared with age-matched controls [ 44 , 45 ]. A urodynamic study also found increased abdominal strength in voiding which constitutes a risk factor for recurrent UTI in women [ 46 ]. The ideal cutoff point for the maximum abdominal pressure in the voiding phase was 28 cmH 2 O. However, in young healthy nonpregnant women, the RU was not different between patients with recurrent UTI and controls [ 47 ]. Most current guidelines suggest that increased RU is an independent risk factor for recurrent UTI, and RU should be measured before management [ 9 , 10 , 41 ].

Behavioral risk factors should be considered first in young women who have recurrent UTI. Sexual intercourse is the strongest behavioral risk factor in recurrent UTI [ 48 ]. The risk is even increased in any lifetime sexual activity and any sexual activity during the past year [ 48 ]. The odds ratio of recurrent UTI was high as 10.3 in young women with intercourse >9 times in the past month. In addition, any new sex partner and spermicide use in the past year also increased the risk. Voiding habits also might be a risk factor. Histories of hesitating to excuse oneself to urinate and voluntary deferral of micturition for 1 h were found to be associated with recurrent UTI in women [ 49 , 50 ]. The role of psychological factors in recurrent UTI has also attracted attention in the past years. Hunt and Waller used several different personality questionnaires and suggested that the neurotic personality type might be related to recurrent UTI [ 51 ]. However, because of the relatively small amount of further research, it is difficult to draw any clear conclusions concerning the role of psychological factors in recurrent UTI. The role of dietary habits in recurrent UTI is also not clear. Only drinking soft drinks was found to be moderately associated with recurrent UTI, and further evidence is still lacking [ 50 ]. Increasing fluid consumption is often recommended for patients with UTI; however, clinical studies showed contradictory results on the influence of fluid intake on the risk of recurrent UTI [ 52 ]. For postmenopausal women, the most significant risk factor is estrogen deficiency [ 10 , 41 ]. Lack of estrogen could cause thinning of the vaginal epithelium and decreased amounts of glycogen, predisposing women to introital colonization with E. coli [ 53 ]. The main vaginal flora usually changes from Lactobacilli to uropathogen such as E. coli after estrogen loss at menopause, leading to UTI recurrence [ 54 ]. The possible risk factors for recurrent UTI are listed in Table 1 .

Possible risk factors for recurrent urinary tract infection

B IOMARKERS

Although many risk factors have been reported in research, clinical patients with recurrent UTI often do not have any identifiable risk factors. Moreover, evidence about some behavioral risk factors is controversial due to unreliable questionnaire estimations [ 55 ]. Objective urine or serum biomarkers for predicting recurrence in patients with a first UTI is important and clinically useful. In the past decade, many possible biomarkers have been investigated in animal and human studies.

S ERUM BIOMARKERS FOR RECURRENT URINARY TRACT INFECTION

Serum antibodies were the first possible biomarkers found in recurrent UTI. Women with recurrent UTI who had complete antibiotic therapy were recruited in a 2001 prospective study [ 56 ]. The levels of serum antibody immunoglobulin (Ig) G, IgM, and IgA in the study patients were significantly higher than those in healthy controls. Hannan et al . investigated serum cytokines in mice with acute bacterial cystitis. The levels of serum hormone granulocyte colony-stimulating factor (CSF) and interleukin-5 (IL-5) at onset were significantly higher in the mice with redevelopment of cystitis than those without reinfection [ 57 ]. The research group further investigated serum cytokines in women with uncomplicated acute cystitis and tried to identify candidate serum biomarkers from 48 different cytokines [ 58 ]. Macrophage CSF was found to be significantly elevated in patients who subsequently developed recurrent UTI. An elevated prostate-specific antigen (PSA) level is well known in the diagnosis of prostate cancer, but it also might have a potential protective role in recurrent UTI [ 59 ]. In a retrospective study, male patients with a PSA level higher than 4 ng/mL at UTI onset were less likely to have recurrent UTI than those with PSA <4 ng/mL (13% vs. 70%, respectively, P < 0.01) [ 59 ]. A bacterial challenge study revealed a significantly decreased frequency of E. coli invasion in PSA-positive prostate epithelium, which suggests a protective role for PSA in recurrent UTI [ 60 ]. In addition, the mean serum levels of Vitamin D among premenopausal women with recurrent UTI were significantly lower than those of controls (9.8 ± 4 ng/mL vs. 23 ± 6 ng/mL; respectively, P < 0.001) [ 61 ]. Vitamin D is important for innate immunity, mainly by increasing neutrophilic phagocytic function and motility [ 61 ]. Deficiency of serum Vitamin D also might be a biomarker for recurrent UTI.

U RINARY BIOMARKERS FOR RECURRENT URINARY TRACT INFECTION

Urinary biomarkers for lower urinary tract diseases have been widely discussed for years. Nerve growth factor (NGF) is a small protein that induces survival and differentiation of neurons [ 62 ]. Urinary NGF levels were significantly increased in women with overactive bladder and were considered a possible biomarker [ 62 ]. In our recent study, we prospectively enrolled women with uncomplicated UTIs and measured urinary NGF levels at baseline and follow-up [ 63 ]. At 12 weeks, the serial urinary NGF levels in women with UTI recurrence were significantly lower than those in women without recurrence. Neutrophil gelatinase-associated lipocalin (NGAL) is an iron-transporting protein and has been regarded as a promising biomarker in acute kidney injury [ 64 ]. In young patients with a first UTI recurrence, the urinary NGAL levels were significantly decreased [ 65 ]. This might result from reduced TLR4 expression and reflect-defective innate immunity [ 65 ]. In a cross-sectional survey of different urinary cytokines in asymptomatic women with a history of recurrent UTI, urinary IL-8 was significantly higher in patients with bacteriuria, and was associated with higher serum neutrophil levels [ 29 ]. Urinary IL-8 levels might have a predictive value in recurrent UTI in women. The above-mentioned serum and urinary biomarkers not only have potential predictive value, but also might involve the systemic or regional pathomechanism in patients with recurrent UTI.

Further prospective clinical trials are necessary to confirm the predictive efficacy. In summary, the possible biomarkers for recurrent UTI are listed in Table 2 .

Possible biomarkers for recurrent urinary tract infection

↑: Elevated in patients with recurrent UTI, ↓: Decreased in patients with recurrent UTI, UTI: Urinary tract infection, Ig: Immunoglobulin, IL: Interleukin, PSA: Prostate-specific antigen, NGF: Nerve growth factor, NGAL: Neutrophil gelatinase-associated lipocalin

P REVENTION OF RECURRENT URINARY TRACT INFECTION

Prevention of recurrent UTI has attracted much interest and was investigated by researchers. The European Association of Urology guideline suggests that the prevention of recurrent UTI should include the following in this order: (1) behavioral modifications and avoidance of risk factors, (2) nonantimicrobial measures, and (3) antimicrobial prophylaxis [ 10 ]. Due to the limited context, the current review mainly focuses on nonantimicrobial treatment of recurrent UTI.

P ROPHYLAXIS WITH CRANBERRY JUICE

Drinking cranberry juice might be the most well-known means of prevention of recurrent UTI. It has been shown to inhibit the adherence of P-fimbriated E. coli to urothelium, and could decrease the virulence in bacterial cystitis [ 66 ]. Early randomized controlled trials showed that cranberry juice decreased the number of symptomatic relapses over a 12-month period in women with recurrent UTIs [ 67 ]. However, further studies suggest that cranberry juice is not as effective as previously reported. The large number of withdrawals from the trials indicates that cranberry juice may not be acceptable over long periods of time. The latest Cochrane database systematic review in 2012 revealed that cranberry products, including juice, tablets, and capsules, did not significantly reduce the relapse rate for women with recurrent UTI [ 68 ]. A large double-blinded, randomized, placebo-controlled trial in 2016 again confirmed that the administration of cranberry capsules versus placebo resulted in no significant difference in UTIs over 1 year [ 69 ]. Currently, most guidelines suggest that cranberry products cannot be recommended for the prevention of UTI recurrence [ 10 , 41 ].

P ROPHYLAXIS WITH PROBIOTICS

Since the urogenital flora of healthy premenopausal women is dominated by Lactobacilli, it has been suggested that restoration of the unhealthy urogenital flora from uropathogens with Lactobacilli may protect against UTI [ 70 ]. A 1988 study revealed that intravaginal administration of Lactobacilli ( Lactobacillus casei GR-1) twice weekly could significantly extend infection-free periods compared with pretreatment in women with recurrent UTI [ 71 ]. A recent randomized, placebo-controlled trial, on 100 young women with a history of recurrent UTI, used intravaginal Lactobacillus crispatus daily for 5 days and then once weekly for 10 weeks [ 72 ]. The UTI recurrence rate was significantly lower in the study group than in the control group. Various Lactobacilli administered orally have also been assessed in clinical study, but the efficacy in the prevention of UTI recurrence is controversial [ 73 , 74 ]. Although some studies showed promising results, pooled data from meta-analyses of available randomized controlled trials (RCTs) show no convincing benefit of Lactobacillus products as prophylaxis for recurrent UTI [ 75 ]. Current guidelines recommend that Lactobacillus should not be used outside of investigational trials [ 10 , 41 ].

Further research must be conducted before oral or intravaginal probiotics can be recommended as a regular prophylaxis.

H ORMONAL REPLACEMENT PROPHYLAXIS

Estrogen loss in postmenopausal women leads to decreasing glycogen, thinning of the epithelium, and alkalization of the vagina [ 54 ]. All these changes could change vaginal flora and predispose to UTI [ 54 ]. Estrogen replacement with either topically applied vaginal cream or oral medications for recurrent UTI in women has been used since the 1980s and has shown favorable results [ 76 , 77 ]. In two RCTs in the 1990s, intravaginal estrogen therapy significantly decreased the incidence of UTI and decreased the vaginal pH in the study group without severe unexpected adverse events [ 78 , 79 ]. The rate of Enterobacter colonization in the vagina was also decreased in the study group but was not changed in the control group. A recent meta-analysis of RCTs also proved the efficacy of vaginal estrogens for preventing UTI recurrence [ 80 , 81 ]. In contrast, these meta-analyses indicated that oral estrogens could not decrease the rate of UTI recurrence and may result in local and systemic side effects [ 80 , 81 ]. Current guidelines suggest that intravaginal estrogen therapy, but not oral estrogen, shows a trend toward preventing UTI recurrence [ 10 , 41 ]. Side effects of intravaginal estrogen might be common but usually not severe. Vaginal irritation is the main adverse effect and might occur in up to 20% of women [ 81 ].

I MMUNOACTIVE AGENT PROPHYLAXIS

One of the possible pathogeneses in recurrent UTI is adaptive immune response dysfunction, especially in defects of pathogen recognition [ 28 ]. Thus, using a vaccine to strengthen active acquired immunity against uropathogens might be a reasonable prevention of UTI recurrence. Systemic vaccination has been used in treating women with recurrent UTI for more than a century [ 82 ]. However, due to the heterogeneity of uropathogens, therapeutic vaccination against UTI has largely been seen as ineffective in the past years [ 83 ]. Recently, there were encouraging results in some animal studies in the development of an E. coli vaccine [ 84 ]. Since 1994, clinical trials have been conducted on intravaginal vaccines in women with recurrent UTI [ 85 , 86 ]. Women using a vaginal vaccine remained free of infections for a significantly longer period than those receiving placebo. The total vaginal and urinary IgG and IgA were also significantly increased in the study groups. Nowadays, both oral and parenteral vaccines have also been shown effective in recurrent UTI, and are available on the market [ 87 , 88 ]. A recent meta-analysis enrolled four clinical trials of an oral vaccine (OM-89), and showed that it significantly decreased the rate of UTI recurrence with a good safety profile [ 81 ]. Headache and gastrointestinal complaints were reported most often (13%, comparable with that in the placebo group), and only one allergic reaction leading to withdrawal was reported. Now, the latest guideline recommends OM-89 for immunoprophylaxis in female patients with recurrent uncomplicated UTI [ 10 ].

A NTIMICROBIAL PROPHYLAXIS

Antimicrobial prophylaxis might be more effective, but it should be used after nonantimicrobial agents because of possible adverse effects [ 10 ]. Antimicrobial prophylaxis for preventing UTI recurrence can be given continuously for long periods of time (3–6 months), or as a single postcoital dose. A Cochrane review found that postcoital prophylaxis was just as effective as low-dose continuous antibiotic prophylaxis in the prevention of a recurrent UTI [ 89 ]. Continuous prophylaxis for 6 or 12 months significantly reduced the rate of UTIs during the prophylaxis period, with no difference between the two treatment groups after cessation of prophylaxis [ 90 ]. Postcoital prophylaxis involves taking a dose of antibiotics within 2 h of intercourse [ 41 ]. It requires smaller amounts of antibiotics than continuous prophylaxis and is associated with fewer side effects [ 91 ]. The antimicrobial prophylaxis regimens and recommended doses from the current guidelines are listed in Table 3 [ 10 , 41 , 92 ].

Antimicrobial prophylaxis regimens and recommend doses from the current guidelines

C ONCLUSION

Recurrent UTI might be one of the most common problems in urology clinics, but may not attract much attention from urologists in Taiwan. Treating UTI might not be difficult, but preventing UTI recurrence sometimes might be very troublesome for both patients and doctors. Recent research has revealed many novel concepts in recurrent UTI, including the pathogenesis, risk factors, biomarkers, and prevention. Nowadays, recurrent UTI may be considered a distinct disease, and patients with recurrent UTI should be managed aggressively. Further basic science studies are needed to elucidate details in the pathogenesis, and RCTs are also necessary to clarify the efficacy of the current management.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

R EFERENCES

Urinary Tract Infections: New research leading to new cures.

In August, the Howell Foundation hosted Dr. Linda Brubaker, a board-certified urogynecologist who specializes in treating adult women with recurrent urinary tract infections.  Dr. Brubaker is Clinical Professor, Reproductive Medicine, Obstetrics and Gynecology at the School of Health Sciences at UCSD.

 “It [recurring urinary tract infection] is a very humiliating and disruptive condition, even though it’s often treatable, always manageable and frequently curable. Urinary health has received very little attention. It’s not so sexy like cancer or heart disease, but it affects the tremendous number of women.”

The main takeaways of her presentation are:

The Backgound

According to Dr. Brubaker, urinary tract infections (UTI) affect half of women at least once in their lifetime.   Women are more likely to have a second UTI after they’ve had the first one.  A subset of women, about 2%-5%, present frequent or recurring infections.  The most common way to treat a urinary tract infection is with antibiotics, even though the collateral effects include disturbing other microbiomes in our body.

“Patients who have recurrent urinary tract infections don’t have good care in America or any place in the world. And so when I retired from surgery, I made it my clinical focus to work in this area to see if I could make some improvements for women with recurrent or frequent urinary tract infections.”

The Bladder is NOT sterile

While for decades it was assumed that the bladder was a totally sterile environment, recent research has shown the contrary: the bladder is NOT a sterile organ.  Furthermore, the bacteria in neighboring organs to the bladder may play a significant role in healthy or unhealthy bacteria in the bladder’s urobiome.  As an example, an unhealthy bowel will affect the bacteria in our vagina, and subsequently, affect the bacteria in our bladders.

“You can actually eat your way to really good health and you can eat your prebiotics and probiotics. And that’s far preferable to the unproven wild west of probiotic supplements.  So eat dark leafy greens, fresh vegetables, and when you can afford it and it’s appropriate for your household, try to go organic.”

The testing

Current testing to determine healthy and unhealthy bacteria is obsolete. Yet the testing technology that was developed in the 1950’s to determine unhealthy bacteria that cause urinary tract infections is still used today.  Traditional methods of testing account for only 2% of the unhealthy bacteria the bladder –the most common one being E-Coli; missing the other 98% of the microbiome in our bladders.

The best way to determine healthy bacteria is based on culture independent techniques, or sequencing.

“We preserve and extract the DNA from urine. We’re interested in the bacterial, the fungal and the viral cells. We use a portion of their DNA and RNA and we sequence it, determining the exact organization of the DNA.  Each sequence is different, and no result is the same.

Everybody’s urobiome is “reproducible”.  Expanded culture techniques allow the appropriate conditions to cultivate the bacteria picked up on sequencing, and identifies some or all of that 98% of missed bacteria. Through statistical and bio-informatic testing the results will determine healthy vs. unhealthy bacteria.”

By turning the urine into a set of data, a specific algorithm can allow the detection of the unhealthy responsible for that causes a UTI.

The state of the bladder’s bacterial community

A recurring urinary tract infection typically occurs when a healthy bacterial community –biosis—becomes dysbiotic – or unbalanced. Even though a healthy biosis is not the same every day, this bacterial community regulates itself.  When that bacterial community is dysbiotic, it can’t regulate itself back into a healthy state.

“Women’s urinary biome plays a significant role in [recurring] UTI’s.  The bacterial community in the urobiome is generally beneficial, and holds lactobacillus that live in the bladder that are different from the lactobacillus that live in the vagina.  Lactobacillus is generally very friendly.  A UTI is not just a matter of having a bad bacteria.  Vulnerability to UTI can also be due to the loss of good bacteria, which is why we try not to overdo it with the antibiotics.”

Identifying and understanding the levels of healthy or unhealthy bacteria helps predict the responses of medication – typically antibiotics, and typically effective about half the time.  This is important because the development of antibiotic resistance and drug side effects has made it difficult to find an effective treatment.  It is estimated that 10,000 people die per year because of antibiotic-resistant bacteria.

Getting a better response to medication is a priority for Dr. Brubaker.

New Research for new treatment of recurring urinary tract infections.

There are two factors to consider when discussing treatment for a UTI:

• The fact that intracellular bacteria hides in the walls of the bladder, making it difficult for antibiotics to clear the infection.
• Bacteria can also hide the organ’s biofilm, which contains about 10 times more bacterial cells. This bacterial biofilm also contains viruses that may infect healthy bacteria.

Based on this, Dr. Brubaker is researching phage therapy as a new alternative to treat severe and recurring urinary tract infections.  Still in its infancy, the use of bacteriophages to treat bacterial infections could be used as an alternative to antibiotics when bacteria are immune to multiple types of drugs, especially at a time where superbugs are becoming a concern with the more frequent use of antibiotics.

This is an excellent example about the impact phage therapy is starting to have in the medical community ; especially in an era where a patient’s health is at risk (of even death) from the overuse of antibiotics. The dedication of researchers like Dr. Brubaker are leading the way into a new era of medicine.

The Doris A. Howell Foundation for Women’s Health Research has been dedicated to keeping the women we love healthy by making a long-term, positive impact on women’s health. It is the premier organization advancing women’s health.

The organization does so by:

• Awarding undergraduate research scholarships  and graduate nursing research grants to scientists researching issues affecting women’s health;
• Presenting the latest medical research findings at our events  and t hrough our Speaker Service progam, where experts and researchers convey timely timely information on topics relevant to women’s health and the health of their families,
• Funding research initiatives  geared towards improving the health of under-served women and increase awareness and advocacy in the community; bringing women’s health research to a full cycle.

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