current UTIs, or persistent UTIs, are distinctly different from one-off UTIs, and can turn into a difficult, ongoing battle. Urinary tract infections (UTIs) are one of the most common infections and affect up to 50% of women in their lifetime, with almost half of these women experiencing a recurrence in 6–12 months. Recurrent UTIs (rUTI), or persistent UTIs, are distinctly different from one-off UTIs, and can turn into a difficult, ongoing battle. These are infections that don’t leave, even after treatment with antibiotics. At a basic level, recurrent UTIs are caused by bacterial populations in the bladder that are not eliminated. Here, we explore the most recent understanding of how these chronic infections develop and how bacteria evade the immune system and antibiotics. Bacteria from a single UTI can lay dormant for weeks or months, eventually leading to another infection or cyclical outbreaks. These recurrent UTIs are caused by the same bacteria that never left. Separate, individual UTIs, spaced further apart, are more likely to be caused by new bacteria being introduced to the urinary tract. rUTI is defined by the occurrence of 2 or more UTIs within 6 months, or 3 or more UTIs within 12 months. Effectively, rUTI is a new disease, separate from acute UTI. These chronic infections are caused by a different, more complicated mechanism, and require different diagnosis and treatment solutions.
Acute UTIs can turn into recurrent UTIs when persistent populations of bacteria from an infection lay dormant within biofilm or within bladder cells. How do UTIs become recurrent UTIs? Bacterial Biofilms During a UTI, bacteria can form a structure called biofilm on the bladder wall, which can often be responsible or involved in persistent infections. A biofilm is a protective extracellular matrix of polysaccharides, proteins, lipids and DNA that are created by the bacteria. These biofilms allow bacteria to stick to each other and to surfaces. Biofilm-forming uropathogens can be difficult to eradicate because the biofilms are difficult to penetrate, which protects the bacteria from antibiotics and immune defenses. Bacteria lay dormant within the biofilm until an opportunistic moment, at which point they can break free, replicate, and cause a new infection and UTI symptoms. Biofilms are difficult to detect, and urine cultures may also come up negative when bacteria are encapsulated within biofilm and not present, free-floating, in the urine. Biofilms are now understood to play an important role in recurrent UTIs and may be a large part of why 26–44% of females with their first UTI will experience a second UTI within 6 months (1). Not all UTI-causing bacteria form biofilms; however, those that do are considerably more virulent, and are associated with higher rates of antibiotic resistance (2). Embedded Bacteria Bacteria from a UTI can also invade the actual cells of the bladder wall, where they can lay dormant. This type of rUTI is sometimes called an “embedded” UTI. This mechanism has been speculated upon but has been difficult to generate evidence for in humans. However, in 2019, researchers at UT Southwestern demonstrated the existence of these communities in bladder epithelial cells in bladder wall biopsies (3). Bacteria from a UTI can invade the cells of the bladder wall creating protected communities that live inside the bladder cells themselves (bacteria are much smaller than human cells). These communities likely consist of multiple types of bacteria, and go on to seed new, recurring infections.
Sometimes, recurrent UTIs can be difficult to detect, leading to negative urine cultures. Why are rUTI difficult to detect? During rUTI, urine cultures can come up negative. It is important to note that a negative urine culture or dipstick does not rule out the presence of an infection. There are a few reasons for this:
Multiple types of bacteria are likely to be involved. When multiple pathogens show up on a standard urine culture, these results are often thrown out as “contamination”.
These bacteria might not be present in a urine sample because they are hiding within the cells of the bladder or in biofilm, and not in the urine or outside of the bladder.
Standard urine cultures are often inaccurate, and cannot identify most pathogens.
Many antibiotics will not affect dormant bacteria, which then live through antibiotic treatment and may lead to recurrent UTIs. Why aren’t antibiotics always effective at treating rUTI? Antibiotics are not always effective at killing the bacteria responsible for rUTI because most antibiotics will not affect bacteria while they are dormant. Protected inside or outside the bladder cells, these bacteria lay dormant, and do not divide. Most antibiotics work by interrupting the bacterial division process. This is very important because if the bacteria are dormant, and not dividing, these antibiotics will not affect them. Antibiotic treatment regimens will have immediate impact by killing off active bacteria, reducing the immediate symptoms, but if bacteria are dormant, they will not be affected. While taking antibiotics, any replicating bacteria will be continuously killed, however, when the round of antibiotics is over, the dormant bacteria can become active, causing cyclical infections and UTI symptoms.
The immune system is in a constant battle with the bacteria responsible for rUTI, leading to a cycle of symptom flare ups and remission. Why are rUTI symptoms so cyclical? Once antibiotic treatment is over, bacteria can quickly multiply within the cells, which causes an inflammatory response and UTI symptoms. As part of this response, white blood cells arrive but do not recognize the bacteria because they are hiding within the cells or biofilm. This can go unresolved, leading to continued inflammation and UTI symptoms while cultures remain negative because the bacteria are housed within the cells rather than the urine. Eventually, these bladder cells might be shed into the urine, at which time the bacteria inside may escape and infect new healthy cells and start a new infection. These dead bladder cells collect in the urethra, and along with the inflammation, can lead to additional UTI symptoms like urgency and difficulty urinating. In rUTI, this tug of war is a constant battle, and a fluid situation. Bacteria are constantly replicating and being eliminated, and it is not until a tipping point is reached that a new infection occurs.
Read more on this connection in our article on ‘Recurrent UTIs As a Possible Explanation for Interstitial Cystitis’. rUTI and Interstitial Cystitis rUTI is now believed to be a leading cause of Interstitial Cystitis (IC), or chronic, undiagnosed bladder pain, in which a patient has chronic UTI symptoms, but has consistently tested negative in a urine culture. In this case, the urine culture may not be good evidence for the lack of an infection. For sufferers of IC, these rUTI are now recognized as a new possible explanation, and should be treated with great care and expertise.
Conclusion In rUTI, bacteria are persistent, and it is likely that both biofilm and embedded bacteria are at work. These infections can be very difficult to diagnose and treat, and they can lead to chronic inflammation and symptoms like urgency, pain, and irritation. The quicker a UTI is stopped, or even better, prevented, the lower the likelihood of developing into rUTI. An initial UTI is just a UTI until those bacteria are able to form biofilm and/ or invade the actual bladder cells. However, once that happens, the UTI is now rUTI. Due to differences of these two disease states, “UTI” should no longer be used not as a blanket term describing these infections. More granular definitions are needed to account for their differences. While certainly not exclusive to the population, rates of rUTI appear to be significantly higher in postmenopausal women (learn more about UTIs in postmenopausal women here). In younger women, rUTI can be caused by changes in the urogenital microbiome and triggered by sexual activity (learn more about why UTIs from sex may not be what you think here). Those suffering from rUTI should seek care from a specialist who understands these infections and the need for close diagnosis and management with the patient.
References 1. Kramer, Melissa. Chronic Urinary Tract Infection vs Recurrent UTI. Live UTI Free. August, 2020. 2. Delcaru C, Alexandru I, Podgoreanu P, Grosu M, Stavropoulos E, Chifiriuc MC, Lazar V. Microbial Biofilms in Urinary Tract Infections and Prostatitis: Etiology, Pathogenicity, and Combating strategies. Pathogens. 2016 Nov 30; 5(4):65. 3. De Nisco NJ, Neugent M, Mull J, Chen L, Kuprasertkul A, de Souza Santos M, Palmer KL, Zimmern P, Orth K. Direct Detection of Tissue-Resident Bacteria and Chronic Inflammation in the Bladder Wall of Postmenopausal Women with Recurrent Urinary Tract Infection. Journal of Molecular Biology. 2019 Oct 4; 431(21):4368-4379.