Persistent/ recurrent UTI is often misdiagnosed, leading to improper treatment, lack of symptom resolution, increased healthcare expenditure and decreased quality of life for patients.

Why are persistent and recurrent UTI often misdiagnosed as IC/ OAB/ UUI?

Misdiagnoses of Interstitial Cystitis, Overactive bladder, Urgency Urinary Incontinence or Bladder Pain Syndrome often occur when patients present with UTI symptoms but have a false negative standard urine culture and/or dipstick urinalysis. In one study, 93% of women diagnosed with IC had a previous diagnosis of UTI but were told their urine culture was negative.

While there can be non-microbial causes for bladder pain, there are many bacterial, fungal and viral infections that are missed due to a false negative standard urine culture (SUC).

False negative SUC and dipstick results occur largely due to two main reasons: testing inaccuracies and embedded bacterial colonies.

Despite being the global standards for UTI testing since the 1950s and 1980s respectively, both the SUC and dipstick urinalyses have high levels of inaccuracy.

Research shows dipsticks have a 70% inaccuracy rate (see also here) causing some to suggest it should be abandoned as a diagnostic tool.

SUC in turn has a false negative rate of at least 20% in E. coli infections (the bacteria it was designed to detect) and misses 88% of other uropathogens. Some research even shows it has a 90% false negative rate in a clinical population without overt UTI diagnosis but mostly presenting with bladder symptoms.

This is due to a multitude of factors:

• The SUC test was never in fact designed as a UTI test, but rather a test to detect patients at risk for pyelonephritis with E. coli. It is based on the (now disproven) premises that 1. urine is sterile and that 2. infections are caused by single agents. Because of this, samples with multiple organisms or lactobacillus are labelled as ‘contaminated’ or ‘mixed growth’ as it is assumed that these bacteria came from other sources. In reality, these bacteria are not contaminants and may well be contributors to the infection, as in some cases infections can be polymicrobial.

• The SUC has a threshold of 100,000 colony forming units per ml, originally designed to detect pyelonephritis. There is still lack of consensus on the correct threshold for UTI, but some studies show that a third or more of symptomatic women have counts below this level. Other studies suggest that there should be different thresholds for different bacteria, since not all grow at the same speed in the same medium.

• In fact, some bacteria do not grow at all in culture mediums. The SUC media is selective for typical microorganisms most commonly responsible for urinary tract infections, including Escherichia coli, Staphylococcus Saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis. Therefore, it is not an applicable test when there is a high clinical suspicion for UTI caused by atypical organisms.

• The SUC also does not pick up on viral or fungal causes of infection, which have been proven to be the cause for certain symptomatic patients with negative culture tests, even in patients that are not immunocompromised.

• The E. coli focused design of the SUC could explain our current E. coli centric view of UTI we have today, since so many other organisms remain undetected. Indeed in one study that analysed 157,000 urine samples using a different technology, E.coli was the dominant species in only 28% of cases.

• The standard urine culture does not test for epithelial cells, which have been proven to shed when confronted with acute intracellular infection.

• The Standard Urine Culture’s threshold for leukocytes (which was established even earlier than the SUC itself) is too high as it does not take into consideration leukocyte deterioration during storage.

• The Standard Urine Culture cannot detect non-culturable but still viable state (VNBC) bacteria. Known human pathogens such as E. coli, .E faecalis, P. aeruginosa and S. aureus are all capable of entering and resuscitating from a VBNC state without losing their virulence. During the VBNC state, the microbes maintain their cellular structure and biology (allowing detection with molecular testing) along with significant gene expression, but they are non-culturable by ‘standard’ laboratory methods.

Significant testing shortcomings aside, another cause for false negative urinalysis is when the bacteria has embedded in the bladder, causing fewer free floating bacteria. This can take as little as a few hours to a few days:

• Bacteria show up less frequently on tests once they become embedded in biofilm.

• Bacteria show up less frequently on tests once they become embedded inside intracellular reservoirs.

How can persitent/ recurrent UTI be treated?

Currently, there is no consensus around a single treatment for persistent/ recurrent UTI, not least since the source and development of the illness can vary. One of Urge’s goals is to bring information about existing and novel methods to the forefront, through our specialist guest lecturers.

For bacterial infections, continuous or prophylactic antibiotics is a much applied method substantiated by research, although there is no consensus on duration or dosage. For viral UTIs, anti-viral medications have demonstrated clinical improvement.

Oestrogen therapy is a common treatment for post-menopausal women with persistent or recurrent UTI, or women with hormonal imbalance.

Electrofulguration of bladder lesions (caused by persistent or recurrent UTI) has demonstrated clinical improvement in a majority of patients in the studies. This method also allows for the physical removal of intracellular bacterial reservoirs in the case of embedded infection and prevents adherence of bacteria on the fulgurated sites.

UTI vaccines have shown positive results in preventing recurrence.

Phage therapy, which has demonstrated effectiveness against infections and is used regularly in Georgia, Russia, Poland as well as other countries, holds promise for treating UTI, as well as some empirical evidence.

Some researchers propose that UTI occurs due to dysbiosis of the urinary microbiome and indeed patients with UUI/OAB where shown to have altered urinary microbiomes relative to healthy control groups, suggesting that an alternate etiology to detrusor muscle activity exists.

Dysbiosis could further explain why persistent UTI can sometimes be so difficult to treat, since re-balancing is so challenging. To this end, therapies including probiotics, gut Fecal Microbiota Transplant or bacterial interference (introduction of competitive non-pathogenic urinary bacteria in the bladder) have been tested with some positive outcomes.

Other treatments that have been explored include beta-glucans, herbal treatments, Chinese Medicine, biofilm disruptors as well as probiotics.

As research and development progresses we hope for new treatments to be available in the near future

Questions or comments?

We’d love to hear from you! Please reach out at:

hi@urgemedical.org