UTI Diagnostics: An opportunity to improve antimicrobial stewardship and women’s health

The blind spots of current diagnostics for urinary tract infections, or UTIs, leave much room to improve both antimicrobial stewardship and women’s health – it’s time for innovation and change.

Not all UTIs are caused by the same bacteria, and not all patients are affected in the same way. Even for UTIs that are easily diagnosed with existing tools, the delay until results are available often means that patients are initially prescribed an antibiotic that may not be appropriate for their infection and will do nothing to alleviate their symptoms. Moreover, patients with UTIs that confound existing diagnostic tests may be incorrectly denied treatment or blindly prescribed several different antibiotics. All of this fuels the growing problem of antimicrobial resistance (AMR).

Antimicrobial susceptibility testing (AST) at the point of care, adoption of molecular methods, and a more thoughtful and research-led approach to testing can all bring huge gains to make sure that all patient needs are met. But as development times for diagnostics can be long, investment to solve this challenge is needed now.

In the meantime, we should remember that UTIs can be complex – and that sometimes patients are the best judge of whether they are currently suffering from one. The one-size-fits-all approach is failing patients and endangering antimicrobial stewardship.

From cancer chemotherapy to C-sections, much of the healthcare we take for granted today will become high-risk if serious infections can no longer be treated with antibiotics. Already, each year over 1 million deaths globally are directly attributable to antimicrobial resistance (AMR).

The rise of AMR is also evident in the field of urinary tract infections. A 2022 study conducted by the WHO estimates that more than 20% of E. coli isolates – the most common cause of UTIs – were resistant to commonly used UTI antibiotic treatments (¹).

The tools doctors currently use to diagnose UTIs were invented a long time ago. They contribute to the growth of AMR by creating a delay before doctors can prescribe a targeted antibiotic to eradicate the infection. For some patients, they fail to identify the cause of the infection altogether, leading to several rounds of blind antibiotic treatment.

But this is not only an AMR problem, it’s also a problem for women’s health.

Each day with a UTI that isn’t treated appropriately is a significant burden for patients. If an effective antibiotic cannot be identified, the infection may progress to a more serious infection treated with more broad-spectrum antibiotics. Diagnostics that cut this vicious cycle and allow targeted treatment of UTIs will improve not only antibiotic stewardship but also women’s health.

UTIs are a common complaint and a major driver of antibiotic prescribing in primary care (²). In 2019, there were an estimated 400 million cases worldwide, with women over 3 times more likely to be affected than men. Worryingly the number of deaths attributable to UTIs has grown 2.4 times between 1990 and 2019 to nearly 250,000 (³).

Most women will experience a UTI at least once in their lifetime and the majority of women suffer multiple episodes. If left untreated, even in otherwise healthy young people, UTIs can progress to serious kidney infections and sepsis, sometimes leading to hospitalization and in rare cases, death.

UTIs are associated with bacterial growth in the bladder, causing inflammation and a range of symptoms to the sufferer. These may include a constant feeling of needing to urinate, urinating more often, burning or stinging when urinating, blood in urine and abdominal discomfort.

Women are more predisposed to urinary tract infections due to their anatomy. The urethra is shorter and nearer to a source of bacteria coming from the bowel. Recent evidence suggests that the vagina may also be a source of bacteria if a person’s microbiome is disrupted or lacks protective organisms such as Lactobacillus species (⁴). The link between the bladder and vaginal microbiomes is an area of current research but understanding is limited.

Men also get UTIs, although less commonly. UTIs can also be problematic for the elderly and those using catheters. The symptoms in the elderly can be particularly distressing and may lead to confusion and delirium. Often UTIs can be a significant step towards increased fragility and loss of independence.

E. coli is behind around three quarters of infections, but various other groups of organisms can be involved, each of which can have a different antimicrobial susceptibility profile.

For example: Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterococcus faecalis, group B Streptococcus (GBS), Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida species are just some of the organisms that can cause UTIs (⁵).

When people suffering from UTI-like symptoms present at medical facilities, a frequent course of action is to test a urine sample using a dipstick that looks for white blood cells (a marker of an immune response to infection), nitrites (a marker of bacterial metabolism) and red blood cells (a marker of damage to the bladder).

A number of studies have shown that the dipstick test lacks sensitivity (^6,7,8,9,10). One telling study found that in symptomatic patients with a negative dipstick test, 3 days of a standard UTI antibiotic significantly reduced symptoms compared to a placebo (¹¹). Another known disadvantage of the dipstick test is that it does not reliably detect some UTI-causing organisms such as Enterococcus species because their metabolism does not produce nitrites.

Another commonly used test is mid-stream urine culture, often referred to as an MSU test or culture. A small volume of urine (typically 1-10 microlitres) is added to an agar plate and incubated for 24 hours.

Any bacterial growth that exceeds a set cut-off value is categorised as a positive urine test. The resulting isolates are then tested for antibiotic susceptibility, so that the correct antibiotic can be prescribed. The whole test takes 2-4 days plus time for transport and reporting.

The weaknesses of MSU culture are well documented. For example, the test is judged positive or negative based on a bacterial colony number cut-off. Historically this has been 100,000 bacteria per mL and this is limit still often applied.

A number of studies question the use of MSU culture and the 100,000/mL cut-off. For example, other techniques such as next generation sequencing, PCR or enhanced culture methods detect known uropathogens in a higher proportion of symptomatic people (^{12,13,14,15,16}). Some healthcare systems use a lower cut-off to catch more genuine UTIs, but a one-size-fits-all limit is still generally applied.

Another issue with the MSU culture method is that the culture conditions used are tailored towards the fast-growing E. coli, the main causative agent for UTIs. However, there are other bacterial and also fungal causes of UTIs. Some of these pathogens grow more slowly or don’t grow at all in the culture conditions used (sometimes called ‘fastidious’ bacteria as they will only grow outside the body in very specific conditions).

The MSU culture method also presumes that the bacteria or other infectious agent causing the UTI symptoms are free-floating in the bladder and thus can be collected in a urine sample. There is some evidence that bacteria form intracellular colonies within the bladder wall, where they may be protected from contact with antibiotics and may be an important cause of recurrent UTIs, though more research is needed (¹⁷).

Patients presenting with UTI symptoms are generally asked for a urine sample which is often tested with a dipstick (as above not very sensitive).

If the dipstick result is positive, antibiotics may be prescribed without knowledge of the causative agent.

This may be according to local guidelines, or the doctor may have a standard ‘go-to’ antibiotic that they favour. The antibiotic prescribed may not be optimal for the organism causing their condition.

For example, Pivmecillinam, a widely used UTI antibiotic, has good activity against E. coli but if the causative agent is from the Enterococcus group this antibiotic will not be effective.

If the dipstick result is negative (as can often be the case even if someone has a genuine UTI), they are often prescribed an antibiotic anyway because clinicians understand that patients can recognise the symptoms themselves.

However, in some cases, the flawed dipstick test result leads some clinicians to turn patients away without adequate treatment. This can be dangerous but also leads to diminished quality of life for the patient. The patient may have to present to medical facilities a number of times before gaining adequate treatment and by this time their infection may be more advanced and difficult to treat.

The remaining urine sample after the dipstick test is often sent away for central lab MSU culture testing (although it may not be if the low sensitivity dipstick test is negative).

When bacteria over the cut-off limit are detected, susceptibility testing is performed to identify the correct antibiotic, which is then prescribed.

This is a good outcome, but by then the patient has had around 3 days of an antibiotic that may not be right for them and will have been suffering for all that time and their condition may have deteriorated.

The delay in starting appropriate antibiotics also presents a selective force for development of antimicrobial resistance. This is particularly true if you consider that the antibiotics not only act in the bladder but also in the digestive system where there is a large and complex bacterial flora. If you multiply this up over all the millions of people getting UTIs worldwide, this represents a huge danger for antimicrobial resistance.

People with a negative MSU culture result will continue on the original antibiotics, which may or may not be working for them. If the antibiotic is not working, they may return to their doctor. In some cases, they may be told that they cannot have a UTI because the test was negative, and they will be denied further treatment. Given the known fallibilities of the MSU culture test, this course of action can really let down patients who are suffering.

Some people with a negative MSU culture will be prescribed an alternative antibiotic to see if that works better but this prescribing is still being done blindly. At this point another urine sample may be sent off for the MSU culture test but, as the person was already taking antibiotics, this means the cut-off threshold is even less likely to be met.

It is not uncommon for patients to go back to their doctors a number of times and be given a variety of antibiotics. From the AMR point of view, this is hugely concerning as it can lead to multiply-resistant bacterial strains.

At human level, the person with UTI symptoms will have been having a very hard time. Their day-to-day life will be severely impacted and feeling ‘normal’ will seem like a far-off dream.

In people who have had a long-running UTI, recurrent UTIs or a UTI that has developed into a kidney infection, more heavy-duty broad-spectrum antibiotics must be used to treat them. Often the treatment course is also much longer than when an initial UTI is treated. These so-called second-line antibiotics are often used for other serious and life-threatening conditions. Because of poor initial testing and treatment of UTIs, there is a greater potential for antimicrobial resistance to develop in these important antibiotic groups. This is yet another example where better UTI diagnostics could help with antimicrobial stewardship.

For some people, UTIs occur frequently and become an unfortunate fact of life. Another important group have near constant low-level UTI-like symptoms known as bladder pain syndrome or interstitial cystitis. These conditions have historically been thought to result from factors other than infection and a diagnosis is made when all other potential causes have been discounted. Research suggests that there may be up to 8 million US women suffering from these conditions (¹⁸). There is a growing belief that in some cases, bladder pain syndrome / interstitial cystitis can be caused by chronic low-level infection by bacteria. Given the deficiencies of diagnostic tests described above, this does seem plausible (¹⁹).

There are steps that healthcare professionals can take right now to improve the experience of people presenting with UTI symptoms.

Firstly, it should be acknowledged that dipstick tests can be useful, but greater awareness is needed among health professionals that they have low sensitivity.

Secondly, the drawbacks of MSU culture tests must be appreciated and a negative result should not be interpreted as “no infection” if the patient is symptomatic.

We must appreciate that the patient is often the best judge of whether or not they have a UTI based on the symptoms they are experiencing. The one-size-fits-all approach may be letting down patients. For example, it may be simplistic to assume that all pathogen species will have the same effect when present at a certain number and that all individuals will be affected in the same way. Can we assume that a certain quantity of bacteria in the bladder will affect an otherwise healthy 20-year-old in the same way as an elderly diabetic person with significant co-morbidity?

These common-sense measures could improve the patient experience, but they do not help with antimicrobial stewardship.

Moving diagnostics nearer to the patient in facilities such as physician’s offices, hospital wards and care homes has many benefits. Samples can be tested immediately, and the patient can be given an appropriate treatment right away.

Point-of-care testing also gives clinicians more control and involvement in the testing their clinical decisions rely upon. Additionally, samples will not degrade or change during transport, meaning a more accurate test result can be generated.

UTI diagnostics that identify the causative agent and its antimicrobial resistance profile as soon as possible, ideally before the patient leaves the medical facility, are hugely beneficial. In this way, the correct antibiotic can be prescribed swiftly, avoiding the problem of over-prescribing of ineffective antibiotics and allowing the patient to regain their quality of life.

A few point-of-care diagnostic systems devices currently on the market or in development work toward this aim. For example, the Flexicult system from SSI Diagnostica is widely used in physician offices in Denmark and other countries.

The system consists of an agar plate divided into six sections, five of which each contain a different antibiotic and the remaining section is just agar. Patient urine samples are added to the plate and are incubated for 16-24 hours. After this time, the bacterial load (down to 1000 cfu per mL) and resistance profile of the dominant organism can be determined.

Of course, this system means that patients must either suffer their symptoms for one more day or be given potentially inappropriate antibiotics for a short time but at least the time is much reduced relative to central lab testing.

Recent, promising innovations in point-of-care systems can allow detection of UTI pathogens and antibiotic resistance profiling before the patient leaves the medical facility. In this way the patient can be immediately provided with the appropriate antibiotic.

For example, the Sysmex PA-100 AST System monitors bacterial growth in real time using microscopy and microfluidics and can provide antibiotic susceptibility profiles for five commonly used antibiotics in 45 minutes. This technology was launched in 2023 and won the prestigious Longitude AMR Prize in 2024.

ODx Diagnostics and TTP have co-developed a system with a similar time to result target. The instrument uses light scattering to monitor bacterial cell growth and susceptibility to commonly used antibiotics.

Point-of-care systems can be enormously beneficial to patients who can receive the correct treatment much sooner and they also have a valuable impact on reducing inappropriate antibiotic prescribing. Many patients with straightforward acute urinary tract infections caused by common pathogens can be treated swiftly and accurately using methods such as this. Hopefully diagnostics such as these will gain traction in healthcare so that many will directly benefit.

However, while a huge step in the right direction, point-of-care culture diagnostics may not catch all cases. Infections may be missed because the UTI is caused by a more unusual organisms with slower or more fastidious growth. The patient may already have been taking an antibiotic which can retard bacterial growth in the timeframe in which point-of-care culture tests operate. Lastly, the pathogen may be at too low a level to be detected or the interpretation of the test may be complicated by mixed infections or detection of harmless bladder microbiome species. In these cases, another approach may be necessary.

For patients who know from their symptoms that they have a UTI, but it may be an unusual species, at a lower level or embedded in the bladder wall, currently used methods are really letting these individuals down and blind antibiotic prescribing is the norm.

There is a great opportunity to use molecular techniques such as next-generation sequencing in the fight against UTIs and antimicrobial resistance. Whereas some UTI-causing organisms cannot be cultured using standard techniques, and some can’t be cultured at all, DNA sequencing can be used to detect all organisms present.

One complication with this method is that the bladder has a bacterial flora and is not actually sterile as had once been thought. It can be hard to decide whether a bacteria is a harmless member of that flora or a UTI causing agent. Additionally, urine samples sometimes include flora from the surrounding skin and genital regions and these isolates may be wrongly attributed to being in the bladder. Nevertheless, when conventional methods have failed, more extensive investigations such as this should be considered.

Patients disillusioned by standard diagnostic testing are already turning to direct-to-consumer molecular detection services. In the UK and Europe, Digital Microbiology currently offer Oxford Nanopore sequencing for pathogen identification. In the US, MicroGenDx offer a PCR and DNA sequencing service to healthcare professionals and also direct to consumers.

A commonly cited downside of molecular testing for UTI-causing organisms is that antimicrobial resistance cannot be determined as reliably as with culture-based phenotypic methods. This is because, while some genetic signatures for resistance are known, many others are not.

Some resistance signatures can be detected, however, and, when used with caution, can be valuable in selecting the right antibiotic. Additionally, knowing the species can be of use in selecting the antibiotic best suited to the organisms (without considering acquired resistance) which is beneficial. Another benefit of molecular species identification is that the correct culture conditions can be used to grow that organism and test for antibiotic sensitivity.

As it stands, the limitations of existing tools have a huge impact on patients in terms of quality of life and impose a huge cost to society in terms of increased antibiotic resistance. We believe that more powerful, sensitive and nuanced solutions are needed urgently.

With this in mind we have put together a list of requirements that UTI test methods should fulfil in order to meet the needs of the patient (disproportionately women whose needs have historically been ignored) and also the very pressing need to combat antimicrobial resistance.

A test or testing pathway should:

Now is the time to improve UTI diagnostics for both the patient and antimicrobial stewardship. There are already some promising developments, such as point-of-care antibiotic susceptibility testing. However, UTIs are complex, and more work is needed to make sure all patient needs are met. As diagnostic development times can be long, this area needs commitment from industry and governments now. Additionally, to promote the adoption of point-of-care tests, there needs to be appropriate reimbursement to incentivise clinicians to use such diagnostics.

The understanding of UTIs, though incomplete, is growing and we should harness this research as well as listen to the voice of patients to inform future directions in UTI diagnostics.