In 2016, Professor James Malone-Lee wrote a piece for the Daily Mail that shook up how many people think about urinary tract infections. His central argument? The standard tests that GPs use to diagnose UTIs are missing a huge number of infections, leaving millions of women (and some men) without proper treatment.

This matters because if you have ever been told your urine test came back “negative” despite painful, burning symptoms that just will not go away, Prof. Malone-Lee’s work might explain why.

Who is Professor James Malone-Lee?

Prof. Malone-Lee spent over 30 years as a consultant physician at University College London, specialising in urinary tract conditions. He ran a specialist clinic at the Whittington Hospital in London that saw patients referred from across the country, often after they had been told repeatedly that nothing was wrong with them.

What made his approach different was a willingness to question established diagnostic methods. Rather than accepting the standard urine culture as the final word on whether an infection existed, he developed microscopy techniques that could detect bacteria missed by conventional testing.

He retired from NHS practice but his research continues to influence how chronic UTI is understood and treated. His work has been particularly important for patients diagnosed with interstitial cystitis or painful bladder syndrome, some of whom may actually have undiagnosed chronic infections.

The problem with dipstick tests

When you visit your GP with UTI symptoms, the first test you will usually get is a urine dipstick. This is a plastic strip dipped in your urine sample that changes colour to indicate the presence of nitrites (produced by certain bacteria) and leukocytes (white blood cells, which suggest inflammation).

The trouble is that dipstick tests have a sensitivity of only around 50-80% for detecting UTIs 1. That means they miss somewhere between one in five and one in two genuine infections. If you have got a UTI and the dipstick comes back negative, you might be sent home without antibiotics.

Why do these tests miss so many infections? Several reasons:

Not all bacteria produce nitrites. The test only detects nitrite-producing organisms like E. coli, but other bacteria can cause UTIs too
The bacteria need time to convert nitrates to nitrites in the bladder. If you have been drinking lots of water or urinating frequently, nitrite levels may be too low to detect
Leukocytes can be absent in early or mild infections
Some chronic infections involve bacteria at concentrations below the detection threshold

Prof. Malone-Lee’s research found that many patients with genuine infections had entirely normal dipstick results. He argued that relying on dipsticks as a first-line screening tool was causing huge numbers of infections to be missed.

Why midstream urine cultures are not much better

If your dipstick is positive, or if your GP suspects an infection despite a negative dipstick, the next step is usually a midstream urine (MSU) culture. Your sample gets sent to a laboratory where they try to grow bacteria from it.

The standard threshold for a “positive” culture is 100,000 colony-forming units per millilitre (10^5 CFU/ml). This threshold dates back to the 1950s, when a researcher named Edward Kass established it for detecting kidney infections in pregnant women 2.

Here is the issue: that threshold was designed for a specific purpose and a specific patient group. Prof. Malone-Lee and others have argued that it is far too high for detecting bladder infections, particularly chronic ones. Lower bacterial counts can still cause significant symptoms.

A 2013 study published in the Journal of Clinical Microbiology found that lowering the threshold to 100 CFU/ml (a thousand times lower than the standard) significantly improved detection of UTIs in symptomatic women 3. Many infections that would have been called “negative” under the old threshold were actually positive when the bar was lowered.

There is also the question of which bacteria laboratories look for. Standard cultures are optimised for fast-growing organisms like E. coli. Slow-growing or fastidious bacteria may not show up in the 24-48 hour culture period. Some bacteria that cause chronic infections may not grow well under standard laboratory conditions at all.

Embedded infections and biofilms

Prof. Malone-Lee’s most important contribution was probably his work on what he called “embedded” or “chronic” UTIs. The idea is that in some patients, bacteria do not just float around in the urine waiting to be detected. They burrow into the bladder wall tissue or form protective communities called biofilms.

Biofilms are clusters of bacteria surrounded by a slimy matrix of proteins and sugars that they produce themselves. This matrix acts like a shield, protecting the bacteria from both the immune system and antibiotics. When you take a standard short course of antibiotics, the bacteria in the biofilm survive. Once you stop the medication, they re-emerge and symptoms return.

Research has shown that uropathogenic E. coli (the main cause of UTIs) can invade bladder epithelial cells and persist there for long periods 4. These intracellular bacteria are protected from antibiotics that do not penetrate well into cells. This might explain why some women experience recurrent UTIs despite taking antibiotics each time.

Prof. Malone-Lee’s approach to treating embedded infections involved long courses of low-dose antibiotics, sometimes lasting many months or even years. The rationale was that short courses could not eliminate bacteria hiding in the tissue, but sustained antibiotic pressure might eventually clear them. This remains controversial, as long-term antibiotic use carries risks including antibiotic resistance and effects on gut bacteria.

What microscopy reveals that cultures miss

Prof. Malone-Lee relied heavily on microscopy, where a drop of fresh, unstained urine is examined under a microscope immediately after the patient provides the sample. This is different from standard cultures, which may be processed hours or days after collection.

Fresh urine microscopy can reveal white blood cells (indicating inflammation), epithelial cells shed from the bladder lining, and sometimes bacteria actually visible in the sample. The presence of white cells in particular was something Prof. Malone-Lee considered highly significant, even when cultures came back negative.

The advantage of immediate microscopy is that it shows what is happening in the bladder right now, rather than relying on whether bacteria can grow in an artificial culture medium over the next two days. Prof. Malone-Lee found that many patients with negative cultures had abundant white cells and bacteria visible under the microscope.

A 2017 study comparing standard cultures with enhanced quantitative urine culture (which uses lower thresholds and extended incubation) found that the enhanced method detected bacteria in over 90% of patients with recurrent UTI symptoms, compared to only about 30% with standard methods 5.

The interstitial cystitis connection

Many patients end up diagnosed with interstitial cystitis/painful bladder syndrome (IC/PBS) after their urine tests come back negative repeatedly. The diagnosis of IC/PBS essentially requires that infection has been ruled out. But what if the tests used to rule out infection are not sensitive enough?

Prof. Malone-Lee suggested that a proportion of IC/PBS patients may actually have undetected chronic UTIs. If true, this would mean they are receiving the wrong treatment entirely. IC/PBS treatments typically focus on bladder instillations, diet changes, nerve medications, and various pain management approaches, none of which address bacteria.

This is not to say that IC/PBS does not exist as a distinct condition. The bladder is a complex organ, and chronic pain can develop for various reasons besides infection. But for some patients, the possibility of an embedded infection might be worth exploring, particularly if their symptoms started with what felt like a UTI.

You can read more about IC/PBS symptoms, diagnosis, and treatment options in our IC/PBS FAQ and treatment guide.

Implications for treatment

If standard tests are missing infections, what does this mean for how patients should be treated?

Prof. Malone-Lee argued that clinical symptoms should carry more weight than laboratory results. If someone has burning, frequency, and urgency, that ought to be taken seriously even if tests come back negative. The NHS does acknowledge that uncomplicated UTIs can sometimes be diagnosed on symptoms alone 6.

There is also the question of antibiotic trials. If symptoms improve dramatically on antibiotics and return when they stop, that pattern itself suggests an infection was present regardless of what the lab reported. Antibiotics should not be handed out freely, but in the right context, watching how someone responds to treatment can tell you more than a dipstick.

For chronic embedded infections, short courses are unlikely to work. Prof. Malone-Lee advocated for longer treatment durations, sometimes months. This is controversial. Long-term antibiotic use carries real risks including resistance and gut problems, and not all doctors are convinced the evidence for embedded UTI as a common phenomenon is strong enough to justify these extended courses. The concern is that over-diagnosing infections could lead to antibiotic overuse at a time when resistance is already a serious problem.

What this means if you have persistent symptoms

If you have been experiencing bladder symptoms for months or years and keep being told your tests are normal, Prof. Malone-Lee’s research offers some validation. You are not imagining things. The tests might simply be inadequate for detecting what is wrong.

That said, getting appropriate treatment is another matter. Most GPs are not trained in the microscopy techniques that Prof. Malone-Lee used, and NHS laboratories generally do not use the lower culture thresholds that might detect low-level infections. Some private clinics now offer more sensitive testing, but this comes at a cost.

If you are struggling with persistent cystitis symptoms, it is worth asking your GP about:

Whether a urine culture has actually been done (not just a dipstick)
What threshold the laboratory used to define a positive result
Whether a trial of antibiotics might be appropriate given your symptoms
Referral to a urologist or specialist in chronic UTI if standard approaches are not working

For general information about UTIs, symptoms, and treatments, see our comprehensive guide: All you need to know about urinary tract infections.

Where does this leave patients?

I find this whole area genuinely difficult. On one hand, there are clearly patients who have been suffering for years, told repeatedly that nothing is wrong, who found relief when someone finally took their symptoms seriously. On the other hand, the medical establishment has legitimate concerns about antibiotic overuse, and the evidence for embedded UTI as a widespread phenomenon is not as solid as some advocates suggest.

What seems undeniable is that standard UTI testing has real limitations. A negative dipstick does not mean you are infection-free. A negative culture does not either. If your symptoms are persistent and classic for a UTI, that mismatch between experience and test results deserves investigation, not dismissal.

Prof. Malone-Lee’s specific treatment protocols may or may not be the right answer. But his willingness to question whether our diagnostic tools were fit for purpose? That was valuable, and the research it sparked continues.

Original Daily Mail article: The rise of ‘super-cystitis’: Poor testing could leave women with symptoms ‘for the rest of their lives’

References

Semeniuk H, Church D. Evaluation of the leukocyte esterase and nitrite urine dipstick screening tests for detection of bacteriuria in women with suspected uncomplicated urinary tract infections. J Clin Microbiol. 1999.
Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians. 1956.
Hooton TM, Roberts PL, Cox ME, Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med. 2013.
Anderson GG, Palermo JJ, Schilling JD, et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science. 2003.
Wolfe AJ, Toh E, Shibata N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012.
NHS. Urinary tract infections (UTIs). Accessed 2024.