News – Blog
27 May 2020
Debilitating pain, depression, embarrassment, damaged relationships, exhaustion, and fear that your next flare up may kill you.
Would you associate this with a urinary tract infection (UTI)? Probably not. It can be all too easy to dismiss a “bladder infection” as something not too serious or as a simple inconvenience. Yet, in a world where bacteria are increasingly resistant to antibiotics, this is the reality for a great many people who develop a chronic UTI caused by a superbug.
92 million people worldwide are affected by UTIs. In England, up to 3% of GP appointments can be attributed to their symptoms, and treatment accounts for 13.7% of all antibiotics prescribed by GPs[1]. 50-60% of women[2] and 12% of men[3] will get a UTI at some point in their life, mostly from Escherichia coli (E. coli). 25% of sepsis cases originate from the urogenital tract[4].
In 2018, there were 172,000 hospital admissions for UTIs in the UK[5] – equivalent to the population of Oxford. Crucially, more than 12,000 patients presented with chronic infections – in other words, 12,000 people for whom antibiotics may no longer work and for whom living with a UTI can be a daily nightmare.[5]
Three years ago, E. coli was added to the list of “priority pathogens” set out by the WHO – a catalogue of 12 families of bacteria that pose the greatest threat to human health because of antibiotic resistance. Not only do UTIs have the very real potential to be life-altering, but when they are resistant to all available antibiotics they are life-threatening.
It is against this context that Challenge Works Longitude Prize and the Royal College of Nursing convened a one-day symposium of 162 clinicians, nurses, health experts and professional bodies working in treating and solving UTIs in the National Health Service, along with diagnostic developers competing to win the Longitude Prize. Most importantly, we welcomed people living with chronic UTIs to ensure the event took place in the full context of their stories and their life experiences.
In 2018, Ronda Windsor underwent laparoscopic surgery to diagnose endometriosis. Within 48 hours she started to suffer from UTI symptoms. She had contracted Citrobacter koseri which developed into sepsis and came very close to killing her. She was treated with IV Gentamicin and a cocktail of other antibiotics to treat the sepsis but was released from hospital still symptomatic of a UTI. A trip to the GP surgery resulted in repeated short courses of trimethoprim and nitrofurantoin, and Erythromycin. They did not work. Ronda experienced severe pain, a sensation or urinating “razor blades”, burning sensations, persistent groin pain, swollen and aching legs and an inability to focus, and now suffers from sporadic attacks of incontinence which she finds very distressing.
The worst pain I experienced was shooting pains – like a knife – inside my vagina that would reduce me to tears. The pain would often wake me up during the night or prevent me from sleeping at all.
Ronda was left feeling desperate and scared that the sepsis would return. Her UTI infection had developed into an obligate intracellular bacterial infection, her pain and discomfort are persistent. The side-effects of certain antibiotics, such as Oxytetracycline and trimethoprim, exacerbated her suffering, creating the sensation of facial skin burning and red itchy blisters. The whole experience has had a severe impact on her mental health and at times feeling that the only escape would be suicide. The infection makes socialising very difficult and intimate relations with her partner practically impossible.
One of the worst things I experienced when I told friends, family and strangers about my ordeal, is that very few understood that a UTI can affect every aspect of one’s life and can potentially develop into sepsis. I may look perfectly well, but that’s not a true reflection of what is going on inside my body and mind. I’m plagued with worry and illness which often makes me feel that my future is very bleak.
The frustrating situation with chronic UTIs is that we can do so much to avoid them by treating infections effectively with the right antibiotics when they are still acute and uncomplicated. Too many chronic infections are avoidable, too much of the suffering is unnecessary. Doctors, nurses and patients in attendance expressed their frustration that the standard dipstick diagnostic test is wrong 30% of the time and that more accurate lab-based culture tests take up to three days to produce results.
Dr Annie Joseph, consultant medical microbiologist at Nottingham University Hospitals NHS Trust raised the excellent point that the way we test for UTIs has not changed in 50 years. It does not reflect modern medical advances and does not build on our knowledge of the urinary microbiome and molecular diagnostics.
As it stands, primary care physicians are in the absurd position of being asked to cut back on antibiotic prescriptions to tackle antimicrobial resistance (AMR), whilst needing to promptly treat patients with painful UTIs without the option of quick, affordable, and highly accurate tests. For most patients, explained Associate Professor Gail Hayward, University of Oxford, test results take days to come back, often after a patient has completed a course of antibiotics that may or may not have been necessary, but worse still may have promoted bacterial resistance. Getting the diagnosis right in primary care is vital to reduce the 172,000 hospital admissions later in the patient journey and to slow the development of superbugs.[5]
Women are 30-times more at risk of contracting a UTI than men. It’s not surprising that UTIs have received so little attention; the historical gender-bias in medical research towards male-centric illnesses and male-centric research data has been well-documented and it is well-understood that women’s medicine has suffered from underfunding as a result.[6]
Missing an infection when it is acute or prescribing an ineffective antibiotic can result in a chronic UTI and even sepsis. Given more than 70% of cases in primary care are E. coli infections, promoting E. coli bacterial resistance whilst at the same time setting up the infected patient for ongoing secondary care in hospital is a recipe for disaster. The patient will have to live with the infection; for the hospital, it risks endangering other patients.
The challenge in hospitals is naturally different to primary care. Professor Peter Wilson of UCLH explained that, “compared to 10 years ago, I’m seeing five to ten times more multidrug-resistant organisms when culturing UTI in hospitals”.
Just over half of hospital UTIs result from E. coli, withgreater incidence of Enterococci, Staphylococci, Klebsiella, Pseudomonas and others causing infections than in primary settings. A particular challenge is the effective diagnosis of older patients; UTIs are a significant cause of mortality in the elderly population.[7]
Professor Wilson used the example of older women, for whom traditional urinalysis testing with a dipstick is far less accurate. Urinalysis is unable to distinguish between symptomatic and non-symptomatic UTIs. In fact, 61% of positive urinalysis specimens, when also sent to a lab to be cultured, turn out to be negative. For this reason, urinalysis is not recommended for patients over 65, instead doctors must rely on the cultures that need up to three days to produce a result and often have low specificity and sensitivity to uropathogens.
This delay in less-than-reliable test results again puts doctors in a position of using their best judgement to treat an infection with antibiotics, without knowing whether they are needed in the first place or, if there is an infection, which one they are fighting. Sadly, this is the grey-space in which AMR is proliferating. Hospitals need rapid tests, but they need them to be specific, to identify the quantity of bacteria in a sample and to understand the antibiotic susceptibility of that infection.
In community settings, the situation is even trickier. The limitations of diagnosis in older patients in hospital is naturally a challenge in the elderly care sector too. Here it is far harder to collect reliable mid-stream urine samples to produce useful diagnostic results. Care homes need to know if there is an active infection and if it could be life threatening. Since the tests we have are not adapted to the elderly population in the community, patients are unnecessarily referred from care homes to hospitals, just in case. This is not good for hospitals (in terms of beds and resources), but worse, it is not good for the elderly person whose life is disrupted significantly.
Studies have suggested admitting frail elderly people to hospital can be detrimental to their physical ability. There is a greater risk of contracting a hospital-acquired infection and it interrupts the existing relationships with carers. There is an increased risk of developing delirium, which can trigger dementia, possibly as a result of the stress of going into hospital. There is an economic impact too, people over 85 account for a quarter of all bed days in the NHS[8]. Rapid point-of-care tests have the potential to drastically improve diagnosis and disrupt unnecessary admission benefiting patients and hospitals alike.
Elsewhere in the community, Marco Motta, pharmaceutical advisor at NHS Kernow, spoke about pharmacy services tackling UTIs. GPs promote self-referral services in pharmacies where the pharmacist is authorised to provide antibiotic prescriptions. Since those pharmacies have no access to GP held records that may reveal a prior history of UTIs and their associated treatments, consultations take place without the right medical context. This lack of context increases the risk of incorrect prescriptions that promote drug resistance rather than eradicate infections.
There is a huge range of symptoms and clinical syndromes associated with UTIs, and yet the diagnostic pathway remains the same. Current urinary diagnostic pathways and tests are inadequate and are not helping a significant proportion of patients. Advancing research that increases our understanding of disease progression will create opportunities for improving diagnosis and treatment.
Given the complicated landscape, one single test is not going to solve the challenges we face, there is no silver bullet in diagnosing UTIs or in slowing AMR. What is for certain is that if we are to make patients’ lives better and prevent infections developing into chronic conditions, we must move on from the decades-old dipstick.
We must also provide developers with better guidance about what is needed.
There’s not one test that will solve the problem, and I think it’s still not very, very clear to us as developers what is needed… that’s because the gold standard of what we have at the moment, the culture-based method, is so poor, so I think that makes everything quite difficult
We need tests that are highly accurate, they must be readily and widely understood by staff working at all levels of the NHS and in community settings. Tests need to be priced in such a way that they can be justifiably procured by the NHS and stand up to cost-benefit scrutiny. Tests need to be grounded in evidence and cannot be rushed; they need accurate data to prove their efficacy and evidence to promote adoption.
If we’re going to show the value of a diagnostic, we actually need real world outputs on clinical outcomes, so you may have a great test, but does it actually improve health? And that’s actually something that needs a lot of time
Fortunately, we are not starting at the bottom of the mountain. A lot of time, resource, research and skill has already gone into developing the next generation of innovative tests. We were pleased to welcome colleagues to the symposium who are developing these point-of-care tests to tackle UTIs in pursuit of the £8m Longitude Prize.
Astrego Diagnostics based in Sweden has developed a single-use disposable cartridge with a nanofluidic chip. A urine sample of just about 100 microliters is required, applied to the chip by a Pasteur pipette, at which point the cartridge is inserted into Astrego’s PA-100 Analyzer – roughly the size of a small shoe box – which does all of the hard work. A microscope and camera capture’s images of the cartridge’s 32 different reservoirs each with different reagents and about 250 single cell traps, whilst the Analyzer regulates temperature and pressure. This enables the PA-100 system to isolate and incubate up to 8000 individual bacterial cells while imaging across 32 separate growth conditions in real time. Taking this approach, it can detect presence of bacteria in urine and generate the antibiotic susceptibility/resistance profile of the infection for 5 different antibiotics in 30 minutes from urine sampling.
The outcome empowers clinicians to make personalised prescriptions, issuing the precise antibiotic that should work against the specific infection present, or if no infection is present, no antibiotics at all. This enables use of existing antibiotics regardless of resistance rates and reserves antibiotics with low resistance rates for those who really need them. A 30-minute, easy-to-use test with a high degree of accuracy and specificity is a far cry from the basic urinalysis currently on offer to GPs and nurses. To catch and cure far more UTIs when they are acute would have an extraordinary impact for patients in primary care and would reduce onward referrals. In a hospital setting, it would free up precious lab time and return reliable results to doctors within minutes.
Module Innovations is one of the many Indian teams working hard to slow AMR. Its diagnostic looks not unlike a credit card, requires a tiny sample placed in the centre of the test, and through embedded reagents can tell the user if an infection is present and which bacteria is the cause. This facilitates a much more informed approach to antibiotic prescription. It is simple to use, requires no additional special equipment to produce a result and goes far beyond the capabilities of current urinalysis. This is hugely important in an Indian context, and in less developed economies where patients may seek treatment in an informal setting rather than a bricks and mortar medical centre. It also has game-changing potential to transform community diagnosis in developed economies, whether in care homes or in a pharmacy setting.
The diagnostic test from BioAmp Diagnostics from the USA is a biochemistry-based approach that detects the activity of target resistance biomarkers directly from unprocessed urine samples. It has developed reagents that produce distinct colour changes in a sample. BioAmp’s solution may sound simple (I assure you the biochemistry is not), but that is precisely what is needed to ensure the new generation of diagnostics are adopted wholesale.
When compared with the current tests on offer to doctors and nurses, being able to see distinct colour changes, rather than having to interpret possible vague changes with current urinalysis tests, is hugely valuable in identifying an infection. Those distinct results are available in minutes, which addresses the well-founded frustrations of clinicians and patients in primary care where presently accurate test results are ready only after a course of antibiotics has been completed.
123 USW from the UK is using relatively new advances in loop-mediated isothermal amplification – or LAMP. The low-cost DNA amplification technique offers an affordable and accurate diagnostic option for doctors and nurses. 123 USW’s analyser costs in the low hundreds of pounds and the team estimates a per test cost of around £2. When stood alongside already cost-effective CRP (C-reactive protein) point-of-care tests used in diagnosing respiratory infections which have a per test cost of around £4 and analysers costing around £2,000[9], it becomes clear that 123 USW’s LAMP diagnostic has great potential in UTI diagnostics. Though in the earlier stages of development than some of the other solutions taking part in the symposium, the team has already been recognised with a Discovery Award grant by the Longitude Prize and is well on its way to developing a rapid affordable point-of-care test that can be in GP surgeries and hospitals in the next few years.
If diagnostics for UTIs improve, not only will we prevent acute infections becoming chronic, we will reduce admissions to hospitals, make diagnosis in the community easier, and, empower medical professionals to have confidence in the results and become their greatest advocates.
Rose Gallagher, Professional Lead for Infection Prevention and Control/AMR and Sustainability Lead at the Royal College of Nursing (RCN) provided an all-important frontline perspective to the day’s proceedings:
whether it’s identification of potential infection, assessment of infection, or supporting patients with antibiotics, the nurses are there at every part of the journey, and we will use the point-of-care tests when they are developed
She explained there is a great need for new diagnostics and better tests to help:
speed up the decision-making around whether or not an antibiotic is needed
Tests cost money, they are complex, they take time to develop and there will not be one test that resolves all the challenges we face in one fell swoop. However, point-of-care tests are worth the investment and they are worth getting right, to prevent the pain and fear of patients like Ronda Windsor and the many women and men who suffer the consequences of misdiagnosed or antibiotic resistant UTIs in often excruciating agony each and every day.
Those of us working in AMR can sometimes be part of a professional bubble – working hard as a community of scientists, doctors, innovators and funders to develop solutions that benefit an end user. Too frequently we forget to invite those end users into the bubble, to make them a part of the innovation journey and engage them on a human level. When we do, these abstract “users” become people with whom we can build personal and emotional bonds. We do ourselves as a disservice as a healthcare community when we forget to engage on this most basic level.
Oliver van Hecke summed things up perfectly:
When introducing new tests onto the NHS there is always the economic argument, but actually it’s the patient experience which is important. Never forget the patient.
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