Acute, recurrent and chronic UTI – how they guide diagnosis and treatment

Infections of the lower urinary tract (the urethra and bladder) can be grouped into 3 types; acute, recurrent and chronic.

Acute UTI

An acute urinary tract infection is usually seen as a one-off infection that gets better within a few days through antibiotics prescribed by your GP or over the counter treatment options.

Recurrent UTI

Recurrent UTI is defined as three episodes of a UTI within a 12 month period or two episodes within the previous six months.

Recurrence usually occurs because the original infection is cleared on treatment with antibiotics but then the same or a different pathogen (infection causing bacteria) gains access to the urinary tract to cause a new infection. This results in another trip to the GP or Emergency room for further antibiotics to clear the infection.

Chronic UTI

Chronic UTI occurs when bacteria which caused the original UTI not being completely cleared from the urine and/or bladder wall by initial antibiotic management. It can remain detectable in the urine, and even after further treatment continues to cause symptoms. The sufferer is thus caught in an ongoing cycle of symptoms and treatment. It is this persistence that is called a chronic urinary tract infection or chronic cystitis.

The problem with standard tests for urinary tract infection

For those with acute, recurrent or chronic UTI symptoms, most seek diagnosis and treatment through a GP or primary health care physician.

However the diagnosis of urinary tract infections in primary and secondary care is based on unreliable and inaccurate urine dipsticks and/or urine culture tests which help guide treatment. Let’s look at these more closely.

Dipsticks

This dipstick test strip is made of paper and can have up to 10 different chemical pads or reagents which react (change colour) when immersed in, and then removed from, a urine sample usually after around 60 seconds. When looking for indications of a bacterial UTI, the dipstick analysis includes testing for the presence of:

  • White blood cells (known as Leukocytes) – only a few white blood cells are normally present in urine. When these numbers increase, the dip test will become positive. This indicates that there is inflammation in the urinary tract or kidneys and the body is excreting more white blood cells. White blood cells also produce antitoxins that neutralise the toxins released by bacteria.
  • Red blood cells – the bladder can bleed due to severe inflammation and the constant urination caused by a UTI shedding red blood cells into your urine. Some people can feel a “razor blade sensation” when urinating during a UTI attack.
  • Protein – the presence of protein can indicate a possible kidney infection as only trace amounts normally filter through the kidneys. Other causes of protein in the urine can include kidney disease or dehydration.
  • Nitrates– Some bacteria that cause a UTI make an enzyme that changes waste urinary nitrates to nitrites. However not all bacteria are able to produce this enzyme.

These ‘Gold standard’ urinary dipsticks, used by GPs in clinics as a first-line UTI diagnostic tool, are noted in one study to “poorly rule out infection” (i). This study published in the British Journal of General Practice in 2010 shows that these dipsticks may in fact only confirm infection in around 30% of consultations in a GP practice.

Dipsticks can miss 60% of chronic urinary tract infections according to published research and are only positive for nitrites in less than 18% of samples and positive for leukocytes in less than 40% of acute UTIs with positive MSU culture.(ii).

Clinical guidelines produced by the National Institute for Clinical Excellence (NICE) in the UK and the European Urology Association also insist on two markers of infection, namely White Blood Cells (Leukocytes) or Nitrites and Red Blood Cells being indicated on dip of the urine by a clinician before a diagnosis of UTI can be made. Where Nitrites are not present in the urine, and only leukocytes are indicated with no additional evidence of red blood cells then guidance is that a UTI may not be the cause of someone presenting with a suspected UTI despite describing obvious signs and symptoms.  This may deny them appropriate treatment.

Factors affecting the accuracy of dipsticks and thus diagnosis of a UTI based on the guidelines above may include:

  • Dilution of the sample by drinking too much liquid (the first urination of the day when you wake up or acidic, concentrated urine is best for analysis). GPs fail to advise patients to wait at least four hours before providing a sample.
  • Usage of previous antibiotics to treat a recent infection. Ideally you need to be off antibiotics for around 7-10 days to clear the medication from your system before providing another urine sample. This is because the continuation of the medication in your system may inhibit bacterial growth even if you still have symptoms.
  • Certain bacterial strains not producing nitrate reductase which converts urinary nitrates to nitrite – as noted above this is a key part of the dipstick analysis to determine a UTI.
  • Various chemicals may also interfere with urine dipstick analysis producing a false negative result. These include ascorbic acid (such as vitamin C) and oxalic acid (an organic compound found in many plants including leafy greens, vegetables, fruits, cocoa, nuts and seeds).
  • Biofilm or embedded bladder wall infections mean that the bacteria are hidden away from the urine, not floating in it. Thus when you urinate, the bacteria will not transfer into the sample pot meaning they cannot be detected on a dipstick.

Find out how to interpret your dipstick test.

Urine cultures – the case against:

Mid-stream urine cultures (MSU), used in clinical laboratories to identify bacteria, are shown through research to miss from 50-80% of urinary infections (iii).  In those with chronic UTI, studies have shown infection is missed in 90% of patients (iv).

Key factors that also affect these poor results include:

  • Research carried out in the 1950s remains the global diagnostic basis for interpreting a urine culture. Lab results must show bacterial counts of a level of more than 100,000 colony forming units of bacteria per millilitre of cultured urine to acknowledge infection. Any counts below this arbitrary, inflexible level are usually considered to indicate contamination of the sample.
  • This contamination will lead to the ‘mixed growth’, ‘low growth’ or ‘no significant growth’ noted on the laboratory report that people often receive via their GP surgery on return of the urine culture analysis. Indeed 1 in 4 samples in a GP setting are returned as contaminated. However should these samples be rejected? – given the knowledge around the twinned vaginal and urinary microbiome and the potential for co-infections – these contaminated samples should be considered more closely.
  • The dismissal of mixed growth bacterial cultures – If two or more bacteria are grown in a sample, microbiological guidelines direct that these results are noted as “mixed growth”. This is reported back to the GP with a recommendation of insufficient evidence of confirmed infection. Someone with a multi-bacterial infection can thus be denied treatment on receipt of these results from their GP.
  • Overwhelming evidence shows the tests used to detect urinary tract infections diagnose an extremely limited number of pathogens, favouring E.coli and other easy-to-grow microbes which develop quickly on laboratory culture within the window of analysis of around 18 hours. (v) This approach is effective in simple and uncomplicated UTI situations. However, this leaves a gap in identification of slow growing bacteria especially if a UTI is being caused by multiple bacteria in the urinary tract. Some bacteria can take up to 5 days to grow in laboratory culture.
  • 80% of infections outside of a hospital environment are attributed to E-coli infections.  However laboratory cultures are highly sensitive towards E.coli because of its ease of growth but detect as little as 12% of other clinically significant species (e.g., gram-positive bacteria; Enterococci and Group B streptococci). It has been demonstrated that the positive predictive value of midstream urine cultures was 93% and 99% for Escherichia coli growth of at least 102 CFU and 104 CFU, respectively, but the positive predictive value was 10% and 33% for Enterococci growth and 8 and 14% for Group B streptococci growth of at least 102 CFU and 104 CFU, respectively (vi) which leads onto the laboratory environment itself.
  • Bacterial species react differently to an oxygenated environment.  The bacteria residing in your bladder have a limited oxygen source but when a urine sample is placed on a petri dish in the laboratory, the oxygen they are exposed to increases. This means that bacteria which flourish beneficially in this type of environment will grow and those that prefer the ecosystem and oxygen levels of the bladder will grow in limited numbers and are often dismissed as contamination.
  • These clinically slow-growing significant species have been less studied than E.coli over preceding years but with recent research showing that infections can be multi-bacterial, focus is now moving to these alternative bacteria and their potential role in urine infections. A study from 2013 published in The American Journal of Microbiology notes “the bacteria we isolated from our LUTS patients, while known uropathogens, were not limited to species typically found in acute UTIs”.
  • Usage of previous antibiotics to treat a recent infection. Ideally you need to be off antibiotics for around 7-10 days to clear the medication from your system before providing another urine sample. Usage of antibiotics may inhibit bacterial growth even if you still have symptoms.
  • As with dipsticks, biofilm or embedded bladder wall infections mean that the bacteria are embedded and hidden away from the urine, not floating in it. This means when you urinate, the bacteria will not transfer into the sample pot thus meaning they cannot be detected during urine analysis in the laboratory.
  • There is limited primary care knowledge around this relatively new multi bacterial science, embedded bladder wall/biofilm infections and the failings of standard mid-stream cultures to diagnose a UTI. Focus remains on the identification of one pure bacterium, usually E.coli, from the laboratory analysis to direct treatment.

Read more about your urine laboratory analysis.

Find out more about about the issues with testing at the Chronic Urinary Tract Infection Campaign and Live UTI Free.

No UK clinician guidelines for chronic UTI only for acute UTI

Those suffering a UTI often comment that during a GP consult, even though they describe symptoms of a UTI these are often not given consideration.  The GP seemingly basing diagnosis via dipstick and laboratory urine analysis as directed by national guidelines. If the dipstick or urine sample results are negative, this can mean no antibiotic treatment is offered to them.

Put simply, there are no guidelines for GPs and clinicians to help support those who have ongoing chronic urinary tract symptoms. There is also no agreed Quality Standard to manage those those with recurrent infections. Clinical guidance provided to GPs and clinicians only covers acute infections.

The National Institute for Clinical Excellence (NICE) in the UK commenting on its Quality Standard page for recurrent UTI states: ‘the need for evidence based guidance for recurrent UTIs’ but ‘no source guidance is currently available’. This placeholder was set in place in 2015 demonstrating the ongoing issue of lack of active clinical research in this area (vii)

In 2018 the Clinical Knowledge Summary published by NICE  recommends primary health clinicians offer those with recurrent symptoms the following:

“Manage as acute UTI as described in the scenario UTI — (no haematuria, not pregnant or catheterized) ensuring that a urine sample has been sent for culture and sensitivities before antibiotics are started”. (viii)

Guidance is then directed towards behavioural and personal hygiene measures, localised HRT if appropriate and single, one-off antibiotic low-dose (prophylaxis) treatment against known triggers.

All this creates a potential situation of antibiotic resistance and insufficient clinical management of an ongoing infection for up to 35% of patients failed by acute infection management strategies allowing the infection to worsen and embed into the wall of the bladder.

In a 2017 article published in The Pulse, it was noted by Dr Jonathan Rees, Chair of the Primary Care Urology Society and a GP in Somerset, UK:

‘I would be delighted to see a review of this often-neglected area of medicine. I am aware through my work, both in general practice and in community urology clinics, of the huge numbers of people suffering from recurrent urinary tract infections. Our diagnostic tools are not up to scratch, and we lack strong guidance on the management particularly of recurrent or chronic symptoms (including when to suspect chronic bladder pain syndrome/interstitial cystitis).’ (ix)

Antibiotic treatment

If someone is showing acute signs of infection via urinary dipstick, a GP may prescribe a first line course of antibiotics for three days without the need for a laboratory analysis.

Alternatively, with a positive urine laboratory analysis, where the bacteria and antibiotic sensitivities are identified, the appropriate antibiotic is usually prescribed for a further period of 3-7 days with an expectation that symptoms should resolve.

A GP or specialist can also offer a repeating prescription for antibiotics which is to be used for those who experience the commencement of a UTI and who can self-manage their infections rather than having to seek treatment via primary care each time. For those who experience less than 2-3 UTI attacks per year or for those who are unable to tolerate long-term low dose, prophylactic antibiotics, a repeat prescription for occasional antibiotic use may be offered in this way.

For those with ongoing, recurrent symptoms, prophylactic antibiotics – that is a low dose of an antibiotic, can be prescribed.  These are available as either a single dose antibiotic – for those who experience a UTI after sex or can be prescribed as a long-term medication taken once a day usually for a maximum of 6-9 months and then reviewed by their specialist. This treatment route can be offered to those women who experience more than 2-3 UTI attacks per year and are able to tolerate the usage of long-term antibiotics.

However, with all these methods of treatment, the bacteria may not be eradicated from the urinary tract even after treatment, due to the low dosage and length of treatment.

Short treatment and prophylactic doses don’t eradicate infection and cause resistance

It is important to know that antibiotics are only effective against active dividing bacteria. Any bacteria embedded in the cells of the bladder wall may lie dormant and do not divide. These bacteria, known as “persisters”, are not targeted by most antibiotics which act at an extracellular level (outside of cells). Even tissue-penetrating antibiotics do not have the capability to kill dormant microbes hence they evade antibiotic attack.

Research has shown that between 25–35 percent of patients treated according to current guidelines and remember these are for acute infections, fail treatment (whether prescribed antibiotics for 3 or 14 days). (x). So whilst you are taking a course of antibiotics, UTI symptoms may reduce but as soon as that antibiotic is stopped, they return.

Infections involving more than one bacteria mean that the bacteria involved won’t replicate at the same rate.  A faster growing bacteria such as E-coli may be susceptible to 3 days of antibiotics but withdraw that medication and those bacteria with slower reproduction and growth rates will come to the ascendancy preventing infection clearance.

An initial antibiotic prescription of a higher, more lethal dosage may lead to the shredding of the DNA of the individual bacteria causing it to die. Longer courses of full-dose antibiotics may suppress bacteria as they emerge from the shed bladder cells, thereby preventing reinfection of young and deeper cells.

A prophylactic dosage (i.e. low dose) which clinicians can offer for up to 6 months can also lead to resistance issues because the bacteria can mutate against the antibiotic or change the structure of their individual cell membranes to prevent antibiotic penetration.

These low dose antibiotics not only mutate bacteria, they also merely stun after exposure. This is due to the strength of the medication dosage, allowing the bacteria to redevelop once the antibiotic has been withdrawn and its formulation has left the body. One study noted:

“Sub-inhibitory antibiotics prime uropathogens for adherence and invasion of urothelial tissues. These changes in initial colonization promoted the establishment of chronic infection”.(xi)

A study published in Science Daily in 2014 which evaluated bacterial biofilms in the ear canal noted that low dose antibiotics were not enough to kill the bacteria. This allowed the bacteria to react to the antibiotic by producing glycogen, a complex sugar often used by bacteria as a food source, to produce stronger biofilms when grown in the laboratory.

So each time you experience a flare up of symptoms or ongoing symptoms, if the same guideline limited, short course antibiotics are prescribed by your GP or specialist, the infection may not clear thus and may indeed benefit from the low dosage prescribed setting up the potential for a chronic infection and bacterial resistance to antibiotics.

What happens if I’m still experiencing UTI symptoms?

If you are still suffering persistent UTI symptoms and your GP has managed your symptoms based on, for example, NICE guidance in the UK for acute or recurrent infections without success, they usually refer to a urologist or uro-gynaecologist for further investigation.

The Chronic Urinary Tract Infection Campaign explain standard investigations and treatments.

Many treatments are invasive and make symptoms worse

Once bladder or renal cancer, stones, prolapse, infection of other pelvic floor organs or physical anomaly to the bladder, prostate, urethra, ureters or kidneys are ruled out, people are often given the diagnosis of Interstitial Cystitis (IC), Painful Bladder Syndrome (PBS) or Overactive Bladder.

These conditions are ‘diagnoses by exclusion’ meaning that no physical cause can be found. They instead describe groups of symptoms – including pain, urgency, frequency, difficulty passing urine and incontinence.

Read more about bladder syndromes at the Chronic Urinary Tract Infection Campaign and Live UTI Free.

Interestingly, the American Urological Association is now recommending that cystoscopy not be carried out for patients exhibiting symptoms of IC unless there is a significant reason that has been identified on X Ray, MRI or ultrasound noting:

“Cystoscopy and/or urodynamics should be considered as an aid to diagnosis only for complex presentations; these tests are not necessary for making the diagnosis in uncomplicated presentations – Expert Opinion”. (xii)

What can happen if an infection is left untreated?

Significant health risks can occur when a UTI is not treated including the risk of kidney infection and urinary sepsis. Fatigue, lack of sleep, fever, a sensation of “brain fog” and ongoing sometimes systematic inflammation and pain are some of the symptoms many chronic UTI sufferers experience as a result.

An infection can also affect someone psychologically because of the cycle of urination, pain, frequency and the avoidance of all potential triggers that may worsen symptoms. Quality of life is significantly impacted by chronic bladder infections with people unable to work, maintain relationships, form families and lead normal functioning lives. There can be a withdrawal from day to day life to focus on and manage symptoms.

Anti-depressants, opiates or anti-cholinergic drugs can dull down symptoms but have serious side effects. These can include headaches, dizziness, drowsiness and exhaustion, blurred vision, fever, flu symptoms, gastro-intestinal problems, weight gain and oedema (fluid retention in parts of the body).

Find out about testing and treatment for recurrent or chronic UTI.

How big is the problem?

  • Urinary tract infection is one of the most common human bacterial infections with over 150 million people worldwide affected each year. (xiii)
  • The global burden of this disease is rising – 16.1% increase in age-standardised incidence between 1990 and 2013. With 58,000 years lost to disability (YLD) in 2003 alone (xiv)
  • 1.7 million women in the UK and a significant number of men and children suffer from Chronic Lower Urinary Tract symptoms (xv)
  • Around 70% of those who experience an acute UTI will find their symptoms resolve with short course antibiotic treatment. However a further 30% will not achieve symptom resolution. (xvi)

References:

(i) Paul Little, Kate Rumsby, Rachel Jones, Greg Warner, Michael Moore, J Andrew Lowes, Helen Smith, Catherine Hawke, Geraldine Leydon and Mark Mullee Validating the prediction of lower urinary tract infection in primary care: sensitivity and specificity of urinary dipsticks and clinical scores in women
British Journal of General Practice 2010; 60 (576): 495-500. DOI: https://doi.org/10.3399/bjgp10X514747

(ii) Sathiananthamoorthy, S., et al., Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection. J Clin Microbiol, 2018.

Gill, K., et al., A blinded observational cohort study of the microbiological ecology associated with pyuria and overactive bladder symptoms. Int Urogynecol J, 2018.
00. Khasriya and Malone-Lee. The Inadequacy of Urinary Dipstick and Microscopy as Surrogate Markers of Urinary Tract Infection in Urological Outpatients with Lower Urinary Tract Symptoms Without Acute Frequency and Dysuria. Journal of Urololgy. 2010 183(5): 1843–1847

Swamy, Gorny and Malone-Lee. Fallacies and Misconceptions in Diagnosing Urinary Tract Infection. July 2014 futuremedicine.com. https://doi.org/10.2217/fmeb2013.13.276

(iii) Khasriya R, Khan S, Lunawat R, et al. The Inadequacy of Urinary Dipstick and Microscopy as Surrogate Markers of Urinary Tract Infection in Urological Outpatients With Lower Urinary Tract Symptoms Without Acute Frequency and Dysuria. JUrol. 2010;183(5):1843-1847.  https://www.ncbi.nlm.nih.gov/pubmed/20303096

(iv) Sathiananthamoorthy, S., et al., Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection. J Clin Microbiol, 2018.

Gill, K., et al., A blinded observational cohort study of the microbiological ecology associated with pyuria and overactive bladder symptoms. Int Urogynecol J, 2018.
00. Khasriya and Malone-Lee. The Inadequacy of Urinary Dipstick and Microscopy as Surrogate Markers of Urinary Tract Infection in Urological Outpatients with Lower Urinary Tract Symptoms Without Acute Frequency and Dysuria. Journal of Urololgy. 2010 183(5): 1843–1847

Swamy, Gorny and Malone-Lee. Fallacies and Misconceptions in Diagnosing Urinary Tract Infection. July 2014 futuremedicine.com. https://doi.org/10.2217/fmeb2013.13.276

(v) Gill K, Kang R, Sathiananthamoorthy S, Khasriya R, Malone-Lee J. A blinded observational cohort study of the microbiological ecology associated with pyuria and overactive bladder symptoms. Int Urogynecol J. 2018. Epub 2018/02/20. doi: 10.1007/s00192-018-3558-x. PubMed PMID: 29455238.

Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013;51(7):2054-62.

Thomas-White K, Forster SC, Kumar N, Van Kuiken M, Putonti C, Stares MD, et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nature communications. 2018;9(1):1557. Epub 2018/04/21. doi: 10.1038/s41467-018-03968-5. PubMed PMID: 29674608; PubMed Central PMCID: PMCPMC5908796.

Brubaker L, Wolfe AJ. The Female Urinary Microbiota/Microbiome: Clinical and Research Implications. Rambam Maimonides medical journal. 2017;8(2). Epub 2017/05/04. doi: 10.5041/rmmj.10292. PubMed PMID: 28467757; PubMed Central PMCID: PMCPMC5415361.

Price TK, Hilt EE, Dune TJ, Mueller ER, Wolfe AJ, Brubaker L. Urine trouble: should we think differently about UTI? Int Urogynecol J. 2017. Epub 2017/12/28. doi: 10.1007/s00192-017-3528-8. PubMed PMID: 29279968.

Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C, et al. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms. J Clin Microbiol. 2016;54(5):1216-22. doi: 10.1128/JCM.00044-16. PubMed PMID: 26962083.

Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871-6. Epub 2013/12/29. doi: 10.1128/jcm.02876-13. PubMed PMID: 24371246; PubMed Central PMCID: PMCPMC3957746.

Brubaker L, Nager CW, Richter HE, Visco A, Nygaard I, Barber MD, et al. Urinary bacteria in adult women with urgency urinary incontinence. International urogynecology journal. 2014;25(9):1179-84. doi: 10.1007/s00192-013-2325-2. PubMed PMID: PMC4128900.

Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5(4):e01283-14. Epub 2014/07/10. doi: 10.1128/mBio.01283-14. PubMed PMID: 25006228; PubMed Central PMCID: PMCPmc4161260.

Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012;50. doi: 10.1128/jcm.05852-11.

Sathiananthamoorthy S. PhD The microbiology of chronic lower urinary tract symptoms. UCL: UCL; 2016.

(vi) Price et al. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms. Journal of Clinical Microbiology. May 2016 (54) 5

Hooton, T.M.; Roberts, P.L.; Cox, M.E.; Stapleton, A.E. Voided midstream urine culture and acute cystitis in premenopausal women. N. Engl. J. Med. 2013, 369, 1883–1891

(vii) Urinary tract infections in adults Quality standard [QS90] Published date: June 2015

(viii) https://cks.nice.org.uk/urinary-tract-infection-lower-women#!scenario:2

(ix) The Pulse 24/05/2017

(x) Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C, et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J Clin Microbiol. 2016;54(5):1216–22

Ross A. Lawrenson, John W. Logie, Antibiotic failure in the treatment of urinary tract infections in young women, Journal of Antimicrobial Chemotherapy, Volume 48, Issue 6, December 2001, Pages 895–901, https://doi.org/10.1093/jac/48.6.895

(xi) Subinhibitory Antibiotic Therapy Alters Recurrent Urinary Tract Infection Pathogenesis through Modulation of Bacterial Virulence and Host Immunity Lee W Goneau, Thomas J Hannan, Roderic A MacPhee, Drew J Schwartz, Jean M Macklaim, Gregory B Gloor, Hassan Razvi, Gregor Read, Scott J Hultgren, Jeremy P Burton doi: 10.1128/mBio.00356-1531 March 2015 mBio vol. 6 no. 2 e00356-15

Sub-lethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis: Michael A. Kohanski, Mark A. DePristo, and James J. Collins 2010 https://doi.org/10.1016/j.molcel.2010.01.003

(xii)  Diagnosis and Treatment Interstitial Cystitis/Bladder Pain Syndrome, American Urological Association Published 2011; Amended 2014

(xiii) Urinary tract infections: epidemiology, mechanisms of infection and treatment options, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457377/

(ixv) Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Aug 22;386(9995):743-800. doi: 10.1016/S0140-6736(15)60692-4.

(xv) UK figures based on Rand Interstitial Cystitis Epidemiology Study 2010

(xvi) Katchman, EA, Milo G, Paul M et al. Three-day vs. longer duration of antibiotic treatment for cystitis in women: systematic review and meta-analysis. Am J Med 2005; 118(11): 1196-207