The Problem with UTI Tests, Diagnosis & Treatment Archives

How big a problem is there with UTI infections?

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)
Approximately one in four people with a previous history of UTI will develop either recurrent or Chronic UTI (xvii)
In one study, 93% of women diagnosed with Interstitial Cystitis or Bladder Pain Syndrome had a previous diagnosis of UTI but were told their urine culture was negative

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.

Mambatta AK, Jayarajan J, Rashme VL, Harini S, Menon S, Kuppusamy J. Reliability of dipstick assay in predicting urinary tract infection. J Family Med Prim Care. 2015 Apr-Jun;4(2):265-8. doi: 10.4103/2249-4863.154672. PMID: 25949979; PMCID: PMC4408713

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.

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: February 2023

(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

(xvii) Chieng, Catherine C.Y. et al. The clinical implications of bacterial pathogenesis and mucosal immunity in chronic urinary tract infection Mucosal Immunology, Volume 16, Issue 1, 61 – 71

What affects the accuracy of the urine test?

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 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.
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. These low count bacteria are not contaminants and may well be contributors to the infection, as in some cases infections can be polymicrobial.
Researchers and specialist clinicians have recently found using enhanced microbial testing resources that chronic UTIs can be polymicrobial – caused by several different types of bacteria. This means the bacteria identified in your UTI may well be different to that found in others and can explain why people experience differing symptoms. However, 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
The standard urine culture is selective for typical microorganisms most commonly responsible for urinary tract infections, including Escherichia coli, Staphylococcus Saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis. However this laboratory culture is 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. Therefore, it is not an applicable test when there is a high clinical suspicion for UTI caused by atypical organisms.
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”. Indeed in another study that analysed 157,000 urine samples using a different technology, E.coli was the dominant species in only 28% of cases.
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.
The standard urine culture 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.
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.