Urine Trouble: Should We Think Differently About UTI?

Urinary Tract Infection (UTI) is widely considered to be a result of pathogenic bacteria colonizing the sterile environment of the bladder. However, the recent discovery of resident communities of bacteria (microbiota) in the bladders of both women [1-9] and men [10-11] challenges this concept. If the bladder and thus urine are not normally sterile, then the definition of infection must move beyond the mere presence of bacteria. We believe that we must revisit the contemporary description of UTI by identifying its limitations: the language of UTI, testing for a UTI, an Escherichia coli-centric view of UTI, and a threshold-based diagnosis for UTI. As the science of the urinary microbiome moves forward, we much acknowledge each of these aspects of UTI or, as our title suggests, ‘urine trouble.’

In 2014, our translational research team (the Loyola Urinary Education and Research Collaboration (LUEREC) developed an expanded quantitative urine culture (EQUC) protocol that isolates many bacteria that the standard urine culture (SUC) does not detect [7]. In fact, EQUC was able to detect bacteria in more than 90% of urine samples that showed no growth by SUC [7]. Others have obtained similar results [2,5]. IN 2016, We then demonstrated the clinical relevance of this observation by showing that SUC misses 50% of pathogenic, or UTI-causing, bacteria in women with severe UTI symptoms [12]. Not surprisingly, over a third of these women with missed pathogens reported no symptom resolution after treatment based on SUC results [12]. This is likely due to biases within the assay, particularly towards detection of Gram-negative bacteria, most often E. coli, but is also a result of a failure to treat pathogens at colony counts below certain thresholds.

The 2016 Price et al. study [12] highlights the clear inadequacies surrounding our current, dichotomous concept of UTIs. Although, all aspects of the path forward are not yet clear, it is very clear that antibiotic use should be used cautiously with a specific, targeted therapeutic goal and heightened awareness of the significant collateral effects.

The bladder should be no different than other body sites, where clinicians now recognize the added complexity of the human microbiota and its role on patient wellbeing. How emerging knowledge about the urinary microbiota will ultimately change our definition and clinical care of UTI remains to be seen; we are optimistic that patients can experience improved UTI care with fewer collateral effects.

Written by:

Price TK¹, Hilt EE¹, Dune TJ², Mueller ER³, Wolfe AJ¹, Brubaker L^4,5

Author Information:

1. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
2. Department of Urology, Center for Female Pelvic Health, Weill Cornell Medicine, New York, NY, USA.
3. Departments of Obstetrics & Gynecology and Urology, Loyola University Medical Center, Maywood, IL, USA.
4. Department of Reproductive Medicine, Division of Female Pelvic Medicine and Reconstructive Surgery, University of California San Diego, San Diego, CA, USA.
5. Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA

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Citations

1. Wolfe AJ, Toh E, Shibatat N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012; 50:1376-1383.
2. Fouts DE, Pieper R, Szpakowski S, et al. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J Transl Med. 2012; 10:174.
3. Brubaker L, Nager CW, Richter HE, et al. Urinary bacteria in adult women with urgency urinary incontinence. Int Urogynecol J. 2014; 25:1179-1184.
4. Pearce MM, Hilt EE, Rosenfeld AB, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. MBio. 2014; 5:e01283-e01214.
5. Khasriya R, Sathiananthamoorthy S, Ismail S, et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013; 51:2054-2062.
6. Siddiqui H, Nederbragt AJ, Lagesen K, et al. Assessing diversity of the female urine microbiota by high throughput sequencing of 16S rDNA amplicons. BMC Microbiol. 2011; 11:244.
7. Hilt EE, McKinley K, Pearce MM, 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; 52:871-876.
8. Pearce MM, Zilliox MJ, Rosenfeld AB, et al. The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol. 2015; 213:347e1-11.
9. Thomas-White KJ, Hilt EE, Fok C, et al. Incontinence medication response relates to the female urinary microbiota. Int Urogynecol J. 2016; 27:723-733.
10. Dong Q, Nelson DE, Toh E, et al. The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens. PLoS One. 2011; 6:e19709.
11. Nelson DE, Dong Q, Van der Pol B, et al. Bacterial communities of the coronal sulcus and distal urethra of adolescent males. PLoS One. 2012; 7:e36298.
12. Price TK, Dune T, Hilt EE, et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J Clin Microbiol. 2016; 54(5):1216-22.

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