Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial

The paper by Kroneneberg, Butikofer et al (BMJ 2017;359:j4784) and the response by Paul Little (BMJ 2017;359:j5037) are welcome. Patients who had typical symptoms of UTI and who were positive on dipstick leucocytes and nitrites did worse when treated with a NSAID instead of a quinolone. We are worried about antibiotic resistance and are striving to find answers, but I ask whether we are looking in the right places?

Today, microscopy of fresh, unspun urine to count pyuria is unchallenged as the best marker of urinary infection that we have1,2 and yet it is rarely used. Quantitative urine culture of 103 to 106 colony forming units µl-1 of a single species of a known urinary pathogen, the gold standard for over 50 years, has been found to be insensitive and misleading3-5 with the dipstick tests for leucocytes and nitrite faring worse1,2 The parlous state of our diagnostic methods is deeply worrying.

The normal healthy bladder is not sterile but, as in UTI, evinces a large, complex, poly-microbial soup, including numerous fastidious or unculturable organisms3-5. Our cultures isolate bacteria that are easy to grow, not a necessary property of pathogenicity. Multiresistant isolates are not axiomatically the culprits. Mixed culture results may not reflect contamination6,7. Abundant epithelial cells, once assumed markers of contamination, now appear to be expressions of the UTI 8.

Patients, with symptoms of urinary tract infection, are routinely exonerated of infection on the evidence of negative dipsticks and/or cultures. But these tests are too insensitive 1,2,9,10. To dismiss infection on negative analyses is to confuse “no evidence of disease” with the wholly different proposition of “evidence of no disease”11.

Uncertain diagnosis should not be our only concern. The treatment of acute cystitis also has its limitations. Whilst success rates of 84% to 100% have been claimed for 3 and 14 day treatments 12, others have reported microbiological and symptomatic failure in up to 28% and 37% of patients after 4 to 14 weeks of treatment 13. The relevant Cochrane review exposes these failure rates only after the tables, found at the back of the full report, have informed a manual calculation13.

Urine infection is more complex than we imagined. It may involve parasitisation of the uroepithelial cells, the formation of surface and intracellular biofilms, and tenacious invasions that are hard to eradicate14-18. There is no evidence that such infections can be cleared in 3 or 14 days, or that our doses penetrate to the affected tissues. Microbes in biofilms divide little, thereby confounding antibiotics.

I, with colleagues, treat patients with recurrent urinary infection and chronic, painful, lower urinary tract symptoms. It is harrowing; after years of much suffering, these victims and their families are distraught. Their lives have been ruined; many cannot work, have sex, travel, socialise, or accomplish many activities of normal life. Their troubles commenced with an initial cystitis, incompletely responsive to guideline management. Further treatment was withheld on the evidence of negative routine tests. They lived through one acute flare after another as the chronic, painful symptoms increase. They have been exposed to the evidence-free domains of urethral dilation, cystodistension19, bladder installations19,20, complementary therapies, restrictive diets and psychodynamic hermeneutics. They manifest microscopic pyuria, correlating with symptoms21, despite their negative dipsticks, cultures 1,2 and systemic inflammatory markers 22. Guided by symptoms, the microscope and pharmacodynamics, first generation, narrow spectrum antimicrobials achieve promising outcomes, regardless of culture results. The methods are inchoate and our data, which are controversial, have been submitted to the scrutiny and criticism of peer review. We must also achieve further clinical trials. But there is hope.

For now, may I pose some questions? Why don’t we own up to the flaws in our urinalyses methods and acknowledge the conjecture plaguing the management protocols? Instead of slavish adherence to dirigiste guidelines that fail, why not come together as thinking clinicians to work with patients to find better, safer solutions to these worrying problems?

1. 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.
2. Kupelian AS, Horsley H, Khasriya R, et al. Discrediting microscopic pyuria and leucocyte esterase as diagnostic surrogates for infection in patients with lower urinary tract symptoms: results from a clinical and laboratory evaluation. Bju Int. 2013;112(2):231-238.
3. Wolfe AJ, Toh E, Shibata N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012;50(4):1376-1383.
4. 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(7):2054-2062.
5. Brubaker L, Wolfe AJ. The Female Urinary Microbiota/Microbiome: Clinical and Research Implications. Rambam Maimonides medical journal. 2017;8(2).
6. Sathiananthamoorthy S, Swamy S, Kupelian A, et al. "Mixed Growth of Doubtful Significance" Is Extremely Significant in Patients with Lower Urinary Tract Symptoms. Neurourology and urodynamics. 2012;31(6):736-737.
7. Sathiananthamoorthy S. PhD The microbiology of chronic lower urinary tract symptoms. UCL: Division of Medicine, UCL Medical School, UCL; 2016.
8. Horsley H, Holland DC, Sathiananthamoorthy S, et al. The Invasive Strategies of Uropathogens in LUTS. PLOS Pathogens, Manuscript submitted for referees. 2013.
9. Heytens S, De Sutter A, Coorevits L, et al. Women with symptoms of a urinary tract infection but a negative urine culture: PCR-based quantification of Escherichia coli suggests infection in most cases. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2017.
10. Wolfe AJ, Toh E, Shibata N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012;50.
11. Taleb NN. Fooled by Randomness: The Hidden Role of Chance in Life and in the Markets. First ed. London: Allen Lane Penguin; 2007.
12. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-120.
13. Milo G, Katchman EA, Paul M, Christiaens T, Baerheim A, Leibovici L. Duration of antibacterial treatment for uncomplicated urinary tract infection in women. CochraneDatabaseSystRev. 2005(2):CD004682.
14. Goneau LW, Hannan TJ, MacPhee RA, et al. Subinhibitory antibiotic therapy alters recurrent urinary tract infection pathogenesis through modulation of bacterial virulence and host immunity. mBio. 2015;6(2).
15. Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA, Hultgren SJ. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev. 2012;36(3):616-648.
16. Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. Intracellular bacterial biofilm-like pods in urinary tract infections. Science. 2003;301(5629):105-107.
17. Horsley H, Malone-Lee J, Holland D, et al. Enterococcus faecalis subverts and invades the host urothelium in patients with chronic urinary tract infection. Plos One. 2013;8(12).
18. O'Brien VP, Hannan TJ, Yu L, et al. A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease. Nature microbiology. 2016;2:16196.
19. Barua JM, Arance I, Angulo JC, Riedl CR. A systematic review and meta-analysis on the efficacy of intravesical therapy for bladder pain syndrome/interstitial cystitis. International urogynecology journal. 2016;27(8):1137-1147.
20. Dawson TE, Jamison J. Intravesical treatments for painful bladder syndrome/ interstitial cystitis. The Cochrane database of systematic reviews. 2007(4):CD006113.
21. Khasriya R, Barcella W, De Iorio M, et al. Lower urinary tract symptoms that predict microscopic pyuria. International urogynecology journal. 2017.
22. Julian-Jimenez A, Gutierrez-Martin P, Lizcano-Lizcano A, Lopez-Guerrero MA, Barroso-Manso A, Heredero-Galvez E. Usefulness of procalcitonin and C-reactive protein for predicting bacteremia in urinary tract infections in the emergency department. Actas Urol Esp. 2015;39(8):502-510.