Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nonantibiotic prevention and management of recurrent urinary tract infection

Nature Reviews Urology volume 15, pages 750–776 (2018)Cite this article

Subjects

Abstract

Urinary tract infections (UTIs) are highly prevalent, lead to considerable patient morbidity, incur large financial costs to health-care systems and are one of the most common reasons for antibiotic use worldwide. The growing problem of antimicrobial resistance means that the search for nonantibiotic alternatives for the treatment and prevention of UTI is of critical importance. Potential nonantibiotic measures and treatments for UTIs include behavioural changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), NSAIDs, probiotics, d-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. Some of the results of trials of these approaches are promising; however, high-level evidence is required before firm recommendations for their use can be made. A combination of these agents might provide the optimal treatment to reduce recurrent UTI, and trials in specific population groups are required.

Key points

  • Rising rates of antimicrobial resistance, fuelled by the overuse of antibiotics in humans, are a serious threat to global public health.

  • Alternatives to antibiotics for the prevention of recurrent urinary tract infection (UTI) are attractive options to reduce the risks of antimicrobial resistance.

  • The most commonly studied nonantibiotic management options for recurrent UTI include cranberries, probiotics, d-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans and immunostimulants.

  • Studies of novel vaccines targeting the adherence mechanisms of uropathogenic bacteria seem promising, but human trials are required to determine the efficacy of this approach.

  • Evidence for the nonantibiotic measures is hampered by considerable heterogeneity, and further placebo-controlled randomized trials of these agents are needed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathogenesis of urinary tract infection.
Fig. 2: Mechanisms of antimicrobial resistance by mobile genetic elements.
Fig. 3: Mechanisms of action of cranberry components in prevention of urinary tract infection.
Fig. 4: A-type and B-type linkages of proanthocyanidins.
Fig. 5: Mechanisms of action of lactobacilli in urinary tract infection prevention.
Fig. 6: Type 1 pili of Escherichia coli and the uroplakin 1a receptor.
Fig. 7: d-Mannose prevents binding of bacteria to urothelial cells.
Fig. 8: Chemical structure of heptyl-α-d-mannose.
Fig. 9: Structure of the glycosaminoglygan layer of the bladder wall.
Fig. 10: Nonantibiotic interventions for urinary tract infection.

Similar content being viewed by others

References

  1. Stamm, W. E. & Norrby, S. R. Urinary tract infections: disease panorama and challenges. J. Infect. Dis. 183, S1–S4 (2001).

    PubMed  Google Scholar 

  2. Laupland, K. B., Ross, T., Pitout, J. D., Church, D. L. & Gregson, D. B. Community-onset urinary tract infections: a population-based assessment. Infection 35, 150–153 (2007).

    CAS  PubMed  Google Scholar 

  3. Mabeck, C. E. Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgrad. Med. J. 48, 69–75 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Foxman, B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am. J. Med. 113 (Suppl 1A), 5s–13s (2002).

    PubMed  Google Scholar 

  5. Nicolle, L. E. Urinary tract infection. Crit. Care Clin. 29, 699–715 (2013).

    PubMed  Google Scholar 

  6. Loveday, H. P. et al. epic3: national evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J. Hosp. Infect. 86, S1–S70 (2014).

    PubMed  Google Scholar 

  7. Flores-Mireles, A. L., Walker, J. N., Caparon, M. & Hultgren, S. J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 13, 269–284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ellis, A. K. & Verma, S. Quality of life in women with urinary tract infections: is benign disease a misnomer? J. Am. Board Fam. Pract. 13, 392–397 (2000).

    CAS  PubMed  Google Scholar 

  9. Foxman, B. & Frerichs, R. R. Epidemiology of urinary tract infection: I. Diaphragm use and sexual intercourse. Am. J. Publ. Health 75, 1308–1313 (1985).

    CAS  Google Scholar 

  10. Akkerman, A. E., Kuyvenhoven, M. M., Verheij, T. J. & van Dijk, L. Antibiotics in Dutch general practice: nationwide electronic GP database and national reimbursement rates. Pharmacoepidemiol. Drug Saf. 17, 378–383 (2008).

    PubMed  Google Scholar 

  11. European Centre for Disease Prevention and Control. ECDC/EMEA Joint Technical Report. The bacterial challenge: time to react (ECDC, 2009).

  12. Llor, C. & Bjerrum, L. Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem. Ther. Adv. Drug Safety 5, 229–241 (2014).

    Google Scholar 

  13. Gupta, K. et al. Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J. Infect. Dis. 178, 446–450 (1998).

    CAS  PubMed  Google Scholar 

  14. Foxman, B. et al. Uropathogenic Escherichia coli are more likely than commensal E. coli to be shared between heterosexual sex partners. Am. J. Epidemiol. 156, 1133–1140 (2002).

    PubMed  Google Scholar 

  15. Mulvey, M. A., Schilling, J. D. & Hultgren, S. J. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect. Immun. 69, 4572–4579 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schilling, J. D., Lorenz, R. G. & Hultgren, S. J. Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic. Escherichia coli. Infect. Immun. 70, 7042–7049 (2002).

    CAS  PubMed  Google Scholar 

  17. Rosen, D. A., Hooton, T. M., Stamm, W. E., Humphrey, P. A. & Hultgren, S. J. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 4, e329 (2007).

    PubMed  PubMed Central  Google Scholar 

  18. World Health Organisation. Antimicrobial resistance: global report on surveillance 2014 (WHO, 2014).

  19. Bryce, A. et al. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. BMJ 352, i939 (2016).

    Google Scholar 

  20. Johnson, J. R., Johnston, B., Clabots, C., Kuskowski, M. A. & Castanheira, M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States. Clin. Infect. Dis. 51, 286–294 (2010).

    PubMed  Google Scholar 

  21. Wang, Y. et al. Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study. Lancet Infect. Dis. 17, 390–399 (2017).

    CAS  PubMed  Google Scholar 

  22. Blair, J. M., Webber, M. A., Baylay, A. J., Ogbolu, D. O. & Piddock, L. J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51 (2015).

    CAS  PubMed  Google Scholar 

  23. Van Boeckel, T. P. et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect. Dis. 14, 742–750 (2014).

    PubMed  Google Scholar 

  24. Munita, J. M. & Arias, C. A. Mechanisms of antibiotic resistance. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.VMBF-0016-2015 (2016).

    Article  PubMed  Google Scholar 

  25. Abraham, E. P. & Chain, E. An enzyme from bacteria able to destroy penicillin. 1940. Rev. Infect. Dis. 10, 677–678 (1988).

    CAS  PubMed  Google Scholar 

  26. Logan, L. K. & Weinstein, R. A. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J. Infect. Dis. 215, S28–S36 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tangden, T., Adler, M., Cars, O., Sandegren, L. & Lowdin, E. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model. J. Antimicrob. Chemother. 68, 1319–1326 (2013).

    PubMed  Google Scholar 

  28. Adler, M., Anjum, M., Andersson, D. I. & Sandegren, L. Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in. Escherichia coli. J. Antimicrob. Chemother. 68, 51–59 (2013).

    CAS  PubMed  Google Scholar 

  29. Ma, L. et al. Widespread dissemination of aminoglycoside resistance genes armA and rmtB in Klebsiella pneumoniae isolates in Taiwan producing CTX-M-type extended-spectrum β-lactamases. Antimicrob. Agents Chemother. 53, 104–111 (2009).

    CAS  PubMed  Google Scholar 

  30. Sanchez, G. V., Baird, A. M., Karlowsky, J. A., Master, R. N. & Bordon, J. M. Nitrofurantoin retains antimicrobial activity against multidrug-resistant urinary Escherichia coli from US outpatients. J. Antimicrob. Chemother. 69, 3259–3262 (2014).

    CAS  PubMed  Google Scholar 

  31. Russell, G. Antibiotic resistance in children with E coli urinary tract infection. BMJ 352, i1399 (2016).

    PubMed  PubMed Central  Google Scholar 

  32. Heinemann, C. & Reid, G. Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. Can. J. Microbiol. 51, 777–781 (2005).

    CAS  PubMed  Google Scholar 

  33. Falagas, M. E., Rafailidis, P. I. & Makris, G. C. Bacterial interference for the prevention and treatment of infections. Int. J. Antimicrob. Agents 31, 518–522 (2008).

    CAS  PubMed  Google Scholar 

  34. Chan, R. C., Reid, G., Irvin, R. T., Bruce, A. W. & Costerton, J. W. Competitive exclusion of uropathogens from human uroepithelial cells by Lactobacillus whole cells and cell wall fragments. Infect. Immun. 47, 84–89 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hooton, T. M. et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N. Engl. J. Med. 335, 468–474 (1996).

    CAS  PubMed  Google Scholar 

  36. Hooton, T. M., Roberts, P. L. & Stamm, W. E. Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin. Infect. Dis. 19, 274–278 (1994).

    CAS  PubMed  Google Scholar 

  37. Xie, J., Foxman, B., Zhang, L. & Marrs, C. F. Molecular epidemiologic identification of Escherichia coli genes that are potentially involved in movement of the organism from the intestinal tract to the vagina and bladder. J. Clin. Microbiol. 44, 2434–2441 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Scholes, D. et al. Risk factors for recurrent urinary tract infection in young women. J. Infect. Dis. 182, 1177–1182 (2000).

    CAS  PubMed  Google Scholar 

  39. Moore, E. E. et al. Sexual intercourse and risk of symptomatic urinary tract infection in post-menopausal women. J. Gen. Intern. Med. 23, 595–599 (2008).

    PubMed  PubMed Central  Google Scholar 

  40. Foxman, B. et al. Urinary tract infection among women aged 40 to 65: behavioral and sexual risk factors. J. Clin. Epidemiol. 54, 710–718 (2001).

    CAS  PubMed  Google Scholar 

  41. Raz, R. et al. Recurrent urinary tract infections in postmenopausal women. Clin. Infect. Dis. 30, 152–156 (2000).

    CAS  PubMed  Google Scholar 

  42. Lema, V. M. Urinary tract infection in young healthy women following heterosexual anal intercourse: case reports. Afr. J. Reproductive Health 19, 134–139 (2015).

    Google Scholar 

  43. Coull, N., Mastoroudes, H., Popert, R. & O’Brien, T. S. Redefining urological history taking - anal intercourse as the cause of unexplained symptoms in heterosexuals. Ann. R. Coll. Surg. Engl. 90, 403–405 (2008).

    PubMed  PubMed Central  Google Scholar 

  44. Gupta, K., Hillier, S. L., Hooton, T. M., Roberts, P. L. & Stamm, W. E. Effects of contraceptive method on the vaginal microbial flora: a prospective evaluation. J. Infect. Dis. 181, 595–601 (2000).

    CAS  PubMed  Google Scholar 

  45. Handley, M. A., Reingold, A. L., Shiboski, S. & Padian, N. S. Incidence of acute urinary tract infection in young women and use of male condoms with and without nonoxynol-9 spermicides. Epidemiology 13, 431–436 (2002).

    PubMed  Google Scholar 

  46. Su, S. B., Wang, J. N., Lu, C. W. & Guo, H. R. Reducing urinary tract infections among female clean room workers. J. Womens Health 15, 870–876 (2006).

    Google Scholar 

  47. Foxman, B. & Chi, J. W. Health behavior and urinary tract infection in college-aged women. J. Clin. Epidemiol. 43, 329–337 (1990).

    CAS  PubMed  Google Scholar 

  48. Adatto, K., Doebele, K. G., Galland, L. & Granowetter, L. Behavioral factors and urinary tract infection. JAMA 241, 2525–2526 (1979).

    CAS  PubMed  Google Scholar 

  49. Nygaard, I. & Linder, M. Thirst at work — an occupational hazard? Int. Urogynecol. J. Pelvic Floor Dysfunct. 8, 340–343 (1997).

    CAS  PubMed  Google Scholar 

  50. Eckford, S. D., Keane, D. P., Lamond, E., Jackson, S. R. & Abrams, P. Hydration monitoring in the prevention of recurrent idiopathic urinary tract infections in pre-menopausal women. Br. J. Urol. 76, 90–93 (1995).

    CAS  PubMed  Google Scholar 

  51. Murphy, F. J., Zelman, S. & Mau, W. Ascorbic acid as a urinary acidifying agent. 2. Its adjunctive role in chronic urinary infection. J. Urol. 94, 300–303 (1965).

    CAS  PubMed  Google Scholar 

  52. McDonald, D. F. & Murphy, G. P. Bacteriostatic and acidifying effects of methionine, hydrolyzed casein, and AA on the urine. N. Engl. J. Med. 261, 803–805 (1959).

    CAS  Google Scholar 

  53. Castello, T., Girona, L., Gomez, M. R., Mena Mur, A. & Garcia, L. The possible value of ascorbic acid as a prophylactic agent for urinary tract infection. Spinal Cord 34, 592–593 (1996).

    CAS  PubMed  Google Scholar 

  54. Peng, M. M., Fang, Y., Hu, W. & Huang, Q. The pharmacological activities of compound salvia plebeia granules on treating urinary tract infection. J. Ethnopharmacol. 129, 59–63 (2010).

    PubMed  Google Scholar 

  55. Yan, D., Jin, C., Xiao, X. H. & Dong, X. P. Antimicrobial properties of berberines alkaloids in Coptis chinensis Franch by microcalorimetry. J. Biochem. Biophys. Methods 70, 845–849 (2008).

    PubMed  Google Scholar 

  56. Flower, A., Wang, L. Q., Lewith, G., Liu, J. P. & Li, Q. Chinese herbal medicine for treating recurrent urinary tract infections in women. Cochrane Database Syst Rev. 6, CD01044 (2015).

    Google Scholar 

  57. Ma, X. Y., Zhi, Y., Zhang, X., Zhao, H. & Gao, G. J. Clinical study of Xianqing Houbu method in treating senile female recurrent urinary tract infection. J. Emergency Tradit. Chinese Med. 20, 1918–1919 (2011).

    Google Scholar 

  58. Shen, Y. & Yao, Q. Clinical observation of “baitouweng decoction” and “erxian decoction” in treating lower urinary infection in 52 postmenopausal women. Shanghai J. Tradit. Chinese Med. 41, 37–38 (2007).

    Google Scholar 

  59. Zhao, K. S. et al. Clinical study of clearing liver fire, removing dampness, strengthening spleen and tonifying kidney methods in treating middle-aged and old woman with chronic urinary tract infection. Int. J. Tradit. Chinese Med. 33, 976–978 (2011).

    Google Scholar 

  60. Chen, M., Wang, Y. & Gu, X. C. Clinical observation of modified “erxian decoction” plus antibiotics in treating chronic urinary tract infection in middle-aged and old women. Shanghai J. Tradit. Chinese Med. 42, 48–49 (2008).

    Google Scholar 

  61. Luo, M. Clinical study of bushen tonglin decoction on female with chronic urinary tract infection. Hubei Uni. Chinese Med. (2011).

  62. Gu, X. C., Xu, Z., Chen, M. & Wang, M. Study of erding erxian docoction compared with sanjin tablet in treating recurrent urinary tract infection. Chinese J. Integr. Tradit. Western Nephrol. 12, 623–624 (2011).

    Google Scholar 

  63. Qin, S. G. Clinical analysis of Ningmitai capsule on 60 cases chronic urinary tract infection. Hebei Med. 10, 700–702 (2004).

    Google Scholar 

  64. Balshem, H. et al. GRADE guidelines: 3. Rating the quality of evidence. J. Clin. Epidemiol. 64, 401–406 (2011).

    PubMed  Google Scholar 

  65. Guay, D. R. Cranberry and urinary tract infections. Drugs 69, 775–807 (2009).

    CAS  PubMed  Google Scholar 

  66. Borukh, I. F., Kirbaba, V. I. & Senchuk, G. V. [Antimicrobial properties of cranberry]. Voprosy Pitaniia 31, 82 (1972).

    CAS  PubMed  Google Scholar 

  67. Hisano, M., Bruschini, H., Nicodemo, A. C. & Srougi, M. Cranberries and lower urinary tract infection prevention. Clinics 67, 661–668 (2012).

    PubMed  PubMed Central  Google Scholar 

  68. Lynch, D. M. Cranberry for prevention of urinary tract infections. Am. Fam. Physician 70, 2175–2177 (2004).

    PubMed  Google Scholar 

  69. Beachey, E. H. Bacterial adherence: adhesin-receptor interactions mediating the attachment of bacteria to mucosal surface. J. Infect. Dis. 143, 325–345 (1981).

    CAS  PubMed  Google Scholar 

  70. Howell, A. B. Bioactive compounds in cranberries and their role in prevention of urinary tract infections. Mol. Nutr. Food Res. 51, 732–737 (2007).

    CAS  PubMed  Google Scholar 

  71. Ofek, I. & Beachey, E. H. Mannose binding and epithelial cell adherence of Escherichia coli. Infect. Immun. 22, 247–254 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Zafriri, D., Ofek, I., Adar, R., Pocino, M. & Sharon, N. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob. Agents Chemother. 33, 92–98 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Hidalgo, G., Chan, M. & Tufenkji, N. Inhibition of Escherichia coli CFT073 fliC expression and motility by cranberry materials. Appl. Environ. Microbiol. 77, 6852–6857 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. O’May, C. & Tufenkji, N. The swarming motility of Pseudomonas aeruginosa is blocked by cranberry proanthocyanidins and other tannin-containing materials. Appl. Environ. Microbiol. 77, 3061–3067 (2011).

    PubMed  PubMed Central  Google Scholar 

  75. Howell, A. B. et al. A-Type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 66, 2281–2291 (2005).

    CAS  PubMed  Google Scholar 

  76. Liu, Y., Black, M. A., Caron, L. & Camesano, T. A. Role of cranberry juice on molecular-scale surface characteristics and adhesion behavior of Escherichia coli. Biotechnol. Bioengineer. 93, 297–305 (2006).

    CAS  Google Scholar 

  77. Vasileiou, I., Katsargyris, A., Theocharis, S. & Giaginis, C. Current clinical status on the preventive effects of cranberry consumption against urinary tract infections. Nutr. Res. 33, 595–607 (2013).

    CAS  PubMed  Google Scholar 

  78. Ren, D. et al. Differential gene expression for investigation of Escherichia coli biofilm inhibition by plant extract ursolic acid. Appl. Environ. Microbiol. 71, 4022–4034 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Grace, M. H., Massey, A. R., Mbeunkui, F., Yousef, G. G. & Lila, M. A. Comparison of health-relevant flavonoids in commonly consumed cranberry products. J. Food Sci. 77, H176–H183 (2012).

    CAS  PubMed  Google Scholar 

  80. Howell, A. B. & Foxman, B. Cranberry juice and adhesion of antibiotic-resistant uropathogens. JAMA 287, 3082–3083 (2002).

    PubMed  Google Scholar 

  81. Avorn, J. et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 271, 751–754 (1994).

    CAS  PubMed  Google Scholar 

  82. Howell, A. B. et al. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect. Dis. 10, 94 (2010).

    PubMed  PubMed Central  Google Scholar 

  83. Beerepoot, M. & Geerlings, S. Non-antibiotic prophylaxis for urinary tract infections. Pathogens 5, E36 (2016).

    PubMed  Google Scholar 

  84. Luis, A., Domingues, F. & Pereira, L. Can cranberries contribute to reduce the incidence of urinary tract infections? A systematic review with meta-analysis and trial sequential analysis of clinical trials. J. Urol. 198, 614–621 (2017).

    PubMed  Google Scholar 

  85. Jepson, R. G., Williams, G. & Craig, J. C. Cranberries for preventing urinary tract infections. Cochrane Database Syst. Rev. 10, CD001321 (2012).

    PubMed  Google Scholar 

  86. Wang, C. H. et al. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and meta-analysis of randomized controlled trials. Arch. Intern. Med. 172, 988–996 (2012).

    PubMed  Google Scholar 

  87. Stothers, L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can. J. Urol. 9, 1558–1562 (2002).

    PubMed  Google Scholar 

  88. Vostalova, J. et al. Are high proanthocyanidins key to cranberry efficacy in the prevention of recurrent urinary tract infection? Phytother. Res. 29, 1559–1567 (2015).

    CAS  PubMed  Google Scholar 

  89. Maki, K. C. et al. Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection. Am. J. Clin. Nutr. 103, 1434–1442 (2016).

    CAS  PubMed  Google Scholar 

  90. Kontiokari, T. et al. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 322, 1571 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Stapleton, A. E. et al. Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin. Proc. 87, 143–150 (2012).

    PubMed  PubMed Central  Google Scholar 

  92. Barbosa-Cesnik, C. et al. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin. Infect. Dis. 52, 23–30 (2011).

    PubMed  PubMed Central  Google Scholar 

  93. Foxman, B. et al. Risk factors for second urinary tract infection among college women. Am. J. Epidemiol. 151, 1194–1205 (2000).

    CAS  PubMed  Google Scholar 

  94. McMurdo, M. E., Argo, I., Phillips, G., Daly, F. & Davey, P. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J. Antimicrob. Chemother. 63, 389–395 (2009).

    CAS  PubMed  Google Scholar 

  95. Beerepoot, M. A. et al. Cranberries versus antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch. Intern. Med. 171, 1270–1278 (2011).

    PubMed  Google Scholar 

  96. Beerepoot, M. A., Geerlings, S. E., van Haarst, E. P., van Charante, N. M. & ter Riet, G. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J. Urol. 190, 1981–1989 (2013).

    CAS  PubMed  Google Scholar 

  97. Caljouw, M. A. et al. Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities. J. Am. Geriatr. Soc. 62, 103–110 (2014).

    PubMed  Google Scholar 

  98. Juthani-Mehta, M. et al. Effect of cranberry capsules on bacteriuria plus pyuria among older women in nursing homes: a randomized clinical trial. JAMA 316, 1879–1887 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Afshar, K., Stothers, L., Scott, H. & MacNeily, A. E. Cranberry juice for the prevention of pediatric urinary tract infection: a randomized controlled trial. J. Urol. 188, 1584–1587 (2012).

    CAS  PubMed  Google Scholar 

  100. Ferrara, P. et al. Cranberry juice for the prevention of recurrent urinary tract infections: a randomized controlled trial in children. Scand. J. Urol. Nephrol. 43, 369–372 (2009).

    PubMed  Google Scholar 

  101. Wing, D. A., Rumney, P. J., Preslicka, C. W. & Chung, J. H. Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study. J. Urol. 180, 1367–1372 (2008).

    PubMed  PubMed Central  Google Scholar 

  102. Dugoua, J. J., Seely, D., Perri, D., Mills, E. & Koren, G. Safety and efficacy of cranberry (Vaccinium macrocarpon) during pregnancy and lactation. Can. J. Clin. Pharmacol. 15, e80–e86 (2008).

    PubMed  Google Scholar 

  103. Hannan, T. J., Mysorekar, I. U., Hung, C. S., Isaacson-Schmid, M. L. & Hultgren, S. J. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog. 6, e1001042 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. Schlager, T. A., LeGallo, R., Innes, D., Hendley, J. O. & Peters, C. A. B cell infiltration and lymphonodular hyperplasia in bladder submucosa of patients with persistent bacteriuria and recurrent urinary tract infections. J. Urol. 186, 2359–2364 (2011).

    CAS  PubMed  Google Scholar 

  105. Hannan, T. J. et al. Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis. EBioMedicine 1, 46–57 (2014).

    PubMed  PubMed Central  Google Scholar 

  106. Wheeler, M. A., Hausladen, D. A., Yoon, J. H. & Weiss, R. M. Prostaglandin E2 production and cyclooxygenase-2 induction in human urinary tract infections and bladder cancer. J. Urol. 168, 1568–1573 (2002).

    CAS  PubMed  Google Scholar 

  107. Bleidorn, J., Gagyor, I., Kochen, M. M., Wegscheider, K. & Hummers-Pradier, E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?—results of a randomized controlled pilot trial. BMC Med. 8, 30 (2010).

    PubMed  PubMed Central  Google Scholar 

  108. Gagyor, I. et al. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ 351, h6544 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Ferry, S. A., Holm, S. E., Stenlund, H., Lundholm, R. & Monsen, T. J. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand. J. Infect. Dis. 36, 296–301 (2004).

    PubMed  Google Scholar 

  110. Christiaens, T. C. et al. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br. J. Gen. Pract. 52, 729–734 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kalle, A. M. & Rizvi, A. Inhibition of bacterial multidrug resistance by celecoxib, a cyclooxygenase-2 inhibitor. Antimicrob. Agents Chemother. 55, 439–442 (2011).

    CAS  PubMed  Google Scholar 

  112. Velraeds, M. M., van der Mei, H. C., Reid, G. & Busscher, H. J. Inhibition of initial adhesion of uropathogenic Enterococcus faecalis by biosurfactants from Lactobacillus isolates. Appl. Environ. Microbiol. 62, 1958–1963 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bruce, A. W., Chadwick, P., Hassan, A. & VanCott, G. F. Recurrent urethritis in women. Can. Med. Assoc. J. 108, 973–976 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Reid, G., Bruce, A. W., Cook, R. L. & Llano, M. Effect on urogenital flora of antibiotic therapy for urinary tract infection. Scand. J. Infect. Dis. 22, 43–47 (1990).

    CAS  PubMed  Google Scholar 

  115. Andreu, A., Stapleton, A. E., Fennell, C. L., Hillier, S. L. & Stamm, W. E. Hemagglutination, adherence, and surface properties of vaginal Lactobacillus species. J. Infect. Dis. 171, 1237–1243 (1995).

    CAS  PubMed  Google Scholar 

  116. Osset, J., Bartolome, R. M., Garcia, E. & Andreu, A. Assessment of the capacity of Lactobacillus to inhibit the growth of uropathogens and block their adhesion to vaginal epithelial cells. J. Infect. Dis. 183, 485–491 (2001).

    CAS  PubMed  Google Scholar 

  117. Mastromarino, P. et al. Characterization and selection of vaginal Lactobacillus strains for the preparation of vaginal tablets. J. Appl. Microbiol. 93, 884–893 (2002).

    CAS  PubMed  Google Scholar 

  118. Barrons, R. & Tassone, D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin. Ther. 30, 453–468 (2008).

    CAS  PubMed  Google Scholar 

  119. Zarate, G. & Nader-Macias, M. E. Influence of probiotic vaginal lactobacilli on in vitro adhesion of urogenital pathogens to vaginal epithelial cells. Lett. Appl. Microbiol. 43, 174–180 (2006).

    CAS  PubMed  Google Scholar 

  120. de Llano, D. G. et al. Strain-specific inhibition of the adherence of uropathogenic bacteria to bladder cells by probiotic Lactobacillus spp. Pathog. Dis. https://doi.org/10.1093/femspd/ftx043 (2017).

    Article  PubMed  Google Scholar 

  121. Manzoor, A., Ul-Haq, I., Baig, S., Qazi, J. I. & Seratlic, S. Efficacy of locally isolated lactic acid bacteria against antibiotic-resistant uropathogens. Jundishapur J. Microbiol. 9, e18952 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. Shim, Y. H., Lee, S. J. & Lee, J. W. Antimicrobial activity of lactobacillus strains against uropathogens. Pediatr. Int. 58, 1009–1013 (2016).

    CAS  PubMed  Google Scholar 

  123. Aroutcheva, A. et al. Defense factors of vaginal lactobacilli. Am. J. Obstetr. Gynecol. 185, 375–379 (2001).

    CAS  Google Scholar 

  124. Atassi, F. & Servin, A. L. Individual and co-operative roles of lactic acid and hydrogen peroxide in the killing activity of enteric strain Lactobacillus johnsonii NCC933 and vaginal strain Lactobacillus gasseri KS120.1 against enteric, uropathogenic and vaginosis-associated pathogens. FEMS Microbiol. Lett. 304, 29–38 (2010).

    CAS  PubMed  Google Scholar 

  125. Alakomi, H. L. et al. Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane. Appl. Environ. Microbiol. 66, 2001–2005 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Amdekar, S., Singh, V. & Singh, D. D. Probiotic therapy: immunomodulating approach toward urinary tract infection. Curr. Microbiol. 63, 484–490 (2011).

    CAS  PubMed  Google Scholar 

  127. Karlsson, M., Scherbak, N., Khalaf, H., Olsson, P. E. & Jass, J. Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-κB activity in Escherichia coli-stimulated urinary bladder cells. FEMS Immunol. Med. Microbiol. 66, 147–156 (2012).

    CAS  PubMed  Google Scholar 

  128. Fettweis, J. M. et al. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiology 160, 2272–2282 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Baerheim, A., Larsen, E. & Digranes, A. Vaginal application of lactobacilli in the prophylaxis of recurrent lower urinary tract infection in women. Scand. J. Prim. Health Care 12, 239–243 (1994).

    CAS  PubMed  Google Scholar 

  130. Colodner, R., Edelstein, H., Chazan, B. & Raz, R. Vaginal colonization by orally administered Lactobacillus rhamnosus GG. Isr. Med. Assoc. J. 5, 767–769 (2003).

    PubMed  Google Scholar 

  131. Reid, G., Millsap, K. & Bruce, A. W. Implantation of Lactobacillus casei var rhamnosus into vagina. Lancet 344, 1229 (1994).

    CAS  PubMed  Google Scholar 

  132. Morelli, L., Zonenenschain, D., Del Piano, M. & Cognein, P. Utilization of the intestinal tract as a delivery system for urogenital probiotics. J. Clin. Gastroenterol. 38, S107–S110 (2004).

    CAS  PubMed  Google Scholar 

  133. Cribby, S., Taylor, M. & Reid, G. Vaginal microbiota and the use of probiotics. Interdiscip. Perspect. Infect. Dis. 2008, 256490 (2008).

    PubMed  Google Scholar 

  134. Mezzasalma, V. et al. Orally administered multispecies probiotic formulations to prevent uro-genital infections: a randomized placebo-controlled pilot study. Arch. Gynecol. Obstetr. 295, 163–172 (2017).

    Google Scholar 

  135. Reid, G. et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol. Med. Microbiol. 35, 131–134 (2003).

    CAS  PubMed  Google Scholar 

  136. Beerepoot, M. A. et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch. Intern. Med. 172, 704–712 (2012).

    CAS  PubMed  Google Scholar 

  137. Lee, S. J., Shim, Y. H., Cho, S. J. & Lee, J. W. Probiotics prophylaxis in children with persistent primary vesicoureteral reflux. Pediatr. Nephrol. 22, 1315–1320 (2007).

    PubMed  Google Scholar 

  138. Mohseni, M. J. et al. Combination of probiotics and antibiotics in the prevention of recurrent urinary tract infection in children. Iranian J. Pediatr. 23, 430–438 (2013).

    Google Scholar 

  139. Reid, G., Bruce, A. W. & Taylor, M. Influence of three-day antimicrobial therapy and lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clin. Ther. 14, 11–16 (1992).

    CAS  PubMed  Google Scholar 

  140. Stapleton, A. E. et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin. Infect. Dis. 52, 1212–1217 (2011).

    PubMed  PubMed Central  Google Scholar 

  141. Schwenger, E. M., Tejani, A. M. & Loewen, P. S. Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst. Rev. 12, CD008772 (2015).

    Google Scholar 

  142. Grin, P. M., Kowalewska, P. M., Alhazzan, W. & Fox-Robichaud, A. E. Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis. Can. J. Urol. 20, 6607–6614 (2013).

    PubMed  Google Scholar 

  143. Davis, J. A. & Freeze, H. H. Studies of mannose metabolism and effects of long-term mannose ingestion in the mouse. Biochim. Biophys. Acta 1528, 116–126 (2001).

    CAS  PubMed  Google Scholar 

  144. Fronzes, R., Remaut, H. & Waksman, G. Architectures and biogenesis of non-flagellar protein appendages in Gram-negative bacteria. EMBO J. 27, 2271–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Choudhury, D. et al. X-Ray structure of the FimC-FimH chaperone-adhesin complex from uropathogenic Escherichia coli. Science 285, 1061–1066 (1999).

    CAS  PubMed  Google Scholar 

  146. Zhou, G. et al. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. J. Cell Sci. 114, 4095–4103 (2001).

    CAS  PubMed  Google Scholar 

  147. Pak, J., Pu, Y., Zhang, Z. T., Hasty, D. L. & Wu, X. R. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem. 276, 9924–9930 (2001).

    CAS  PubMed  Google Scholar 

  148. Eto, D. S., Jones, T. A., Sundsbak, J. L. & Mulvey, M. A. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog. 3, e100 (2007).

    PubMed  Google Scholar 

  149. Mydock-McGrane, L. K., Cusumano, Z. T. & Janetka, J. W. Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn’s disease. Expert Opin. Ther. Patents 26, 175–197 (2016).

    CAS  Google Scholar 

  150. Michaels, E. K., Chmiel, J. S., Plotkin, B. J. & Schaeffer, A. J. Effect of D-mannose and D-glucose on Escherichia coli bacteriuria in rats. Urol. Res. 11, 97–102 (1983).

    CAS  PubMed  Google Scholar 

  151. Schaeffer, A. J., Chmiel, J. S., Duncan, J. L. & Falkowski, W. S. Mannose-sensitive adherence of Escherichia coli to epithelial cells from women with recurrent urinary tract infections. J. Urol. 131, 906–910 (1984).

    CAS  PubMed  Google Scholar 

  152. Wellens, A. et al. Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. PLOS ONE 3, e2040 (2008).

    PubMed  PubMed Central  Google Scholar 

  153. Cusumano, C. K. et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci. Transl Med. 3, 109ra115 (2011).

    PubMed  PubMed Central  Google Scholar 

  154. Spaulding, C. N. et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546, 528–532 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Mydock-McGrane, L. K., Hannan, T. J. & Janetka, J. W. Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease. Expert Opin. Drug Discov. 12, 711–731 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kranjcec, B., Papes, D. & Altarac, S. D-Mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J. Urol. 32, 79–84 (2014).

    CAS  PubMed  Google Scholar 

  157. Phe, V. et al. Open label feasibility study evaluating D-mannose combined with home-based monitoring of suspected urinary tract infections in patients with multiple sclerosis. Neurourol. Urodyn. 36, 1770–1775 (2017).

    CAS  PubMed  Google Scholar 

  158. Vicariotto, F. Effectiveness of an association of a cranberry dry extract, D-mannose, and the two microorganisms Lactobacillus plantarum LP01 and Lactobacillus paracasei LPC09 in women affected by cystitis: a pilot study. J. Clin. Gastroenterol. 48, S96–S101 (2014).

    CAS  PubMed  Google Scholar 

  159. Naves, P. et al. Effects of human serum albumin, ibuprofen and N-acetyl-L-cysteine against biofilm formation by pathogenic Escherichia coli strains. J. Hosp. Infect. 76, 165–170 (2010).

    CAS  PubMed  Google Scholar 

  160. Palleschi, G. et al. Prospective study to compare antibiosis versus the association of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract in preventing urinary tract infections in patients submitted to urodynamic investigation. Arch. Ital. Urol. Androl. 89, 45–50 (2017).

    CAS  PubMed  Google Scholar 

  161. Hamilton-Miller, J. M. & Brumfitt, W. Methenamine and its salts as urinary tract antiseptics: variables affecting the antibacterial activity of formaldehyde, mandelic acid, and hippuric acid in vitro. Invest. Urol. 14, 287–291 (1977).

    CAS  PubMed  Google Scholar 

  162. Neely, W. B. Action of formaldehyde on microorganisms. III. Bactericidal action of sublethal concentrations of formaldehyde on aerobacter aerogenes. J. Bacteriol. 86, 445–448 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Musher, D. M. & Griffith, D. P. Generation of formaldehyde from methenamine: effect of pH and concentration, and antibacterial effect. Antimicrob. Agents Chemother. 6, 708–711 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Lee, B. S., Bhuta, T., Simpson, J. M. & Craig, J. C. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst. Rev. 10, CD003265 (2012).

    PubMed  Google Scholar 

  165. Nahata, M. C., Cummins, B. A., McLeod, D. C. & Butler, R. Predictability of methenamine efficacy based on type of urinary pathogen and pH. J. Am. Geriatr. Soc. 29, 236–239 (1981).

    CAS  PubMed  Google Scholar 

  166. Nahata, M. C., Cummins, B. A., McLeod, D. C., Schondelmeyer, S. W. & Butler, R. Effect of urinary acidifiers on formaldehyde concentration and efficacy with methenamine therapy. Eur. J. Clin. Pharmacol. 22, 281–284 (1982).

    CAS  PubMed  Google Scholar 

  167. Sander, S. & Jakobsen, A. Jr. [Preventive Hiprex in urinary tract operations]. Tidsskr. Nor. Laegeforen. 96, 167–169 (1976).

    CAS  PubMed  Google Scholar 

  168. Thomlinson, J., Williams, J. D. & Cope, E. Persistence of bacteriuria following gynaecological surgery: a trial of methenamine hippurate. Br. J. Urol. 40, 479–482 (1968).

    CAS  PubMed  Google Scholar 

  169. ISRCTN registry. Alternatives to prophylactic antibiotics for the treatment of recurrent urinary tract infection in women. BMC http://www.isrctn.com/ISRCTN70219762 (2016).

  170. Mulvey, M. A., Schilling, J. D., Martinez, J. J. & Hultgren, S. J. Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses. Proc. Natl Acad. Sci. USA 97, 8829–8835 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Teng, J., Wang, Z. Y., Jarrard, D. F. & Bjorling, D. E. Roles of estrogen receptor α and β in modulating urothelial cell proliferation. Endocr. Relat. Cancer 15, 351–364 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Simpson, E. R. Sources of estrogen and their importance. J. Steroid Biochem. Mol. Biol. 86, 225–230 (2003).

    CAS  PubMed  Google Scholar 

  173. Raz, R. Hormone replacement therapy or prophylaxis in post-menopausal women with urinary tract infection. J. Infect. Dis. 183, 74–76 (2001).

    Google Scholar 

  174. Marshburn, P. B. & Carr, B. R. Hormone replacement therapy. Protection against the consequences of menopause. Postgrad. Med. 92, 145–148, 151–142, 157–149 (1992).

    CAS  PubMed  Google Scholar 

  175. Luthje, P., Hirschberg, A. L. & Brauner, A. Estrogenic action on innate defense mechanisms in the urinary tract. Maturitas 77, 32–36 (2014).

    CAS  PubMed  Google Scholar 

  176. Robinson, D. & Cardozo, L. Oestrogens and the lower urinary tract. BJOG 111 (Suppl. 1), 10–14 (2004).

    CAS  PubMed  Google Scholar 

  177. Hannan, T. J., Hooton, T. M. & Hultgren, S. J. Estrogen and recurrent UTI: what are the facts? Sci. Transl Med. 5, 190fs123 (2013).

    Google Scholar 

  178. Mirmonsef, P. et al. Exploratory comparison of vaginal glycogen and Lactobacillus levels in premenopausal and postmenopausal women. Menopause 22, 702–709 (2015).

    PubMed  PubMed Central  Google Scholar 

  179. Miller, L. et al. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstetr. Gynecol. 96, 431–439 (2000).

    CAS  Google Scholar 

  180. Raz, R. & Stamm, W. E. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med. 329, 753–756 (1993).

    CAS  PubMed  Google Scholar 

  181. Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).

    CAS  PubMed  Google Scholar 

  182. Luthje, P. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl Med. 5, 190ra180 (2013).

    Google Scholar 

  183. Stern, J. A., Hsieh, Y. C. & Schaeffer, A. J. Residual urine in an elderly female population: novel implications for oral estrogen replacement and impact on recurrent urinary tract infection. J. Urol. 171, 768–770 (2004).

    CAS  PubMed  Google Scholar 

  184. Christiansen, C. & Riis, B. J. 17 β-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J. Clin. Endocrinol. Metab. 71, 836–841 (1990).

    CAS  PubMed  Google Scholar 

  185. Rossouw, J. E. et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297, 1465–1477 (2007).

    CAS  PubMed  Google Scholar 

  186. Cardozo, L., Lose, G., McClish, D. & Versi, E. A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder. Acta Obstet. Gynecol. Scand. 83, 892–897 (2004).

    PubMed  Google Scholar 

  187. Brown, J. S. et al. Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstetr. Gynecol. 98, 1045–1052 (2001).

    CAS  Google Scholar 

  188. Cardozo, L., Benness, C. & Abbott, D. Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br. J. Obstetr. Gynaecol. 105, 403–407 (1998).

    CAS  Google Scholar 

  189. Kirkengen, A. L. et al. Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women. Scand. J. Prim. Health Care 10, 139–142 (1992).

    CAS  PubMed  Google Scholar 

  190. Ouslander, J. G. et al. Effects of oral estrogen and progestin on the lower urinary tract among female nursing home residents. J. Am. Geriatr. Soc. 49, 803–807 (2001).

    CAS  PubMed  Google Scholar 

  191. Perrotta, C., Aznar, M., Mejia, R., Albert, X. & Ng, C. W. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst. Rev. 2, CD005131 (2008).

    Google Scholar 

  192. Raz, R. et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin. Infect. Dis. 36, 1362–1368 (2003).

    CAS  PubMed  Google Scholar 

  193. Suckling, J., Lethaby, A. & Kennedy, R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst. Rev. 4, CD001500 (2006).

    Google Scholar 

  194. Eriksen, B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am. J. Obstetr. Gynecol. 180, 1072–1079 (1999).

    CAS  Google Scholar 

  195. Xu, R., Wu, Y. & Hu, Y. [Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women]. Zhonghua Fu Chan Ke Za Zhi 36, 531–533 (2001).

    CAS  PubMed  Google Scholar 

  196. Parsons, C. L., Boychuk, D., Jones, S., Hurst, R. & Callahan, H. Bladder surface glycosaminoglycans: an epithelial permeability barrier. J. Urol. 143, 139–142 (1990).

    CAS  PubMed  Google Scholar 

  197. Parsons, C. L., Pollen, J. J., Anwar, H., Stauffer, C. & Schmidt, J. D. Antibacterial activity of bladder surface mucin duplicated in the rabbit bladder by exogenous glycosaminoglycan (sodium pentosanpolysulfate). Infect. Immun. 27, 876–881 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Parsons, C. L., Greenspan, C. & Mulholland, S. G. The primary antibacterial defense mechanism of the bladder. Invest. Urol. 13, 72–78 (1975).

    CAS  PubMed  Google Scholar 

  199. Ruggieri, M. R., Hanno, P. M. & Levin, R. M. The effects of heparin on the adherence of five species of urinary tract pathogens to urinary bladder mucosa. Urol. Res. 12, 199–203 (1984).

    CAS  PubMed  Google Scholar 

  200. Parsons, C. L. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 69, 9–16 (2007).

    PubMed  Google Scholar 

  201. Cicione, A. et al. Restoring the glycosaminoglycans layer in recurrent cystitis: experimental and clinical foundations. Int. J. Urol. 21, 763–768 (2014).

    PubMed  Google Scholar 

  202. Lee, D. G. et al. Preventive effects of hyaluronic acid on Escherichia coli-induced urinary tract infection in rat. Urology 75, 949–954 (2010).

    PubMed  Google Scholar 

  203. Hauser, P. J. et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J. Urol. 182, 2477–2482 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Yildiz, N. et al. Intravesical hyaluronic acid treatment improves bacterial cystitis and reduces cystitis-induced hypercontractility in rats. Int. J. Urol. 22, 598–603 (2015).

    CAS  PubMed  Google Scholar 

  205. Tasdemir, S. et al. Intravesical hyaluronic acid and chondroitin sulfate alone and in combination for urinary tract infection: assessment of protective effects in a rat model. Int. J. Urol. 19, 1108–1112 (2012).

    CAS  PubMed  Google Scholar 

  206. Nishimura, M. et al. Role of chondroitin sulfate-hyaluronan interactions in the viscoelastic properties of extracellular matrices and fluids. Biochim. Biophys. Acta 1380, 1–9 (1998).

    CAS  PubMed  Google Scholar 

  207. Freissler, E., Meyer auf der Heyde, A., David, G., Meyer, T. F. & Dehio, C. Syndecan-1 and syndecan-4 can mediate the invasion of OpaHSPG-expressing Neisseria gonorrhoeae into epithelial cells. Cell. Microbiol. 2, 69–82 (2000).

    CAS  PubMed  Google Scholar 

  208. Laquerre, S. et al. Heparan sulfate proteoglycan binding by herpes simplex virus type 1 glycoproteins B and C, which differ in their contributions to virus attachment, penetration, and cell-to-cell spread. J. Virol. 72, 6119–6130 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Constantinides, C. et al. Prevention of recurrent bacterial cystitis by intravesical administration of hyaluronic acid: a pilot study. BJU Int. 93, 1262–1266 (2004).

    CAS  PubMed  Google Scholar 

  210. Lipovac, M. et al. Prevention of recurrent bacterial urinary tract infections by intravesical instillation of hyaluronic acid. Int. J. Gynaecol. Obstetr. 96, 192–195 (2007).

    CAS  Google Scholar 

  211. Damiano, R. et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur. Urol. 59, 645–651 (2011).

    CAS  PubMed  Google Scholar 

  212. De Vita, D. & Giordano, S. Effectiveness of intravesical hyaluronic acid/chondroitin sulfate in recurrent bacterial cystitis: a randomized study. Int. Urogynecol J. 23, 1707–1713 (2012).

    PubMed  Google Scholar 

  213. Cicione, A. et al. Intravesical treatment with highly-concentrated hyaluronic acid and chondroitin sulphate in patients with recurrent urinary tract infections: results from a multicentre survey. Can. Urol. Assoc. J. 8, E721–E727 (2014).

    PubMed  PubMed Central  Google Scholar 

  214. Gugliotta, G. et al. Is intravesical instillation of hyaluronic acid and chondroitin sulfate useful in preventing recurrent bacterial cystitis? A multicenter case control analysis. Taiwan J. Obstet. Gynecol. 54, 537–540 (2015).

    PubMed  Google Scholar 

  215. Torella, M. et al. Intravesical therapy in recurrent cystitis: a multi-center experience. J. Infect. Chemother. 19, 920–925 (2013).

    CAS  PubMed  Google Scholar 

  216. Ciani, O. et al. Intravesical administration of combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the treatment of female recurrent urinary tract infections: a European multicentre nested case-control study. BMJ Open 6, e009669 (2016).

    PubMed  PubMed Central  Google Scholar 

  217. De Vita, D., Antell, H. & Giordano, S. Effectiveness of intravesical hyaluronic acid with or without chondroitin sulfate for recurrent bacterial cystitis in adult women: a meta-analysis. Int. Urogynecol J. 24, 545–552 (2013).

    PubMed  Google Scholar 

  218. Chan, C. Y., St John, A. L. & Abraham, S. N. Mast cell interleukin-10 drives localized tolerance in chronic bladder infection. Immunity 38, 349–359 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Brumbaugh, A. R. & Mobley, H. L. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert Rev. Vaccines 11, 663–676 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Schmidhammer, S. et al. An Escherichia coli-based oral vaccine against urinary tract infections potently activates human dendritic cells. Urology 60, 521–526 (2002).

    PubMed  Google Scholar 

  221. Van Pham, T., Kreis, B., Corradin-Betz, S., Bauer, J. & Mauel, J. Metabolic and functional stimulation of lymphocytes and macrophages by an Escherichia coli extract (OM-89): in vitro studies. J. Biol. Response Mod. 9, 231–240 (1990).

    PubMed  Google Scholar 

  222. Ha, U. S. & Cho, Y. H. Immunostimulation with Escherichia coli extract: prevention of recurrent urinary tract infections. Int. J. Antimicrob. Agents 31, S63–S67 (2008).

    CAS  PubMed  Google Scholar 

  223. Huber, M., Baier, W., Serr, A. & Bessler, W. G. Immunogenicity of an E. coli extract after oral or intraperitoneal administration: induction of antibodies against pathogenic bacterial strains. Int. J. Immunopharmacol. 22, 57–68 (2000).

    CAS  PubMed  Google Scholar 

  224. Lee, S. J., Kim, S. W., Cho, Y. H. & Yoon, M. S. Anti-inflammatory effect of an Escherichia coli extract in a mouse model of lipopolysaccharide-induced cystitis. World J. Urol. 24, 33–38 (2006).

    PubMed  Google Scholar 

  225. Wagenlehner, F. M. et al. A randomized, double-blind, parallel-group, multicenter clinical study of Escherichia coli-lyophilized lysate for the prophylaxis of recurrent uncomplicated urinary tract infections. Urol. Intern. 95, 167–176 (2015).

    Google Scholar 

  226. Naber, K. G., Cho, Y. H., Matsumoto, T. & Schaeffer, A. J. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int. J. Antimicrob. Agents 33, 111–119 (2009).

    CAS  PubMed  Google Scholar 

  227. Bonkat, G. et al. European Association of Urology Guidelines on urological infections. EAU https://uroweb.org/guideline/urological-infections/ (2018).

  228. Das, P. Vaginal vaccine for recurrent urinary-tract infections. Lancet Infect. Dis. 2, 68 (2002).

    PubMed  Google Scholar 

  229. Hopkins, W. J., Elkahwaji, J., Beierle, L. M., Leverson, G. E. & Uehling, D. T. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J. Urol. 177, 1349–1353 (2007).

    PubMed  Google Scholar 

  230. Uehling, D. T., Hopkins, W. J., Elkahwaji, J. E., Schmidt, D. M. & Leverson, G. E. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J. Urol. 170, 867–869 (2003).

    PubMed  Google Scholar 

  231. Benito-Villalvilla, C. et al. MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88. Mucosal Immunol. 10, 924–935 (2017).

    CAS  PubMed  Google Scholar 

  232. Lorenzo-Gomez, M. F. et al. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections. Frontiers Cell. Infect. Microbiol. 5, 50 (2015).

    Google Scholar 

  233. Yang, B. & Foley, S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune®. BJU Int. 121, 289–292 (2018).

    PubMed  Google Scholar 

  234. Lorenzo-Gomez, M. F. et al. Evaluation of a therapeutic vaccine for the prevention of recurrent urinary tract infections versus prophylactic treatment with antibiotics. Int. Urogynecol J. 24, 127–134 (2013).

    CAS  PubMed  Google Scholar 

  235. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02543827. (2018).

  236. Marinova, S. et al. Cellular and humoral systemic and mucosal immune responses stimulated by an oral polybacterial immunomodulator in patients with chronic urinary tract infections. Int. J. Immunopathol. Pharmacol. 18, 457–473 (2005).

    CAS  PubMed  Google Scholar 

  237. Langermann, S. et al. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 181, 774–778 (2000).

    CAS  PubMed  Google Scholar 

  238. Dupuis, M. et al. Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell. Immunol. 186, 18–27 (1998).

    CAS  PubMed  Google Scholar 

  239. Asadi Karam, M. R., Oloomi, M., Mahdavi, M., Habibi, M. & Bouzari, S. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine 31, 1210–1216 (2013).

    CAS  PubMed  Google Scholar 

  240. Roberts, J. A. et al. Antibody responses and protection from pyelonephritis following vaccination with purified Escherichia coli PapDG protein. J. Urol. 171, 1682–1685 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Goluszko, P. et al. Vaccination with purified Dr Fimbriae reduces mortality associated with chronic urinary tract infection due to Escherichia coli bearing Dr adhesin. Infect. Immun. 73, 627–631 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Flores-Mireles, A. L., Pinkner, J. S., Caparon, M. G. & Hultgren, S. J. EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci. Transl Med. 6, 254ra127 (2014).

    PubMed  PubMed Central  Google Scholar 

  243. Brumbaugh, A. R., Smith, S. N. & Mobley, H. L. Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. Infect. Immun. 81, 3309–3316 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. van den Dobbelsteen, G. P. et al. Immunogenicity and safety of a tetravalent E. coli O-antigen bioconjugate vaccine in animal models. Vaccine 34, 4152–4160 (2016).

    PubMed  Google Scholar 

  245. Huttner, A. et al. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect. Dis. 17, 528–537 (2017).

    CAS  PubMed  Google Scholar 

  246. Darouiche, R. O. et al. Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder. Urology 78, 341–346 (2011).

    PubMed  Google Scholar 

  247. Sunden, F., Hakansson, L., Ljunggren, E. & Wullt, B. Escherichia coli 83972 bacteriuria protects against recurrent lower urinary tract infections in patients with incomplete bladder emptying. J. Urol. 184, 179–185 (2010).

    PubMed  Google Scholar 

  248. Koves, B. et al. Rare emergence of symptoms during long-term asymptomatic Escherichia coli 83972 carriage without an altered virulence factor repertoire. J. Urol. 191, 519–528 (2014).

    PubMed  Google Scholar 

Download references

Acknowledgements

Reviewer information

Nature Reviews Urology thanks T. J. Hannan, F. Wagenlehner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Department of Urology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    Néha Sihra, Rhana Zakri, Arun Sahai & Sachin Malde

  2. Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    Anna Goodman

Authors
  1. Néha Sihra
    View author publications

    Search author on:PubMed Google Scholar

  2. Anna Goodman
    View author publications

    Search author on:PubMed Google Scholar

  3. Rhana Zakri
    View author publications

    Search author on:PubMed Google Scholar

  4. Arun Sahai
    View author publications

    Search author on:PubMed Google Scholar

  5. Sachin Malde
    View author publications

    Search author on:PubMed Google Scholar

Contributions

N.S., A.G., R.Z., A.S. and S.M. researched data for the article. S.M. made substantial contributions to discussions of content. All authors wrote the manuscript, and S.M. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Sachin Malde.

Ethics declarations

Competing interests

N.S., A.G. and R.Z. declare no competing interests. A.S. has received an unrestricted educational grant, is an adviser to and has received speaker fees from Allergan Ltd. and has received monies from Medtronic for promotional purposes. S.M. has received monies from Medtronic for promotional purposes.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sihra, N., Goodman, A., Zakri, R. et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol 15, 750–776 (2018). https://doi.org/10.1038/s41585-018-0106-x

Download citation

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41585-018-0106-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing