Wednesday, 31 October 2018

Nonantibiotic prevention and management of recurrent urinary tract infection

Review Article | Published: 25 October 2018 Néha Sihra, Anna Goodman, Rhana Zakri, Arun Sahai & Sachin Malde Nature Reviews Urology (2018) | Download Citation 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. Access options Subscribe to Journal Get full journal access for 1 year $199.00 only $16.58 per issue Subscribe All prices are NET prices. VAT will be added later in the checkout. Rent or Buy article Get time limited or full article access on ReadCube. from$8.99 Rent or Buy All prices are NET prices. Additional access options: Log inOpenAthensShibboleth Additional information Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Stamm, W. E. & Norrby, S. R. Urinary tract infections: disease panorama and challenges. J. Infect. Dis. 183, S1–S4 (2001). Show context for reference 1 PubMedArticle 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). Show context for reference 2 CASPubMedArticle Google Scholar 3. Mabeck, C. E. Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgrad. Med. J. 48, 69–75 (1972). Show context for reference 3 CASPubMedArticlePubMed 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). Show context for reference 4 PubMedArticle Google Scholar 5. Nicolle, L. E. Urinary tract infection. Crit. Care Clin. 29, 699–715 (2013). Show context for reference 5 PubMedArticle 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). Show context for reference 6 PubMedArticle 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). Show context for reference 7 CASPubMedArticlePubMed 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). Show context for reference 8 CASPubMedArticle 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). Show context for reference 9 CASArticle 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). Show context for reference 10 PubMedArticle Google Scholar 11. European Centre for Disease Prevention and Control. ECDC/EMEA Joint Technical Report. The bacterial challenge: time to react (ECDC, 2009). Show context for reference 11 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). Show context for reference 12 Article 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). Show context for reference 13 CASPubMedArticle 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). Show context for reference 14 PubMedArticle 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). Show context for reference 15 CASPubMedArticlePubMed 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). Show context for reference 16 CASPubMedArticle 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). Show context for reference 17 PubMedArticlePubMed Central Google Scholar 18. World Health Organisation. Antimicrobial resistance: global report on surveillance 2014 (WHO, 2014). Show context for reference 18 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). Show context for reference 19 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). Show context for reference 20 PubMedArticle 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). Show context for reference 21 CASPubMedArticle 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). Show context for reference 22 CASPubMedArticle 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). Show context for reference 23 PubMedArticle Google Scholar 24. Munita, J. M. & Arias, C. A. Mechanisms of antibiotic resistance. Microbiol. Spectr. (2016). Show context for reference 24 ArticlePubMedPubMed Central Google Scholar 25. Abraham, E. P. & Chain, E. An enzyme from bacteria able to destroy penicillin. 1940. Rev. Infect. Dis. 10, 677–678 (1988). Show context for reference 25 CASPubMedArticle 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). Show context for reference 26 PubMedArticlePubMed 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). Show context for reference 27 PubMedArticleCAS 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). Show context for reference 28 CASPubMedArticle 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). Show context for reference 29 CASPubMedArticle 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). Show context for reference 30 CASPubMedArticle Google Scholar 31. Russell, G. Antibiotic resistance in children with E coli urinary tract infection. BMJ 352, i1399 (2016). Show context for reference 31 PubMedArticlePubMed 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). Show context for reference 32 CASPubMedArticle 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). Show context for reference 33 CASPubMedArticle 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). Show context for reference 34 CASPubMedPubMed 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). Show context for reference 35 CASPubMedArticle 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). Show context for reference 36 CASPubMedArticle 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). Show context for reference 37 CASPubMedArticlePubMed 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). Show context for reference 38 CASPubMedArticle 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). Show context for reference 39 PubMedArticlePubMed 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). Show context for reference 40 CASPubMedArticle Google Scholar 41. Raz, R. et al. Recurrent urinary tract infections in postmenopausal women. Clin. Infect. Dis. 30, 152–156 (2000). Show context for reference 41 CASPubMedArticle 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). Show context for reference 42 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). Show context for reference 43 PubMedArticlePubMed 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). Show context for reference 44 CASPubMedArticle 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). Show context for reference 45 PubMedArticle 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). Show context for reference 46 Article 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). Show context for reference 47 CASPubMedArticle Google Scholar 48. Adatto, K., Doebele, K. G., Galland, L. & Granowetter, L. Behavioral factors and urinary tract infection. JAMA 241, 2525–2526 (1979). Show context for reference 48 CASPubMedArticle Google Scholar 49. Nygaard, I. & Linder, M. Thirst at work — an occupational hazard? Int. Urogynecol. J. Pelvic Floor Dysfunct. 8, 340–343 (1997). Show context for reference 49 CASPubMedArticle 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). Show context for reference 50 CASPubMedArticle 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). Show context for reference 51 CASPubMedArticle 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). Show context for reference 52 CASArticle 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). Show context for reference 53 CASPubMedArticle 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). Show context for reference 54 PubMedArticle 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). Show context for reference 55 PubMedArticleCAS 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). Show context for reference 56 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). Show context for reference 57 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). Show context for reference 58 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). Show context for reference 59 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). Show context for reference 60 Google Scholar 61. Luo, M. Clinical study of bushen tonglin decoction on female with chronic urinary tract infection. Hubei Uni. Chinese Med. (2011). Show context for reference 61 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). Show context for reference 62 Google Scholar 63. Qin, S. G. Clinical analysis of Ningmitai capsule on 60 cases chronic urinary tract infection. Hebei Med. 10, 700–702 (2004). Show context for reference 63 Google Scholar 64. Balshem, H. et al. GRADE guidelines: 3. Rating the quality of evidence. J. Clin. Epidemiol. 64, 401–406 (2011). Show context for reference 64 PubMedArticle Google Scholar 65. Guay, D. R. Cranberry and urinary tract infections. Drugs 69, 775–807 (2009). Show context for reference 65 CASPubMedArticle Google Scholar 66. Borukh, I. F., Kirbaba, V. I. & Senchuk, G. V. [Antimicrobial properties of cranberry]. Voprosy Pitaniia 31, 82 (1972). Show context for reference 66 CASPubMed Google Scholar 67. Hisano, M., Bruschini, H., Nicodemo, A. C. & Srougi, M. Cranberries and lower urinary tract infection prevention. Clinics 67, 661–668 (2012). Show context for reference 67 PubMedArticlePubMed Central Google Scholar 68. Lynch, D. M. Cranberry for prevention of urinary tract infections. Am. Fam. Physician 70, 2175–2177 (2004). Show context for reference 68 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). Show context for reference 69 CASPubMedArticle 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). Show context for reference 70 CASPubMedArticle Google Scholar 71. Ofek, I. & Beachey, E. H. Mannose binding and epithelial cell adherence of Escherichia coli. Infect. Immun. 22, 247–254 (1978). Show context for reference 71 CASPubMedPubMed 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). Show context for reference 72 CASPubMedArticlePubMed 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). Show context for reference 73 CASPubMedArticlePubMed 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). Show context for reference 74 PubMedArticleCASPubMed Central Google Scholar 75. Howell, A. B. et al. A-Type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 66, 2281–2291 (2005). Show context for reference 75 CASPubMedArticle 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). Show context for reference 76 CASArticle 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). Show context for reference 77 CASPubMedArticle 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). Show context for reference 78 CASPubMedArticlePubMed 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). Show context for reference 79 CASPubMedArticle Google Scholar 80. Howell, A. B. & Foxman, B. Cranberry juice and adhesion of antibiotic-resistant uropathogens. JAMA 287, 3082–3083 (2002). Show context for reference 80 PubMedArticle Google Scholar 81. Avorn, J. et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 271, 751–754 (1994). Show context for reference 81 CASPubMedArticle 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). Show context for reference 82 PubMedArticlePubMed Central Google Scholar 83. Beerepoot, M. & Geerlings, S. Non-antibiotic prophylaxis for urinary tract infections. Pathogens 5, E36 (2016). Show context for reference 83 PubMedArticleCAS 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). Show context for reference 84 PubMedArticle Google Scholar 85. Jepson, R. G., Williams, G. & Craig, J. C. Cranberries for preventing urinary tract infections. Cochrane Database Syst. Rev. 10, CD001321 (2012). Show context for reference 85 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). Show context for reference 86 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). Show context for reference 87 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). Show context for reference 88 CASPubMedArticle 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). Show context for reference 89 CASPubMedArticle 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). Show context for reference 90 CASPubMedArticlePubMed 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). Show context for reference 91 PubMedArticlePubMed 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). Show context for reference 92 PubMedArticlePubMed 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). Show context for reference 93 CASPubMedArticle 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). Show context for reference 94 CASPubMedArticle 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). Show context for reference 95 PubMedArticle 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). Show context for reference 96 CASPubMedArticle 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). Show context for reference 97 PubMedArticle 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). Show context for reference 98 CASPubMedArticlePubMed 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). Show context for reference 99 CASPubMedArticle 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). Show context for reference 100 PubMedArticle 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). Show context for reference 101 PubMedArticlePubMed 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). Show context for reference 102 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). Show context for reference 103 PubMedArticleCASPubMed 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). Show context for reference 104 CASPubMedArticle Google Scholar 105. Hannan, T. J. et al. Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis. EBioMedicine 1, 46–57 (2014). Show context for reference 105 PubMedArticlePubMed 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). Show context for reference 106 CASPubMedArticle 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). Show context for reference 107 PubMedArticleCASPubMed 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). Show context for reference 108 PubMedArticleCASPubMed 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). Show context for reference 109 PubMedArticle 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). Show context for reference 110 CASPubMedPubMed 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). Show context for reference 111 CASPubMedArticle 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). Show context for reference 112 CASPubMedPubMed 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). Show context for reference 113 CASPubMedPubMed 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). Show context for reference 114 CASPubMedArticle 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). Show context for reference 115 CASPubMedArticle 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). Show context for reference 116 CASPubMedArticle 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). Show context for reference 117 CASPubMedArticle 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). Show context for reference 118 CASPubMedArticle 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). Show context for reference 119 CASPubMedArticle 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. (2017). Show context for reference 120 ArticlePubMed 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). Show context for reference 121 PubMedArticleCASPubMed 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). Show context for reference 122 CASPubMedArticle Google Scholar 123. Aroutcheva, A. et al. Defense factors of vaginal lactobacilli. Am. J. Obstetr. Gynecol. 185, 375–379 (2001). Show context for reference 123 CASArticle 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). Show context for reference 124 CASPubMedArticle 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). Show context for reference 125 CASPubMedArticlePubMed 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). Show context for reference 126 CASPubMedArticle 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). Show context for reference 127 CASPubMedArticle 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). Show context for reference 128 CASPubMedArticlePubMed 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). Show context for reference 129 CASPubMedArticle 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). Show context for reference 130 PubMed Google Scholar 131. Reid, G., Millsap, K. & Bruce, A. W. Implantation of Lactobacillus casei var rhamnosus into vagina. Lancet 344, 1229 (1994). Show context for reference 131 CASPubMedArticle 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). Show context for reference 132 CASPubMedArticle Google Scholar 133. Cribby, S., Taylor, M. & Reid, G. Vaginal microbiota and the use of probiotics. Interdiscip. Perspect. Infect. Dis. 2008, 256490 (2008). Show context for reference 133 PubMedArticleCAS 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). Show context for reference 134 Article 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). Show context for reference 135 CASPubMedArticle 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). Show context for reference 136 CASPubMedArticle 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). Show context for reference 137 PubMedArticle 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). Show context for reference 138 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). Show context for reference 139 CASPubMed 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). Show context for reference 140 PubMedArticlePubMed 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). Show context for reference 141 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). Show context for reference 142 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). Show context for reference 143 CASPubMedArticle 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). Show context for reference 144 CASPubMedArticlePubMed 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). Show context for reference 145 CASPubMedArticle 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). Show context for reference 146 CASPubMed 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). Show context for reference 147 CASPubMedArticle 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). Show context for reference 148 PubMedArticleCAS 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). Show context for reference 149 CASArticle 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). Show context for reference 150 CASPubMedArticle 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). Show context for reference 151 CASPubMedArticle 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). Show context for reference 152 PubMedArticleCASPubMed 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). Show context for reference 153 PubMedArticleCASPubMed 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). Show context for reference 154 CASPubMedPubMed 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). Show context for reference 155 CASPubMedArticlePubMed 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). Show context for reference 156 CASPubMedArticle 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). Show context for reference 157 CASPubMedArticle 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). Show context for reference 158 CASPubMedArticle 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). Show context for reference 159 CASPubMedArticle 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). Show context for reference 160 CASPubMedArticle 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). Show context for reference 161 CASPubMed 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). Show context for reference 162 CASPubMedPubMed 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). Show context for reference 163 CASPubMedArticlePubMed 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). Show context for reference 164 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). Show context for reference 165 CASPubMedArticle 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). Show context for reference 166 CASPubMedArticle Google Scholar 167. Sander, S. & Jakobsen, A. Jr. [Preventive Hiprex in urinary tract operations]. Tidsskr. Nor. Laegeforen. 96, 167–169 (1976). Show context for reference 167 CASPubMed 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). Show context for reference 168 CASPubMedArticle Google Scholar 169. ISRCTN registry. Alternatives to prophylactic antibiotics for the treatment of recurrent urinary tract infection in women. BMC (2016). Show context for reference 169 170. 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). Show context for reference 170 CASPubMedArticle 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). Show context for reference 171 CASPubMedArticlePubMed Central Google Scholar 172. Simpson, E. R. Sources of estrogen and their importance. J. Steroid Biochem. Mol. Biol. 86, 225–230 (2003). Show context for reference 172 CASPubMedArticle 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). Show context for reference 173 Article 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). Show context for reference 174 CASPubMedArticle 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). Show context for reference 175 CASPubMedArticle Google Scholar 176. Robinson, D. & Cardozo, L. Oestrogens and the lower urinary tract. BJOG 111 (Suppl. 1), 10–14 (2004). Show context for reference 176 CASPubMedArticle 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). Show context for reference 177 ArticleCAS 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). Show context for reference 178 PubMedArticlePubMed Central Google Scholar 179. Miller, L. et al. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstetr. Gynecol. 96, 431–439 (2000). Show context for reference 179 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). Show context for reference 180 CASPubMedArticle 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). Show context for reference 181 CASPubMedArticle Google Scholar 182. Luthje, P. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl Med. 5, 190ra180 (2013). Show context for reference 182 ArticleCAS 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). Show context for reference 183 CASPubMedArticle 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). Show context for reference 184 CASPubMedArticle 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). Show context for reference 185 CASPubMedArticle 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). Show context for reference 186 PubMedArticle 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). Show context for reference 187 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). Show context for reference 188 CASArticle 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). Show context for reference 189 CASPubMedArticle 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). Show context for reference 190 CASPubMedArticle 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). Show context for reference 191 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). Show context for reference 192 CASPubMedArticle Google Scholar 193. Suckling, J., Lethaby, A. & Kennedy, R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst. Rev. 4, CD001500 (2006). Show context for reference 193 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). Show context for reference 194 CASArticle 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). Show context for reference 195 CASPubMed 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). Show context for reference 196 CASPubMedArticle 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). Show context for reference 197 CASPubMedPubMed 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). Show context for reference 198 CASPubMed 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). Show context for reference 199 CASPubMedArticle 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). Show context for reference 200 PubMedArticle 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). Show context for reference 201 PubMedArticle 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). Show context for reference 202 PubMedArticle 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). Show context for reference 203 CASPubMedArticlePubMed 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). Show context for reference 204 CASPubMedArticle 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). Show context for reference 205 CASPubMedArticle 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). Show context for reference 206 CASPubMedArticle 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). Show context for reference 207 CASPubMedArticle 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). Show context for reference 208 CASPubMedPubMed 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). Show context for reference 209 CASPubMedArticle 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). Show context for reference 210 CASArticle 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). Show context for reference 211 CASPubMedArticle 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). Show context for reference 212 PubMedArticle 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). Show context for reference 213 PubMedArticlePubMed 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). Show context for reference 214 PubMedArticle Google Scholar 215. Torella, M. et al. Intravesical therapy in recurrent cystitis: a multi-center experience. J. Infect. Chemother. 19, 920–925 (2013). Show context for reference 215 CASPubMedArticle 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). Show context for reference 216 PubMedArticlePubMed 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). Show context for reference 217 PubMedArticle 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). Show context for reference 218 CASPubMedArticlePubMed 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). Show context for reference 219 CASPubMedArticlePubMed 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). Show context for reference 220 PubMedArticle 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). Show context for reference 221 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). Show context for reference 222 CASPubMedArticle 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). Show context for reference 223 CASPubMedArticle 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). Show context for reference 224 PubMedArticle 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). Show context for reference 225 Article 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). Show context for reference 226 CASPubMedArticle Google Scholar 227. Bonkat, G. et al. European Association of Urology Guidelines on urological infections. EAU (2018). Show context for reference 227 228. Das, P. Vaginal vaccine for recurrent urinary-tract infections. Lancet Infect. Dis. 2, 68 (2002). Show context for reference 228 PubMedArticle 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). Show context for reference 229 PubMedArticle 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). Show context for reference 230 PubMedArticle 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). Show context for reference 231 CASPubMedArticle 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). Show context for reference 232 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). Show context for reference 233 PubMedArticle 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). Show context for reference 234 CASPubMedArticle Google Scholar 235. US National Library of Medicine. (2018). Show context for reference 235 236. 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). Show context for reference 236 CASPubMedArticle 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). Show context for reference 237 CASPubMed Google Scholar 238. Dupuis, M. et al. Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell. Immunol. 186, 18–27 (1998). Show context for reference 238 CASPubMedArticle 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). Show context for reference 239 CASPubMedArticle 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). Show context for reference 240 CASPubMedArticlePubMed 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). Show context for reference 241 CASPubMedArticlePubMed 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). Show context for reference 242 PubMedArticleCASPubMed 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). Show context for reference 243 CASPubMedArticlePubMed 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). Show context for reference 244 PubMedArticleCAS 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). Show context for reference 245 CASPubMedArticle 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). Show context for reference 246 PubMedArticle 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). Show context for reference 247 PubMedArticle 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). Show context for reference 248 PubMedArticleCAS 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 Affiliations Department of Urology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Néha Sihra, Rhana Zakri, Arun Sahai & Sachin Malde Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Anna Goodman 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. 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. Corresponding author Correspondence to Sachin Malde. Rights and permissions To obtain permission to re-use content from this article visit RightsLink.