Urinary tract infections (UTIs) were first documented in Egypt in 1550 BC, and are still among the most common bacterial infections in the world . The prevalence of UTI seems to be a J-shaped distribution, with higher frequency among very young children which gradually increases with age . It is estimated to affect 150 million people each year worldwide, with an annual incidence of 12.6% in women and 3% in men . Although most UTIs can be effectively treated by antibiotics, UTI recurrence is a common problem and sometimes may be very troublesome. Recurrent UTIs, which include relapses and reinfection, are traditionally defined as ≥2 uncomplicated UTIs in the past 6 months, or ≥3 infections within the preceding year . UTI can recur easily in young immunocompetent women with anatomically normal urinary tracts. In one study, 27% of young college-age women with their first UTI experienced at least one recurrence within the following 6 months, and in another study, 53% of women over 55 years old reported UTI recurrence . Although recurrent UTIs usually are not life-threatening, the high incidence significantly increases health-care costs and has a negative impact on patients' life quality .
The risk factors, pathogenesis, and prophylaxis of UTI have been well investigated since the early 20th century. In the recent years, research on UTI recurrence has also attracted a wide attention. Rather than treating recurrent UTI with antibiotics alone, if symptoms relapse, the current guidelines suggest aggressive management, such as avoidance of risk factors or medical prophylaxis . Although most clinical and laboratory studies have focused on the first UTI, new evidence suggests a distinct pathogenesis in recurrent UTI. Thus, the aim of the current review is to update clinicians on the latest evidence on recurrent UTI, including the pathogenesis, risk factors, biomarkers and prevention, and present recent advances in research.
There are two possible pathways in the pathogenesis of recurrent UTI; frequent repeat ascending infections and chronic/persistent infections in the bladder. Each pathway also might result from two possible mechanisms; bacterial factors and deficiencies in host defense.
UTIs might be caused by Gram-negative or Gram-positive bacteria, and the most common causative pathogen is Escherichia coli . In studies using pulsed-field gel electrophoresis, 52%–77% of recurrent UTIs were caused by an E. coli strain which was identical to the primary infecting strain . Since the 1960s, several specific strains of E. coli had been found to be significantly increased in recurrent UTIs . Adherence of vaginal isolates in different E. coli strains was associated with recurrent UTI . E. coli with DNA papG coding for a P-fimbriae was also significantly associated with recurrent UTIs . In a prospective study, 148 women with a total of 558 recurrent UTIs were recruited, and the E. coli isolated from urine culture was routinely serologically classified for 131 O groups . The ten most common O-serogroups accounted for 76% of recurrent UTIs, and nearly 50% of recurrent UTIs were caused by the three most common groups (O4, O6, and O75). In the genetic aspect, phylogenetic classification was also associated with recurrent UTIs . Virulence factor genes KpsM II K2 and agn43a were independently associated with persistence or relapse of UTIs. Patients with frequent recurrent UTIs might just be infected by a special strain of E. coli.
Another possible mechanism for frequent recurrent UTIs is the survival of bacteria in the bladder through progression of intracellular bacterial communities (IBCs). Early studies showed that E. coli could replicate intracellularly, form a loose collection of bacteria, and then escape into the bladder lumen . In 2004, Justice et al. used time-lapse fluorescence videomicroscopy and discovered that E. coli could form a complex of IBCs within the superficial umbrella cells of the bladders in mice . IBCs in the bladder could form 4–16 h after bacterial infection, and then develop a persistent quiescent intracellular reservoir 2 weeks later . These IBCs could be quiescent for extended periods despite antibacterial therapy, and then re-emerge to cause recurrent UTI. These IBCs are difficult to detect in urine specimens, but immunofluorescence evidence showed 18% of women with acute uncomplicated cystitis presented IBCs in the bladder . In an animal study, higher numbers of IBCs were also predictive of persistent bacteriuria after acute cystitis . In addition, a recent study revealed that bacteria in the IBCs had highly upregulated lacZ and yeaR genes, which contributed to utilizing a galactoside for metabolism and oxidative stress resistance, respectively . Since studies propose that most recurrent UTIs are caused by E. coli strains which are identical to the primary infection, IBCs and a quiescent intracellular reservoir might play important roles in the pathogenesis of recurrent UTIs.
DEFICIENCIES IN HOST DEFENSE
It is well known that patients with immunodeficiency tend to have frequent, recurrent, and severe UTIs . However, recurrent UTIs in some immunocompetent patients might also be caused by host defense deficiencies. The host defense in lower UTI consists of two main mechanisms; innate immune responses and urothelium barrier function . The innate immune response in the bladder comprises different inflammatory cells and cells with recognition receptors, such as toll-like receptors (TLRs), which can recognize pathogens and induce a robust inflammatory immune response. TLRs are essential for the activation of immune responses and may be associated with recurrent UTI. In a cross-sectional study, genotyped polymorphisms were investigated in women with a history of recurrent UTIs . Polymorphism of TLR2 G2258A, a variant associated with decreased lipopeptide-induced signaling, was associated with an increased risk of bacteriuria. TLR5 C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of recurrent UTI in adult women . On the contrary, TLR polymorphism including TLR4 A896G and TLR1 G1805T might have potential roles in protection from recurrent UTI . Patients with specific TLR polymorphisms may have deficiency of pathogen recognition in the bladder, which then leads to higher prevalence of recurrent UTIs.
The urothelium in the urinary tract is the first-line barrier against pathogens and toxic substances. The urothelium can secrete pro-inflammatory cytokines and protective glycoprotein plaques such as uroplakin and Tamm–Horsfall protein (THP) on the bladder surface as anatomical barriers . The urothelium's antibacterial adherence mechanism is fundamental in host defense, and it had been proven to be less potent in patients with recurrent UTI . Uroplakins are the essential structural components of the urothelium and a deficiency compromises the urothelial permeability barrier . Uroplakins also serve as the urothelium receptor for Type 1-fimbriated E. coli and play a role in bacterial adhesion . Decreased or entirely absent uroplakin expression in the urothelium has been found in patients with recurrent UTI . On the other hand, animal studies showed that urinary THP has the potential to prevent bacteria from interacting or aggregating in the urothelium . However, clinical evidence is still lacking. The levels of urinary THP in patients with recurrent UTI were not significantly different from healthy controls in previous studies . In our recent immunofluorescence study, we found increased mast cell and apoptotic activity, and decreased E-cadherin expression in the urothelium of patients with recurrent UTI . Current evidence supports the idea that urothelial dysfunction impacts the pathogenesis of recurrent UTI. Further clinical and laboratory studies are necessary to elucidate the mechanism.
Patients with recurrent UTI should undergo a comprehensive investigation to identify the possible risk factors . The evaluations should include a history review and a physical examination to rule out urogenital anatomical anomalies, immunodeficiency, voiding dysfunction, and health behavioral problems . Urinary tract abnormalities, including obstruction and calculi, are well-known causative factors in UTI . A high residual urinary volume (RU) was significantly associated with recurrent UTI in male patients, even in the patients without lower urinary tract symptoms . An RU of 180 mL or greater had the best specificity and sensitivity in predicting bacteriuria in asymptomatic adult men . In women, the role of large RU in recurrent UTI is controversial. Postmenopausal women with recurrent UTI had a significantly increased RU and reduced urine flow compared with age-matched controls . A urodynamic study also found increased abdominal strength in voiding which constitutes a risk factor for recurrent UTI in women . The ideal cutoff point for the maximum abdominal pressure in the voiding phase was 28 cmH2O. However, in young healthy nonpregnant women, the RU was not different between patients with recurrent UTI and controls . Most current guidelines suggest that increased RU is an independent risk factor for recurrent UTI, and RU should be measured before management .
Behavioral risk factors should be considered first in young women who have recurrent UTI. Sexual intercourse is the strongest behavioral risk factor in recurrent UTI . The risk is even increased in any lifetime sexual activity and any sexual activity during the past year . The odds ratio of recurrent UTI was high as 10.3 in young women with intercourse >9 times in the past month. In addition, any new sex partner and spermicide use in the past year also increased the risk. Voiding habits also might be a risk factor. Histories of hesitating to excuse oneself to urinate and voluntary deferral of micturition for 1 h were found to be associated with recurrent UTI in women . The role of psychological factors in recurrent UTI has also attracted attention in the past years. Hunt and Waller used several different personality questionnaires and suggested that the neurotic personality type might be related to recurrent UTI . However, because of the relatively small amount of further research, it is difficult to draw any clear conclusions concerning the role of psychological factors in recurrent UTI. The role of dietary habits in recurrent UTI is also not clear. Only drinking soft drinks was found to be moderately associated with recurrent UTI, and further evidence is still lacking . Increasing fluid consumption is often recommended for patients with UTI; however, clinical studies showed contradictory results on the influence of fluid intake on the risk of recurrent UTI . For postmenopausal women, the most significant risk factor is estrogen deficiency . Lack of estrogen could cause thinning of the vaginal epithelium and decreased amounts of glycogen, predisposing women to introital colonization with E. coli . The main vaginal flora usually changes from Lactobacilli to uropathogen such as E. coli after estrogen loss at menopause, leading to UTI recurrence . The possible risk factors for recurrent UTI are listed in Table 1.
Although many risk factors have been reported in research, clinical patients with recurrent UTI often do not have any identifiable risk factors. Moreover, evidence about some behavioral risk factors is controversial due to unreliable questionnaire estimations . Objective urine or serum biomarkers for predicting recurrence in patients with a first UTI is important and clinically useful. In the past decade, many possible biomarkers have been investigated in animal and human studies.
SERUM BIOMARKERS FOR RECURRENT URINARY TRACT INFECTION
Serum antibodies were the first possible biomarkers found in recurrent UTI. Women with recurrent UTI who had complete antibiotic therapy were recruited in a 2001 prospective study . The levels of serum antibody immunoglobulin (Ig) G, IgM, and IgA in the study patients were significantly higher than those in healthy controls. Hannan et al. investigated serum cytokines in mice with acute bacterial cystitis. The levels of serum hormone granulocyte colony-stimulating factor (CSF) and interleukin-5 (IL-5) at onset were significantly higher in the mice with redevelopment of cystitis than those without reinfection . The research group further investigated serum cytokines in women with uncomplicated acute cystitis and tried to identify candidate serum biomarkers from 48 different cytokines . Macrophage CSF was found to be significantly elevated in patients who subsequently developed recurrent UTI. An elevated prostate-specific antigen (PSA) level is well known in the diagnosis of prostate cancer, but it also might have a potential protective role in recurrent UTI . In a retrospective study, male patients with a PSA level higher than 4 ng/mL at UTI onset were less likely to have recurrent UTI than those with PSA <4 ng/mL (13% vs. 70%, respectively, P < 0.01) . A bacterial challenge study revealed a significantly decreased frequency of E. coli invasion in PSA-positive prostate epithelium, which suggests a protective role for PSA in recurrent UTI . In addition, the mean serum levels of Vitamin D among premenopausal women with recurrent UTI were significantly lower than those of controls (9.8 ± 4 ng/mL vs. 23 ± 6 ng/mL; respectively, P < 0.001) . Vitamin D is important for innate immunity, mainly by increasing neutrophilic phagocytic function and motility . Deficiency of serum Vitamin D also might be a biomarker for recurrent UTI.
URINARY BIOMARKERS FOR RECURRENT URINARY TRACT INFECTION
Urinary biomarkers for lower urinary tract diseases have been widely discussed for years. Nerve growth factor (NGF) is a small protein that induces survival and differentiation of neurons . Urinary NGF levels were significantly increased in women with overactive bladder and were considered a possible biomarker . In our recent study, we prospectively enrolled women with uncomplicated UTIs and measured urinary NGF levels at baseline and follow-up . At 12 weeks, the serial urinary NGF levels in women with UTI recurrence were significantly lower than those in women without recurrence. Neutrophil gelatinase-associated lipocalin (NGAL) is an iron-transporting protein and has been regarded as a promising biomarker in acute kidney injury . In young patients with a first UTI recurrence, the urinary NGAL levels were significantly decreased . This might result from reduced TLR4 expression and reflect-defective innate immunity . In a cross-sectional survey of different urinary cytokines in asymptomatic women with a history of recurrent UTI, urinary IL-8 was significantly higher in patients with bacteriuria, and was associated with higher serum neutrophil levels . Urinary IL-8 levels might have a predictive value in recurrent UTI in women. The above-mentioned serum and urinary biomarkers not only have potential predictive value, but also might involve the systemic or regional pathomechanism in patients with recurrent UTI.
Further prospective clinical trials are necessary to confirm the predictive efficacy. In summary, the possible biomarkers for recurrent UTI are listed in Table 2.
PREVENTION OF RECURRENT URINARY TRACT INFECTION
Prevention of recurrent UTI has attracted much interest and was investigated by researchers. The European Association of Urology guideline suggests that the prevention of recurrent UTI should include the following in this order: (1) behavioral modifications and avoidance of risk factors, (2) nonantimicrobial measures, and (3) antimicrobial prophylaxis . Due to the limited context, the current review mainly focuses on nonantimicrobial treatment of recurrent UTI.
PROPHYLAXIS WITH CRANBERRY JUICE
Drinking cranberry juice might be the most well-known means of prevention of recurrent UTI. It has been shown to inhibit the adherence of P-fimbriated E. coli to urothelium, and could decrease the virulence in bacterial cystitis . Early randomized controlled trials showed that cranberry juice decreased the number of symptomatic relapses over a 12-month period in women with recurrent UTIs . However, further studies suggest that cranberry juice is not as effective as previously reported. The large number of withdrawals from the trials indicates that cranberry juice may not be acceptable over long periods of time. The latest Cochrane database systematic review in 2012 revealed that cranberry products, including juice, tablets, and capsules, did not significantly reduce the relapse rate for women with recurrent UTI . A large double-blinded, randomized, placebo-controlled trial in 2016 again confirmed that the administration of cranberry capsules versus placebo resulted in no significant difference in UTIs over 1 year . Currently, most guidelines suggest that cranberry products cannot be recommended for the prevention of UTI recurrence .
PROPHYLAXIS WITH PROBIOTICS
Since the urogenital flora of healthy premenopausal women is dominated by Lactobacilli, it has been suggested that restoration of the unhealthy urogenital flora from uropathogens with Lactobacilli may protect against UTI . A 1988 study revealed that intravaginal administration of Lactobacilli (Lactobacillus casei GR-1) twice weekly could significantly extend infection-free periods compared with pretreatment in women with recurrent UTI . A recent randomized, placebo-controlled trial, on 100 young women with a history of recurrent UTI, used intravaginal Lactobacillus crispatus daily for 5 days and then once weekly for 10 weeks . The UTI recurrence rate was significantly lower in the study group than in the control group. Various Lactobacilli administered orally have also been assessed in clinical study, but the efficacy in the prevention of UTI recurrence is controversial . Although some studies showed promising results, pooled data from meta-analyses of available randomized controlled trials (RCTs) show no convincing benefit of Lactobacillus products as prophylaxis for recurrent UTI . Current guidelines recommend that Lactobacillus should not be used outside of investigational trials .
Further research must be conducted before oral or intravaginal probiotics can be recommended as a regular prophylaxis.
HORMONAL REPLACEMENT PROPHYLAXIS
Estrogen loss in postmenopausal women leads to decreasing glycogen, thinning of the epithelium, and alkalization of the vagina . All these changes could change vaginal flora and predispose to UTI . Estrogen replacement with either topically applied vaginal cream or oral medications for recurrent UTI in women has been used since the 1980s and has shown favorable results . In two RCTs in the 1990s, intravaginal estrogen therapy significantly decreased the incidence of UTI and decreased the vaginal pH in the study group without severe unexpected adverse events . The rate of Enterobacter colonization in the vagina was also decreased in the study group but was not changed in the control group. A recent meta-analysis of RCTs also proved the efficacy of vaginal estrogens for preventing UTI recurrence . In contrast, these meta-analyses indicated that oral estrogens could not decrease the rate of UTI recurrence and may result in local and systemic side effects . Current guidelines suggest that intravaginal estrogen therapy, but not oral estrogen, shows a trend toward preventing UTI recurrence . Side effects of intravaginal estrogen might be common but usually not severe. Vaginal irritation is the main adverse effect and might occur in up to 20% of women .
IMMUNOACTIVE AGENT PROPHYLAXIS
One of the possible pathogeneses in recurrent UTI is adaptive immune response dysfunction, especially in defects of pathogen recognition . Thus, using a vaccine to strengthen active acquired immunity against uropathogens might be a reasonable prevention of UTI recurrence. Systemic vaccination has been used in treating women with recurrent UTI for more than a century . However, due to the heterogeneity of uropathogens, therapeutic vaccination against UTI has largely been seen as ineffective in the past years . Recently, there were encouraging results in some animal studies in the development of an E. coli vaccine . Since 1994, clinical trials have been conducted on intravaginal vaccines in women with recurrent UTI . Women using a vaginal vaccine remained free of infections for a significantly longer period than those receiving placebo. The total vaginal and urinary IgG and IgA were also significantly increased in the study groups. Nowadays, both oral and parenteral vaccines have also been shown effective in recurrent UTI, and are available on the market . A recent meta-analysis enrolled four clinical trials of an oral vaccine (OM-89), and showed that it significantly decreased the rate of UTI recurrence with a good safety profile . Headache and gastrointestinal complaints were reported most often (13%, comparable with that in the placebo group), and only one allergic reaction leading to withdrawal was reported. Now, the latest guideline recommends OM-89 for immunoprophylaxis in female patients with recurrent uncomplicated UTI .
Antimicrobial prophylaxis might be more effective, but it should be used after nonantimicrobial agents because of possible adverse effects . Antimicrobial prophylaxis for preventing UTI recurrence can be given continuously for long periods of time (3–6 months), or as a single postcoital dose. A Cochrane review found that postcoital prophylaxis was just as effective as low-dose continuous antibiotic prophylaxis in the prevention of a recurrent UTI . Continuous prophylaxis for 6 or 12 months significantly reduced the rate of UTIs during the prophylaxis period, with no difference between the two treatment groups after cessation of prophylaxis . Postcoital prophylaxis involves taking a dose of antibiotics within 2 h of intercourse . It requires smaller amounts of antibiotics than continuous prophylaxis and is associated with fewer side effects . The antimicrobial prophylaxis regimens and recommended doses from the current guidelines are listed in Table 3 .
Recurrent UTI might be one of the most common problems in urology clinics, but may not attract much attention from urologists in Taiwan. Treating UTI might not be difficult, but preventing UTI recurrence sometimes might be very troublesome for both patients and doctors. Recent research has revealed many novel concepts in recurrent UTI, including the pathogenesis, risk factors, biomarkers, and prevention. Nowadays, recurrent UTI may be considered a distinct disease, and patients with recurrent UTI should be managed aggressively. Further basic science studies are needed to elucidate details in the pathogenesis, and RCTs are also necessary to clarify the efficacy of the current management.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Nickel JC. Management of urinary tract infections: Historical perspective and current strategies: Part 1 – Before antibiotics J Urol. 2005;173:21–6
2. Johnson CC. Definitions, classification, and clinical presentation of urinary tract infections Med Clin North Am. 1991;75:241–52
3. Stamm WE, Norrby SR. Urinary tract infections: Disease panorama and challenges J Infect Dis. 2001;183(Suppl 1):1S–4S
4. Epp A, Larochelle A, Lovatsis D, Walter JE, Easton W, Farrell SA, et al Recurrent urinary tract infection
J Obstet Gynaecol Can. 2010;32:1082–101
5. Foxman B. Recurring urinary tract infection
: Incidence and risk factors Am J Public Health. 1990;80:331–3
6. Ikäheimo R, Siitonen A, Heiskanen T, Kärkkäinen U, Kuosmanen P, Lipponen P, et al Recurrence
of urinary tract infection
in a primary care setting: Analysis of a 1-year follow-up of 179 women Clin Infect Dis. 1996;22:91–9
7. Renard J, Ballarini S, Mascarenhas T, Zahran M, Quimper E, Choucair J, et al Recurrent lower urinary tract infections have a detrimental effect on patient quality of life: A prospective, observational study Infect Dis Ther. 2015;4:125–35
8. Ciani O, Grassi D, Tarricone R. An economic perspective on urinary tract infection
: The “costs of resignation” Clin Drug Investig. 2013;33:255–61
9. Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection
in women Can Urol Assoc J. 2011;5:316–22
10. Grabe M, Bartetti R, Johansen TE, Cai T, Cek M, Koves B, et al Guidelines on Urological Infections. EAU Guideline. 2015Last accessed on 2015 Mar 25 Available from: http://www.uroweb.org/wp-content/uploads/19-Urological-infections_LR2.pdf
11. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options Nat Rev Microbiol. 2015;13:269–84
12. Ejrnæs K. Bacterial characteristics of importance for recurrent urinary tract infections caused by Escherichia coli
Dan Med Bull. 2011;58:B4187
13. Luo Y, Ma Y, Zhao Q, Wang L, Guo L, Ye L, et al Similarity and divergence of phylogenies, antimicrobial susceptibilities, and virulence factor profiles of Escherichia coli
isolates causing recurrent urinary tract infections that persist or result from reinfection J Clin Microbiol. 2012;50:4002–7
14. McGeachie J. Serological grouping of urinary Escherichia coli
J Clin Pathol. 1965;18:428–31
15. Pryles CV, Glagovsky A. Serological characterization of Escherichia coli
. Study in acute and recurrent urinary tract infections in infants and children Pediatrics. 1965;36:219–24
16. Schaeffer AJ, Jones JM, Falkowski WS, Duncan JL, Chmiel JS, Plotkin BJ. Variable adherence of uropathogenic Escherichia coli
to epithelial cells from women with recurrent urinary tract infection
J Urol. 1982;128:1227–30
17. Norinder BS, Lüthje P, Yadav M, Kadas L, Fang H, Nord CE, et al Cellulose and PapG are important for Escherichia coli
causing recurrent urinary tract infection
in women Infection. 2011;39:571–4
18. Vosti KL. A prospective, longitudinal study of the behavior of serologically classified isolates of Escherichia coli
in women with recurrent urinary tract infections J Infect. 2007;55:8–18
19. Ejrnæs K, Stegger M, Reisner A, Ferry S, Monsen T, Holm SE, et al Characteristics of Escherichia coli
causing persistence or relapse of urinary tract infections: Phylogenetic groups, virulence factors and biofilm formation Virulence. 2011;2:528–37
20. Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells EMBO J. 2000;19:2803–12
21. Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a persistent Escherichia coli
reservoir during the acute phase of a bladder infection Infect Immun. 2001;69:4572–9
22. Justice SS, Hung C, Theriot JA, Fletcher DA, Anderson GG, Footer MJ, et al Differentiation and developmental pathways of uropathogenic Escherichia coli
in urinary tract pathogenesis Proc Natl Acad Sci U S A. 2004;101:1333–8
23. Mysorekar IU, Hultgren SJ. Mechanisms of uropathogenic Escherichia coli
persistence and eradication from the urinary tract Proc Natl Acad Sci U S A. 2006;103:14170–5
24. Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection
PLoS Med. 2007;4:e329
25. Schwartz DJ, Chen SL, Hultgren SJ, Seed PC. Population dynamics and niche distribution of uropathogenic Escherichia coli
during acute and chronic urinary tract infection
Infect Immun. 2011;79:4250–9
26. Conover MS, Hadjifrangiskou M, Palermo JJ, Hibbing ME, Dodson KW, Hultgren SJ. Metabolic requirements of Escherichia coli
in intracellular bacterial communities during urinary tract infection
pathogenesis MBio. 2016;7:e00104–16
27. Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions Br J Haematol. 2009;145:709–27
28. Abraham SN, Miao Y. The nature of immune responses to urinary tract infections Nat Rev Immunol. 2015;15:655–63
29. Hawn TR, Scholes D, Wang H, Li SS, Stapleton AE, Janer M, et al Genetic variation of the human urinary tract innate immune response and asymptomatic bacteriuria in women PLoS One. 2009;4:e8300
30. Hawn TR, Scholes D, Li SS, Wang H, Yang Y, Roberts PL, et al Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women PLoS One. 2009;4:e5990
31. Wu XR, Kong XP, Pellicer A, Kreibich G, Sun TT. Uroplakins in urothelial biology, function, and disease Kidney Int. 2009;75:1153–65
32. Ruggieri MR, Levin RM, Hanno PM, Witkowski BA, Gill HS, Steinhardt GF. Defective antiadherence activity of bladder extracts from patients with recurrent urinary tract infection
J Urol. 1988;140:157–9
33. Zhou G, Mo WJ, Sebbel P, Min G, Neubert TA, Glockshuber R, et al Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli
: Evidence from in vitro
FimH binding J Cell Sci. 2001;114(Pt 22):4095–103
34. Schlager TA, LeGallo R, Innes D, Hendley JO, Peters CA. B cell infiltration and lymphonodular hyperplasia in bladder submucosa of patients with persistent bacteriuria and recurrent urinary tract infections J Urol. 2011;186:2359–64
35. Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, et al Tamm-Horsfall protein knockout mice are more prone to urinary tract infection
: Rapid communication Kidney Int. 2004;65:791–7
36. Mo L, Zhu XH, Huang HY, Shapiro E, Hasty DL, Wu XR. Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli
Am J Physiol Renal Physiol. 2004;286:F795–802
37. Lose G, Sørensen K, Frandsen B, Nathan E. Excretion of urinary Tamm-Horsfall glycoprotein in girls with recurrent urinary tract infections Urol Res. 1987;15:249–50
38. Reinhart H, Obedeanu N, Hooton T, Stamm W, Sobel J. Urinary excretion of Tamm-Horsfall protein in women with recurrent urinary tract infections J Urol. 1990;144:1185–7
39. Reinhart HH, Spencer JR, Zaki NF, Sobel JD. Quantitation of urinary Tamm-Horsfall protein in children with urinary tract infection
Eur Urol. 1992;22:194–9
40. Liu HT, Jiang YH, Kuo HC. Alteration of urothelial inflammation, apoptosis, and junction protein in patients with various bladder conditions and storage bladder symptoms suggest common pathway involved in underlying pathophysiology Low Urin Tract Symptoms. 2015;7:102–7
41. Aydin A, Ahmed K, Zaman I, Khan MS, Dasgupta P. Recurrent urinary tract infections in women Int Urogynecol J. 2015;26:795–804
42. Truzzi JC, Almeida FM, Nunes EC, Sadi MV. Residual urinary volume and urinary tract infection
– When are they linked? J Urol. 2008;180:182–5
43. May M, Brookman-Amissah S, Hoschke B, Gilfrich C, Braun KP, Kendel F. Post-void residual urine as a predictor of urinary tract infection
– Is there a cutoff value in asymptomatic men? J Urol. 2009;181:2540–4
44. Stern JA, Hsieh YC, Schaeffer AJ. Residual urine in an elderly female population: Novel implications for oral estrogen replacement and impact on recurrent urinary tract infection
J Urol. 2004;171(2 Pt 1):768–70
45. Raz R, Gennesin Y, Wasser J, Stoler Z, Rosenfeld S, Rottensterich E, et al Recurrent urinary tract infections in postmenopausal women Clin Infect Dis. 2000;30:152–6
46. Salinas J, Virseda M, Méndez S, Menéndez P, Esteban M, Moreno J. Abdominal strength in voiding cystometry: A risk factor for recurrent urinary tract infections in women Int Urogynecol J. 2015;26:1861–5
47. Hooton TM, Stapleton AE, Roberts PL, Winter C, Scholes D, Bavendam T, et al Perineal anatomy and urine-voiding characteristics of young women with and without recurrent urinary tract infections Clin Infect Dis. 1999;29:1600–1
48. Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection
in young women J Infect Dis. 2000;182:1177–82
49. Adatto K, Doebele KG, Galland L, Granowetter L. Behavioral factors and urinary tract infection
50. Foxman B, Frerichs RR. Epidemiology of urinary tract infection
: II. Diet, clothing, and urination habits Am J Public Health. 1985;75:1314–7
51. Hunt JC, Waller G. Psychological factors in recurrent uncomplicated urinary tract infection
Br J Urol. 1992;69:460–4
52. Beetz R. Mild dehydration: A risk factor of urinary tract infection
? Eur J Clin Nutr. 2003;57(Suppl 2):52S–8S
53. Pfau A, Sacks T. The bacterial flora of the vaginal vestibule, urethra and vagina in premenopausal women with recurrent urinary tract infections J Urol. 1981;126:630–4
54. Gupta K, Stamm WE. Pathogenesis and management of recurrent urinary tract infections in women World J Urol. 1999;17:415–20
55. Hunt J, Waller G. The reliability of self-report of behaviours associated with recurrent urinary tract infection
Br J Urol. 1994;74:308–10
56. Suman E, Gopalkrishna Bhat K, Hegde BM. Bacterial adherence and immune response in recurrent urinary tract infection
Int J Gynaecol Obstet. 2001;75:263–8
57. Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ. Early severe inflammatory responses to uropathogenic E.coli predispose to chronic and recurrent urinary tract infection
PLoS Pathog. 2010;6:e1001042
58. Hannan TJ, Roberts PL, Riehl TE, van der Post S, Binkley JM, Schwartz DJ, et al Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis EBioMedicine. 2014;1:46–57
59. Fenner A. Infection: Potential protective role of raised PSA in recurrent UTI Nat Rev Urol. 2013;10:495
60. Townes CL, Ali A, Gross N, Pal D, Williamson S, Heer R, et al Prostate specific antigen enhances the innate defence of prostatic epithelium against Escherichia coli
infection Prostate. 2013;73:1529–37
61. Nseir W, Taha M, Nemarny H, Mograbi J. The association between serum levels of Vitamin D and recurrent urinary tract infections in premenopausal women Int J Infect Dis. 2013;17:e1121–4
62. Liu HT, Chen CY, Kuo HC. Urinary nerve growth factor in women with overactive bladder syndrome BJU Int. 2011;107:799–803
63. Chuang FC, Liu HT, Kuo HC. Lower levels of urinary nerve growth factor might predict recurrent urinary tract infections in women Int Neurourol J. 2016;20:33–9
64. Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): A new marker of kidney disease Scand J Clin Lab Invest Suppl. 2008;241:89–94
65. Forster CS, Johnson K, Patel V, Wax R, Rodig N, Barasch J, et al Urinary NGAL deficiency in recurrent urinary tract infections Pediatr Nephrol. 2017;32:1077–80
66. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli
to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries N Engl J Med. 1998;339:1085–6
67. Jepson RG, Mihaljevic L, Craig J. Cranberries for preventing urinary tract infections Cochrane Database Syst Rev. 2004;2:CD001321
68. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections Cochrane Database Syst Rev. 2012;10:CD001321
69. Juthani-Mehta M, Van Ness PH, Bianco L, Rink A, Rubeck S, Ginter S, et al Effect of cranberry capsules on bacteriuria plus pyuria among older women in nursing homes: A Randomized Clinical Trial JAMA. 2016;316:1879–87
70. Falagas ME, Betsi GI, Tokas T, Athanasiou S. Probiotics for prevention of recurrent urinary tract infections in women: A review of the evidence from microbiological and clinical studies Drugs. 2006;66:1253–61
71. Bruce AW, Reid G. Intravaginal instillation of lactobacilli for prevention of recurrent urinary tract infections Can J Microbiol. 1988;34:339–43
72. Stapleton AE, Au-Yeung M, Hooton TM, Fredricks DN, Roberts PL, Czaja CA, 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. 2011;52:1212–7
73. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus
GG drink for the prevention of urinary tract infections in women BMJ. 2001;322:1571
74. Kontiokari T, Laitinen J, Järvi L, Pokka T, Sundqvist K, Uhari M. Dietary factors protecting women from urinary tract infection
Am J Clin Nutr. 2003;77:600–4
75. Grin PM, Kowalewska PM, Alhazzan W, Fox-Robichaud AE. Lactobacillus
for preventing recurrent urinary tract infections in women: Meta-analysis Can J Urol. 2013;20:6607–14
76. Parsons CL, Schmidt JD. Control of recurrent lower urinary tract infection
in the postmenopausal woman J Urol. 1982;128:1224–6
77. Brandberg A, Mellström D, Samsioe G. Low dose oral estriol treatment in elderly women with urogenital infections Acta Obstet Gynecol Scand Suppl. 1987;140:33–8
78. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections N Engl J Med. 1993;329:753–6
79. 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 Obstet Gynecol. 1999;180:1072–9
80. Dueñas-Garcia OF, Sullivan G, Hall CD, Flynn MK, O'Dell K. Pharmacological agents to decrease new episodes of recurrent lower urinary tract infections in postmenopausal women. A systematic review Female Pelvic Med Reconstr Surg. 2016;22:63–9
81. Beerepoot MA, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G. Nonantibiotic prophylaxis for recurrent urinary tract infections: A systematic review and meta-analysis of randomized controlled trials J Urol. 2013;190:1981–9
82. Hicks HT. Pyelitis of pregnancy treated with coli vaccine Br Med J. 1909;1:203–4
83. Hektoen LI. Vaccine therapy: Result of a questionnaire to American physicians JAMA. 1929;92:864–9
84. Billips BK, Schaeffer AJ, Klumpp DJ. Molecular basis of uropathogenic Escherichia coli
evasion of the innate immune response in the bladder Infect Immun. 2008;76:3891–900
85. Uehling DT, Hopkins WJ, Dahmer LA, Balish E. Phase I clinical trial of vaginal mucosal immunization for recurrent urinary tract infection
J Urol. 1994;152(6 Pt 2):2308–11
86. Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections J Urol. 2003;170:867–9
87. Kochiashvili D, Khuskivadze A, Kochiashvili G, Koberidze G, Kvakhajelidze V. Role of the bacterial vaccine Solco-Urovac ® in treatment and prevention of recurrent urinary tract infections of bacterial origin Georgian Med News. 2014;231:11–6
88. Bauer HW, Alloussi S, Egger G, Blümlein HM, Cozma G, Schulman CCMulticenter UTI Study Group. . A long-term, multicenter, double-blind study of an Escherichia coli
extract (OM-89) in female patients with recurrent urinary tract infections Eur Urol. 2005;47:542–8
89. Hooton TM. Recurrent urinary tract infection
in women Int J Antimicrob Agents. 2001;17:259–68
90. Albert X, Huertas I, Pereiró II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection
in non-pregnant women Cochrane Database Syst Rev. 2004;3:CD001209
91. Lichtenberger P, Hooton TM. Antimicrobial prophylaxis in women with recurrent urinary tract infections Int J Antimicrob Agents. 2011;38(Suppl):36S–41S
92. Kodner CM, Thomas Gupton EK. Recurrent urinary tract infections in women: Diagnosis and management Am Fam Physician. 2010;82:638–43