Urinary tract infections (UTI) are among the most common bacterial infections in humans. Approximately 50%-60% of adult women experience a UTI during their lifetime. Furthermore, a significant number of patients can be characterized as having recurrent UTIs if they meet the criteria of ≥2 uncomplicated UTIs in 6 months or ≥3 positive cultures within the preceding 12 months. Applying this definition, it is estimated that recurrent UTIs affect 25% of women with a history of UTI.
E. coli represents the main causative pathogen in recurrent UTI and is responsible for approximately 80% of all episodes of infection. Further important pathogens include Proteus mirabilis, Staphylococcus saprophyticus, and Klebsiella pneumonia.
Symptomatic UTIs cause significant discomfort such as dysuria, polyuria, and suprapubic tenderness. If left untreated, a UTI can progress to acute pyelonephritis with the risk of permanent renal scarring and loss of renal function.
Patients with recurrent urinary tract infections undergo frequent antibiotic treatment and/or low-dose antibiotic prophylaxis. Additionally, a subset of patients is required to undergo a systematic radiological and endoscopic evaluation of the urinary tract in order to rule out any underlying structural abnormalities or urinary calculi. The immense use of antibiotics for the treatment of urinary tract infections has resulted in the development of considerable bacterial resistance and therefore, increasing difficulties in eradicating infections. Due to the development of bacterial resistance, UTIs are a substantial economic burden and a noteworthy public health issue. Therefore, new treatment strategies and preventive measures against UTIs such as immune-stimulation/modulation, vaccine development, the use of probiotics, and the instillation of attenuated bacteria into the urinary bladder are currently being researched.
This chapter will review the most recent literature and provide up-to-date information on developments in immune-based treatment strategies for patients with recurrent UTIs from a pre-clinical and clinical point of view.
2. Material and methods
To identify all relevant materials, comprehensive literature searches were performed via the data sources: MEDLINE, EMBASE, CINAHL and OVID using the key words: urinary tract infection, urine culture, UTI, vaccines, adherence, fimbriae, biofilms, probiotics. Relevant articles and references between 1970 and 2012 were reviewed and analyzed. Reference lists from relevant review articles were also searched. Only articles published as formal papers in peer-reviewed journals were selected for inclusion if they reported findings of interest. The data base searches resulted in 710 articles, of which 75 of 710 pertained directly to immune-based treatment strategies. The entirety of these articles was reviewed, forming the basis for the current review.
Plant-derived therapies have long been used in Ayurvedic and traditional Chinese medicine (Wollenweber, 1988). The interest in plant antimicrobials for treatment or prevention of UTIs has been driven both by the prevalence of antibiotic-resistant uropathogens and growing popularity of complementary and alternative medicine. Still, little evidence exists for the effectiveness of these treatments and therapeutic dose requirements. More than 5000 plant polyphenols have been identified so far. The spectrum of biological effects include anti-microbiol, anti-inflammatory and anti-carcinogenic activities (Beretz et al., 1978). Plant derived extracts contain different chemical compounds with multiple antimicrobial activities (Burt, 2004). The most studied species include cranberry, berberine, blueberry, bearberry, and certain herbs such as cinnamon. According to Ohno et al., the potential for bacteria to develop resistance to plant derived anti-microbials is relatively small (Ohno et al., 2003).
Cranberry, Vaccinium macrocapron, is the best known and most studied plant-derived therapy for UTIs (Seeram, 2008). Historically its antimicrobial effects were believed to be due increased excretion of hippuric acid and urinary acidification, although this was disproved in the 1950’s (Bodel et al., 1959). More recent studies have proved Cranberry compounds fructose and proanthocyanidin to inhibit E. Coli adhesins
Berberine sulfate is an alkaloid found in the Berberine arisata plant, as well as the roots of Oregon Grape (Mahonia aquifolium), Goldenseal (hydrastis canadensis), and Goldenthread (Coptis chinesis). It is present in the root, rhizome, and stem bark of the plants (Yarnell, 2002). Head et al. could show that berberine extracts are effective against a variety of organisms, including bacteria, viruses, fungi, and protozoans (Head, 2008). Growth inhibitory effects were described for several bacterial pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa,, E. coli, Bacillus subtilis and Chlamydia (Cernakova &Kostalova, 2002, Head, 2008, Scazzocchio et al., 2001). In one study berberine was found to decrease synthesis and expression of E. Coli Pap fimbriae, thus decreasing bacterial adhesion to epithelia
Blueberry, part of the Vaccinium genus, is closely related to cranberry. Studies suggest that high molecular weight pranthocyanidins found in wild blueberry inhibit E. Coli adhesion
Bearberry, Arcystaphylos uva-ursi, is a member of the Ericaceae family, as are cranberry and blueberry. The glycoside arbutin is the main constituent of bearberry leaves and dried preparation. Arbutin is metabolized into hydroquinone, which has a urinary availability of approximately 65% of the administered arbutin dose (Schindler et al., 2002). Hydroquinone is an antimicrobial according to
Currently, bearberry is used in Germany to cure mild UTI, defined as asymptomatic or bacteriuria less than 105 colony-forming units/mL (Schindler et al., 2002). It is not, however, recommended for long-term prevention due to concern of hydroquinone carcinogenic effects (DeCaprio, 1999).
Trans-cinnamaldehyde is an extract of the bark of cinnamon (Adams et al., 2004). It has a wide margin of safety between conservative estimates of intake and no observed adverse effects (Adams et al., 2004).
These results justify further pre-clinical studies and make trans-cinnamaldehyde a potential candidate for use as an antimicrobial agent for controlling UTIs.
The existing literature lists many other herbs for the treatment of UTIs, while most of them lack a scientific basis for this purpose. They include Taraxacum officinalis leaf (dandelion), Juniperus communis (juniper), Hydrangea aborescens (hydrangea), Agrimonia eupatoria (agrimony), Elymus repens (couchgrass), Althea officinalis (marshmallow), Zea mays (corn silk), Apium graveolens (celery seed), Ulmus fulva (slippery elm), Arctium lappa (burdock), and Mentha piperita (peppermint). For others some scientific background exists. Extracts from Salvia officinalis (Garden sage or common sage) has been shown to be active against Klebsiella, Enterobacter species, UPEC, Proteus mirabilis and Morganella morganii obtained from the urine samples from patients with UTIs (Pereira et al., 2004).
Another potentially useful herb is Barosma betulina (bachu). It has been used in the treatment of UTI and urethritis for a long time. It was found to have anti-microbial effects against uropathogens
3.2. Vaginal probiotics/lactobacilli
Studies could demonstrate that Lactobacilllus species in the form of probiotics reduced the risk of UTIs and vaginal infections (Bruce &Reid, 2003, Reid et al.,1985). However, despite ongoing research the mechanisms are poorly understood (Spiegel et al., 1980). In the literature were different mode of action proposed including downregulation of pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha) (Anukam et al., 2009), production of hydrogen peroxide, which protects against the UPEC (Czaja et al., 2007) production of a 29-kDa biosurfactant proteins which inhibits bacterial adhesion (Osset et al., 2001, Xia et al., 2006). Some of the commensal bacteria such as Lactobacillus species and Bifidobacteria species are known to produce immunoregulatory factors that modulate the immune response and may therefore decrease UTIs (Wilson et al., 1998). From a clinical standpoint, there is a close correlation between loss of the normal genital microbiota, particularly Lactobacillus species, and an increased incidence of genital and bladder infections. Vaginal colonization with Lactobacillus spp. was found to prevent recurrent UTIs (Bruce &Reid, 1988, Reid et al., 1992). A Phase I clinical trial assessed the safety of the use of vaginal Lactobacillus suppositories to prevent recurrent (Czaja et al., 2007). Reid et al. investigated in a randomized study the role of probiotic lactobacilli in controlling re-infection in women after treatment of an acute UTI (Reid et al., 1992). 235 patients were treated with antibiotics for three days. Recurrence occurred in 41% of the patients. Individuals with recurrence were randomly assigned to Lactobacillus suppositories treatment group or placebo suppository group. Treatment was given twice weekly for two weeks, then once a month for the next two months. The recurrence rate was 21% in the Lactobacillus group compared to 47% in the placebo group. Oral use of Lactobacilli was also investigated. Reid et al. demonstrated L. rhamonosus GR-1 and L. fermentum RC-14 taken orally lead to colonization of vaginal epithelium within one week. In pediatric patients the oral intake of L. rhamnosus GG resulted in a reduction in UTI incidence rate compared to the placebo group (Dani et al., 2002). These results are promising and warrant further pre-clinical and clinical studies for the use of probiotics in controlling UTIs.
Currently, low-dose antibiotic treatment has been the most effective prophylaxis for the prevention of recurrent UTI. However, cessation of antibiotic treatment usually results in recurrence of infection in most patients (Ha &Cho, 2008). Furthermore, with the number of antibiotic resistant strains of uropathogenic bacteria causing recurrent UTI on the rise, a substantial amount of research in alternative treatment modalities such as immuno-stimulation and attenuated vaccines is being performed. The target of such modalities consists of the Mucosa-Associated Lymphoid Tissue (MALT) lining much of the GI, respiratory, and genitourinary tract, the activation of specific receptors on dendritic cells within the genitourinary tract, and increasing the concentration bacteria-specific immunoglobulins (Ha &Cho, 2008). The objective of such therapies is to reduce the frequency and severity of UTI as well as reduce the consumption of antibiotics used to treat them.
Uro-Vaxom® (OM-89) is an extract of 18 strains of E. coli that is obtained by alkaline lysis, which destroys lipopolysaccharide (LPS) molecules produced by the gram negative bacteria and modifies other bacterial antigens, maintaining their antigenic potential (Ha &Cho, 2008). Taken orally, Uro-Vaxom® achieves immuno-stimulation by increasing the proliferation of Mucosal Associated Lymphoid Tissue (MALT) within the GI tract leading to elevated concentrations of bacteria-specific IgG, mucosal-derived IgA along with serum IgA. Furthermore, OM-89 increases the rate of dendritic cell maturation within the genitourinary tract, leading to increased numbers of circulating memory T-cells as well as an overall increase in inflammatory mediators such as TNF-alpha, IL-2, and IL-6 (Bessler et al., 2009). Treatment studies of sexually active females between the age of 20 and 50 shows that Uro-Vaxom® reduces the recurrence of UTI by 36% after 6 months of therapy compared to placebo (Bessler et al., 2009).
Solco Urovac, which is currently under phase 2 clinical trials, is a treatment modality that utilizes the vaginal mucosa via suppository to induce an immune response. The Solco Urovac vaccine consists of 6 E. coli strains along with several recombinant antigenic factors such as fimbriae proteins and 1 strain each of Proteus mirabilis, Morganella morganii, Klebsiella pneumonia, and Enterococcus faecalis (Hopkins et al., 2007). SolcoUrovac works in a similar manner to that of OM-89, however it achieves a higher overall mucosal concentration of IgA in the vagina and bladder. One characteristic of SolcoUrovac is that it must be administered on a booster schedule or else the maximum efficacy will not be achieved. The overall reduction of UTIs in female patients between the age of late teens to early 70s treated with SolcoUrovac plus multiple boosters was measured to be 46.0% (Hopkins et al., 2007).
Siderophores, such as the IroN-cell surface protein found on most strains of E. Coli, are potential targets for immune-therapy. A significant systemic-compartment IroN IgG-specific antibody response developed in serum. However, there was no IroN IgA-specific antibody response in either the systemic or the mucosal compartment. Subcutaneous immunization with denatured IroN resulted in a significant IroN immunoglobulin G (IgG)-specific response in serum but not a systemic or mucosal IroN-specific IgA response (Russo et al., 2003).
3.4. Inhibition of bacterial adhesion
UPEC strains express a number of virulence factors used for colonization of their host. One important virulence factor is located on type 1 pili, allowing UPEC to adhere and invade host cells within the urinary tract. FimH interactions with several host factors have been documented. These include components of the glycocalyx that sparsely covers the bladder surface, carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family members, soluble Tamm-Horsfall protein, the glycosylphosphatidylinositol (GPI)-anchored protein CD48, the leukocyte adhesion molecules CD11 and CD18, and uroplakin 1a (Klein et al.). Adherence to mannose residues prevents the rapid clearance of E. coli from the urinary tract by the flow of urine and enables the invasion of the host cells (Wellens et al., 2008). The binding of type one pili to bladder epithelial cells activates the innate immune system via the Toll-like receptor 4 pathway which recruits neutrophils and other inflammatory mediators to the site of insult (Wellens et al., 2008). Next, the complement system opsonizes the UPEC and counter intuitively facilitates invasion of the bacteria into the epithelial cell.
Type 1 pili are the most prevalent fimbriae encoded by UPEC, consisting of the four subunits FimA, FimF, FimG, and FimH, the latter located at the tip of the pili (Wellens et al., 2008). The FimH moiety, which is the primarily subunit responsible for the initiation of bacterial adherence and invasion, is a prime target of immune-stimulation. Experiments done in mice have shown that both direct inoculation with immunogloblins against FimH, innoculation with synthetic peptides within the binding moiety for FimH, or gene knock-out of FimH could specifically block type 1 fimbriae-mediated bacterial adherence to bladder epithelial cells resulting in a dramatic loss of virulence(Thankavel et al., 1997). In experiments that utilized synthetic peptides to induce an immune response, dramatic increases in serum IgG and IgM were observed via ELISA (Thankavel et al., 1997). In addition, urine collections showed a marked increase in IgG and mucosal derived IgA along with elevated activity of mast cells within the bladder epithelium when faced with a bacterial challenge (Thankavel et al., 1997).
3.5. Inhibition of bacterial biofilms
Catheter–associated urinary tract infections are common and often related to the existence of bacterial bio-films. Progress in this area is limited. Preventive strategies include avoiding unnecessary catheterization, limit duration of catheterization, using closed drainage system, and appropriate hygiene, including frequent catheter changes and emptying of the drainage bags (Jacobsen et al., 2008, Newman, 1998). Many mechanisms of biofilm resistance against antibiotic treatment were reported over the years. The most important type of the biofilm resistance is the development of a diffusion barrier formed by the bio-film matrix (Ishida et al., 1998). The biofilm prevents access of antimicrobial agents and even of antibodies. Despite the antibiotic treatment, the infection often persists until the device is removed (Schierholz &Beuth, 2001). Over the last 2 decades different coatings were explored to reduce the risk of bacterial bio-film formation and bacterial colonization and subsequently infection. Coating substances included various antibiotics, silvercoating and others. Infections could not be prevented, however the “abacterial window” could be prolonged. Schaeffer et al. demonstrated that in patients with acute spinal cord injury, who received long-term urinary catheters, the silver-coated catheters delayed but did not prevent the onset of bacteriuria (Schaeffer et al., 1988). The same findings were reported for antibiotic impregnation of catheters (Darouiche et al., 1999, Guay, 2001, Johnson et al., 1999). These findings are important for short-term use of urinary catheters but not for long-term use (Trautner &Darouiche, 2004). Several other substances were reported to inhibit development of bacterial bio-film formation including type A proanthocyanidins, hesperidin, apigenin,naringin and rhoifolina, and others. None of these substances made it into clinical trials so far.
3.6. Stimulation of cyclic adenosine/forskolin
One important survival mechanism of UPEC is the creation of an intracellular reservoir. Within the epithelial cell, the UPEC are able to resist antibiotic treatment by binding to Rab 27 b/CD 63 positive vesicles. Forskolin, the active component of the Coleus forskohlii, has been proven to increase the content of cyclical adenosine monophosphate (cAMP) in urothelial cells, leading uropathogenic bacteria to exit the urothelial cells. It was shown that cAMP levels regulate the exocytosis of these vesicles depending on the bladder distension. These findings could lead to new approaches for the treatment and prevention of recurrent urinary tract infections (Bishop et al., 2007, Gonzalez-Chamorro et al.).
3.7. Hormone therapy
Hormonal deficiency in postmenopausal women results in thinning of the vaginal and urethral mucosa and more importantly to disruption of the normal vaginal flora and therefore to an increased risk for UTIs (Head, 2008). Several studies could demonstrate, that replacing estrogene in this patient population can reduce the incidence of UTIs.
In a randomized study postmenopausal women received either intra-vaginally administered estradiol or placebo. At the end of the study a significant reduction in the incidence of UTIs in the treatment group compared to the placebo group was noted. Of interest is also the observation that Lactobacilli that were absent in the vaginal cultures of patients of the treatment group at the beginning of the trial reappeared in 61% (Raz &Stamm, 1993).
3.8. Instillation of attenuated bacteria into the urinary bladder
Darouiche et al. conducted a prospective, randomized, placebo-controlled, double-blind pilot trial to examine the efficacy of bacterial interference in preventing urinary tract infection (Darouiche et al., 2005). In this study 27 patients with spinal cord injury were included. Patients were randomly assigned either to have their bladders inoculated with either E. coli 83972 (experimental group) or sterile normal saline (control group). Patients whose bladders became colonized with E. coli 83972 were half as likely (P=.01) than non-colonized patients to develop UTI during the subsequent year.
Billips et al. demonstrated recently that deletion of the O antigen ligase gene, waaL, from the uropathogenic E. coli isolate NU14 results in a strain that stimulates enhanced urothelial cytokine secretion (Billips et al., 2009). They could show that NU14 DwaaL stimulated an enhanced interleukin-6 secretion by mouse macrophages, compared with secretion by the wild type. Of great importance is the fact that mice vaccinated via instillation into the bladder developed protective responses that prevented persistent colonization after bladder challenge with NU14, yet NU14 DwaaL failed to persistently colonize the mouse bladder. They could also show that the mice were additionally protected against challenge with a broad range of clinical UPEC isolates and developed immunity that lasted more than 8 weeks (Billips et al., 2009). These findings open a new avenue for future treatment strategies of recurrent urinary tract infection by caused by UPEC.
Immune-based treatment strategies for patients with recurrent UTIs are of special interest. Several promising new approaches including bladder colonization with attenuated bacteria and intravesical vaccination were published recently and discussed in this chapter. Furthermore, studies suggest that the use of inhibitors of bacterial adherence to urothelial cell and inhibitors of biofilm formation receptors hold great promise. Moreover, stimulators of cyclic AMP inside urothelial cells and the recent advancements in the development of vaccines are an interesting initiative in this field. For some of the plant –based prevention and treatment strategies only little scientific evidence for the prevention and treatment of urinary tract infection exist.
We would like to thank the library staff from Texas Tech University Health Sciences Center, Lubbock for their extraordinary support and assistance. On a special note, we would like to thank again Carrie Gassett who showed great interest and support in our project.
Adams T. B. et al. 2004 The FEMA GRAS assessment of cinnamyl derivatives used as flavor ingredients.Food Chem Toxicol, 42 2Feb 2004), 157 185Print)
Amalaradjou M. A. Narayanan A. . Venkitanarayanan K. Trans-cinnamaldehyde decreases attachment and invasion of uropathogenic Escherichia coli in urinary tract epithelial cells by modulating virulence gene expressionJ Urol, 185 4Apr 1526 1531Electronic)
Anukam K. C. et al. 2009 Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 may help downregulate TNF-Alpha, IL-6, IL-8, IL-10 and IL-12 (p70) in the neurogenic bladder of spinal cord injured patient with urinary tract infections: a two-case studyAdv Urol, Vol. 2009 680363Print)
Avorn J. et al. 1994 Reduction of bacteriuria and pyuria after ingestion of cranberry juice.Jama, 271 10Mar 9 1994), 751 754Print)
Beaux D. Fleurentin J. . Mortier F. 1999 Effect of extracts of Orthosiphon stamineus Benth, Hieracium pilosella L., Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in ratsPhytother Res, 13 3May 1999), 222 225X (Print)
Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med, Beerepoot M. A. et al. 171 14Jul 25 1270 1278Electronic)
Beretz A. Anton R. . Stoclet J. C. 1978 Flavonoid compounds are potent inhibitors of cyclic AMP phosphodiesterase. 34 8Aug 15 1978), 1054 1055Print)
Bessler W. G. et al. 2009 Immunomodulating effects of OM-89, a bacterial extract from Escherichia coli, in murine and human leukocytesArzneimittelforschung, 59 11 571 577Print)
Billips B. K. et al. 2009 A live-attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli.J Infect Dis, 200 2Jul 15 2009), 263 272Print)
Bishop B. L. et al. 2007 Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells.Nat Med, 13 5May 2007), 625 630Print)
Bodel P. T. Cotran R. . Kass E. H. 1959 Cranberry juice and the antibacterial action of hippuric acid.J Lab Clin Med, 54No. (Dec 1959), 881 888Print)
Bruce A. W. . Reid G. 1988 Intravaginal instillation of lactobacilli for prevention of recurrent urinary tract infections.Can J Microbiol, 34 3Mar 1988), 339 343
Bruce A. W. . Reid G. 2003 Probiotics and the urologist.Can J Urol, 10 2Apr 2003), 1785 1789
Burt S. 2004 Essential oils: their antibacterial properties and potential applications in foods--a review.Int J Food Microbiol, 94 3Aug 1 2004), 223 253Print)
Cernakova M. . Kostalova D. 2002 Antimicrobial activity of berberine--a constituent of Mahonia aquifolium.Folia Microbiol (Praha), 47 4 375 378Print)
Czaja C. A. et al. 2007 Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in womenInfect Dis Obstet Gynecol, 2007 2007 35387
Dani C. et al. 2002 Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infantsA prospective double-blind study. Biol Neonate, 82 2Aug 2002), 103 108
Darouiche R. O. et al. 1999 Efficacy of antimicrobial-impregnated bladder catheters in reducing catheter-associated bacteriuria: a prospective, randomized, multicenter clinical trial. 54 6Dec 1999), 976 981Electronic)
Darouiche R. O. et al. 2005 Bacterial interference for prevention of urinary tract infection: a prospective, randomized, placebo-controlled, double-blind pilot trial.Clin Infect Dis, 41 10Nov 15 2005), 1531 1534Electronic)
De Caprio A. P. 1999 The toxicology of hydroquinone--relevance to occupational and environmental exposure.Crit Rev Toxicol, 29 3May 1999), 283 330Print)
Domadia P. N. et al. 2008 Berberine targets assembly of Escherichia coli cell division protein FtsZ 47 10Mar 11 2008), 3225 3234Print)
Frohne D. 1970The urinary disinfectant effect of extract from leaves uva ursi]. Planta Med, 18 1Jan 1970), 1 25Print)
Gill, A O &Holley, R A. 2006Disruption of Escherichia coli, Listeria monocytogenes and Lactobacillus sakei cellular membranes by plant oil aromatics. Int J Food Microbiol, 108 1Apr 15 2006), 1 9Print)
Urinary tract infections and their prevention]. Actas Urol Esp, Gonzalez-Chamorro F. et al. [. 36 1Jan 48 53Electronic)
Guay D. R. 2009Cranberry and urinary tract infections. Drugs, 69 7 775 807Print)
Guay D. R. 2001An update on the role of nitrofurans in the management of urinary tract infections. Drugs, 61 3 353 364Print)
Ha, U S &Cho, Y H. 2008Immunostimulation with Escherichia coli extract: prevention of recurrent urinary tract infections. Int J Antimicrob Agents, 31Suppl 1, No. (Feb 2008), S63 S67Print)
Head K. A. 2008Natural approaches to prevention and treatment of infections of the lower urinary tract. Altern Med Rev, 13 3Sep 2008), 227 244Print)
Hopkins W. J. et al. 2007Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol, 177 4Apr 2007), 1349 1353quiz 1591, 0022-5347 (Print)
Howell A. B. et al. 2005A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry, 66 18Sep 2005), 2281 2291Print)
Ishida H. et al. 1998In vitro and in vivo activities of levofloxacin against biofilm-producing Pseudomonas aeruginosa. Antimicrob Agents Chemother, 42 7Jul 1998), 1641 1645Print)
Jacobsen S. M. et al. 2008Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis. Clin Microbiol Rev, 21 1Jan 2008), 26 59Electronic)
Jepson, R G &Craig, J C. 2008Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev, Vol. 1 CD001321X (Electronic)
Jepson R. G. Mihaljevic L. . Craig J. 2000Cranberries for treating urinary tract infections. Cochrane Database Syst Rev, Vol. 2 CD001322X (Electronic)
Johnson J. R. Delavari P. . Azar M. 1999Activities of a nitrofurazone-containing urinary catheter and a silver hydrogel catheter against multidrug-resistant bacteria characteristic of catheter-associated urinary tract infection. Antimicrob Agents Chemother, 43 12Dec 1999), 2990 2995Print)
Klein, T et al. FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. J Med Chem, Vol. 53, No. 24, (Dec 23 pp. 8627-8641, 1520-4804 (Electronic)
Kontiokari T. et al. 2001Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. Bmj, 322 7302Jun 30 2001), 1571Print)
Kubo M. et al. 1990Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. I. Combined effect of 50% methanolic extract from Arctostaphylos uva-ursi (L.) Spreng. (bearberry leaf) and prednisolone on immuno-inflammation]. Yakugaku Zasshi, 110 1Jan 1990), 59 67Print)
Lavigne J. P. et al. 2008In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules. Clin Microbiol Infect, 14 4Apr 2008), 350 355X (Print)
Liu Y. et al. 2006Role of cranberry juice on molecular-scale surface characteristics and adhesion behavior of Escherichia coli. Biotechnol Bioeng, 93 2Feb 5 2006), 297 305Print)
Mac Micking. J. Xie Q. W. . Nathan C. 1997Nitric oxide and macrophage function. Annu Rev Immunol, 15 1997 323 350Print)
Newman D. K. 1998Managing indwelling urethral catheters. Ostomy Wound Manage, 44 12Dec 1998), 26 28passim, 0889-5899 (Print)
Ofek I. Goldhar J. . Sharon N. 1996Anti-Escherichia coli adhesin activity of cranberry and blueberry juices. Adv Exp Med Biol, 408 1996 179 183Print)
Ofek I. et al. 1991Anti-Escherichia coli adhesin activity of cranberry and blueberry juices. N Engl J Med, 324 22May 30 1991), 1599Print)
Ohnishi R. et al. 2006Urinary excretion of anthocyanins in humans after cranberry juice ingestion. Biosci Biotechnol Biochem, 70 7Jul 2006), 1681 1687Print)
Ohno T. et al. 2003Antimicrobial activity of essential oils against Helicobacter pylori. Helicobacter, 8 3Jun 2003), 207 215Print)
Osset J. et al. 2001Assessment of the capacity of Lactobacillus to inhibit the growth of uropathogens and block their adhesion to vaginal epithelial cells. J Infect Dis, 183 3Feb 1 2001), 485 491
Pereira R. S. et al. 2004Antibacterial activity of essential oils on microorganisms isolated from urinary tract infection]. Rev Saude Publica, 38 2Apr 2004), 326 328
Perez-Lopez F. R. Haya J. . Chedraui P. 2009Vaccinium macrocarpon: an interesting option for women with recurrent urinary tract infections and other health benefits. J Obstet Gynaecol Res, 35 4Aug 2009), 630 639Print)
Raz R. Chazan B. . Dan M. 2004Cranberry juice and urinary tract infection. Clin Infect Dis, 38 10May 15 2004), 1413 1419Electronic)
Raz R. . Stamm W. E. 1993A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med, 329 11Sep 9 1993), 753 756Print)
Reid G. Bruce A. W. . Taylor M. 1992Influence of three-day antimicrobial therapy and lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clin Ther, 14 1Jan-Feb 1992), 11 16
Reid G. et al. 1985Prevention of urinary tract infection in rats with an indigenous Lactobacillus casei strain. Infect Immun, 49 2Aug 1985), 320 324
Russo T. A. et al. 2003The Siderophore receptor IroN of extraintestinal pathogenic Escherichia coli is a potential vaccine candidate. Infect Immun, 71 12Dec 2003), 7164 7169Print)
Scazzocchio F. et al. 2001Antibacterial activity of Hydrastis canadensis extract and its major isolated alkaloids. Planta Med, 67 6Aug 2001), 561 564Print)
Schaeffer A. J. Story K. O. . Johnson S. M. 1988Effect of silver oxide/trichloroisocyanuric acid antimicrobial urinary drainage system on catheter-associated bacteriuria. J Urol, 139 1Jan 1988), 69 73Print)
Schierholz J. M. . Beuth J. 2001Implant infections: a haven for opportunistic bacteria. J Hosp Infect, 49 2Oct 2001), 87 93Print)
Schindler G. et al. 2002Urinary excretion and metabolism of arbutin after oral administration of Arctostaphylos uvae ursi extract as film-coated tablets and aqueous solution in healthy humans. J Clin Pharmacol, 42 8Aug 2002), 920 927Print)
Schmidt B. M. et al. 2004Effective separation of potent antiproliferation and antiadhesion components from wild blueberry (Vaccinium angustifolium Ait.) fruits. J Agric Food Chem, 52 21Oct 20 2004), 6433 6442Print)
Seeram N. P. 2008Berry fruits for cancer prevention: current status and future prospects. J Agric Food Chem, 56 3Feb 13 2008), 630 635Print)
Sikkema J;de. Bont J. A. . Poolman B. 1994Interactions of cyclic hydrocarbons with biological membranes. J Biol Chem, 269 11Mar 18 1994), 8022 8028Print)
Simpson D. 1998Buchu--South Africa’s amazing herbal remedy. Scott Med J, 43 6Dec 1998), 189 191
Smith-Palmer A. Stewartt J. . Fyfe L. 2002Inhibition of listeriolysin O and phosphatidylcholine-specific production in Listeria monocytogenes by subinhibitory concentrations of plant essential oils. J Med Microbiol, 51 7Jul 2002), 567 574
Spiegel C. A. et al. 1980Anaerobic bacteria in nonspecific vaginitis. N Engl J Med, 303 11Sep 11 1980), 601 607
Stothers L. 2002A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol, 9 3Jun 2002), 1558 1562Print)
Sun D. Abraham S. N. . Beachey E. H. 1988Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli. Antimicrob Agents Chemother, 32 8Aug 1988), 1274 1277Print)
Sun D. Courtney H. S. . Beachey E. H. 1988Berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells, fibronectin, and hexadecane. Antimicrob Agents Chemother, 32 9Sep 1988), 1370 1374Print)
Thankavel K. et al. 1997Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection. J Clin Invest, 100 5Sep 1 1997), 1123 1136Print)
Trautner, B W &Darouiche, R O. 2004Catheter-associated infections: pathogenesis affects prevention. Arch Intern Med, 164 8Apr 26 2004), 842 850Print)
Turi M. et al. 1997Influence of aqueous extracts of medicinal plants on surface hydrophobicity of Escherichia coli strains of different origin. Apmis, 105 12Dec 1997), 956 962Print)
Wellens A. et al. 2008Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. PLoS One, 3 4 e2040Electronic)
Wilson M. Seymour R. . Henderson B. 1998Bacterial perturbation of cytokine networks. Infect Immun, 66 6Jun 1998), 2401 2409
Wollenweber E. 1988Occurrence of flavonoid aglycones in medicinal plants. Prog Clin Biol Res, 280 1988 45 55Print)
Xia Y. Yamagata K. . Krukoff T. L. 2006Differential expression of the CD14/TLR4 complex and inflammatory signaling molecules following i.c.v. administration of LPS. Brain Res, 1095 1Jun 20 2006), 85 95
Yarnell E. 2002Botanical medicines for the urinary tract. World J Urol, 20 5Nov 2002), 285 293Print)