Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial.

OBJECTIVE: To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6-month period in women ingesting cranberry vs placebo juice daily. PATIENTS AND METHODS: Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits. RESULTS: A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0.29 in the cranberry juice group and 0.37 in the placebo group (P=.82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0.68 (95% confidence interval, 0.33-1.39; P=.29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43.5%) in the cranberry juice group and 8 of 10 (80.0%) in the placebo group (P=.07). The mean dose adherence was 91.8% and 90.3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24.2% of those in the cranberry juice group and 12.5% in the placebo group (P=.07). CONCLUSION: Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128128.

Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.

BACKGROUND: Urinary tract infections (UTIs) are common among women and frequently recur. Depletion of vaginal lactobacilli is associated with UTI risk, which suggests that repletion may be beneficial. We conducted a double-blind placebo-controlled trial of a Lactobacillus crispatus intravaginal suppository probiotic (Lactin-V; Osel) for prevention of recurrent UTI in premenopausal women. METHODS: One hundred young women with a history of recurrent UTI received antimicrobials for acute UTI and then were randomized to receive either Lactin-V or placebo daily for 5 d, then once weekly for 10 weeks. Participants were followed up at 1 week and 10 weeks after intervention and for UTIs; urine samples for culture and vaginal swabs for real-time quantitative 16S ribosomal RNA gene polymerase chain reaction for L. crispatus were collected. RESULTS: Recurrent UTI occurred in 7/48 15% of women receiving Lactin-V compared with 13/48 27% of women receiving placebo (relative risk [RR], .5; 95% confidence interval, .2-1.2). High-level vaginal colonization with L. crispatus (≥10(6) 16S RNA gene copies per swab) throughout follow-up was associated with a significant reduction in recurrent UTI only for Lactin-V (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01). CONCLUSIONS: Lactin-V after treatment for cystitis is associated with a reduction in recurrent UTI. Larger efficacy trials of this novel preventive method for recurrent UTI are warranted. CLINICAL TRIALS REGISTRATION. NCT00305227.

Escherichia coli DraE adhesin-associated bacterial internalization by epithelial cells is promoted independently by decay-accelerating factor and carcinoembryonic antigen-related cell adhesion molecule binding and does not require the DraD invasin.

The Dr family of Escherichia coli adhesins are virulence factors associated with diarrhea and urinary tract infections. Dr fimbriae are comprised of two subunits. DraE/AfaE represents the major structural, antigenic, and adhesive subunit, which recognizes decay-accelerating factor (DAF) and carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) CEA, CEACAM1, CEACAM3, and CEACAM6 as binding receptors. The DraD/AfaD subunit caps fimbriae and has been implicated in the entry of Dr-fimbriated E. coli into host cells. In this study, we demonstrate that DAF or CEACAM receptors independently promote DraE-mediated internalization of E. coli by CHO cell transfectants expressing these receptors. We also found that DraE-positive recombinant bacteria adhere to and are internalized by primary human bladder epithelial cells which express DAF and CEACAMs. DraE-mediated bacterial internalization by bladder cells was inhibited by agents which disrupt lipid rafts, microtubules, and phosphatidylinositol 3-kinase (PI3K) activity. Immunofluorescence confocal microscopic examination of epithelial cells detected considerable recruitment of caveolin, beta(1) integrin, phosphorylated ezrin, phosphorylated PI3K, and tubulin, but not F-actin, by cell-associated bacteria. Finally, we demonstrate that the DraD subunit, previously implicated as an "invasin," is not required for beta(1) integrin recruitment or bacterial internalization.

Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women.

OBJECTIVES: We performed a phase I trial to assess the safety and tolerance of a Lactobacillus vaginal suppository for prevention of recurrent UTI. METHODS: Premenopausal women with a history of recurrent UTI were randomized to use L. crispatus CTV-05 or placebo vaginal suppositories daily for five days. RESULTS: 30 women were randomized (15 to L. crispatus CTV-05). No severe adverse events occurred. Mild to moderate vaginal discharge and genital irritation were reported by women in both study arms. Seven women randomized to L. crispatus CTV-05 developed pyuria without associated symptoms. Most women had high concentrations of vaginal H202-producing lactobacilli before randomization. L. crispatus, L. jensenii, and L. gasseri were the most common Lactobacillus species identified, with stable prevalence over time. CONCLUSIONS: L. crispatus CTV-05 can be given as a vaginal suppository with minimal sideeffects to healthy women with a history of recurrent UTI. Mild inflammation of the urinary tract was noted in some women.

Clonal analysis reveals high rate of structural mutations in fimbrial adhesins of extraintestinal pathogenic Escherichia coli.

Type 1 fimbriae of Escherichia coli mediate mannose-specific adhesion to host epithelial surfaces and consist of a major, antigenically variable pilin subunit, FimA, and a minor, structurally conserved adhesive subunit, FimH, located on the fimbrial tip. We have analysed the variability of fimA and fimH in strains of vaginal and other origin that belong to one of the most prominent clonal groups of extraintestinal pathogenic E. coli, comprised of O1:K1-, O2:K1- and O18:K1-based serotypes. Multiple locus sequence typing (MLST) of this group revealed that the strains have identical (at all but one nucleotide position) eight housekeeping loci around the genome and belong to the ST95 complex defined by the publicly available E. coli MLST database. Multiple highly diverse fimA alleles have been introduced into the ST95 clonal complex via horizontal transfer, at a frequency comparable to that of genes defining the major O- and H-antigens. However, no further significant FimA diversification has occurred via point mutation after the transfers. In contrast, while fimH alleles also move horizontally (along with the fimA loci), they acquire point amino acid replacements at a higher rate than either housekeeping genes or fimA. These FimH mutations enhance binding to monomannose receptors and bacterial tropism for human vaginal epithelium. A similar pattern of rapid within-clonal structural evolution of the adhesive, but not pilin, subunit is also seen, respectively, in papG and papA alleles of the di-galactose-specific P-fimbriae. Thus, while structurally diverse pilin subunits of E. coli fimbriae are under selective pressure for frequent horizontal transfer between clones, the adhesive subunits of extraintestinal E. coli are under strong positive selection (Dn/Ds > 1 for fimH and papG) for functionally adaptive amino acid replacements.