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Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

ABSTRACT: Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small-molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium. Here, we optimized these compounds for oral bioavailability and demonstrated their fast-acting efficacy in treating chronic urinary tract infections in a preclinical murine model. These compounds also prevented infection in vivo when given prophylactically and strongly potentiated the activity of the current standard of care therapy, trimethoprim-sulfamethoxazole, against clinically resistant PBC-1 UPEC bacteria. These compounds have therapeutic efficacy after oral administration for the treatment of established urinary tract infections in vivo. Their unique mechanism of action-targeting the pilus tip adhesin FimH-circumvents the conventional requirement for drug penetration of the outer membrane, minimizing the potential for the development of resistance. The small-molecular weight compounds described herein promise to provide substantial benefit to women suffering from chronic and recurrent urinary tract infections.

SUBMITTER: Cusumano CK

PROVIDER: S-EPMC3694776 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

Cusumano Corinne K CK Pinkner Jerome S JS Han Zhenfu Z Greene Sarah E SE Ford Bradley A BA Crowley Jan R JR Henderson Jeffrey P JP Janetka James W JW Hultgren Scott J SJ

Science translational medicine 20111101 109

Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small-molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, wh ...[more]

PMID: 22089451

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Project description:BackgroundThe guideline on urinary tract infections (UTI) of the Dutch College of General Practitioners provides recommendations on patient-initiated treatment and prevention of recurring UTI.AimTo study familiarity with self-management skills for prevention of recurring UTI amongst adult women.Design and settingsAn online questionnaire was developed, based on the UTI guideline and interviews with women having recurring UTI. Pharmacists in a postgraduate education programme (N = 76) aimed to invite 10 adult women with a recurring UTI prescription to complete the questionnaire. Women were asked for informed consent to link medication record data to questionnaire data.MethodWe calculated proportions of the scores for self-management skills and analysed differences between age groups with chi-square test.ResultsComplete questionnaires were available for 719 women (mean age 55.1 ± 18.5 years). The proportions of women 18-50 years and women 51 years or older were 36.4% and 63.6%, respectively. Education levels of women 18-50 years were significantly higher than those of women 51 years and older. Before consulting a general practitioner (GP) for symptoms, 32.1% of all women increased fluid intake; additionally, 15.0% used analgesics and increased fluid intake. Of all women, 33.9% searched internet for information on self-management and 18% occasionally received a prescription for patient-initiated treatment, half of these prescriptions for use during vacation. Cranberry was used by 47%, d-mannose by 5% and vitamin C by 29% of all women. Awareness of different preventive behavioural measures (eg, fluid intake, washing without soap and emptying bladder after sexual intercourse) varied between 20% and 90%.ConclusionAlmost half of all women applied self-management (increased fluid intake, analgesics) before consulting a GP for recurring UTI. Awareness of preventive behavioural measures for recurring UTI varied considerably. Thus, education of women about the use of analgesics and behavioural measures deserves attention.

Project description:ImportanceRecurrent urinary tract infection (UTI) is a common debilitating condition in women, with limited prophylactic options. d-Mannose has shown promise in trials based in secondary care, but effectiveness in placebo-controlled studies and community settings has not been established.ObjectiveTo determine whether d-mannose taken for 6 months reduces the proportion of women with recurrent UTI experiencing a medically attended UTI.Design, setting, and participantsThis 2-group, double-blind randomized placebo-controlled trial took place across 99 primary care centers in the UK. Participants were recruited between March 28, 2019, and January 31, 2020, with 6 months of follow-up. Participants were female, 18 years or older, living in the community, and had evidence in their primary care record of consultations for at least 2 UTIs in the preceding 6 months or 3 UTIs in 12 months. Invitation to participate was made by their primary care center. A total of 7591 participants were approached, 830 responded, and 232 were ineligible or did not proceed to randomization. Statistical analysis was reported in December 2022.InterventionTwo grams daily of d-mannose powder or matched volume of placebo powder.Main outcomes and measuresThe primary outcome measure was the proportion of women experiencing at least 1 further episode of clinically suspected UTI for which they contacted ambulatory care within 6 months of study entry. Secondary outcomes included symptom duration, antibiotic use, time to next medically attended UTI, number of suspected UTIs, and UTI-related hospital admissions.ResultsOf 598 women eligible (mean [range] age, 58 [18-93] years), 303 were randomized to d-mannose (50.7%) and 295 to placebo (49.3%). Primary outcome data were available for 583 participants (97.5%). The proportion contacting ambulatory care with a clinically suspected UTI was 150 of 294 (51.0%) in the d-mannose group and 161 of 289 (55.7%) in the placebo group (risk difference, -5%; 95% CI, -13% to 3%; P = .26). Estimates were similar in per protocol analyses, imputation analyses, and preplanned subgroups. There were no statistically significant differences in any secondary outcome measures.Conclusions and relevanceIn this randomized clinical trial, daily d-mannose did not reduce the proportion of women with recurrent UTI in primary care who experienced a subsequent clinically suspected UTI. d-Mannose should not be recommended for prophylaxis in this patient group.Trial registrationisrctn.org Identifier: ISRCTN13283516.

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Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

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Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

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