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Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

ABSTRACT: Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.

SUBMITTER: Mydock-McGrane L

PROVIDER: S-EPMC5087331 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

Mydock-McGrane Laurel L Cusumano Zachary Z Han Zhenfu Z Binkley Jana J Kostakioti Maria M Hannan Thomas T Pinkner Jerome S JS Klein Roger R Kalas Vasilios V Crowley Jan J Rath Nigam P NP Hultgren Scott J SJ Janetka James W JW

Journal of medicinal chemistry 20161014 20

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and in ...[more]

PMID: 27689912

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Project description:INTRODUCTION:Urinary tract infections (UTI) are a common indication for antibiotic use in the emergency department (ED). With antibiotic resistance on the rise, it is essential that antibiotics be prescribed appropriately for UTIs. Our objective was to evaluate the appropriateness of antibiotic prescriptions by ED providers for uncomplicated cystitis and pyelonephritis. METHODS:We conducted a retrospective study of females ages 2-50 years seen in an academic ED from January 2017 to April 2018 diagnosed with UTI. We assessed the appropriateness of discharge antibiotic prescriptions, as determined by adherence to clinical practice guidelines, best evidence for the particular indication (cystitis vs pyelonephritis for children and adults), and the local antibiogram. RESULTS:A total of 421 patients were included in this study. Of these, 60 children and 198 adults were diagnosed with cystitis, and 47 children and 116 adults were diagnosed with pyelonephritis. Treatment in the absence of true infection was common, with culture-confirmed UTI occurring in only 17/50 (34%) of children and 60/129 (47%) of adults diagnosed with cystitis, and 23/40 (58%) of children and 58/87 (67%) of adults diagnosed with pyelonephritis, among patients who had urine cultures. The type of antibiotic prescribed was appropriate in 53/60 (88%) of children and 135/198 (68%) of adults with cystitis, and 38/47 (81%) of children and 53/116 (46%) of adults with pyelonephritis. The most common inappropriate antibiotic types were beta-lactams in adults (n = 92), nitrofurantoin for pyelonephritis (n = 16), and amoxicillin (n = 15). Dosing and duration errors were also common, occurring in 122/279 (44%) of prescriptions of an appropriate antibiotic type. The frequency of errors in the type of antibiotic prescribed was similar among provider types (attending physician, resident physician, and advanced practice clinician; p = 0.926). CONCLUSION:This study reveals room for improvement in antibiotic prescription practices across provider cohorts in the ED for the management of uncomplicated cystitis and pyelonephritis in females.

Project description:ImportanceEmpirical antibiotic prescribing in nursing homes (NHs) is often suboptimal. The potential for antibiograms to improve empirical antibiotic decision-making in NHs remains poorly understood.ObjectiveTo determine whether providing NH clinicians with a urinary antibiogram improves empirical antibiotic treatment of urinary tract infections (UTIs).Design, setting, and participantsThis was a survey study using clinical vignettes. Participants were recruited via convenience sampling of professional organization listservs of NH clinicians practicing in the US from December 2021 through April 2022. Data were analyzed from July 2022 to June 2023.InterventionsRespondents were randomized to complete vignettes using a traditional antibiogram (TA), a weighted-incidence syndromic combination antibiogram (WISCA), or no tool. Participants randomized to antibiogram groups were asked to use the antibiogram to empirically prescribe an antibiotic. Participants randomized to the no tool group functioned as controls.Main outcomes and measuresEmpirical antibiotic selections were characterized as microbiologically (1) active and (2) optimal according to route of administration and spectrum of activity.ResultsOf 317 responses, 298 (95%) were included in the analysis. Duplicate responses (15 participants), location outside the US (2 participants), and uninterpretable responses (2 participants) were excluded. Most respondents were physicians (217 respondents [73%]) and had over 10 years of NH practice experience (155 respondents [52%]). A mixed-effects logistic model found that use of the TA (odds ratio [OR], 1.41; 95% CI, 1.19-1.68; P < .001) and WISCA (OR, 1.54; 95% CI, 1.30-1.84; P < .001) were statistically superior to no tool when choosing an active empirical antibiotic. A similarly constructed model found that use of the TA (OR, 1.94; 95% CI, 1.42-2.66; P < .001) and WISCA (OR, 1.7; 95% CI, 1.24-2.33; P = .003) were statistically superior to no tool when selecting an optimal empirical antibiotic. Although there were differences between tools within specific vignettes, when compared across all vignettes, the TA and WISCA performed similarly for active (OR, 1.09; 95% CI, 0.92-1.30; P = .59) and optimal (OR, 0.87; 95% CI, 0.64-1.20; P = .69) antibiotics.Conclusions and relevanceProviding NH clinicians with a urinary antibiogram was associated with selection of active and optimal antibiotics when empirically treating UTIs under simulated conditions. Although the antibiogram format was not associated with decision-making in aggregate, context-specific effects may have been present, supporting further study of syndromic antibiograms in clinical practice.

Project description:BackgroundUrinary tract infections (UTI) are among the most common cause to prescribe antibiotics in primary care. Diagnosis is based on the presence of clinical symptoms in combination with the results of laboratory tests. Antibiotic therapy is the primary approach to the treatment of UTIs; however, some studies indicate that therapeutics in UTIs may be suboptimal, potentially leading to therapeutic failure and increased bacterial resistance.MethodsThis study aimed to analyze the antibiotic prescription patterns in adult patients with suspected UTIs and to evaluate the appropriateness of the antibiotic prescription. This is a cross-sectional study of patients treated in outpatient centers and in a second-level hospital of the Ministry of Public Health (MOPH) in a city in Ecuador during 2019. The International Classification of Disease Tenth Revision (ICD-10) was used for the selection of the acute UTI cases. The patients included in this study were those treated by family, emergency, and internal medicine physicians.ResultsWe included a total of 507 patients in the analysis and 502 were prescribed antibiotics at first contact, constituting an immediate antibiotic prescription rate of 99.01%. Appropriate criteria for antibiotic prescription were met in 284 patients, representing an appropriate prescription rate of 56.02%. Less than 10% of patients with UTI had a urine culture. The most frequently prescribed antibiotics were alternative antibiotics (also known as second-line antibiotics), such as ciprofloxacin (50.39%) and cephalexin (23.55%). Factors associated with inappropriate antibiotic prescribing for UTIs were physician age over forty years, OR: 2.87 (95% CI, 1.65-5.12) p<0.0001, medical care by a general practitioner, OR: 1.89 (95% CI, 1.20-2.99) p = 0.006, not using point-of-care testing, OR: 1.96 (95% CI, 1.23-3.15) p = 0.005, and care at the first level of health, OR: 15.72 (95% CI, 8.57-30.88) p<0.0001.ConclusionsThe results of our study indicate an appropriate prescription rate of 56.02%. Recommended antibiotics such as nitrofurantoin and fosfomycin for UTIs are underutilized. The odds for inappropriate antibiotic prescription were 15.72 times higher at the first level of care compared to the second. Effective strategies are needed to improve the diagnosis and treatment of UTIs.

Dataset Information

Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

Publications

Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

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