Dataset Information

1281. Longitudinal and Spatial Variation in the Human Microbiome in a Phase 2a Clinical Study of Gepotidacin in Adult Females with Uncomplicated Urinary Tract Infection

ABSTRACT: Abstract

Background

Gepotidacin (GSK2140944) is a first in class novel oral triazaacenaphthylene bacterial topoisomerase inhibitor. In this study, we evaluated the potential impact of orally administered gepotidacin on the human microbiome, across three body-sites and at three specific time-points, as an exploratory endpoint in a Phase 2a clinical trial for the treatment of uncomplicated Urinary Tract Infection (uUTI) (ClinicalTrials.gov: NCT03568942).

Methods

Through DNA sequencing of the 16S rRNA variable region 4, we analyzed samples collected with consent from study subjects from the gastrointestinal tract or GIT (stool), pharyngeal cavity (saliva swabs) and vagina (vaginal swabs). Samples were taken at three time points which were pre-dosing (Day 1), end of dosing (Day 5) and follow-up visit (Day 28 ±3 days). A total of 156 samples were collected and 141 samples passed quality control criteria for DNA sequence analyses. Using a rigorous computational work-flow, changes in microbiome diversity and relative abundances of microbial species were quantified.

Results

Time series analyses showed that microbiota alpha diversity dropped, relative to pre-dose, by the end of gepotidacin dosing but trended a return trajectory to original pre-dose levels by the follow-up visit, for all body sites (Figure). However, the character and extent of the microbiota changes varied by location. The relative ordering from least to greatest changes in microbiota diversity of body sites is vaginal, pharyngeal and GIT. We found no statistically significant occurrences of pathogen related taxa, such as Clostridioides or Enterobacterales spp., at the final timepoints.

Conclusion

Since gepotidacin is both orally dosed and elimination includes the biliary route, it was predicted to affect the GIT microbiome, however changes in the distal pharyngeal and vaginal microbiota were also observed. Gepotidacin alteration of the endogenous microbial community appears to be temporary and reversible as microbiota diversity rebounded to near pre-dosing status within a period of several weeks. Our study illustrates how microbiome analyses in antibiotic clinical studies can quantify patterns of microbiota disruption and recovery.

Disclosures

Andrea Nuzzo, PHD, GlaxoSmithKline (Employee) Stephanie Van Horn, B.Sc., GlaxoSmithKline (Employee) Christopher Traini, PHD, GlaxoSmithKline (Employee) Caroline R. Perry, PhD, GlaxoSmithKline (Employee) Etienne Dumont, MD, GlaxoSmithKline (Employee) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) David Gardiner, MD, GlaxoSmithKline (Employee) James R. Brown, PhD, GlaxoSmithKline (Employee)

SUBMITTER: Nuzzo A

PROVIDER: S-EPMC7776697 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:BackgroundUncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics. Here, we describe the designs of two near-identical phase III clinical trials (EAGLE-2 and EAGLE-3) evaluating gepotidacin for the treatment of uUTI.MethodsThese are phase III, randomized, multicenter, parallel-group, double-blind, double-dummy, comparator-controlled, noninferiority studies, comparing the efficacy and safety of gepotidacin to nitrofurantoin in the treatment of uUTI. Eligible participants are women aged ≥ 12 years with ≥ 2 uUTI symptoms, randomized (1:1) to receive oral gepotidacin (1500 mg) plus placebo or nitrofurantoin (100 mg) plus placebo, twice daily for 5 days. The primary therapeutic endpoint is composite clinical and microbiological efficacy, with noninferiority comparisons made in individuals with a qualifying (≥ 105 colony-forming units/mL urine) nitrofurantoin-susceptible uropathogen.ResultsThese trials were designed in accordance with US Food and Drug Administration (2019) and European Medicines Agency (2018) guidance, particularly the composite endpoint and microbiological evaluability requirements. Across the trials ~ 5000 participants are planned to be enrolled from > 200 centers globally.ConclusionsGepotidacin represents an important potential treatment option being evaluated to address the need for novel oral antibiotics to treat uUTI. These trials are registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ ) where the full protocols can be accessed under trial IDs: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

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