Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK140944)

Abstract

Background: With increasing concerns about the impact of frequent antibiotic usage on the human microbiome, it is important to characterize the potential for such effects in early antibiotic drug development clinical trials. In a randomised Phase 2a clinical trial study that evaluated the pharmacokinetics of repeated oral doses of gepotidacin, a first-in-chemical-class triazaacenaphthylene antibiotic with a distinct mechanism of action, in adult females with uncomplicated urinary tract infections for gepotidacin (GSK2140944) we evaluated the potential changes in microbiome composition across multiple time points and body-sites ( ClinicalTrials.gov : NCT03568942).

Results: Samples of gastrointestinal tract (GIT), pharyngeal cavity and vaginal microbiota were collected with consent from 22 patients at three time points relative to the gepotidacin dosing regimen; Day 1 (pre-dose), Day 5 (end of dosing) and Follow-up (Day 28 ± 3 days). Microbiota composition was determined by DNA sequencing of 16S rRNA gene variable region 4 amplicons. By Day 5, significant changes were observed in the microbiome diversity relative to pre-dose across the tested body-sites. However, by the Follow-up visit, microbiome diversity changes were reverted to compositions comparable to Day 1. The greatest range of microbiome changes by body-site were GIT followed by the pharyngeal cavity then vagina. In Follow-up visit samples we found no statistically significant occurrences of pathogenic taxa.

Conclusion: Our findings suggest that gepotidacin alteration of the human microbiome after 5 days of dosing is temporary and rebound to pre-dosing states is evident within the first month post-treatment. We recommend that future antibiotic drug trials include similar exploratory investigations into the duration and context of microbiome modification and recovery.

Trial registration: NCT03568942 . Registered 26 June 2018.

Keywords: Antibiotic; Clinical trial; Gepotidacin; Microbiome; Urinary tract infection.

Fig. 1

Overview of microbiome dynamics during gepotidacin Phase 2a clinical trial. (A) Phylum level changes in the relative abundance of microbiota across different body sites and time points. (B) Changes in microbiota community as measured by different indices of alpha diversity. The initial, lower placed value in each comparison is from the overall ANOVA (* P value ≤0.05; ** P value ≤0.005, ns = nonsignificant)

Fig. 2

Beta diversity index of microbial communities using unweighted UniFrac distances with PCoA (A) or NMDS (B) projections on different body sites over time. (C) Violin plots showing the distribution of the first CCA scores for each visit and body type (* P value ≤0.05; ** P value ≤0.005; *** P value ≤0.0001 ns = nonsignificant, Wilcoxon test with Benjamini-Hochberg FDR correction)

Fig. 3

Changes in specific microbiota genera at Day 5 and Follow-up compared to Day 1 for the (A) gastro-intestinal tract (GIT); (B) pharyngeal cavity and (C) vagina. Size represents -log₁₀ of FDR-adjusted P-value and lines represent CI at 95%

Fig. 4

Overall trends in changes for specific pathogenic genera including Bacillus, Clostridioides, Escherichia-Shigella, Haemophilus, Neisseria, Staphylococcus and Streptococcus. (* P value ≤0.05; ** P value ≤0.005; *** P value ≤0.0001 ns = nonsignificant)

Fig. 5

Species level changes in abundance for E. coli species using phylogenetic analyses of their 16S rRNA-V4 sequences and closely related sequences from the NCBI public database