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

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Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
Authors
Nuzzo A, Van Horn S, Traini C, Perry CR, Dumont EF, Scangarella-Oman NE, Gardiner DF, Brown JR
Journal
BMC microbiology
Year
2021
Keywords:
Antibiotic, Clinical trial, Gepotidacin, Microbiome, Urinary tract infection
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.

Experiment 1


Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Subjects

Location of subjects
United States of America
Host species Species from which microbiome was sampled (if applicable)
Homo sapiens
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
urinary tract infection INFECTION, URINARY TRACT,TRACT, INFECTION OF URINARY,urinary tract infection,urinary tract infection (disease)
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Day 1 (pre-dose)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Day 5
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
End of dosing (this is relative to the gepotidacin dosing regimen).
Group 0 sample size Number of subjects in the control (unexposed) group
22
Group 1 sample size Number of subjects in the case (exposed) group
22

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
DESeq2
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.01
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5

NCBI Quality ControlLinks
Phascolarctobacterium
Megasphaera
Flavonifractor
Actinobacillus
Mobiluncus
Fretibacterium
Lachnoanaerobaculum
Streptococcus
Anaerococcus
Finegoldia
Alloprevotella
Selenomonas
Peptostreptococcus
Oribacterium
Gardnerella
Blautia
Ruminiclostridium
Neisseria
Oscillospiraceae
Leptotrichia
Roseburia
Parvimonas
Romboutsia
Anaerostipes
Rothia
Bacteroides
Oscillibacter
Lawsonella
Lactobacillus
Fournierella
Actinomyces
Pseudomonas
Sutterella

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5

NCBI Quality ControlLinks
Tyzzerella
Parabacteroides
Enterococcus
Dialister
Fusobacterium
Veillonella

Revision editor(s): Atrayees

Experiment 2


Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Follow-up
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Day 28 ± 3 days (this is relative to the gepotidacin dosing regimen).

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up

NCBI Quality ControlLinks
Leptotrichia
Rothia
Neisseria
Campylobacter
Ruminiclostridium
Fusobacterium
Roseburia
Oscillospiraceae
Lawsonella
Blautia
Romboutsia
Selenomonas
Anaerostipes
Bifidobacterium
Eubacterium coprostanoligenes
Prevotella
Sutterella
Phascolarctobacterium

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/14

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Follow-up

NCBI Quality ControlLinks
Collinsella
Parabacteroides
Fusicatenibacter
Treponema
Oscillibacter
Bacteroides
Lactobacillus
Gardnerella
Granulicatella
Rikenellaceae
Rothia

Revision editor(s): Atrayees

Experiment 3


Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Differences from previous experiment shown

Subjects

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Saliva Sailva normalis,Saliva atomaris,Saliva molecularis,Salivary gland secretion,Saliva
Group 1 name Corresponds to the case (exposed) group for case-control studies
Day 5
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
End of dosing (this is relative to the gepotidacin dosing regimen).

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5

NCBI Quality ControlLinks
Aerococcus
Shuttleworthia
Acidaminococcus
Faecalibacterium
Megasphaera
Ruminococcus

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5

NCBI Quality ControlLinks
Bacteroides
Campylobacter
Neisseria
Actinobacillus
Alloprevotella
Prevotella
Porphyromonas
Aggregatibacter
Selenomonas
Dialister
Stomatobaculum
Granulicatella
Catonella
Fusobacterium
Veillonella
Leptotrichia
[Ruminococcus] torques
Lawsonella
Parabacteroides
Ruminiclostridium
Finegoldia
Capnocytophaga
Streptococcus
Lachnoanaerobaculum

Revision editor(s): Atrayees

Experiment 4


Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Follow-up
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Day 28 ± 3 days (this is relative to the gepotidacin dosing regimen).

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up

NCBI Quality ControlLinks
Acidaminococcus
Megasphaera
Subdoligranulum
Oscillospiraceae
Faecalibacterium

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Follow-up

NCBI Quality ControlLinks
Dialister
Porphyromonas
Candidatus Soleaferrea
Flavonifractor
Peptostreptococcus
Agathobacter
Prevotella
Sneathia
Atopobium
Parabacteroides
Bacteroides
Fastidiosipila
Peptoniphilus
Anaerococcus

Revision editor(s): Atrayees

Experiment 5


Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Differences from previous experiment shown

Subjects

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Vagina Distal oviductal region,Distal portion of oviduct,Vaginae,Vagina


Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Follow-up

NCBI Quality ControlLinks
Peptoniphilus
Gemella
Corynebacterium
Peptostreptococcus
Fusicatenibacter
Granulicatella
metagenome
Faecalibacterium
Roseburia
Alistipes
Lachnospiraceae
Lachnoanaerobaculum
Oscillospiraceae
Acidaminococcus
Prevotella
Eubacterium coprostanoligenes
[Ruminococcus] torques
Capnocytophaga
Actinomyces
Parabacteroides
Tyzzerella
Alloprevotella
Christensenellaceae
Oribacterium

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up

NCBI Quality ControlLinks
Fretibacterium
Selenomonas
Parvimonas
Oscillibacter
Mitsuokella
Lachnospira
Pseudomonas
Treponema
Ruminiclostridium
Butyricicoccus
Eubacterium ventriosum
Bifidobacterium

Revision editor(s): Atrayees

Experiment 6


Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Day 5
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
End of dosing (this is relative to the gepotidacin dosing regimen).

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5

NCBI Quality ControlLinks
Pseudomonas
Entamoebidae
Paraprevotella
Sutterella
Prevotella
Rothia
[Eubacterium] yurii

Revision editor(s): Atrayees

Signature 2

Needs review

Curated date: 2023/06/15

Curator: Atrayees

Revision editor(s): Atrayees

Source: Supplementary Data File S1, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5

NCBI Quality ControlLinks
Corynebacterium
Agathobacter
Eggerthella
Actinobacillus
Anaerococcus
Ruminococcus
Prevotella
Anaeroglobus
Fusicatenibacter
Subdoligranulum
Bacteroides
metagenome
Parabacteroides
Christensenellaceae
Alloscardovia
[Ruminococcus] torques
Actinomyces
Lachnospira
Lactococcus
Negativibacillus
Dialister
Alloprevotella
Leptotrichia
Parvimonas
Oribacterium
Treponema
Capnocytophaga
Streptococcus

Revision editor(s): Atrayees