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

From BugSigDB
Reviewed Marked as Reviewed by Folakunmi on 2023-12-12
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


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

Subjects

Location of subjects
United States of America
Host species Species from which microbiome was sampled. Contact us to have more species added.
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,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),Urinary tract infection
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 (end of dosing or post-dose)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This represented the condition at the end of the 5-day regimen of gepotidacin treatment in the GIT microbiome
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).
raw counts
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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: Within results text(under "Changes in detected abundances of bacterial genera"line 8-14), Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5 (end of dosing or post-dose)

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

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: Within results text(under "Changes in detected abundances of bacterial genera"line 8-14), Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5 (end of dosing or post-dose)

NCBI Quality ControlLinks
Dialister
Enterococcus
Fusobacterium
Parabacteroides
Prevotella sp.
Selenomonas
Treponema
Tyzzerella
Veillonella
unclassified Lachnospiraceae

Revision editor(s): Chinelsy, Folakunmi

Experiment 2


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Follow-up (visit around Day 28 ± 3 days).
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This represented the condition approximately one month post-treatment, after the cessation of gepotidacin in the GIT microbiome

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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: Within results text(under "Changes in detected abundances of bacterial genera"line 8-14), Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up (visit around Day 28 ± 3 days).

NCBI Quality ControlLinks
Actinomyces
Anaerostipes
Bifidobacterium
Blautia
Campylobacter
Eubacterium coprostanoligenes
Fusobacterium
Lachnospiraceae bacterium NK4A136
Lawsonella
Leptotrichia
Neisseria
Oscillospiraceae
Phascolarctobacterium
Prevotella sp.
Romboutsia
Roseburia
Rothia
Ruminiclostridium sp.
Selenomonas
Sutterella
Veillonella
unclassified Lachnospiraceae
unclassified Muribaculaceae
uncultured Oscillospiraceae bacterium
uncultured bacterium

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: Within results text(under "Changes in detected abundances of bacterial genera"line 8-14), Figure 3

Description: Relative abundances of assigned bacterial taxa

Abundance in Group 1: decreased abundance in Follow-up (visit around Day 28 ± 3 days).

NCBI Quality ControlLinks
Actinomyces
Bacteroides
Collinsella
Dialister
Fusicatenibacter
Gardnerella
Granulicatella
Lachnospiraceae bacterium NK4A136
Lactobacillus
Oscillibacter
Parabacteroides
Prevotella sp.
Rikenellaceae incertae sedis
Rothia
Ruminiclostridium sp.
Ruminococcus
Treponema
Veillonella
unclassified Oscillospiraceae
uncultured Oscillospiraceae bacterium

Revision editor(s): Chinelsy, Folakunmi

Experiment 3


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

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,saliva
Group 1 name Corresponds to the case (exposed) group for case-control studies
Day 5 (end of dosing or post-dose)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This represented the condition at the end of the 5-day regimen of gepotidacin treatment in the pharyngeal cavity microbiome.

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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 2, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5 (end of dosing or post-dose)

NCBI Quality ControlLinks
Acidaminococcus
Aerococcus
Faecalibacterium
Megasphaera
Ruminococcus
Shuttleworthella
Lactobacillus
Faecalibacterium sp. UBA1819
uncultured Oscillospiraceae bacterium
Bacteroides
Campylobacter

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 2, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5 (end of dosing or post-dose)

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

Revision editor(s): Chinelsy, Folakunmi

Experiment 4


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Follow-up (visit around Day 28 ± 3 days).
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This represented the condition approximately one month post-treatment, after the cessation of gepotidacin in the pharyngeal cavity microbiome.

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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 2, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up (visit around Day 28 ± 3 days).

NCBI Quality ControlLinks
Acidaminococcus
Faecalibacterium
Megasphaera
Peptoniphilus
Subdoligranulum
Veillonella
[Ruminococcus] torques
uncultured Oscillospiraceae bacterium

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 2,, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Follow-up (visit around Day 28 ± 3 days).

NCBI Quality ControlLinks
Agathobacter
Anaerococcus
Atopobium
Bacteroides
Candidatus Absconditabacterales
Dialister
Fastidiosipila
Flavonifractor
Parabacteroides
Peptoniphilus
Peptostreptococcus
Porphyromonas
Prevotella
Pseudomonas
Ruminiclostridium
Sneathia
Candidatus Soleaferrea
unclassified Enterobacteriaceae
unclassified Lachnospiraceae
unclassified Veillonellaceae
uncultured Oscillospiraceae bacterium

Revision editor(s): Chinelsy, Folakunmi

Experiment 5


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Vagina Vagina,vagina,Distal oviductal region,Distal portion of oviduct,Vaginae
Group 1 name Corresponds to the case (exposed) group for case-control studies
Day 5 (end of dosing or post-dose)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This represented the condition at the end of the 5-day regimen of gepotidacin treatment in vaginal microbiome.

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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 3, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Day 5 (end of dosing or post-dose)

NCBI Quality ControlLinks
Entamoebidae
Paraprevotella
Prevotella
Pseudomonas
Rothia
Sutterella
[Eubacterium] yurii
Ruminiclostridium
Faecalibacterium
Campylobacter
Eubacterium coprostanoligenes
Fusobacterium
Veillonella
Lactobacillus
Phascolarctobacterium

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 3, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Day 5 (end of dosing or post-dose)

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

Revision editor(s): Chinelsy, Folakunmi

Experiment 6


Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Follow-up (visit around Day 28 ± 3 days).
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
this represented the condition approximately one month post-treatment, after the cessation of gepotidacin in vaginal microbiome

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

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 3, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: increased abundance in Follow-up (visit around Day 28 ± 3 days).

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

Revision editor(s): Chinelsy, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2023-12-12

Curated date: 2023/11/14

Curator: Chinelsy

Revision editor(s): Chinelsy, Folakunmi

Source: within results text under "changes in detected abundances in bacterial genera", paragraph 3, Figure 3

Description: Relative abundances of assigned bacterial taxa.

Abundance in Group 1: decreased abundance in Follow-up (visit around Day 28 ± 3 days).

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

Revision editor(s): Chinelsy, Folakunmi