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6. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation

Author

Taylor, Stephanie N, Morris, David H, Avery, Ann K, Workowski, Kimberly A, Batteiger, Byron E, Tiffany, Courtney A, Perry, Caroline R, Raychaudhuri, Aparna, Scangarella-Oman, Nicole E, Hossain, Mohammad, and Dumont, Etienne F

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Sexually Transmitted Infections, Digestive Diseases, Urologic Diseases, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Acenaphthenes, Administration, Oral, Adolescent, Adult, Aged, Anti-Bacterial Agents, Drug Administration Schedule, Female, Female Urogenital Diseases, Gonorrhea, Heterocyclic Compounds, 3-Ring, Humans, Male, Male Urogenital Diseases, Microbial Sensitivity Tests, Middle Aged, Neisseria gonorrhoeae, Pharyngeal Diseases, Rectal Diseases, Young Adult, gepotidacin, urogenital, gonorrhea, Biological Sciences, Medical and Health Sciences, Microbiology, Clinical sciences
Abstract

BackgroundIn this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea.MethodsAdult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin.ResultsThe microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose.ConclusionsThis study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea.Clinical trials registrationNCT02294682.

Published
2018

9. 2832. Gepotidacin Efficacy in E. coli Drug-Resistant Phenotypes: A Pooled Analysis of the EAGLE-2 and EAGLE-3 Randomized Controlled Trials in Uncomplicated Urinary Tract Infection

Author

Hooton, Thomas M, primary, Perry, Caroline R, additional, Janmohamed, Salim, additional, Sheets, Amanda, additional, Dennison, Jeremy, additional, Millns, Helen, additional, Jarvis, Emily, additional, Scangarella-Oman, Nicole E, additional, and Huang, Chun, additional

Published
2023
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11. 2837. Impact of Regulatory Guidelines on Therapeutic, Clinical, and Microbiological Success Rates in Uncomplicated Urinary Tract Infection: Results from a Two Phase 3 Randomized Controlled Trials of Oral Gepotidacin (EAGLE-2 and EAGLE-3)

Author

Wagenlehner, Florian, primary, Perry, Caroline R, additional, Hooton, Thomas M, additional, Scangarella-Oman, Nicole E, additional, Millns, Helen, additional, Jarvis, Emily, additional, Dennison, Jeremy, additional, Sheets, Amanda, additional, and Janmohamed, Salim, additional

Published
2023
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14. Co-resistance Among Escherichia coliand Klebsiella pneumoniaeUrine Isolates from Female Outpatients with Presumed UTI: A Retrospective US Cohort Study

Author

Kaye, Keith S., Gupta, Vikas, Mulgirigama, Aruni, Joshi, Ashish V., Scangarella-Oman, Nicole E., Yu, Kalvin, Watts, Janet, and Mitrani-Gold, Fanny S.

Abstract

Introduction: Urinary tract infections (UTIs) caused by antimicrobial-resistant Enterobacterales are a global health threat. There are limited surveillance data available to characterize the prevalence of antimicrobial resistance among outpatients in the United States (US). Methods: This retrospective cohort (database) study investigated co-resistance among Escherichia coliand Klebsiella pneumoniaeurinary isolates from US female outpatients aged ≥ 12 years with presumed uncomplicated UTI (uUTI), ≥ 3 months of data (2011–2019), and antimicrobial susceptibility testing results. Eligible isolates were the first urinary E. colior K. pneumoniaeisolate per patient collected within 30 days; classified as not susceptible (NS) if antimicrobial susceptibility testing results were intermediate or resistant to each antibiotic tested. Four resistance phenotypes were identified: NS to fluoroquinolones (FQ), trimethoprim/sulfamethoxazole (SXT), nitrofurantoin (NTF), and extended-spectrum β-lactamase+/third-generation cephalosporin (ESBL+/3GC NS). Co-resistance phenotypes included all possible combinations of resistance to ≥ 2 drug classes. Results: Of 1,513,882 E. coliisolates and 250,719 K. pneumoniaeisolates, 856,918 and 187,459 isolates with ≥ 1 resistance phenotype were included in the analysis, respectively. The most common resistance phenotypes were SXT NS for the E. coliisolates (44.8%) and NTF NS for the K. pneumoniaeisolates (75.5%), while ESBL+/3GC NS comprised 11.2 and 5.9%, respectively. Among ESBL+/3GC NS E. coliisolates, 72.4, 56.7, and 46.6% were co-resistant to FQ, SXT, and FQ + SXT, respectively. For ESBL+/3GC NS K. pneumoniaeisolates, 65.7 and 45.7% were co-resistant to SXT and FQ + SXT. Conclusion: Both species exhibited high rates of co-resistance, emphasizing the need to raise awareness of co-resistance and of the unmet need for effective treatment options for uUTI.

Published
2024
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15. P31 Efficacy and safety of oral gepotidacin in the treatment of uncomplicated urinary tract infection: results of two randomized, multicentre Phase 3 trials (EAGLE-2 and EAGLE-3)

Author

Wagenlehner, Florian, primary, Perry, Caroline R, additional, Hooton, Thomas M, additional, Scangarella-Oman, Nicole E, additional, Millns, Helen, additional, (Ed) Feng, Hwa-ping, additional, Powell, Marcy, additional, Jarvis, Emily, additional, Dennison, Jeremy, additional, Sheets, Amanda, additional, Butler, Deborah, additional, Breton, John, additional, and Janmohamed, Salim, additional

Published
2023
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16. Older patient age and prior antimicrobial use strongly predict antimicrobial resistance in Escherichia coli isolates recovered from urinary tract infections among female outpatients

Author

Mitrani-Gold, Fanny S., primary, Kaye, Keith S., additional, Gupta, Vikas, additional, Mulgirigama, Aruni, additional, Trautner, Barbara W., additional, Scangarella-Oman, Nicole E., additional, Yu, Kalvin C., additional, Ye, Gang, additional, and Joshi, Ashish V., additional

Published
2023
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17. New Antimicrobial Agents... but No Susceptibility Tests!

Author

Ambler, Jane E., Krause, Kevin M., Steenbergen, Judith N., Scangarella-Oman, Nicole E., Miller, Linda A., Bhagwat, Sachin S., Serio, Alisa W., Chesnel, Laurent, Mahoney, Nicole M., Motyl, Mary R., Critchley, Ian A., Iaconis, Joseph P., Stone, Gregory G., Alder, Jeff, Xerri, Luigi, McCurdy, Sandra P., van Veenhuyzen, David F., Grossman, Trudy, Echols, Roger M., Williams, Gregory, and Bradford, Patricia A.

Published
2016
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23. Risk Factors Associated With Antimicrobial Resistance and Adverse Short-Term Health Outcomes Among Adult and Adolescent Female Outpatients With Uncomplicated Urinary Tract Infection

Author

Trautner, Barbara W, primary, Kaye, Keith S, additional, Gupta, Vikas, additional, Mulgirigama, Aruni, additional, Mitrani-Gold, Fanny S, additional, Scangarella-Oman, Nicole E, additional, Yu, Kalvin, additional, Ye, Gang, additional, and Joshi, Ashish V, additional

Published
2022
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25. Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea.

Author

Scangarella-Oman, Nicole E., Hossain, Mohammad, Perry, Caroline R., Tiffany, Courtney, Powell, Marcy, Swift, Brandon, and Dumont, Etienne F.

Abstract

Background: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of Neisseria gonorrhoeae (N. gonorrhoeae). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea.Methods: For dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression against N. gonorrhoeae isolates with gepotidacin MICs ≤1 µg/mL.Results: Two 3000 mg gepotidacin doses, administered 10-12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration-time curve over 24 hours to the MIC (fAUC0-24/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations ≥14 µg/mL.Conclusions: Two gepotidacin 3000 mg oral doses 10-12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC N. gonorrhoeae isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Additional file 4 of Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)

Author

Nuzzo, Andrea, Van Horn, Stephanie, Traini, Christopher, Perry, Caroline R., Dumont, Etienne F., Scangarella-Oman, Nicole E., Gardiner, David F., and Brown, James R.

Abstract

Additional file 4: Supplementary Figure S2. Multivariate analyses of changes in microbial community using constrained correspondence analysis (CCA) on Bray-Curtis distances showing recovery at Follow-up (A) and violin plots showing the distribution of the first CCA scores for each visit and body type (B) (* P value ≤0.05; ** P value ≤0.005; *** P value ≤0.0001 ns = nonsignificant, Wilcoxon test with Benjamini-Hochberg FDR correction).

Published
2021
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32. Additional file 6 of Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)

Author

Nuzzo, Andrea, Van Horn, Stephanie, Traini, Christopher, Perry, Caroline R., Dumont, Etienne F., Scangarella-Oman, Nicole E., Gardiner, David F., and Brown, James R.

Abstract

Additional file 6: Supplementary Figure S4. Species-level changes in abundance for Clostridioides species using phylogenetic analyses of their 16S rRNA-V4 sequences as well as related sequences from NCBI public database. Occurrence of C. difficile in the GIT samples from four subjects at Follow-up is labeled.

Published
2021
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33. Additional file 1 of Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)

Author

Nuzzo, Andrea, Van Horn, Stephanie, Traini, Christopher, Perry, Caroline R., Dumont, Etienne F., Scangarella-Oman, Nicole E., Gardiner, David F., and Brown, James R.

Abstract

Additional file 1: Supplementary Table S1. Summary of samples collected and passing quality control (QC) for subsequent analyses.

Published
2021
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34. Additional file 5 of Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)

Author

Nuzzo, Andrea, Van Horn, Stephanie, Traini, Christopher, Perry, Caroline R., Dumont, Etienne F., Scangarella-Oman, Nicole E., Gardiner, David F., and Brown, James R.

Abstract

Additional file 5: Supplementary Figure S3. Species-level changes in abundance for Neisseria gonorrhoeae related species using phylogenetic analyses of their 16S rRNA gene -V4 sequences as well as related sequences from NCBI public database.

Published
2021
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35. Additional file 3 of Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)

Author

Nuzzo, Andrea, Van Horn, Stephanie, Traini, Christopher, Perry, Caroline R., Dumont, Etienne F., Scangarella-Oman, Nicole E., Gardiner, David F., and Brown, James R.

Abstract

Additional file 3: Supplementary Figure S1. Changes in microbiota community as measured by different indices of alpha diversity (A) and pairwise statistical analysis of alpha diversity values for the subset of patients having the full set of three visit throughout the trial (n = 16) (B). The initial, lower placed value in each comparison is from the overall ANOVA (* P value ≤0.05; ** P value ≤0.005, ns = nonsignificant).

Published
2021
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36. Using rapid point-of-care tests to inform antibiotic choice to mitigate drug resistance in gonorrhoea

Author

Vegvari, Carolin, primary, Grad, Yonatan H, additional, White, Peter J, additional, Didelot, Xavier, additional, Whittles, Lilith K, additional, Scangarella-Oman, Nicole E, additional, Mitrani-Gold, Fanny S, additional, Dumont, Etienne, additional, Perry, Caroline R, additional, Gilchrist, Kim, additional, Hossain, Mohammad, additional, Mortimer, Tatum D, additional, Anderson, Roy M, additional, and Gardiner, David, additional

Published
2020
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38. Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

Author

Overcash, J. Scott, primary, Tiffany, Courtney A., additional, Scangarella-Oman, Nicole E., additional, Perry, Caroline R., additional, Tao, Yu, additional, Hossain, Mohammad, additional, Barth, Aline, additional, and Dumont, Etienne F., additional

Published
2020
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39. In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

Author

Scangarella-Oman, Nicole E., primary, Ingraham, Karen A., additional, Tiffany, Courtney A., additional, Tomsho, Lynn, additional, Van Horn, Stephanie F., additional, Mayhew, David N., additional, Perry, Caroline R., additional, Ashton, Theresa C., additional, Dumont, Etienne F., additional, Huang, Jianzhong, additional, Brown, James R., additional, and Miller, Linda A., additional

Published
2020
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41. Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae

Author

Scangarella-Oman, Nicole E., primary, Hossain, Mohammad, additional, Dixon, Paula B., additional, Ingraham, Karen, additional, Min, Sharon, additional, Tiffany, Courtney A., additional, Perry, Caroline R., additional, Raychaudhuri, Aparna, additional, Dumont, Etienne F., additional, Huang, Jianzhong, additional, Hook, Edward W., additional, and Miller, Linda A., additional

Published
2018
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43. Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

Author

O'Dwyer, Karen, primary, Spivak, Aaron T., additional, Ingraham, Karen, additional, Min, Sharon, additional, Holmes, David J., additional, Jakielaszek, Charles, additional, Rittenhouse, Stephen, additional, Kwan, Alan L., additional, Livi, George P., additional, Sathe, Ganesh, additional, Thomas, Elizabeth, additional, Van Horn, Stephanie, additional, Miller, Linda A., additional, Twynholm, Monique, additional, Tomayko, John, additional, Dalessandro, Marybeth, additional, Caltabiano, Madelyn, additional, Scangarella-Oman, Nicole E., additional, and Brown, James R., additional

Published
2015
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47. Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections

Author

O'Dwyer, Karen, Spivak, Aaron T., Ingraham, Karen, Min, Sharon, Holmes, David J., Jakielaszek, Charles, Rittenhouse, Stephen, Kwan, Alan L., Livi, George P., Sathe, Ganesh, Thomas, Elizabeth, Van Horn, Stephanie, Miller, Linda A., Twynholm, Monique, Tomayko, John, Dalessandro, Marybeth, Caltabiano, Madelyn, Scangarella-Oman, Nicole E., and Brown, James R.

Abstract

ABSTRACTGSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coliisolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coliisolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.)

Published
2014
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48. Multicenter Investigation of Gepotidacin (GSK2140944) Agar Dilution Quality Control Determinations for Neisseria gonorrhoeaeATCC 49226

Author

Jones, Ronald N., Fedler, Kelley A., Scangarella-Oman, Nicole E., Ross, James E., and Flamm, Robert K.

Abstract

ABSTRACTGepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a new class of type IIA topoisomerase inhibitors with activity against many biothreat and conventional pathogens, including Neisseria gonorrhoeae. To assist ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory quality assurance investigation determined the reference organism (N. gonorrhoeaeATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.8% of gepotidacin MIC results at the 0.5 μg/ml mode).

Published
2016
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49. Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeaeHollow-Fiber In VitroInfection Model

Author

VanScoy, Brian D., Scangarella-Oman, Nicole E., Fikes, Steven, Min, Sharon, Huang, Jianzhong, Ingraham, Karen, Bhavnani, Sujata M., Conde, Haley, and Ambrose, Paul G.

Abstract

Multidrug-resistant Neisseria gonorrhoeaehas emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeaewas examined using a 7-day hollow-fiber in vitroinfection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens. Study drug concentration-time profiles were simulated in the in vitrosystem for a single oral 0.

Published
2020
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50. In VitroActivity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

Author

Scangarella-Oman, Nicole E., Ingraham, Karen A., Tiffany, Courtney A., Tomsho, Lynn, Van Horn, Stephanie F., Mayhew, David N., Perry, Caroline R., Ashton, Theresa C., Dumont, Etienne F., Huang, Jianzhong, Brown, James R., and Miller, Linda A.

Abstract

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints.

Published
2020
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