Co-resistance Among Escherichia coli and Klebsiella pneumoniae Urine Isolates from Female Outpatients with Presumed UTI: A Retrospective US Cohort Study.

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 coli and Klebsiella pneumoniae urinary isolates from US female outpatients aged ≥ 12 years with presumed uncomplicated UTI (uUTI), ≥ 3 months of data (2011-2019), and antimicrobial susceptibility testing results.

Prevalence, regional distribution, and trends of antimicrobial resistance among female outpatients with urine Klebsiella spp. isolates: a multicenter evaluation in the United States between 2011 and 2019.

Background: Antimicrobial resistance research in uncomplicated urinary tract infection typically focuses on the main causative pathogen, Escherichia coli; however, little is known about the antimicrobial resistance burden of Klebsiella species, which can also cause uncomplicated urinary tract infections. This retrospective cohort study assessed the prevalence and geographic distribution of antimicrobial resistance among Klebsiella species and antimicrobial resistance trends for K. pneumoniae in the United States (2011-2019).

Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials.

Background: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections.

Efficacy and Safety of Gepotidacin as Treatment of Uncomplicated Urogenital Gonorrhea (EAGLE-1): Design of a Randomized, Comparator-Controlled, Phase 3 Study.

Introduction: Gonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class, bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility.

Analysis of the effect of urine on the in vitro activity of gepotidacin and levofloxacin against Escherichia coli, Staphylococcus epidermidis, and Staphylococcus saprophyticus.

Gepotidacin is a novel agent in development for treatment of gonorrhea and uncomplicated urinary tract infection. This study determined the effect of urine on the in vitro activity of gepotidacin and levofloxacin against relevant bacteria. Study strains were tested by Clinical and Laboratory Standards Institute broth microdilution and with method variations: CAMHB with 25%, 50%, 100% urine and pH adjusted 100% urine.

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

Background: Increasing prevalence of antimicrobial resistance (AMR), including multidrug resistance (MDR), among Escherichia coli (E. coli) makes treatment of uncomplicated urinary tract infection (uUTI) difficult. We assessed risk factors for fluoroquinolone (FQ)-not-susceptible (NS) and MDR E.

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

Background: Increasing antimicrobial resistance makes treating uncomplicated urinary tract infections (uUTIs) difficult. We compared whether adverse short-term outcomes among US female patients were more common when initial antimicrobial therapy did not cover the causative uropathogen.

Methods: This retrospective cohort study used data from female outpatients aged ≥12 years, with a positive urine culture and dispensing of an oral antibiotic ±1 day from index culture.

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

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 (). 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.

Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections.

Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC).

Activity of Gepotidacin against Gram-Negative and Gram-Positive Anaerobes.

Gepotidacin (formerly GSK2140944) is a first-in-class triazaacenaphthylene antibacterial currently in phase III clinical trials. When tested against Gram-negative (= 333) and Gram-positive (= 225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates at concentrations of 4 and 2 μg/mL, respectively. Given gepotidacin's activity against the anaerobic isolates tested, further study is warranted to better understand the utility of gepotidacin in the treatment of infections caused by clinically relevant anaerobic organisms.

Gepotidacin Pharmacokinetics-Pharmacodynamics against Escherichia coli in the One-Compartment and Hollow-Fiber Infection Model Systems.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action with an spectrum of activity that includes Escherichia coli. Our objectives herein were the following: (i) to identify the pharmacokinetic-pharmacodynamic (PK-PD) index associated with the efficacy of gepotidacin against E. coli; (ii) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction endpoints for E.

Analysis of antimicrobial susceptibility testing methods and variables and in vitro activity of gepotidacin against urogenital Neisseria gonorrhoeae in men.

Gepotidacin is a triazaacenaphthylene antibiotic with activity against Neisseria gonorrhoeae including strains resistant to current agents. We tested 145 N. gonorrhoeae isolates by agar dilution according to Gonococcal Isolate Surveillance Program and Clinical and Laboratory Standards Institute methodologies.

Antimicrobial Resistance Trends in Urine Escherichia coli Isolates From Adult and Adolescent Females in the United States From 2011 to 2019: Rising ESBL Strains and Impact on Patient Management.

Background: Uncomplicated urinary tract infection (uUTI) is predominantly caused by Escherichia coli, which has increasing antimicrobial resistance (AMR) at the United States (US)-community level. As uUTI is often treated empirically, assessing AMR is challenging, and there are limited contemporary data characterizing period prevalence in the US.

Methods: This was a retrospective study of AMR using Becton, Dickinson and Company Insights Research Database (Franklin Lakes, New Jersey, US) data collected 2011-2019.

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

BackgroundThe first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits.

Comparison of minimum inhibitory concentration results for gepotidacin obtained using agar dilution and broth microdilution methods.

Gepotidacin (GSK2140944) is a first in class, novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in Phase 3 clinical development for the treatment of gonorrhea and uncomplicated urinary tract infections (acute cystitis). This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by two reference susceptibility testing methods, agar dilution and broth microdilution, for gepotidacin when tested against various gram-positive and gram-negative organisms. Equivalency, measured as the essential agreement >89.

Relationship between Gepotidacin Exposure and Prevention of On-Therapy Resistance Amplification in a Neisseria gonorrhoeae Hollow-Fiber Infection Model.

Multidrug-resistant has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant was examined using a 7-day hollow-fiber infection model. The study design included both inactive (no-treatment and ciprofloxacin) and active (ceftriaxone) control regimens.

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

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants ( = 22) were confined to the clinic at baseline, received oral gepotidacin at 1,500 mg twice daily for 5 days (on-therapy period; days 1 to 5), and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits.

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.

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. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines.

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.

We evaluated microbiological correlates for the successful treatment of isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.

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

Background: In 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.

Methods: Adult 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.

Multicenter Investigation of Gepotidacin (GSK2140944) Agar Dilution Quality Control Determinations for Neisseria gonorrhoeae ATCC 49226.

Gepotidacin, 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. gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.

A randomized, double-blind, comparative study to assess the safety and efficacy of topical retapamulin ointment 1% versus oral linezolid in the treatment of secondarily infected traumatic lesions and impetigo due to methicillin-resistant Staphylococcus aureus.

Objective: To evaluate the clinical and bacteriological efficacy of topical retapamulin ointment 1% versus oral linezolid in the treatment of patients with secondarily infected traumatic lesions (SITLs; excluding abscesses) or impetigo due to methicillin-resistant Staphylococcus aureus (MRSA).

Design: A randomized, double-blind, double-dummy, multicenter, comparative study (NCT00852540).

Setting: Patients recruited from 36 study centers in the United States.