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). METHODS: K. pneumoniae and K. oxytoca urine isolates (30-day, non-duplicate) among female outpatients (aged ≥ 12 years) with presumed uUTI at 304 centers in the United States were classified by resistance phenotype(s): not susceptible to nitrofurantoin, trimethoprim/sulfamethoxazole, or fluoroquinolone, extended-spectrum ß-lactamase-positive/not susceptible; and multidrug-resistant based on ≥ 2 and ≥ 3 resistance phenotypes. Antimicrobial resistance prevalence by census division and age, as well as antimicrobial resistance trends over time for Klebsiella species, were assessed using generalized estimating equations. RESULTS: 270,552 Klebsiella species isolates were evaluated (250,719 K. pneumoniae; 19,833 K. oxytoca). The most frequent resistance phenotypes in 2019 were nitrofurantoin not susceptible (Klebsiella species: 54.0%; K. pneumoniae: 57.3%; K. oxytoca: 15.1%) and trimethoprim/sulfamethoxazole not susceptible (Klebsiella species: 10.4%; K. pneumoniae: 10.6%; K. oxytoca: 8.6%). Extended-spectrum ß-lactamase-positive/not susceptible prevalence was 5.4%, 5.3%, and 6.8%, respectively. K. pneumoniae resistance phenotype prevalence varied (p < 0.0001) geographically and by age, and increased over time (except for the nitrofurantoin not susceptible phenotype, which was stable and > 50% throughout). CONCLUSIONS: There is a high antimicrobial resistance prevalence and increasing antimicrobial resistance trends among K. pneumoniae isolates from female outpatients in the United States with presumed uncomplicated urinary tract infection. Awareness of K. pneumoniae antimicrobial resistance helps to optimize empiric uncomplicated urinary tract infection treatment.

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. METHODS: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed. FINDINGS: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred. INTERPRETATION: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients. FUNDING: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.

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. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea. METHODS: This phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12 years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000 mg 10-12 h apart) or ceftriaxone (500 mg, intramuscular) plus azithromycin (1 g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit. PLANNED OUTCOMES: This trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04010539.

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. coli among US female outpatients. METHODS: This retrospective cohort study utilized data from female outpatients aged ≥ 12 years with E. coli positive urine culture and oral antimicrobial prescription ± 1 day from index. We assessed patient-level factors within 90 and 91-360 days prior to index as predictors of FQ NS (intermediate/resistant) and MDR (NS to ≥ 1 drug across ≥ 3 classes) E. coli: age, prior oral antimicrobial dispensing, prior AMR phenotypes, prior urine culture, and prior hospitalization. RESULTS: Among 1,858 outpatients with urine-isolated E. coli, 369 (19.9%) had FQ NS and 59 (3.2%) had MDR isolates. After multivariable adjustment, independent risk factors (p < 0.03) for FQ NS E. coli were older age, prior FQ NS isolates, prior dispensing of FQ, and dispensing of any oral antibiotic. Independent risk factors (p < 0.02) for MDR were prior extended-spectrum ß-lactamase-producing isolates (ESBL+), prior FQ dispensing, and prior oral antibiotic dispensing. CONCLUSIONS: In women with uUTI due to E. coli, prior dispensing of FQ or any oral antibiotic within 90 days predicted FQ NS and MDR urine E. coli. Prior urine culture with FQ NS isolates and older age were predictive of FQ NS E. coli. Prior ESBL+ was predictive of MDR E. coli. These data could help identify patients at risk for AMR E. coli and inform empiric prescribing.

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. Mean dilution difference (DD) of urine minimum inhibitory concentration (MICs) were <1 dilution of CAMHB MICs with some exceptions: Gepotidacin mean DD: Escherichia coli and Staphylococcus saprophyticus 100% urine (1.5 and 1.2, respectively) and S. saprophyticus pH 7.3 and 8.1 adjusted 100% urine (1.5 and 1.4, respectively); Levofloxacin mean DD: S. saprophyticus pH 7.3 adjusted 100% urine (1.5) and all species pH 8.1 adjusted 100% urine (1.2-1.8). Effects of urine on gepotidacin and levofloxacin MICs was minimal and not inclusive of all strains. Further analysis is warranted to fully assess the impact of urine on gepotidacin activity.

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 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.

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). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies, including in vitro activity, in vivo animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500-mg oral dose twice daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144).

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. Isolate susceptibility to the antimicrobial initially dispensed, patient age, and history of antimicrobial exposure, resistance, and all-cause hospitalization within 12 months of index culture were evaluated for associations with adverse outcomes during 28-day follow up. Outcomes assessed were new antimicrobial dispensing, all-cause hospitalization, and all-cause outpatient emergency department/clinic visits. Results: Of 2366 uUTIs, 1908 (80.6%) were caused by isolates susceptible and 458 (19.4%) by isolates not susceptible (intermediate/resistant) to initial antimicrobial treatment. Within 28 days, patients with episodes caused by not susceptible isolates were 60% more likely to receive a new antimicrobial versus episodes with susceptible isolates (29.0% vs 18.1%; 95% confidence interval, 1.3-2.1; P < .0001). Other variables associated with new antibiotic dispenses within 28 days were older age, prior antimicrobial exposure, or prior nitrofurantoin-not-susceptible uropathogens (P < .05). Older age, prior antimicrobial-resistant urine isolates, and prior hospitalization were associated with all-cause hospitalization (P < .05). Prior fluoroquinolone-not-susceptible isolates or oral antibiotic dispensing within 12 months of index culture were associated with subsequent all-cause outpatient visits (P < .05). Conclusions: New antimicrobial dispensing within the 28-day follow-up period was associated with uUTIs where the uropathogen was not susceptible to initial antimicrobial treatment. Older age and prior antimicrobial exposure, resistance, and hospitalization also identified patients at risk of adverse outcomes.

In Vitro 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 (n = 333) and Gram-positive (n = 225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates at concentrations of 4 and 2 µg/mL, respectively. Given gepotidacin's in vitro 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 In Vitro 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 in vitro 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. coli; and (iii) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-h one-compartment in vitro infection model was used to investigate the first two study objectives, and a 10-day hollow-fiber in vitro infection model was used to evaluate the third objective. For the dose-fractionation studies (objective i) in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug area under the concentration-time curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as the PK-PD index most closely associated with change in bacterial burden (r2 = 0.925). For the dose-ranging studies (objective ii), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/liter) were studied, the magnitude of the median gepotidacin free-drug AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log10 CFU reductions for the pooled data set was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective iii), in which one isolate (E. coli NCTC 13441; gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug AUC/MIC ratios of 275 and greater were sufficient to suppress on-therapy resistance amplification. Together, the data generated from these studies will be useful to support discrimination among candidate dosing regimens for future clinical study.

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. Gepotidacin demonstrated a minimum inhibitory concentration (MIC)50 of 0.25 µg/mL and a MIC90 of 0.5 µg/mL (highest gepotidacin MIC was 1 µg/mL) against the 145 N. gonorrhoeae isolates tested. We also assessed the impact of test variables on antimicrobial susceptibility test results for gepotidacin, ciprofloxacin, and ceftriaxone against 10 N. gonorrhoeae isolates. Media type had the biggest effect but wasn't specific to gepotidacin. Gepotidacin MICs were also affected by inoculum, pH, and 10% CO2. These in vitro data indicate that further study of gepotidacin is warranted for potential use in treating gonorrhea infections and highlight the importance of controlling for media type, inoculum, CO2, and pH when performing MIC testing with gepotidacin.

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. Thirty-day, nonduplicate Escherichia coli urine isolates from US female outpatients (aged ≥12 years) were included. Isolates were evaluated for nonsusceptibility (intermediate/resistant) to trimethoprim-sulfamethoxazole, fluoroquinolones, or nitrofurantoin, and assessed for extended-spectrum ß-lactamase production (ESBL+) and for ≥2 or ≥3 drug-resistance phenotypes. Generalized estimating equations were used to model AMR trends over time and by US census region. RESULTS: Among 1 513 882 E. coli isolates, the overall prevalence of isolates nonsusceptible to trimethoprim-sulfamethoxazole, fluoroquinolones, and nitrofurantoin was 25.4%, 21.1%, and 3.8%, respectively. Among the isolates, 6.4% were ESBL+, 14.4% had ≥2 drug-resistance phenotypes, and 3.8% had ≥3. Modeling demonstrated a relative average yearly increase of 7.7% (95% confidence interval [CI], 7.2-8.2%) for ESBL+ isolates and 2.7% (95% CI, 2.2-3.2%) for ≥3 drug-phenotypes (both P < .0001). Modeling also demonstrated significant variation in AMR prevalence between US census regions (P < .001). CONCLUSIONS: Period prevalence of AMR among US outpatient urine-isolated E. coli was high, and for multidrug-resistance phenotypes increased during the study period with significant variation between census regions. Knowledge of regional AMR rates helps inform empiric treatment of community-onset uUTI and highlights the AMR burden to physicians.

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

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.

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. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the 'stepping-stone' mutation to gepotidacin resistance.AimTo investigate how POCTs detecting Neisseria gonorrhoeae resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.MethodsWe use individual-based stochastic simulations to formally investigate the aim.ResultsThe level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1-13%.ConclusionMutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.

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 >89.9%, was established between the two methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp., and Escherichia coli. However, for Neisseria gonorrhoeae and Haemophilus influenzae, equivalency was not established. Agar dilution remains the sole dilution reference method for determining gepotidacin MICs against N. gonorrhoeae.

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

Multidrug-resistant Neisseria gonorrhoeae has emerged as a threat to global health. The relationship between gepotidacin exposure and prevention of on-therapy amplification of drug-resistant N. gonorrhoeae was examined using a 7-day hollow-fiber in vitro infection 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 vitro system for a single oral 0.5 g ciprofloxacin dose, a single intramuscular 0.25 g ceftriaxone dose, and single or two (8 to 12 h apart) oral gepotidacin doses ranging from 0.75 to 12 g. The initial bacterial burden inoculated in the model was 106 CFU/ml. The gepotidacin, ciprofloxacin, and ceftriaxone broth MIC values for the challenge isolate (N. gonorrhoeae GSK #8) were 0.5, 2, and 0.002 mg/liter, respectively. Samples were collected for enumeration of total and drug-resistant bacterial populations and drug concentrations. The no-treatment control reached a bacterial density greater than 108 CFU/ml over 24 h and remained consistent over the 7-day study period. The bacterial density in the model system of the ciprofloxacin regimen matched that of the growth control throughout the study duration, while the ceftriaxone regimen sterilized the model system by the end of day 1. For gepotidacin, a full dose-response relationship was observed. While failure was observed for the 0.75-, 1.5-, and 3-g single-dose regimens, all gepotidacin single- or divided-dose regimens totaling at least 4.5 g prevented resistance amplification and sterilized the model system. These data are useful to provide gepotidacin dose selection support for treating patients with gonorrhea infections.

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 (n = 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. Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 h postdose. Steady state was attained by day 3. Urinary exposure over the dosing interval increased from 3,742 µg·h/ml (day 1) to 5,973 µg·h/ml (day 4), with trough concentrations of 322 to 352 µg/ml from day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up visits, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥105 CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <103 CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up visits, respectively. Plasma area under the free-drug concentration-time curve over 24 h at steady state divided by the MIC (fAUC0-24/MIC) and urine AUC0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (This study has been registered in ClinicalTrials.gov under identifier NCT03568942.).

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.

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. Staphylococcus aureus accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA), and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 µg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.).

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 Neisseria gonorrhoeae 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 N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90 = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of ≥48 and decreased to 63% (5/8) for fAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).