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AIMS To develop physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models to predict effective doses of gepotidacin in paediatrics for the treatment of pneumonic plague (Yersinia pestis). METHODS A gepotidacin PBPK model was constructed using a population-based absorption, distribution, metabolism and excretion simulator, Simcyp®, with physicochemical and in vitro data, optimized with clinical data from a dose-escalation intravenous (IV) study and a human mass balance study. A PopPK model was developed with pooled PK data from phase 1 studies with IV gepotidacin in healthy adults. RESULTS For both the PopPK and PBPK models, body weight was found to be a key covariate affecting gepotidacin clearance. With PBPK, ~90% of the predicted PK for paediatrics fell between the 5th and 95th percentiles of adult values except for subjects weighing ≤5 kg. PopPK-simulated paediatric means for Cmax and AUC(0-τ) were similar to adult exposures across various weight brackets. The proposed dosing regimens were weight-based for subjects ≤40 kg and fixed-dose for subjects >40 kg. Comparison of observed and predicted exposures in adults indicated that both PBPK and PopPK models achieved similar AUC and Cmax for a given dose, but the Cmax predictions with PopPK were slightly higher than with PBPK. The two models differed on dose predictions in children

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open‐label, multicenter, 2‐part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects. Compared to subjects with normal hepatic function, gepotidacin plasma area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) and maximum concentration significantly increased by 1.7‐ and 1.9‐fold, respectively, in severe hepatic impairment; increases in moderate impairment were not statistically significant. No significant effect was observed for gepotidacin plasma elimination half‐life (geometric mean range, 8.2–9.1 hours) across hepatic groups. Renal clearance increased in moderate (16%) and severe (52%) hepatic impairment vs normal. The mean fraction of gepotidacin dose excreted in urine increased with increasing hepatic impairment (normal, 7.5%; moderate, 11.2%; and severe, 19.9%). Urine gepotidacin concentrations remained high for 12 hours in all hepatic groups after dosing. Saliva gepotidacin concentrations displayed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC and elimination half‐life were not affected by hepatic impairment. These data indicate that gepotidacin dose adjustment is not required in mild to moderate hepatic impairment; severe hepatic impairment may require increases in dosing interval or dose reduction.

Community-acquired pneumonia (CAP) is a common infection with a constantly evolving etiological spectrum. This changing etiology conditions the adequate selection of optimal therapeutic regimens, both in empirical and definitive treatments. In recent years, new antimicrobials have been approved by regulatory authorities for use in CAP, although it is necessary to continue incorporating new antimicrobial agents that improve the activity profile in relation to the appearance of bacterial resistance in certain pathogens, such as pneumococcus, Staphylococcus aureus or Pseudomonas aeruginosa. Delafloxacin, omadacycline and lefamulin are the most recently approved antibiotics for CAP. These three antibiotics have shown non-inferiority to their comparators for the treatment of CAP with an excellent safety profile. However, in the 2019 ATS/IDSA guidelines, it has been considered that more information is needed to incorporate these new drugs into community-based treatment. New antimicrobials, such as solithromycin and nemonoxacin, are currently being studied in Phase III clinical trials. Both drugs have shown non-inferiority against the comparators and an acceptable safety profile; however, they have not yet been approved by the regulatory authorities. Several drugs are being tested in Phase I and II clinical trials. These include zabofloxacin, aravofloxacin, nafithromycin, TP-271, gepotidacin, radezolid, delpazolid, and CAL02. The preliminary results of these clinical trials allow us to assure that most of these drugs may play a role in the future treatment of CAP.

Mycoplasma genitalium has developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is only 75% effective. Gepotidacin, a novel triazaacenaphthylene topoisomerase II inhibitor, blocks bacterial DNA replication. We determined the in vitro activity of gepotidacin alone and in combination with doxycycline against a diverse collection of Mycoplasma genitalium isolates (n = 54). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined by a Vero-cell culture method. Macrolide resistance was present in 31 (57%) isolates, fluoroquinolone resistance in 18 (33%) isolates, and 17 (31%) had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard analysis for two macrolide- and two dual-resistant isolates. Gepotidacin was active against all 54 M. genitalium isolates with median and modal MICs of 0.125 mg/L and MIC90 of 0.25 mg/L (range ≤0.016–0.5 mg/L). No difference in gepotidacin MIC between macrolide-resistant and -susceptible isolates (p = 0.24) or between fluoroquinolone-, dual-resistant and -susceptible isolates (p = 0.2) was demonstrated. Gepotidacin MBCs were available for 44 M. genitalium isolates with median MIC of 0.064 mg/L and median MBC of 0.125 mg/L. All isolates had ≤4-fold difference between MIC and MBC, suggesting bactericidal effect for gepotidacin. Checkerboard analysis indicated synergistic effect for gepotidacin in combination with doxycycline [fractional inhibitory concentration index (ΣFICI) of 0.5] for two isolates and additive/indifference (ΣFICI at 0.62 and 0.75) for two isolates. Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of gepotidacin resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) is among the most frequent causative agents of acute bacterial skin and skin-structure infections (ABSSSI) and has been associated with increased ...

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80-to-1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher than the reference (ratio, 1.15; 90% CI, 1.0113, 1.3047). In the healthy adult (n = 16) and adolescent (n = 17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose or 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo was administered. The single-dose mean Cmax was ∼27% higher in adolescents than in adults, and area under the concentration-time curve (AUC) values were comparable in both populations. After 2 doses were administered, the mean Cmax values were similar for both age groups, and the mean AUC was ∼35% higher in adolescents than in adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar for both age groups. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy. (This study has been registered at ClinicalTrials.gov under identifiers NCT02853435 and NCT04079790.)

Rising levels of antibiotic resistance in uncomplicated N gonorrhoeae infection have led to changes in recommended treatment and suggestions for new management paradigms. It is, however, unclear how these new approaches to treatment should be reflected in managing gonococcal pelvic inflammatory disease (PID). Gonorrhoea remains an important but relatively uncommon cause of PID for which treatment is often commenced prior to identification of the causative organisms. Those at highest risk (severe symptoms, partner with gonorrhoea, gram negative diplococci on microscopy) should have therapy which includes cover for N gonorrhoeae. Newer agents, such as lefamulin, gepotidacin and zoliflodacin have not been evaluated in women with pelvic infections but frequently have a wide spectrum of activity covering not just gonorrhoea but many of the other bacteria associated with PID, and achieve good tissue levels in the upper genital tract. However, optimal dosing regimens for PID to achieve clearance of infection but minimise the risk of developing future resistance need to be determined.

Background The 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. Aim To investigate how POCTs detecting Neisseria gonorrhoeae resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin. Methods We use individual-based stochastic simulations to formally investigate the aim. Results The 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%. Conclusion Mutation 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.

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.

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., 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

Background The discovery of antibiotics several decades ago was a defining moment in history. They were used to treat previously incurable diseases and save many lives. However, the use of antibiotics is not benign. Antibiotic resistance occurs due to the natural evolution of bacteria and gene transfer between bacteria via vertical and horizontal routes, resulting in protective mechanisms that render antibacterial agents ineffective. Aim of the review To list and describe current, novel pipeline antibiotics indicated for multidrug-resistant gram-negative bacteria. This review discusses the limited number of novel pipeline drugs available to combat the rapidly increasing number of multidrug-resistant bacteria and the need for initiatives to research and discover more novel antibiotics. Method A search of MEDLINE/PubMed using the search terms antibacterial pipeline OR antibiotic pipeline including publications between 1 January 2018 through 23 January 2020 resulted in 230 items. The results obtained were narrowed by adding the search term AND multi-drug resistant which resulted in 12 items. Then, ClinicalTrials.gov was searched for phase 2–3 “interventional” trials registered between 1 January 2018 and 23 January 2020 with the status “recruiting” or “completed” function and including World Health Organization-defined priority pathogens in the “condition or disease” field. The search process was then completed by introducing the term antibacterial agents in the “other terms” field. The trials search and selection resulted in 13 items. Relevant English-language studies and those conducted in humans were considered. Those drugs belonging to new antibiotic classes or to antibiotic classes already known but with new chemical structure were defined as “novel antibiotics”. Results The studies selected and reviewed were those referring to a novel antibiotics. Thus, from MEDLINE/PubMed, we found only 1 item referred to a novel chemical class (Murepavadin n = 1). From ClinicalTrials.gov a total of 4 citations were identified (Ftortiazinon n = 1, Zoliflodacin n = 1, Gepotidacin n = 1, ETX2514 + sulbactam n = 1). Conclusion The antibiotics annually approved by the Food and Drug Administration (FDA) mostly belong to existing classes of antibiotics and have specific indications, limiting their use in many multidrug-resistant infections. There are limited novel drug classes targeting gram-negative infections in the pipeline. Providers must be vigilant with the use of current antibiotics, especially until research and development (R&D) advancements are made.

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., 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.)

In this phase 2 study, single oral doses of gepotidacin were ≥95% effective for bacterial eradication in culture-proven uncomplicated urogenital gonorrhea. New antibiotics for drug-resistant Neisseria gonorrhoeae are urgently needed. With additional evaluation, gepotidacin may provide an alternative therapeutic option., 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. 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. Results The 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. Conclusions This 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 Registration NCT02294682.

Background Gepotidacin (GSK2140944) is a first in class novel oral triazaacenaphthylene bacterial topoisomerase inhibitor. In this study, we evaluated the potential impact of orally administered gepotidacin on the human microbiome, across three body-sites and at three specific time-points, as an exploratory endpoint in a Phase 2a clinical trial for the treatment of uncomplicated Urinary Tract Infection (uUTI) (ClinicalTrials.gov: NCT03568942). Methods Through DNA sequencing of the 16S rRNA variable region 4, we analyzed samples collected with consent from study subjects from the gastrointestinal tract or GIT (stool), pharyngeal cavity (saliva swabs) and vagina (vaginal swabs). Samples were taken at three time points which were pre-dosing (Day 1), end of dosing (Day 5) and follow-up visit (Day 28 ±3 days). A total of 156 samples were collected and 141 samples passed quality control criteria for DNA sequence analyses. Using a rigorous computational work-flow, changes in microbiome diversity and relative abundances of microbial species were quantified. Results Time series analyses showed that microbiota alpha diversity dropped, relative to pre-dose, by the end of gepotidacin dosing but trended a return trajectory to original pre-dose levels by the follow-up visit, for all body sites (Figure). However, the character and extent of the microbiota changes varied by location. The relative ordering from least to greatest changes in microbiota diversity of body sites is vaginal, pharyngeal and GIT. We found no statistically significant occurrences of pathogen related taxa, such as Clostridioides or Enterobacterales spp., at the final timepoints. Conclusion Since gepotidacin is both orally dosed and elimination includes the biliary route, it was predicted to affect the GIT microbiome, however changes in the distal pharyngeal and vaginal microbiota were also observed. Gepotidacin alteration of the endogenous microbial community appears to be temporary and reversible as microbiota diversity rebounded to near pre-dosing status within a period of several weeks. Our study illustrates how microbiome analyses in antibiotic clinical studies can quantify patterns of microbiota disruption and recovery. Disclosures Andrea Nuzzo, PHD, GlaxoSmithKline (Employee) Stephanie Van Horn, B.Sc., GlaxoSmithKline (Employee) Christopher Traini, PHD, GlaxoSmithKline (Employee) Caroline R. Perry, PhD, GlaxoSmithKline (Employee) Etienne Dumont, MD, GlaxoSmithKline (Employee) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) David Gardiner, MD, GlaxoSmithKline (Employee) James R. Brown, PhD, GlaxoSmithKline (Employee)

Background Gepotidacin (GEP) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor targeting both bacterial DNA gyrase and topoisomerase IV by a different mechanism from fluoroquinolone antibiotics. Although in vitro frequency of resistance to GEP in Neisseria gonorrhoeae (NG) is low, during a phase 2 trial, clinical resistance to gepotidacin in NG emerged in a subset of fluoroquinolone-resistant NG isolates that contained a pre-existing ParC D86N mutation by introduction of a new GyrA A92T mutation. The objective of this study was to evaluate the role of GyrA A92T & Parc D86N mutations in resistance to GEP. Methods We utilized the high frequency of natural transformation to introduce GyrA A92T and ParC D86N mutations, individually and in combination, into NG isolates either with GyrA S91F D95G mutations or with wild type (WT) GyrA by selection on ciprofloxacin (CIP) or GEP to generate isogenic strains for susceptibility evaluation. Results Results are summarized in enclosed table. Overall, GyrA A92T and ParC D86N mutations alone did not confer a significant (>4-fold) increase in GEP MIC; whereas together they gave >16-fold increases in GEP MIC. Importantly, quinolone target mutations (GyrA S91F D95G and ParC D86N) together showed no significant effect on the GEP MIC; while they gave >1000-fold increase in CIP MIC. As expected, GyrA A92T and ParC D86N mutations alone or together in WT GyrA background had no significant effect on CIP susceptibility. Susceptibility of isogenic NG strains to gepotidacin and ciprofloxacin Conclusion Our results indicated that unlike fluoroquinolones that primarily target DNA gyrase in NG, there is no obvious primary target for GEP, supporting well-balanced dual targeting of DNA gyrase and topoisomerase IV by GEP in NG. Though, the pre-existing ParC D86N mutation is a potential risk marker for clinical resistance development, as this mutation compromises dual targeting of GEP, our studies provide mechanistic insight for appropriate clinical dose selection to potentially suppress further resistance development in this subset of clinical isolates. Disclosures Pan Chan, PhD, GlaxoSmithKline (Employee, Shareholder) Karen Ingraham, MS, GlaxoSmithKline (Employee, Shareholder) Sharon Min, MS, GlaxoSmithKline (Employee, Shareholder) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) Steve Rittenhouse, PhD, GlaxoSmithKline (Employee, Shareholder) Jianzhong Huang, PhD, GlaxoSmithKline (Employee, Shareholder)

Background Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in Phase 3 clinical development for the treatment of gonorrhea and uncomplicated urinary tract infections (UTI). This study reports on interim results from a global surveillance program to monitor the in vitro activity of gepotidacin and comparator agents when tested against contemporary Escherichia coli (EC) and Staphylococcus saprophyticus (SSAP) clinical isolates collected from patients with UTIs worldwide as part of the SENTRY Antimicrobial Surveillance Program. Methods A total of 1,467 EC and 92 SSAP isolates were collected from 73 medical centers located in US (38), Europe (27), Asia-Pacific region (4), and Latin America (4). These isolates were tested for susceptibility by reference methods in a central laboratory (JMI Laboratories). MIC results for gepotidacin and comparators were interpreted as per US FDA and EUCAST criteria. Isolates were from UTIs, 70% of which were from ambulatory, outpatient, emergency, and family practice medical services. Results Gepotidacin (MIC50/90, 2/4 mg/L) displayed activity against 1,467 EC isolates with 98.2% of all observed MICs ≤ 4 mg/L. Susceptibility rates of trimethoprim-sulfamethoxazole (TMP-SMX; MIC50/90, ≤ .12/ > 16 mg/L), ciprofloxacin (MIC50/90, 0.015/ > 4 mg/L), and amoxicillin-clavulanate (MIC50/90, 8/16 mg/L) were 67.1%, 72.9%, and 78.7% (CLSI), respectively. Greater susceptibility against EC isolates was seen for fosfomycin (MIC50/90, 0.5/1 mg/L; 99.0%S), nitrofurantoin (MIC50/90, 16/32 mg/L; 97.4%S), and meropenem (≤ 0.015/0.03 mg/L; 100%S). An ESBL phenotype was observed in 15.3% of EC isolates; gepotidacin (MIC50/90, 2/4 mg/L) remained active against these isolates. Gepotidacin (MIC50/90, 0.06/0.12 mg/L) also was active against 92 SSAP isolates, with 100% of MICs ≤ 0.25 mg/L. Susceptibility of SSAP isolates to TMP-SMX, ciprofloxacin, or nitrofurantoin was greater than 98.8% (CLSI), while fosfomycin showed little activity (MIC50/90, 64/ > 256 mg/L; 98.9% R [EUCAST]). Conclusion Gepotidacin demonstrated potent activity against contemporary Escherichia coli, including ESBL-producing isolates and S. saprophyticus isolates collected worldwide. Table 1 Disclosures S. J. Ryan Arends, PhD, Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support) Deborah Butler, n/a, GlaxoSmithKline (Employee) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)

Background Mycoplasma genitalium has rapidly developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is difficult to source and only 80% effective. Consequently, there is an urgent need for alternative therapies, and to protect new antimicrobials against development and/or spread of resistance. Resistance-guided therapy and combination with other antimicrobials are important tools. Gepotidacin is a novel, first-in-class triazaacenaphthylene topoisomerase II inhibitor inhibiting DNA replication by a mechanism distinct from fluoroquinolones. Limited studies have shown activity against fluoroquinolone susceptible M. genitalium strains Methods We determined the gepotidacin minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) in 54 M. genitalium isolates by the Vero-cell culture method. Macrolide resistance was present in 31 isolates, fluoroquinolone resistance in 18 (33%) isolates; 17 had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard titration for four macrolide or dual resistant isolates. Results Gepotidacin was active against all 54 M. genitalium isolates with median and modal MIC of 0.125 mg/L and MIC90 at 0.25 mg/L (range ≤0.016–0.5 mg/L). No difference in MIC between macrolide resistant and susceptible isolates (p=0.24) or between fluoroquinolone and dual-resistant and susceptible isolates (p=0.2) was demonstrated. Gepotidacin MBC was available for 45 M. genitalium isolates with a median MIC of 0.064 and a median MBC of 0.125 mg/L and all isolates had ≤4 fold difference between MIC and MBC suggesting bactericidal effect. Checkerboard titrations showed synergistic or additive effect with a Fractional Inhibitory Concentration Index (ΣFIC) of 0.5 for two isolates (one macrolide resistant and one dual resistant) and additive effect (ΣFIC at 0.62 and 0.75) for a macrolide and a dual resistant isolate, respectively. Conclusion Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of resistance. Disclosure No significant relationships.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open‐label, parallel‐group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end‐stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects. Dosing in severe renal impairment with and without hemodialysis resulted in significant increases in plasma drug levels and decreases in clearance. The geometric mean elimination half‐life (t½) was minimally impacted (range 9.45 to 11.5 hours) in all the renal‐impairment groups relative to normal renal function. Regardless of renal function, urine gepotidacin concentrations remained considerably high over a 12‐hour period. Saliva concentrations displayed a linear relationship with plasma concentrations. The t½ in saliva was not impacted in the moderate‐impairment and ESRD subjects and was comparable to t½ in plasma. Over a 4‐hour dialysis, approximately 6% of the gepotidacin dose was removed. Overall, subjects with severe renal impairment and ESRD with and without hemodialysis may require adjustment in dose or dosing frequency.

Background Uncomplicated urinary tract infections (uUTIs) are very common, with approximately 11% of women >18 years of age experiencing at least 1 episode of acute cystitis per year [Foxman, 2000]. Multidrug resistance has now emerged at the community level and has made treatment approaches for UTIs more difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. Gepotidacin (GEP), a first-in-class, novel triazaacenaphthylene antibacterial has demonstrated in vitro activity against uropathogens, including E. coli. With its unique ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, GEP warrants further study as a potential opportunity to address an unmet medical need by providing a new and effective oral treatment option for acute cystitis. Methods All participants received oral GEP 1500 mg BID for 5 days (total of 10 doses) and PK sampling was performed on Days 1–5. Results GEP was rapidly absorbed with median Tmax values of 1.50 to 1.92 hours. Steady-state was attained by Day 3 with moderate accumulation in plasma following BID dosing (1.4 fold), which is consistent with an effective elimination half-life of 6.6 hours. Steady-state urine trough levels were high and remained above an MIC of 4 µg/mL over 12 hours. Approximately 20% of the dose was excreted in urine over the 12-hour dosing interval on Day 1, which increased to 31% on Day 4. Urinary AUC24hr (11945 µg hours/mL) was higher than the free plasma AUC24hr (39.4 µg hours/mL). Slightly higher GEP plasma and urine exposures were observed in uUTI patients compared with Phase I healthy subjects. Conclusion Oral dosing of 1500 mg BID produces urine GEP exposures that exceed free plasma exposures by ~300-fold. Urine concentrations were also higher than the GEP MIC90 values for common UTI pathogens, such as E. coli (MIC90 = 4 µg/mL), suggesting that GEP warrants further clinical study for the treatment of uUTI. Disclosures All authors: No reported disclosures.

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 (88.8% of gepotidacin MIC results at the 0.5 μg/ml mode).

Introduction Mycoplasma and Ureaplasma spp. are important pathogens of the respiratory and urogenital tracts. Antimicrobial resistance limits treatment options. Gepotidacin (GEP), a novel triazaacenaphthylene topoisomerase II inhibitor that inhibits DNA replication by a mechanism and target distinct from fluoroquinolones was tested against 85 isolates of Mycoplasma pneumoniae (Mp), Mycoplasma hominis (Mh), Mycoplasma genitalium (Mg), Ureaplasma parvum (Up), and Ureaplasma urealyticum (Uu) in comparison to azithromycin (AZI), clindamycin (CLI), tetracycline (TET), levofloxacin (LEV), and moxifloxacin (MOX). Organisms tested included strains known to be resistant to TET, LEV, and/or AZI. This work was supported by GSK and funded through OTA HHSO100201300011C with HHS/BARDA. Methods MICs were determined using broth microdilution in accordance with Clinical and Laboratory Standards Institute Guidelines. Results GEP was active against 25 Mp, MIC range 0.032–0.125 µg/ml, including 5 that were AZI-resistant, with MIC90 (0.125 µg/ml), equivalent to MOX. GEP was active against 10 Mg. MIC90 (0.032 µg/ml) was 4-fold 3 dilutions > MICs, indicating bacteriostatic effect. Conclusion GEP warrants further study to treat infections due to Mycoplasma spp., particularly organisms resistant to other antimicrobials as it was active against isolates resistant to AZI, TET, LEV, and/or MOX.

Introduction Gonorrhoea is currently the second most common bacterial sexually transmitted infection and represents a serious public health threat. The increasing antimicrobial resistance in Neisseria gonorrhoeae (GC) to currently available therapies is driving an urgent need for new novel agents. Gepotidacin (GEP) is a novel, first in class triazaacenaphthylene antibacterial which inhibits bacterial DNA replication. This multicenter (11 US and 1 UK) trial evaluated GEP as a single oral dose in men and women. Methods Patients with signs and symptoms of urogenital gonorrhoea, a prior culture or nucleic acid amplification test (NAAT) positive for GC, a urethral Gram stain with intracellular diplococci, or who had sexual contact with an individual diagnosed with gonorrhoea in the past 14 days were eligible for enrollment. Participants were randomised 1:1 to receive either 1.5g or 3g GEP orally. The primary efficacy endpoint was culture confirmed microbiological eradication at test-of-cure (TOC) visit 3–7 days post dose. Results 106 patients (101 men and 5 women) were randomised and 105 received treatment. Baseline GC isolates were identified in 69 (65%) urogenital, 3 (3%) pharyngeal, and 4 (4%) rectal specimens. Microbiological success was achieved by 97% and 95% of subjects with urogenital GC in the 1.5g and 3g treatment groups, respectively. Isolates from 2 subjects developed resistance to GEP between baseline and TOC. The most common GEP-related AEs were gastrointestinal (diarrhoea, flatulence, abdominal pain and nausea) with the majority being mild or moderate in intensity. Treatment-related AEs of moderate intensity occurred with a higher incidence in the 3g treatment group than the 1.5g treatment group (15% and 10%, respectively). There were no AEs that led to study withdrawal and no SAEs were reported. Conclusions Both the GEP 1.5g and 3g single doses eradicated urogenital GC with microbiological success rates of 29/30 (97%) and 37/39 (95%), respectively. The data support further development of GEP in this indication. Support: This study was supported by GSK (BTZ116576; NCT02294682). This project was funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced. Research and Development Authority (BARDA), under agreement # HHSO100201300011C

Introduction Gepotidacin (GEP), a novel triazaacenaphthylene antibacterial, inhibits bacterial DNA replication. A Phase 2 study evaluated GEP as a single oral dose (1.5 or 3g) in subjects with urogenital gonorrhoea. Methods Pre-dose specimens were obtained for culture and susceptibility testing by agar dilution. Microbiological success (MS), was culture confirmed eradication of N. gonorrhoeae (GC) at test-of-cure (TOC), 3–7 days post dose, in the microbiological evaluable (ME) population which consisted of all randomised subjects with culture confirmed urogenital gonorrhoea at baseline, who received any dose of GEP and returned for TOC. Results Against 69 GC isolates recovered from baseline urogenital specimens in the ME population, GEP minimum inhibitory concentration [MIC (µg/mL)] range was ≤0.06–1 and MIC90 was 0.5. Resistance (R) to comparators were 33%, 28%, 20%, 0%, 0% and 0% for ciprofloxacin (CIP), penicillin, tetracycline, ceftriaxone, cefixime and spectinomycin, respectively. 2 isolates had elevated azithromycin MICs (MICs=2). Overall MS was 96% (66/69) in the ME population. PK/PD analysis showed 100% (61/61) MS when the free area under the curve/MIC ratio ( f AUC/MIC) was ≥48. MS decreased to 63% (5/8) at f AUC/MICs ≤24. All isolates from the 3 urogenital failures were CIP-R, had a baseline GEP MIC=1 and a pre-existing D86N mutation in ParC, a critical residue in GEP binding. 2 were treated with a 3g GEP dose ( f AUC/MICs=24) and 1 was treated with a 1.5g GEP dose ( f AUC/MIC=12). 5 additional isolates with D86N were MS (2 at GEP MIC=1, 3 at GEP MIC ≤0.25). Isolates from 2 failed subjects (3g GEP dose) demonstrated R emergence to GEP (MICs increased ≥32 fold) and had an additional mutation (A92T) in GyrA, also located in GEP binding pocket. Conclusion Subjects with f AUC/MICs ≥48 were MS, including 3 with D86N ( f AUC/MICs ≥96). Further study of GEP, in the treatment of gonorrhoea is warranted, including demonstration that higher exposures suppress R in key isolate subsets.

Gepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs). This phase 2, randomized, 2-part, multicenter, dose-ranging, response-adaptive study with optional intravenous-oral switch evaluated the efficacy and safety of gepotidacin for the treatment of Gram-positive ABSSSIs in 122 adult patients in the United States. The study had a double-blind phase (part 1; intravenous [750 mg or 1,000 mg every 12 h {q12h}]) and an open-label phase (part 2; intravenous [750 mg q12h, 1,000 mg q12h, or 1,000 q8h]). The primary endpoint was a composite of efficacy and safety which consisted of the early cure rate and the withdrawal rate due to drug-related adverse events and utilized a clinical utility index for dose selection. At the early efficacy visit (48 to 72 h after the first dose), the 750-mg q12h and 1,000-mg q8h groups met prespecified success criteria for clinical utility in terms of efficacy and safety; however, the 1,000-mg q12h group did not meet these criteria due to observed lower efficacy rates. The most frequently reported adverse events were nausea (20%) and diarrhea (13%). These encouraging phase 2 results demonstrate the potential for gepotidacin to meet the medical need for novel antibacterial agents to treat ABSSSIs due to drug-resistant pathogens through a unique mechanism of action. (This study has been registered at ClinicalTrials.gov under registration no. NCT02045797.)

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, crossover thorough QT study in healthy subjects who were administered intravenous (i.v.) gepotidacin as a therapeutic (1,000-mg) dose and supratherapeutic (1,800-mg) dose, placebo, and 400 mg oral moxifloxacin in 4 separate treatment periods. Gepotidacin caused a mild effect on heart rate, with a largest placebo-corrected change-from-baseline heart rate of 7 and 10 beats per minute at the end of the 1,000-mg and 1,800-mg infusion, respectively. Gepotidacin caused an increase of change-from-baseline QTcF (ΔQTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ΔQTcF (ΔΔQTcF) was 12.1 ms (90% confidence interval [CI], 9.5 to 14.8) and 22.2 ms (90% CI, 19.6 to 24.9) after 1,000 mg and 1,800 mg, respectively. ΔΔQTcF rapidly fell after the end of the infusion, with a mean ΔΔQTcF of 6.1 ms 60 min after the 1,800-mg dose. Exposure-response analysis demonstrated a statistically significant positive relationship between gepotidacin plasma levels and ΔΔQTcF, with a slope of 1.45 ms per μg/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ΔΔQTcF can be predicted to be 11 and 20 ms at the observed mean peak plasma concentration after the infusion of gepotidacin at 1,000 mg (7 μg/ml) and 1,800 mg (13 μg/ml), respectively. In conclusion, gepotidacin caused QT prolongation in this thorough QT study, and a mean effect can be predicted to less than 15 ms at the highest expected plasma concentration, 9 μg/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.)

Background Gepotidacin (GSK2140944) is a first in class novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study was undertaken to determine the effect of various urine parameters on the in vitro activity of gepotidacin and a comparative agent, levofloxacin, against a variety of bacteria. Methods Study strains were tested according to the reference CLSI broth microdilution method using cation-adjusted Mueller–Hinton broth (CAMHB) and the following method variations: CAMHB with 25%, 50%, and 100% urine (not pH adjusted) and 100% urine (pH adjusted to 7.2–7.4, and 8). Quality control strains were concurrently tested each day. Results MIC endpoints in the reference method and in 100% urine were easily determined (i.e., clear buttons of growth up to the first well of no growth). Gepotidacin MIC results are summarized in the table. For E. coli and S. saprophyticus, there was a trend for higher gepotidacin MIC results with the addition of increasing amounts of urine. However, the increase was minimal such that mean dilution differences were ≤ 1.54. Against S. epidermidis, gepotidacin MICs were not significantly impacted by the addition of urine as 100% of urine condition MICs were within ±1 doubling dilution of the reference method MIC. The gepotidacin results for E. coli indicate that the average 1–2 dilution MIC increase observed in the unadjusted 100% pooled urine MIC may be associated with lower pH. A similar increase in levofloxacin MIC results for E. coli were also associated with pH, but at the higher pH of 8.0. In contrast, the increase in MIC observed in both the gepotidacin and levofloxacin S. saprophyticus results in 100% pooled urine do not appear to be a function of pH. Conclusion Overall, the effect of urine on the gepotidacin and levofloxacin MICs was minimal and not inclusive of all strains tested. Disclosures All authors: No reported disclosures.

Background Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro and in vivo efficacy activity against key pathogens, including drug-resistant strains, associated with a range of infections. In a previous absorption, distribution, metabolism, and excretion study for GEP, the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 52.5%, respectively, of [14C]-GEP administered as a single oral dose. GEP was eliminated mainly as parent in urine, accounting for approximately 20% of the administered dose. Elimination via metabolism accounted for a total of 13% to 19% of the dose. Average total intravenous clearance of approximately 43 L/hour and renal clearance (CLr) of approximately 16 L/hour provides a hepatic clearance of 27 L/hour, suggesting that hepatic clearance is a major route of elimination of GEP. Methods Participants with normal and varying degrees of hepatic impairment (HI) received a single oral dose of GEP 1,500 mg. PK collections of blood, urine and saliva were performed. Results Relative to normal hepatic function, GEP Cmax and AUC(0-∞) in plasma were increased by 1.2-fold in subjects with moderate, and between 1.7-fold to 1.9-fold in severe HI. The fraction of dose excreted in urine increased with an increase in hepatic impairment. GEP urine concentrations remained high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma (both total and unbound) concentrations (R2 = 0.76). The geometric mean ratio of saliva AUC to unbound plasma AUC values ranged from 0.746 to 0.839 across all groups. Administration of 1,500 mg oral GEP was generally tolerated. Conclusion An increase in the dosing interval or dose reduction may be required in patients with severe hepatic impairment. Disclosures All authors: No reported disclosures.

Background Gepotidacin (GSK2140944) is a first in class novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study assessed the in vitro activity of gepotidacin and comparators against a collection of 649 Gram-positive and Gram-negative anaerobic bacterial clinical isolates. Methods A total of 649 clinically significant Gram-negative (333) and Gram-positive (316) anaerobic clinical isolates previously collected and frozen at −70°C were tested. Isolates came from North America (315/48.5%) and Europe (334/51.5%) and were collected between 2000 and 2017. Minimum inhibitory concentrations (MICs) for gepotidacin and 6 comparators were determined by agar dilution (AD) for all isolates, and by both AD and broth microdilution (BMD) for Bacteroides spp. according to CLSI guidelines (CLSI M11-A8). Most Lactobacillus spp. tested in this study require anaerobic conditions for growth and were tested by anaerobic AD. Results The in vitro activity results of gepotidacin and comparators are shown in the table below. The gepotidacin MIC90 for all Gram-negative anaerobic isolates tested in this study was 4 µg/mL and for the comparators tested was as follows: ceftriaxone 512 μg/mL, clindamycin >8 μg/mL, imipenem 0.5 μg/mL, metronidazole 2 μg/mL, moxifloxacin 8 μg/mL and piperacillin–tazobactam 16 μg/mL. Gepotidacin had the lowest MIC90 (2 μg/mL) for the Gram-positive anaerobic isolates compared with the other antibiotics tested, with the exception of metronidazole (MIC90 = 0.5 µg/mL). Conclusion Gepotidacin showed in vitro activity against a collection of 649 anaerobic Gram-negative and Gram-positive clinical isolates, with an MIC90 value against all Gram-negative anaerobic isolates of 4 µg/mL, and against all Gram-positive anaerobic isolates of 2 µg/mL. Disclosures All authors: No reported disclosures.

Background GEP, a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens implicated in a range of infections, including drug-resistant strains of E. coli associated with acute cystitis. Methods PK and PD studies were conducted in murine (male CD-1 mice) thigh and kidney infections. The administered doses ranged from 1 to 200 mg/kg SC every 6 hours starting 1-hour post-infection. Infected tissues were evaluated for bacterial burden at 24-h post-infection (baseline controls at 1-hour post-infection). Plasma and tissue samples (kidney or thigh homogenates) were collected at 15, 30, 60, 120, 240 and 360 minutes. A population PK (PopPK) model was built in NONMEM using plasma exposures. Efficacy was determined against E. coli ALL, 997577, ATCC25922, IR5 and NCTC13441 (MICs of 1 to 4 µg/mL) in thigh-infected neutropenic (I-) mice and against E. coli ALL in kidney-infected immunocompetent (I+) and I- mice. The PopPK model was used to determine GEP exposures associated with efficacy. PK-PD analyses were conducted using Phoenix WinNonLin 6.3 (Pharsight). The change in log10 colony-forming units (CFU) from baseline were correlated with free drug (f) AUC:MIC using an inhibitory model from the Phoenix library, and model parameter values for each isolate were used to calculate the plasma fAUC:MIC associated with stasis, 1- or 2-log10 reductions in CFU. Results Plasma PK data were best fit by a 1-compartment IV model with first-order elimination and were similar in I+ vs. I- and thigh- vs. kidney-infected mice. The AUC0-6 of GEP in kidney was approximately 4- to 5-fold higher than in plasma while the AUC0-6 in thigh was approximately half of plasma. In the I- thigh model, median plasma fAUC:MIC ratios for stasis, 1- or 2-log10 reductions in CFU were 11, 16, and 25 (ranges 3–17, 4–25 and 7–40), respectively. Efficacy vs. E. coli ALL was similar in I- mice infected in thigh or kidney. In I+ mice, the PK-PD target was reduced by half. Conclusion Median plasma fAUC:MIC targets ranged from 11 to 25. Higher drug levels in kidney vs. plasma or thigh did not translate into improved efficacy in pyelonephritis vs. thigh-infection models. Disclosures All authors: No reported disclosures.

Background Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens, including drug-resistant strains, associated with a range of infections. Methods This phase IIa single-center study evaluated the safety, tolerability, pharmacokinetics, and efficacy of oral GEP 1,500 mg BID for 5 days in female subjects with acute cystitis. Clean catch mid-stream urine specimens were obtained for quantitative culture by standard methods. Susceptibility testing by CLSI broth microdilution and gradient diffusion (fosfomycin only) was conducted. Inclusion in the microbiological intent-to-treat population (micro-ITT) required growth of a qualifying baseline uropathogen (≥ 105 CFU/mL). Microbiological success was defined as culture-confirmed eradication (no growth, Results Of 22 participants, 8 (36%) had a baseline qualifying uropathogen (5 E. coli, 1 S. saprophyticus, 1 K. pneumoniae, and 1 C. koseri) and were included in the micro-ITT. GEP MICs against the 8 qualifying uropathogens ranged from 0.06 to 4 µg/mL. Two E. coli isolates were multidrug-resistant (defined as resistance to ≥3 antibiotic classes) due to resistance to ampicillin, trimethoprim-sulfamethoxazole and ciprofloxacin/levofloxacin or cefazolin. One additional E. coli isolate was ampicillin-resistant. Of the 8 participants in the micro-ITT, 7 (88%), and 6 (75%) were microbiological successes at the Test of Cure (TOC) and Follow-up Visits, respectively. The one microbiological failure at TOC (E. coli) was due to an unreportable (out of stability) urine specimen. For the 4 participants with available steady-state PK, qualifying Enterobacteriaceae uropathogens and who were microbiological successes at TOC, plasma fAUC24h/MICs ranged from 7 to 90.5 and urine AUC24h/MICs from 1292 to 121,698. The participant with the lowest plasma fAUC/MIC (7) and urine AUC24h/MIC (1292) had a K. pneumoniae with a gepotidacin MIC of 4 µg/mL. Conclusion This first report of microbiological efficacy in the treatment of acute cystitis supports further clinical study of GEP as a first-in-class, novel mechanism of action antibacterial. Disclosures All authors: No reported disclosures.

Background Urinary tract infections (UTIs) are very common, with approximately 11% of women >18 years of age experiencing at least 1 episode of acute cystitis per year. Multidrug resistance, typically associated with nosocomial infections, has now emerged at the community level making treatment options for UTIs more difficult. Gepotidacin (GEP), a first-in-class, novel triazaacenaphthylene antibacterial has demonstrated in vitro activity against uropathogens including E. coli and provides high and sustained urine concentrations. It selectively inhibits bacterial DNA replication through a unique mechanism not utilized by any currently approved antibacterial. GEP presents an opportunity to address an unmet medical need and warrants study as a potential new and effective oral treatment for acute cystitis. Methods This Phase IIa single-center study was designed primarily to evaluate plasma and urine pharmacokinetics (PK) of gepotidacin in female participants with acute cystitis. Safety data and clinical and microbiological efficacy of gepotidacin were also assessed as secondary and exploratory endpoints. All participants received oral gepotidacin 1,500 mg BID for 5 days (total of 10 doses) during clinic confinement. Pretreatment and posttreatment PK collections were performed together with safety, efficacy, microbiological, and exploratory assessments throughout the study. Results Summary of Exploratory Endpoints (ITT Population). Clinical Efficacy: All subjects had significant improvement of clinical symptoms (dysuria, frequency, urgency, lower abdominal pain) within 24 to 48 hours of treatment. Most subjects, (20/22; 90.9%) achieved symptom resolution at test of cure (ToC) and follow-up (F/U). Microbiological eradication was achieved independent of baseline CFU’s (see microbiology abstract). Safety Endpoint: Most common AEs involved the GI tract (diarrhea (18/22 [82%] and nausea 17/22 [77%]). Per investigator observation, tolerance to nausea was observed with repeat dosing. No withdrawal due to AE. There were no clinically relevant trends in safety laboratories, ECG, or vital signs. Conclusion This first report of efficacy and safety in the treatment of acute cystitis supports further study of the clinical use of GEP in this indication. Disclosures All authors: No reported disclosures.

Background Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by 2 reference susceptibility testing methods, agar dilution (AD) and broth microdilution (BMD), for gepotidacin against Gram-positive and Gram-negative organisms. Methods Susceptibility testing for both methods was performed on a total of 733 clinical isolates recovered largely in 2016 from over 120 medical centers worldwide. For N. gonorrhoeae, only the AD method is recommended by CLSI, therefore BMD was performed using Fastidious Broth for comparison purposes. Essential agreement (EA) based on evaluable results was calculated as the number of isolates with MICs within one 2-fold dilution of the reference method divided by the total number of results. Equivalency was defined using the 95% criteria from the FDA’s class II controls document. Results The EA observed for gepotidacin with these 2 methods was 85.8% overall and 98.3% when H. influenzae and N. gonorrhoeae isolates were excluded. Slightly higher gepotidacin MICs were observed when tested by BMD for each of these species/groups; this trend was especially prominent for E. coli and S. pyogenes. Gepotidacin tested against H. influenzae (73.1%) or N. gonorrhoeae (28.6%) species had much lower EAs. Conclusion Equivalency (EA >95%) was established between AD and BMD methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp. and E. coli. However, for N. gonorrhoeae and H. influenzae, equivalency between the 2 methods was not established; therefore, future antimicrobial susceptibility testing for gepotidacin against these organisms should adhere to the methods for which quality control ranges and breakpoints are approved. Disclosures All authors: No reported disclosures.

Neisseria gonorrhoeae, the causative agent of gonorrhoea, has rapidly evolved from an exquisitely susceptible pathogen into a ‘superbug’ with the capacity to exhibit an extensively drug resistant (XDR) phenotype. The threat of untreatable gonorrhoea now looms on the horizon while the arsenal of effective antimicrobial agents diminishes with time. Ceftriaxone remains the mainstay of first-line therapy as a single agent or as the backbone of a dual therapy regimen. The implementation of new assays to facilitate ‘precision’ treatment, based on the prediction of N. gonorrhoeae susceptibility to old anti-gonococcal drugs, may enable sparing use of ceftriaxone in those countries that can afford this technology. A few existing drugs, such as ertapenem, can be repositioned to help manage multi-drug resistant and XDR gonorrhoea. Recent clinical trials involving solithromycin and delafloxacin have generated disappointing results in that both agents failed to show non-inferiority to conventional ceftriaxone-based regimens. At present, zoliflodacin and gepotidacin appear to be the most promising antimicrobial agents in clinical development. Both drugs performed well in eradicating urogenital gonorrhoea in recent Phase 2 trials; however, treatment failures were reported at the oropharyngeal site, which is an important site of infection in men who have sex with men and sex workers. Given this observation, it is unlikely that either of these new agents could be promoted for monotherapy of gonorrhoea. The pre-clinical pipeline remains relatively empty of agents likely to progress to clinical development for gonorrhoea treatment and increased investment into gonorrhoea-specific drug discovery is recommended.