Abstract Background The increasing prevalence of obesity worldwide merits an examination of the efficacy and safety profiles of agents dosed by weight. Methods Data for patients (n = 1037) were obtained from the pooled IGNITE1 and IGNITE4 randomized double-blind trials in which patients with complicated intra-abdominal infections received eravacycline 1 mg/kg (actual body weight [ABW]) every 12 hours or comparator (ertapenem 1 g every 24 hours or meropenem 1 g every 8 hours) intravenously. This post hoc analysis evaluated clinical cure rates, adverse events, and drug discontinuation rates stratified by body mass index (BMI) categories of BMI >40 kg/m2 (Obese, Class III), BMI 35–39.9 kg/m2 (Obese, Class II), BMI 30–34.9 kg/m2 (Obese, Class I), BMI 25–29.9 kg/m2 (Overweight), BMI 18.5–24.9 kg/m2 (Healthy weight), and BMI <18.5 kg/m2 (Underweight). Results Clinical cure rates were high across BMI categories and ranged from 82% to 94% in the eravacycline group and 88.5%–100% in the comparator group. Similar cure rates were observed among eravacycline-treated healthy weight (126/134; 94%), overweight (127/146; 87%), and obese (BMI ≥30 kg/m2; 110/129; 85.3%) patients. In the comparator group, a similar proportion of patients demonstrated clinical response (healthy weight [132/145; 91%], overweight [130/144; 90.3%], and obese [115/129; 89.1%]). Of the treatment-emergent adverse events that occurred in eravacycline-treated obese patients, a larger proportion were gastrointestinal-related (ie, nausea and vomiting); however, discontinuation rates were low and similar between eravacycline and carbapenems. Conclusions This post hoc analysis demonstrates the therapeutic utility and acceptable safety profile of eravacycline dosed by ABW in obese patients (BMI ≥30 kg/m2).

Abstract Background Eravacycline (ERV) is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The purpose of this study was to describe the in vitro activity of ERV against Gram-negative pathogens, including multi-drug resistant (MDR) isolates, collected in 2018. Methods Isolates were collected during 2018 from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using the most updated CLSI breakpoints, except for ERV and tigecycline (TGC) where FDA breakpoints established in 2018 and 2005 respectively, were used. MDR was defined as resistance to ≥3 antibiotics from aztreonam, a carbapenem (meropenem or ertapenem [ETP]), cefepime/cefotaxime/ceftazidime/ceftriaxone (any one), gentamicin, levofloxacin, piperacillin-tazobactam TZP, tetracycline or TGC. Results Summary MIC data for ERV and select comparators are shown in the Table. ERV MIC90 for all-Enterobacteriaceae was 0.5 μg/ml and for MDR-Enterobacteriaceae was 1μg/ml. The susceptibilities for all-Enterobacteriaceae were 93%, 95%, 93% and 82% for ERV, TGC, ETP and TZP, respectively. ERV further demonstrated higher rates of susceptibility than ETP and TZP against MDR-Enterobateriaceae, 81% vs 71% vs 38%. ERV MIC50/90 for carbapenem-resistant Acinetobacter baumannii (CRAB) were 4-fold lower than TGC. Table Conclusion ERV in vitro activity was demonstrated and comparable susceptibility rates were observed for clinically important Gram-negative pathogens, including resistant isolates. Overall, ERV MIC90 values were 2- to 8- fold lower than TGC. this study further highlights the in vitro activity of ERV against Gram-negative pathogens identified in patients with cIAI. Disclosures Virgil Lijfrock, PharMD, Tetraphase (Employee) Steven Morgan, PharMD, Tetraphase Pharmaceuticals (Employee) Sara Hwang, PharMD, Tetraphase Pharmaceuticals (Employee) Ekaterina Efimova, PharMD, Tetraphase Pharmaceuticals (Employee) Kenneth Lawrence, PharmD, Tetraphase Pharmaceuticals (Employee) Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Ian Morrissey, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator)

Durlobactam (DUR; also known as ETX2514) is a novel beta-lactamase inhibitor with broad activity against Ambler class A, C, and D beta-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii . The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a co-hort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR rang-ing from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug in-teraction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii .

Background. Expert guidelines discourage use of antipseudomonal B-lactams and fluoroquinolones in lower-risk patients with community-acquired complicated intra-abdominal infection (CA cIAI). Compliance with these recommendations across US hospitals is unclear. This study sought to determine treatment patterns and associated outcomes among adult hospitalized lower-risk patients with CA cIAI. Methods. A study using data from the Premier I Iealthcare Database (10/2015-12/2017) was performed. Inclusion criteria: age >= 18 years; hospitalized; had a cIAI at admission; and received antibiotics within the first 4 hospital days. Patients were excluded if they were high risk, were transferred from another health care facility, had a recent hospital admission, or received dialysis within 30 days of admission. Empiric antibiotic treatment patterns and associated outcomes were quantified. Results. Overall, 46 722 (66%) patients with cIAIs met the lower-risk CA IAI study criteria. Among lower-risk CA IAI patients, the mean (SD) age was 53.4 (18.2) years, and 71% had a Charlson Comorbidity Index score of 0. The most common diagnosis was acute appendicitis with peritonitis (59.7%). Among lower-risk CA IAI patients, 54% received piperacillin/tazobactam, 20% received a fluoroquinolone (FQ), 11% received ceftriaxone, and 7% received ampicillin/sulbactam. Overall, the median hospital length of stay was 4 days and median costs were $12 345 USD. Nearly 90% of patients were discharged home, and <1% died. Outcomes were similar across all empiric treatments received. Conclusions. Overuse of antipseudomonal beta-lactams and fluoroquinolones was commonplace among lower-risk CA IAI patients. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics.

Objectives: To determine antimicrobial nonsusceptibility rates for Enterobacteriaceae and Acinetobacter spp. in US hospitals. Methods: We analyzed antimicrobial susceptibilities of non-duplicate Enterobacteriaceae and Acinetobacter spp. isolates reported in 2017 from 375 US hospitals in the BD Insights Research Database. Logistic and Poisson regression modeling methods were used to estimate proportions of resistant isolates and rates per 1000 hospital admissions. National projections were generated based on raking (weighting) methods. Results: The nationwide proportions of resistant isolates in inpatients were an estimated 12.6%, 6.6%, and 1.2% for Enterobacteriaceae with extended-spectrum beta-lactamase (ESBL), multidrug resistant (MDR), and carbapenem-nonsusceptible (Carb-NS) phenotypes, respectively, and 42.4% and 34.5% for Acinetobacter spp. with MDR and Carb-NS phenotypes. Resistance varied by geographic region and hospital size/type. Estimated nationwide rates per 1000 hospital admissions ranged from a high of 7.1 for ESBL Enterobacteriaceae to a low of 0.3 for Carb-NS Acinetobacter spp. The estimated number of isolates occurring in US inpatients each year was 290,220 ESBL, 173,984 MDR, and 30,194 Carb-NS for Enterobacteriaceae and 12,274 MDR and 9,991 Carb-NS for Acinetobacter spp. Conclusions: National prevalence estimates suggest high levels of antimicrobial resistance and a substantial number of patients with resistant Enterobacteriaceae and Acinetobacter spp. in US hospitals. (C) 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

AbstractBackgroundCarbapenems are a frequent firstline therapy in complicated intra-abdominal infections (cIAIs). We examined the microbiology, epidemiology, and outcomes among patients hospitalized in the United States with culture-positive cIAIs in the context of their exposure to empiric carbapenem treatment (ECT).MethodsWe performed a multicenter retrospective cohort study of Premier database of ~180 hospitals, 2013–2017. Using an International Classification of Diseases (ICD)-9/10-based algorithm, we identified all culture-positive adult patients hospitalized with cIAI and examined their microbiology, epidemiology, and outcomes.ResultsAmong 4453 patients with cIAIs, 3771 (84.7%) had a gram-negative (GN) and 1782 (40.0%) a gram-positive organism; 1185 (26.6%) received ECT. Compared with those on non-ECT, patients on ECT were less frequently admitted from home (82.5% vs 86.0%) or emergently (76.0% vs 81.4%; P < .05 for each); E. coli were less frequent, whereas P. aeruginosa and Enterococcus spp. were more prevalent and resistance to third-generation cephalosporins (C3R; 10.1% vs 5.1%; P < .001) and carbapenems (CR; 3.6% vs 1.2%; P < .001) was more common. In adjusted analyses, ECT was associated with no rise in mortality, shorter postinfection length of stay (–0.59 days; 95% confidence interval [CI], –1.15 to –0.03), but higher postinfection costs ($3844; 95% CI, $1921 to $5767) and risk of Clostridioides difficile (odds ratio, 2.15; 95% CI, 1.02 to 4.50).ConclusionsAmong patients hospitalized with cIAI, the majority were gram-negative. Despite a 10% prevalence of C3R, fully one-quarter of all empiric regimens contained a carbapenem. ECT was a marker for slightly lower postinfection length of stay, but higher costs and risk of hospital complications.

Abstract Background Current cIAI guidelines recommend that broad-spectrum antibiotics (abs) like anti-pseudomonal β-lactams should be reserved for “high-risk” CO cIAI patients. Fluoroquinolone (FQ) use is also discouraged in geographic areas with a high incidence of FQ-resistance. Compliance with these recommendations are unclear as there are limited data on empiric treatment (tx) patterns for adult patients with cIAI across US hospitals. This study sought to evaluate empiric tx patterns for patients with CO LR cIAI and assess compliance with cIAI guideline recommendations. Methods A retrospective multi-center study using data from the Premier Research Database (October 2015–December 2017) was performed. Inclusion criteria: age ≥ 18 years; hospitalized; primary cIAI diagnosis and a cIAI surgical procedure or a secondary cIAI diagnosis and cIAI surgical procedure within 5 days of admission; and received an ab within first 4 hospital days. For patients with multiple cIAI admissions, only the first cIAI was considered. Apt was classified as high-risk (HR) if they met any one of the following criteria: sepsis, severe sepsis, septic shock; ≥3 components of sepsis; or ≥2 two physiologic risk factors (age ≥ 70 years, malignancy, kidney dysfunction, hepatic dysfunction, hypoalbuminemia, and significant cardiovascular compromise). Empiric tx was abs received during the first 4 hospital days. Incidence of empiric tx regimen including one of the following abs was determined among LR patients: piperacillin/tazobactam (TZP), meropenem (MER), cefepime (CFP), and FQ. Results Overall, 70,275 patients met study criteria; 11,382 (16%) were HR and 58,893 (84%) were LR. Among LR CO cIAI patients, the mean (SD) age was 54.3 (18.1), 52% were male, and the median (IQR) for Charlson Comorbidity Index was 0 (0–1). The most common diagnosis among LR patients was acute appendicitis with peritonitis (53%). The 10 most common empiric antibiotics administered are shown in table. Among LR patients, 52% received TZP, 3% received MER, 3% received CFP, and 20% received a FQ; 8% received ≥2 of these agents. Conclusion Overuse of non-guideline concordant broad-spectrum abs was commonplace among CO cIAI patients classified as LR. These findings can serve as the basis for an antimicrobial stewardship initiative in hospitals aspiring to reduce the use of broad-spectrum antibiotics. Disclosures All authors: No reported disclosures.

Abstract Background Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. Methods IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4–14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25–31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. Results Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, –0.5%; 95% confidence interval [CI], –6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, –4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI –2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. Conclusions Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. Clinical Trials Registration NCT01844856.

Abstract Background Complicated intra-abdominal infections (cIAI) remain an important cause for hospitalization. Evidence-based guidelines recommend reserving broad-spectrum antibiotic coverage for high-risk cases in order to reduce overuse of certain antibiotic classes, particularly in the face of emerging carbapanem resistance. We examined the factors associated with use of empiric carbapenem treatment (ECT) among hospitalized patients with cIAI. Methods We performed a multicenter retrospective cohort study in the Premier database of approximately 180 hospitals, 2013–2017. Using an ICD-9/10 based algorithm including a requirement for a laparotomy/laparoscopy, we identified all adult patients hospitalized with cIAI and included those with a positive blood or abdominal culture. We derived and tested a multivariable logistic regression model to examine predictors of ECT. Results Among 321,317 hospitalized patients with cIAI, 4,453 (1.4%) were culture-positive, 1,185 (26.6%) of whom received ECT. Among those given ECT, >50% (682) had no risk factors for resistance, and in only 120 (10.1%) was an organism resistant to a third-generation cephalosporin (C3R extended spectrum β-lactamase [ESBL] phenotype) isolated. The top 5 variables associated with ECT use were: pre-cIAI anti-fungal therapy (OR 2.57, 95% CI 1.91, 3.45) urgent (vs. emergent) admission (OR 1.56, 95% CI 1.21, 2.01), corticosteroids (OR 1.50, 95% CI 1.13, 1.99), ICU admission (OR 1.46, 95% CI 1.17, 1.82), and presence of sepsis/septic shock (OR 1.43, 95% CI 1.18, 1.74). The model had a moderately good fit (c-statistic = 0.683; 95% CI (0.665, 0.700), Hosmer-Lemeshow P value = 0.411). Conclusion Among patients hospitalized with a cIAI, 26.6% received ECT despite >50% lacking risk factors for resistance, and an only 10% prevalence of C3R in this cohort. This suggests that there remains an opportunity for carbapanem-sparing strategies. Further stratification of the risk for resistance is needed among patients with markers of high illness severity, such as those identified in our model. Disclosures All authors: No reported disclosures.

Background Trends in antimicrobial resistance help inform infection control efforts. We examined trends in resistance for Enterobacteriaceae and Acinetobacter spp. from 2013 to 2017 in hospitalized US patients. Methods We analyzed antimicrobial susceptibility of non-duplicate isolates in hospitalized patients (not limited to hospital-acquired infections) in the US BD Insights Research Database. Resistance profiles of interest were extended-spectrum beta-lactamase (ESBL)-producing, multidrug resistant (MDR), and carbapenem-nonsusceptible (Carb-NS) phenotypes of Enterobacteriaceae, and MDR and Carb-NS Acinetobacter spp. Time series models were used to evaluate the patterns of resistance trends in rate per 100 hospital admissions and proportion per isolates tested. Results More than 1 million Enterobacteriaceae isolates were obtained from 411 hospitals; 12.05% were ESBL, 1.21% Carb-NS, and 7.08% MDR. Urine was the most common source. For Acinetobacter spp. (n = 19,325), 37.48% were Carb-NS, 47.66% were MDR, and the most common source was skin/wound cultures. Trend analyses showed that the rates of ESBL and Carb-NS Enterobacteriaceae per 100 hospital admissions increased significantly between 2013 and 2017. Rates of MDR Enterobacteriaceae and Carb-NS and MDR Acinetobacter spp. decreased during this time period. Trends in proportions of resistant isolates generally mirrored trends in rates per 100 hospital admissions. MDR Enterobacteriaceae and Carb-NS and MDR Acinetobacter spp. were more common in winter than summer. Conclusions In this large-scale study of patients in US hospitals, rates of ESBL and Carb-NS Enterobacteriaceae per 100 hospital admissions increased between 2013 and 2017. MDR Enterobacteriaceae and MDR and Carb-NS Acinetobacter spp. isolates decreased over this period. These data support continuing infection control and stewardship efforts and the development of new therapeutic options.

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum β-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG; (ii) the US National Strategy for combating antimicrobial-resistant bacteria; (iii) surveillance needs, challenges, and novel technologies; (iv) plasmid-mediated and chromosomally mediated mechanisms of AMR in NG; (v) novel therapeutic (eg, sialic acid analogs, factor H [FH]/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (eg, peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives, and collaborations across academic and commercial research and public health programs.

Abstract Background Eravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated for the treatment of complicated intra-abdominal infections (cIAI) in two Phase 3 (IGNITE1 and IGNITE4) clinical trials. The objective of this analysis was to evaluate microbiological response at the test of cure (TOC) visit in patients with baseline bacteremia who received eravacycline vs. comparators (ertapenem and meropenem). Methods Pooled data from IGNITE1 and IGNITE4 studies were analyzed. All patients enrolled were randomized (1:1) to receive eravacycline (1 mg/kg IV q12h) or ertapenem 1 g IV q24h, (IGNITE1 study) or meropenem 1g IV q8h, (IGNITE4 study) for 4–14 days. Blood (aerobic and anaerobic bottles) and intra-abdominal samples were collected from all patients. Clinical outcome at the TOC visit (28 days after randomization) in the microbiological-intention to treat population (micro-ITT) was the primary efficacy endpoint. Results Four hundred fifteen patients were treated with eravacycline and 431 with comparators of which 39 (9.4%) and 40 (9.3%), respectively, had concurrent bacteremia. Demographic and baseline characteristics were similar among the groups. In the micro-ITT population, the pooled clinical response at the TOC visit for eravacycline vs. comparators was 88.7% and 89.3% (−0.7; 95% CI, −4.9, 3.6), respectively. The baseline pathogens associated with concurrent bacteremia and the microbiological eradication for selected pathogens are presented in Table 1.Table 1. Microbiological Eradication at the Test of Cure Visit by Baseline Pathogen from Blood Specimen Eravacycline, (N = 415), n (%) Comparatorsa, (N = 431), n (%) Gram-negative 14/15 (93.3) 14/15 (93.3) E. coli 5/6 (83.3) 6/7 (85.7) Gram-positive 15/15 (100) 11/11 (100) Streptococcus spp. 8/8 (100) 4/4 (100) Enterococcus spp. 2/2 (100) 5/5 (100) Anaerobes 9/9 (100) 13/14 (92.9) Bacteroides spp. 6/6 (100) 8/8 (100) aMeropenem and ertapenem. Conclusion Eravacycline demonstrated a similar microbiological eradication rate as comparator agents in patients with cIAI associated with secondary bacteremia. Disclosures K. Lawrence, Tetraphase Pharmaceuticals: Employee, Salary. M. Olesky, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. S. Izmailyan, Tetraphase Pharmaceuticals: Employee, Salary. L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary.

Background Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. Methods We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 62 days after treatment, followed by a safety visit 312 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. Results From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. Conclusions The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections.

ETX2514 is a novel BLI with broad spectrum activity against Ambler class A, C and D β-lactamases. The addition of ETX2514 to sulbactam (SUL) in vitro restores SUL activity against Acinetobacter baumannii; SUL-ETX2514 (ETX2514SUL) MIC90 4 mg/L (>1,800 globally diverse, recent clinical isolates). ETX2514SUL is under development for the treatment of A. baumannii infections. A Phase 1, randomized, placebo-controlled trial in 4 parts (15 cohorts) was conducted in 124 healthy subjects to assess the plasma and urine PK of ETX2514 either alone or in combination with SUL and/or imipenem/cilastatin (IMP/CIL): Part A (Cohorts 1–8): ETX2514 single ascending dose (SAD) (0.25–8 g) including an elderly cohort (1 g); Part B (Cohorts 9–12): ETX2514 multiple ascending dose (MAD) (0.25–2 g); Part C (Cohorts 13–14): drug–drug interaction (DDI) between ETX2514 (1 g) with SUL (1 g) and/or IMP/CIL (0.5/0.5 g); Part D (Cohort 15): 11 days of ETX2514SUL (1/1 g) and IMP/CIL (0.5/0.5 g). ETX2514 and SUL were infused over 3 hours (except Cohort 2, 2 hours). Concentrations of ETX2514, SUL, and IMP/CIL were quantified by LC-MS/MS. Non-compartmental analysis was performed using Phoenix WinNonlin v6.4 to determine PK parameters. Results from Parts A, B, and C are complete (112 subjects; ETX2514:Placebo 84:28). ETX2514 was generally safe and well tolerated either alone or in combination with SUL and/or IMP/CIL; no significant changes in hematology, clinical chemistry, vital signs or ECGs were noted. In SAD, ETX2514 demonstrated linear dose proportional exposure across the dose range with renal excretion as a predominant clearance mechanism. ETX2514 demonstrated lower total clearance and renal clearance in the elderly cohort. In MAD, ETX2514 demonstrated linear dose proportional exposure across the dose range studied with minimal accumulation at Day 8. There was no DDI (either way) between ETX2514 and SUL and/or IMP/CIL. ETX2514, either alone or in combination with SUL and/or IMP/CIL, was generally well tolerated at doses predicted to be clinically efficacious. ETX2514 PK is consistent with a therapeutic dose in the range 0.5–1 g IV q6hour in combination with SUL 1 g. Further evaluation of ETX2514SUL to treat A. baumannii infections is warranted. J. Lickliter, Entasis: Investigator, Funding to conduct the clinical trial; K. Lawrence, Entasis Therapeutics: Employee, Salary. J. O’Donnell, Entasis therapeutics: Employee, Salary; R. Isaacs, Entasis Therapeutics: Employee, Salary.

Antimicrobial resistance in Neisseria gonorrhoeae has severely limited the number of treatment options, and the emergence of extended-spectrum cephalosporin resistance threatens the effectiveness of the last remaining recommended treatment regimen. This study assessed the in vitro susceptibility of N. gonorrhoeae to ETX0914, a novel spiropyrimidinetrione that inhibits DNA biosynthesis. In vitro activity was determined by agar dilution against 100 N. gonorrhoeae isolates collected from men presenting with urethritis in the USA during 2012-2013 through the Gonococcal Isolate Surveillance Project. The minimum inhibitory concentration (MIC) that inhibited growth in 50% (MIC50) and 90% (MIC90) of isolates was calculated for each antimicrobial agent. ETX0914 demonstrated a high level of antimicrobial activity against N. gonorrhoeae, including isolates with decreased susceptibility or resistance to currently available agents. The ability of ETX0914 to inhibit the growth of N. gonorrhoeae was similar to ceftriaxone, which is currently recommended in combination with azithromycin to treat gonorrhoea. The data presented in this study strongly suggest that ETX0914 should be evaluated in a clinical trial for the treatment of N. gonorrhoeae. Published by Elsevier B.V.

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.