Shionogi (United States)

The reference method for determining cefiderocol MIC is broth microdilution (BMD) using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB). However, laboratories have reported variable MIC findings and difficulties in determining MIC endpoints. To investigate this, the BMD method was re-evaluated by examining the chelation time for iron depletion of the media and by testing reproducibility using four MHB sources (BD-BBL, BD-Difco, Oxoid, and Merck) and 85 Gram-negative isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii), of which 63 were previously evaluated in vivo. Extending chelation time to 6 h provided optimal iron reduction to ≤0.03 µg/mL for all media. MIC reproducibility was high for each medium source and varied by species (93.3%-99.0% of MIC values within one dilution of modal MIC values); however, different sources of ID-CAMHB produced (reproducible) different modal MIC values for isolates. ID-CAMHB from BD-BBL and BD-Difco showed the best correlation with 96.5% of isolates showing modal MIC values within one dilution between media. MIC values generated with these two media were the most predictive of efficacy in vivo. When trailing was observed, it was seen across all media, and refined reading guidelines were applied to enhance reproducibility of determining the MIC endpoint. The 6-h chelation and the refined reading guidelines for trailing are now incorporated into the Clinical and Laboratory Standards Institute M100 document. When using the BMD method to determine cefiderocol susceptibility, the impact of media should be considered, and based on these results, ID-CAMHB prepared with BD-BBL or BD-Difco is recommended.IMPORTANCEThe reference antibiotic susceptibility testing method for cefiderocol is the broth microdilution method approved by the Clinical and Laboratory Standards Institute in 2016, using iron-depleted cation-adjusted Mueller-Hinton broth. A few manual devices have come to the market replicating this method, but inconsistent results with these devices have been reported. The current study identified the source of Mueller-Hinton broth as a variable in cefiderocol MIC determinations and provides detailed description of the preparation of iron-depleted cation-adjusted Mueller-Hinton broth, and revised reading guidance to improve reproducibility of cefiderocol MIC determinations for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The recommendations made in this study should enhance the reproducibility of cefiderocol broth microdilution susceptibility testing.

An extensive and perplexing plurality of psychometric assesments, experimental-tasks, and biophysical measurement modalities have evolved alongside increasingly biopsychosocial models of behavior and psychopathology. Yet, despite alarming recent increasing rates of mental health problems, cumulative progress regarding the validity and comparative utility of wide-ranging measures to predict, isolate, or explain hallmark features and interacting systems in depression, anxiety, and ADHD remains concerningly enigmatic. Utilizing adolescent (Age 9–14) and parent data when available (combined N=~23,760) across 5 years from the ABCD dataset - we parcellated over a thousand unique biopsychosocial measures from all time points into 30 theoretically relevant, commonly-used, or potentially-informative domains. We then assessed their hierarchical and interactive predictive power using a novel integrative ensemble stacking of 4 state-of-the-art ML models. Further, addressing prior tradeoffs between high-dimensional prediction and interpretability, several synergistic methods were applied to provide uncertainty estimation, central features, and possible causal developmental dynamics. Results reveal notable overlapping transdiagnostic features as well as pronounced hierarchical differences between measurement-domains in predicting psychiatric, social, and cognitive outcomes. Myriad subjective-report metrics accounted for 27–76 fold more variation in ADHD, depression, and anxiety than an extensive available range of biophysical and experimental-task measurements. Still, many domain-specific features were highly predictive of several clinically meaningful operationalizations of depression and psychopathology. Illustrated are robust, consistent, and often bidirectional interactions between specific trait-like characteristics and dynamic features of coextensive psychopathology, somatic, social, and family relationships - accounting for substantial variation in ADHD, anxiety, and depression (r2=.49–.56). Psychiatric and social-quality targets in adults using available parent data exhibited similar hierarchical predictive patterns but also reveal important developmental differences. Collectively, these findings underscore the comparative predictive utility of wide-ranging current biopsychosocial measurements across several cardinal explanatory targets in psychiatry, and illuminate the structure and dynamics of the most prevalent mental-health challenges across the lifespan in novel detail, with implications for prediction, explanation, and control.

Multidrug-resistant Gram-negative bacterial infections are increasing globally in neonates, infants and children; antibiotic options are limited. This international, multicenter, open-label phase 2 study, investigated the pharmacokinetics, safety and tolerability of single-dose and multiple-dose cefiderocol [as a 3-hour infusion (every 8 hours) dosed at 2000 mg for body weight ≥34 kg and at 60 mg/kg for body weight <34 kg], over a range of renal function, in hospitalized pediatric patients with aerobic Gram-negative bacterial infection; multiple-dose patients required standard-of-care systemic antibiotics for 5-14 days. Four cohorts of pediatric patients were enrolled (cohort 1: 12 to <18 years, cohort 2: 6 to <12 years, cohort 3: 2 to <6 years and cohort 4: 3 months to <2 years). A total of 53 patients (median age: 73.5 months) were enrolled. Plasma concentration profiles were similar with single-dose (n = 24) and multiple-dose (n = 29) cefiderocol, irrespective of age and body weight in those with normal renal function or mild renal impairment. Geometric mean concentrations at the end of infusion ranged between 72.7 and 97.1 μg/mL for single-dose cefiderocol and between 88.8 and 106.0 μg/mL after multiple doses. At 8 hours, corresponding trough concentrations ranged from 7.86 to 10.8 μg/mL with single-dose cefiderocol and from 9.64 to 18.1 μg/mL with multiple doses. There were no deaths, no cefiderocol-related serious adverse events, significant related laboratory abnormalities or discontinuations. Multiple-dose cefiderocol, administered for 5-14 days and according to body weight, achieved steady-state plasma concentrations that remained above the susceptibility breakpoints of Gram-negative bacteria throughout the dosing period. Cefiderocol was well tolerated.

Assess the outcomes of various therapeutic regimens to treat initial endoscopic postoperative recurrence despite biologic prophylaxis. Postoperative biologic prophylaxis reduces postoperative Crohn's disease (CD) recurrence rates. Optimal treatment strategies for endoscopic recurrence have not been elucidated. Retrospective cohort study of adult CD patients who underwent ileocolonic resection between 2009 and 2020. Patients with endoscopic postoperative recurrence despite prophylactic biologic therapy and ≥1 subsequent colonoscopy were included. Treatment changes after recurrence were categorized as (1) therapy optimization or continuation or (2) new biologic class. The primary outcome was composite endoscopic or surgical recurrence at the time of or prior to subsequent follow-up colonoscopy. Eighty-one CD patients with endoscopic recurrence (54.3% i2b, 22.2% i3, and 23.5% i4) despite biologic prophylaxis (86.4% anti-tumor necrosis factor, 8.6% vedolizumab, 4.9% ustekinumab) were included. Most patients received therapy optimization or continuation (76.3%, n=61) following recurrence compared to being started on a new biologic class. Sixty patients (N=48 therapy optimization; N=12 new biologic class) experienced composite recurrence (78.3% endoscopic, 21.7% surgical). On multivariable modeling, initiation of a new biologic class was associated with reduced risk for composite recurrence compared to therapy optimization or continuation (aOR: 0.26; P =0.04). Additionally, initiation of a new biologic class was associated with endoscopic improvement when adjusting for endoscopic severity at the time of recurrence (aOR: 3.4; P =0.05). On sensitivity analysis, a new biologic class was associated or trended with improved rates of endoscopic healing and composite recurrence when directly compared to therapy optimization or continuation. In patients with CD who experience endoscopic recurrence despite biologic prophylaxis, changing the mechanism of biologic action may promote endoscopic improvement.

We pursued structure-based drug design(SBDD)targeting the 3CL protease of SARS-CoV-2 in order to develop a COVID-19 therapeutic drug. Through virtual screening using our in-house compound library, we identified hit compounds and optimized them while leveraging the co-crystal structure with the 3CL protease. As a result, we successfully achieved over 600-fold improvement in enzyme inhibition activity within a short period of time and finally developed ensitrelvir, which exhibited excellent antiviral activity and pharmacokinetic profile.

Abstract Background Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative bacteria including multi-drug resistant organisms. The in vitro activity of CFDC and comparator agents was evaluated against Enterobacterales isolates collected during 2020-2022 in the SENTRY Antimicrobial Surveillance Program, stratified by infection type. Methods 11,805 Enterobacterales from the USA were tested for susceptibility (%S) using CLSI broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) or iron-depleted CAMHB for CFDC. Comparator agents included β-lactam/β-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R) meropenem-vaborbactam (MVB), piperacillin-tazobactam (P/T) as well as meropenem (MEM), cefepime (FEP) and ceftazidime (CAZ). Susceptibility was interpreted according to 2022 CLSI &amp; FDA breakpoints. Carbapenem resistant Enterobacterales (CRE) was defined as resistant to imipenem (IPM) and MEM. Multidrug-resistant (MDR) Enterobacterales was defined as nonsusceptible to at least 1 drug from ≥ 3 classes and extensively drug resistant (XDR) as susceptible to ≤ 2 classes per 2022 CLSI criteria. Results The most common infection type from which isolates were collected was urinary tract infection (UTI; n=4,136), followed by bloodstream infection (BSI; n=3,256), pneumonia (PNA; n=2,731), intra-abdominal infections (IAI; n=1,015), and skin-soft tissue infections (SSTI; n=667). Among CRE and MDR isolates, CFDC was the most active agent ( &amp;gt; 98%S) for isolates from BSI, PNA, and UTI. Among XDR isolates from BSI and PNA, %S to CFDC ( &amp;gt; 97%) was highest amongst all agents tested. Of the Bl/BLIs, C/T and P/T demonstrated the lowest %S against CRE and MDR isolates from BSI, PNA, UTI and among XDR isolates from BSI and PNA. Conclusion CFDC demonstrated high in vitro activity against Enterobacterales regardless of infection type. Susceptibility for comparator agents was generally lower against isolates with CRE, MDR, and XDR phenotypes. CFDC represents a potential early treatment option for infections caused by Enterobacterales with presumed or defined CRE, MDR, XDR phenotypes, regardless of infection type. Disclosures Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson &amp; Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi &amp; Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee

Abstract Background Cefiderocol (CFDC) has a broad activity against Gram-negative (GN) pathogens. This study describes the usage of CFDC in US hospitals in patients with microbiology data during the initial phase of commercialization. Methods This retrospective study included patients with laboratory-confirmed GN infections in US hospitals treated with CFDC consecutively for ≥3 days between March 2020 to June 2021, as captured by Premier Healthcare data. This study describes the clinical characteristics, microbiology profile, CFDC usage, and post-CFDC initiation 14-day and 28-day in-hospital all-cause mortality (IH-ACM). Index culture was defined as the last day that culture sample(s) was taken before CFDC initiation or the first day the culture sample(s) was taken after CFDC initiation if no microbiology data before CFDC use was available. Index pathogens were all pathogens identified from the index culture(s). The index culture site was where the index culture was taken. Results A total 187 in-patients received ≥3 days CFDC and had ≥1 microbiological result(s). The clinical characteristics of the patients and index culture results are provided in Table 1 and Table 2. About 60% of patients had at least one positive respiratory culture. The most frequent pathogens from the index culture were Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Acinetobacter baumannii. Nearly 75% of patients had one index pathogen, and 91% with one culture site. Almost 30% of patients had either one pathogen identified in multiple culture sites, or multiple pathogens from ≥1 culture site. Crude 28-day IH-ACM for patients with any A. baumannii was 8.3% (95%CI: 0% -19.4%), any P. aeruginosa was 17.3% (95%CI: 9.9-24.8%), any S. maltophilia was 18.4%, (95%CI: 6.1%-44.0%) and any K. pneumoniae was 26.1% (95%CI: 8.1%-44.0%). Crude 28-day IH-ACM for patients with positive respiratory culture was five times higher in COVID patients than non-COVID patients. Conclusion During the initial phase of CFDC availability, the most frequent pathogens treated using CFDC were non-fermenters, and the most frequent culture site was respiratory. IH-ACM appears to be affected by infection characteristics, especially COVID-19 status. Disclosures Bin Cai, MD, PhD, Shionogi: Shionogi employee Yun Zhou, MS, Shionogi: Employee of CRO hired by Shionogi Andrew Cooper, PhD, Shionogi: Shionogi employee.

Introduction:The primary aim of this study was to compare the incidence of venousthromboembolism (VTE) among women initiating ospemifene vs other selectiveestrogen receptor modulator (SERM) therapies for estrogen-deficiencyconditions or breast cancer prevention, and vs women with untreated vulvarand vaginal atrophy (VVA). The secondary objective examined numerousadditional safety outcomes.Methods:This was a retrospective cohort study using the IBM Watson MarketScan claimsdatabase. Women receiving ospemifene, another SERM, or with a new diagnosisof VVA with no treatment from 1 May 2013 to 2 October 2018 were followedthrough the claims for incident adverse outcomes. The primary outcome wasthe first occurrence of VTE following cohort entry; secondary outcomesincluded cerebrovascular events and other adverse events potentiallyassociated with SERM use. Cox models compared the risk of VTE betweenospemifene and comparators, using a variety of approaches to control forconfounding.Results:The incidence of VTE during the first continuous treatment episode was 3.39(95% confidence interval [CI]: 1.55–6.43) events per 1,000 person-years (PY)for ospemifene (N = 8977), 11.30 (95% CI: 8.81–14.28)events per 1,000 PY for comparator SERM (N = 12,621), and10.92 (95% CI: 10.49–11.37) events per 1,000 PY for untreated VVA(N = 242,488). Cox models indicated no increase in riskof VTE for ospemifene vs other SERMs (hazard ratio [HR]: 0.40, 95% CI:0.19–0.82), and vs untreated VVA (HR: 0.47, 95% CI: 0.24–0.91).Conclusion:This real-world safety analysis found no increase in risk of VTE or otheradverse events with use of ospemifene in postmenopausal women.Plain Language SummaryIntroduction: This study assessed the risk of venousthromboembolism (VTE) among women treated with ospemifene or anotherselective estrogen receptor modulator (SERM) therapy and women withuntreated vulvar and vaginal atrophy (VVA). Numerous additional safetyoutcomes were examined.Methods: This study was conducted in the IBM Watson MarketScanclaims database. Women receiving ospemifene, another SERM, or with a newdiagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 werefollowed through the claims for adverse outcomes, including VTE,cerebrovascular events (such as stroke), and other outcomes that might occurwith use of a SERM. The analyses compared the risk of VTE between ospemifeneand the other two groups, using methods that accounted for differences inpatient characteristics between the groups. Because few women over 72 yearsold used ospemifene, the main analyses examined women aged 54–72 years.Results: The analyses included 8,977 ospemifene users, 12,621other SERM users, and 242,488 women with untreated VVA. Among women aged54–72 years, only 9 experienced a VTE during ospemifene treatment, while 55other SERM users and 1,788 women with untreated VVA had a VTE. The analysesthat accounted for differences between the groups confirmed that the risk ofVTE was no higher in ospemifene users than in either comparison group.Conclusion: This real-world safety analysis found no increase inrisk of VTE or other adverse events with use of ospemifene in postmenopausalwomen.