bluuebunny/crossref_metadata_2025_split huggingface dataset:
155. Structural homologs of Enterococcus faecalis LiaX-like genes in Bacillus subtilis provides new insights into the LiaFSR-mediated response associated with daptomycin resistance
Authors: Hood Kara S , Arias Cesar A , Shamoo Yousif 
Published: December 2022

Abstract

Background
VRE (Vancomycin Resistant Enterococci)-associated infections are prevalent in healthcare settings and pose a significant therapeutic challenge. The lipopeptide antimicrobial daptomycin (DAP) is one of the last resort options to treat these organisms. Among VRE, mutations that confer DAP resistance (DAP-R) arise in proteins in the three-component signaling system LiaFSR, which is highly conserved in other Gram-positive pathogens. Similar to Enterococcus faecalis (Efs), LiaFSR in Bacillus subtilis (Bsu) is specifically activated by DAP and, thus, serves as a proxy for studying mechanisms of DAP-R. In Bsu, LiaF inhibits LiaR phosphorylation; however, the current model for DAP-R in Efs positions LiaF as an activator of LiaFSR directly regulated by the enterococcal-specific protein LiaX. We postulate that the intimate association between LiaX and LiaF is crucial for DAP-R in enterococci. Using an in silico approach, we compared LiaF from Efs and Bsu and searched for LiaX-like proteins in Bsu.

Methods
Protein predictions were determined by the RoseTTAFold algorithm (RoBetta, David Baker, UW). Structural comparisons were conducted using MatchMaker in UCSF Chimera. Paired sequence alignments were assembled through EMBOSS Needle.

Results
Efs and Bsu LiaF are arranged similarly with 4 transmembrane helices (TMH) in the N-terminal domain (NTD) and a β-sheet (βS) C-terminal domain (CTD). We identified LiaX-like gene products upstream from Bsu LiaFSR. Analysis of the predicted structures of LiaIHG showed that LiaI is a peptide with 4 TMH and structurally like the N-terminus of Bsu LiaF. Also, LiaH contains 3 putative α-helices akin to the N-terminus of LiaX. LiaG has 1 TMH connected to a large βS domain-like the C-terminus of LiaX. Each protein shared structural and sequence similarity that was not identified through BLAST searches.

Conclusion
We identified Bsu LiaIHG as structural homologs to Efs LiaX, which was not previously known due to lack of sequence identity and empirical structural data. The findings further supports our model for LiaX and LiaF as core pieces in DAP-R development.

Disclosures
Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support.
216. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Beta-lactamase inhibitor Xeruborbactam Alone and in Combination Meropenem in Healthy Adult Subjects
Authors: Griffith David , Roberts Jason , Wallis Steven , Hernandez-Mitre Maria Patricia , Morgan Elizabeth , Gehrke Shawnee , Dudley Michael , Loutit Jeff 
Published: December 2022

Abstract

Background
Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem.

Methods
Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods.

Results
XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below.
No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity.

Conclusion
XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem.

Disclosures
David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.
225. Efficacy and safety of sulbactam-durlobactam are consistent across regions in the global ATTACK phase 3 trial in the treatment of carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections
Authors: Miller Alita , Shapiro Adam B , McLeod Sarah , Rana Khurram , Lewis Drew , Altarac David 
Published: December 2022

Abstract

Background
ATTACK is a randomized, active-controlled, noninferiority trial that evaluated the efficacy and safety of sulbactam-durlobactam (SUL-DUR) compared to colistin for CRABC infections. The primary efficacy endpoint of all-cause mortality (ACM) at day 28 and the primary safety objective of incidence of nephrotoxicity based on RIFLE criteria were met. Due to the global variation of carbapenem and multi-drug resistance, geographic subgroups were evaluated to explore consistency of efficacy and safety across regions.

Methods
Patients were randomized to SUL-DUR or colistin treatment for 7-14 days and all patients received imipenem/cilastatin as background therapy. The primary efficacy analysis in the CRABC population consisted of 125 patients: SUL-DUR (N=63) and colistin (N=62). The primary safety population included 177 patients who received any amount of drug. Secondary efficacy endpoints included ACM at day 14, clinical cure and microbiological favorable assessment at end-of treatment (EOT), test-of-cure (TOC) and late follow-up (LFU). Results are described geographically by the following regions: the Americas, Asia-Pacific and Europe.

Results
Overall, ACM at day 28 in the SUL-DUR arm and colistin arm was 12/63 (19.0%) vs. 20/62 (32.3%), respectively; ACM at day 14 overall in the SUL-DUR arm and colistin arm was 4/63 (6.3%) vs. 12/62 (19.4%), respectively (Table 1). Day 28 ACM, and secondary endpoints were similar across the geographic regions and consistent with overall findings (Table 1). Criteria for RIFLE nephrotoxicity were met more often in the colistin arm than the SUL-DUR arm in all regions (Table 1).

Conclusion
ACM, clinical outcomes, microbiological favorable assessment, and RIFLE-assessed nephrotoxicity were consistently favorable in patients treated with SUL-DUR versus colistin across regions. These findings suggest, that if approved, SUL-DUR could be an important global therapeutic option for Acinetobacter infections including carbapenem-resistant and multidrug-resistant strains.

Disclosures
Alita Miller, PhD, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Adam B. Shapiro, Ph.D, Entasis Therapeutics: Employee|Entasis Therapeutics: Stocks/Bonds Sarah McLeod, PhD, Entasis Therapeutics: Employee|Entasis Therapeutics: Stocks/Bonds Khurram Rana, PharmD, Entasis Therapeutics: Employee|Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Drew Lewis, MD, MTM&H, Entasis Therapeutics: employee|Entasis Therapeutics: employee|Entasis Therapeutics: Stocks/Bonds|Entasis Therapeutics: Stocks/Bonds David Altarac, MD, MPA, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds.
375. Performance Evaluation of RT-qPCR and RT-dPCR Platforms for the wastewater surveillance of SARS-CoV-2
Authors: Choi Hosoon , Coppin John David , Chatterjee Piyali , Xu Jing , Mayo Lynn , Brackens Emma , Hwang Munok , Bennett Morgan , Gamage Shantini D , Jinadatha Chetan 
Published: December 2022

Abstract

Background
The COVID-19 pandemic is an ongoing global health emergency. Wastewater-based epidemiology is a valuable tool for supplementing clinical testing in identifying infected individuals early thus containing disease transmission. To assess early detection of COVID-19, a building-level wastewater-based surveillance pilot project was implemented within VHA. Here, we report the results from 2 methods of polymerase chain reaction (PCR) testing of 1073 wastewater samples from VHA CLCs (i.e., nursing homes).

Methods
Daily (Monday-Friday) wastewater samples were collected (January 11, 2021, to July 2, 2021) at eight CLCs located across the US and shipped overnight for processing. The samples were heat inactivated by incubating samples in a 65±1°C heating circulating water bath for 90 minutes. The virus in the wastewater was concentrated using InnovaPrep concentrating pipette select, and RNA was isolated from the concentrate and subjected to reverse transcription quantitative PCR (RT-qPCR) and RT-digital PCR. If SARS-CoV-2 was detected in the wastewater within the prior 10 days of a virus-positive occupant, the wastewater positivity was regarded as an early warning.

Results
Twenty-seven positives and 7 inconclusive results were reported by RT-qPCR during the surveillance. Among the 27, 15 wastewater positives qualified as early warning and 12 positives were not verified by occupant positivity. Digital PCR with a cutoff value of 0.25 copies/uL of RNA for defining positivity had 28 positives qualifying as early warnings, and 115 positives were not verified by occupant positivity (Figure 1). Figure 1Differences between RT-PCR and Digital PCR Positivity

Conclusion
The overall viral loads of the wastewater samples were very low corresponding to the dip in cases seen in the US during the pilot period. Although sensitivity of digital PCR appears (based on 0.25 copies/uL of RNA for defining positivity) higher than that of RT-qPCR, there were more occurrences of unverified early warning that could impact precision. The cut-off selected for RT-digital PCR reported here is arbitrary and lacks industry consensus. More controlled studies are needed to determine sensitivity and precision as well as to standardize RT-digital PCR cutoffs to define positivity for routine use.

Disclosures
Piyali Chatterjee, PhD, AHRQ Grant # 1R03HS027667-01: Grant/Research Support|AHRQ Grant # 1R03HS027667-01: Central Texas Veterans Health Care System Chetan Jinadatha, MD, MPH, AHRQ R01 Grant-5R01HS025598: Grant/Research Support|EOS Surfaces: Copper Coupons and materials for testing.
379. A budget impact analysis of bezlotoxumab for the management of recurrent Clostridioides difficile infection in the United States
Authors: Jiang Yiling , Deshpande Abhishek , Li Qinghua , Siegartel Lisa , Siddiqui Fakhar , Obi Engels N 
Published: December 2022

Abstract

Background
Clostridioides difficile infection (CDI) is one of the most frequently reported healthcare-associated infections in the US with almost half a million cases reported annually. The most recent IDSA guidelines recommend use of bezlotoxumab (BEZ) in addition to standard of care (SoC) antibiotics for patients who have a CDI episode and at least one risk factor for recurrence. The objective of this study was to estimate the budget impact of the use of BEZ+SoC vs SoC alone from a hospital perspective in the US.

Methods
A decision analytic model was developed, considering treatment of the index recurrent CDI (rCDI) episode and subsequent recurrences (a maximum of two) over a one-year period, in patients who had at least one risk factor of rCDI. Two scenarios were compared: one with BEZ+SoC, and one with SoC alone. The analysis included costs and payments of medications and the cost of managing rCDI, as well as proportion of BEZ utilization across management settings (with the assumption of 50% inpatient and 50% outpatient). Parameters were retrieved from published sources and expert opinion was sought. The budget impact was calculated as the difference in revenue (difference in payments and costs) between scenarios. One-way sensitivity analyses were performed on key parameters. Costs were expressed in 2021/2 US dollars.

Results
Among 10,000 hypothetical hospitalizations, treatment with BEZ+SoC of at-risk patients instead of SoC alone in the base case analysis was estimated to result in a potential savings of $53,361 at the hospital level, $497 per treated rCDI patient, and $5.34 per admitted patient. The additional cost of BEZ was offset by the lower rCDI rate in those treated with BEZ. Sensitivity analyses demonstrated the robustness of results.

Conclusion
For patients with CDI and at risk for recurrence, treatment with BEZ+SoC is cost saving from a hospital perspective. Broader benefits of BEZ+SoC should be considered by healthcare stakeholders and policy makers when making decisions about formulary inclusion and adoption.

Disclosures
Yiling Jiang, MSc, MSD (UK) Ltd.: Employment|MSD (UK) Ltd.: Stocks/Bonds Abhishek Deshpande, MD, PhD, Clorox: Grant/Research Support|Merck: Advisor/Consultant|Seres Therapeutics: Grant/Research Support Qinghua Li, PhD, Merck & Co., Inc.: employee Lisa Siegartel, MPH, Merck & Co., Inc.: Employee|Merck & Co., Inc.: Ownership Interest Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Engels N. Obi, PhD, Merck & Co., Inc.: Employee|Merck & Co., Inc.: Stocks/Bonds.
443. Do people living with HIV lose weight on GLP-1 agonist therapy?
Authors: Tauhid Lamiya , Fondong Mima , Lovett Aish , Kissinger Patricia J , Bennani Yussef , Clement Meredith E 
Published: December 2022

Abstract

Background
Anti-retroviral therapy (ART) has been associated with significant weight gain and metabolic derangements in persons with HIV (PWH), and many PWH on ART experience comorbid obesity. GLP-1 receptor agonists (GLP-1RA) are used to treat type-2 diabetes and obesity in people without HIV infection, but data on the use of these agents in PWH on ART are limited.

Methods
We extracted data from electronic medical records of PWH on ART receiving care at a clinic in New Orleans, LA who had been started on GLP-1RA therapy. We tracked weight (change in body weight, body mass index [BMI]) and changes in hemoglobin A1c (Hba1c) over time from initiation of GLP-1RA to April 2022. A control group of PWH on metformin only will be compared to those on GLP-1RA at a later stage of analysis.

Results
Of 35 PWH on GLP-1RA, the mean age was 55.2 (standard deviation [SD] 10.0); 29 (83%) were Black/African American, 14 (40%) were assigned female at birth, 21 (60%) were assigned male at birth, and 2 were non-binary. Average BMI was 35.7 (SD 9.8) and average HbA1c was 9.5 (SD 2.6) at baseline. Integrase inhibitors were prescribed for 31 (89%) and metformin was prescribed for 20 (57%). Other baseline characteristics are shown in Figure 1. Mean duration of GLP-1RA therapy was 20.6 months (SD 14.0), and 20 (57%) had greater than 12 months of follow-up. Most (23, 66%) on GLP-1RA lost weight, 3 (9%) had a stable weight, and 9 (26%) gained weight. Five percent or more of body weight was lost by 11 (31%) of the total cohort (those with any amount of time on GLP-1RA) and by 9/20 (45%) of those on GLP-1RA for more than 12 months.

Conclusion
Our data show moderate weight loss among PWH on GLP-1RA. This study is limited by small sample size and limited follow-up time. Further research is needed to determine whether GLP-1RAs are an effective treatment option for obesity in PWH.

Disclosures
Meredith E. Clement, MD, Gilead Sciences: Grant/Research Support|Roche: Advisor/Consultant|Viiv Healthcare: Advisor/Consultant|Viiv Healthcare: Grant/Research Support.
446. Hyperlactatemia and Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI): Still present even with modern antiretroviral therapy (ART)
Authors: Malvestutto Carlos , Patel Yesha 
Published: December 2022

Abstract

Background
Hyperlactatemia and lactic acidosis represent a rare but dangerous manifestation of mitochondrial toxicity associated with NRTIs. Although mitochondrial toxicity has been linked to the NRTI class, it is more prevalent with older agents such as zidovudine (AZT), didanosine (ddI) and stavudine (d4t).

Methods
Prompted by the diagnosis of symptomatic hyperlactatemia in 4 people with HIV on newer NRTIs between September 2019 and December 2021, we present a single-center case series to illustrate its subtle presentation and management. Hyperlactatemia was defined as a serum lactate of 1.6-4 mmol/L and lactic acidosis was defined as a serum lactate of &gt; 4mmol/L.

Results
75% of the patients were male, the mean age was 57.8 years, and 100% were Caucasian. 75% (3/4) were either overweight or obese (body mass index &gt; 25 kg/m2). 75% had a CD4 lymphocyte count &lt; 200 cells/mm3 at the time of human immunodeficiency virus (HIV) diagnosis and 50% had the diagnosis for &gt;10 years. The most common symptom reported was non-specific fatigue (100%), followed by widespread myalgias (75%). 1 patient reported severe peripheral neuropathy affecting activities of daily living and 1 patient reported palpitations and night sweats. The mean duration of symptoms prior to reporting was 27.5 months. At the time of diagnosis of symptomatic hyperlactatemia, 75% had a CD4 lymphocyte count &gt; 200 cells/mm3, the mean serum lactate was 2.7 mmol/L (1.9 mmol/L - 3.9 mmol/L), 50% were on abacavir (ABC) and lamivudine (3TC), and 50% were on tenofovir alafenamide (TAF) and emtricitabine (FTC). After stopping ART for 2 weeks, mean serum lactate decreased to 0.6 mmol/L (0.4 mmol/L – 1.1 mmol/L). 100% reported an improvement in quality of life after NRTI cessation and were managed with an NRTI-sparing regimen. Clinical characteristics are noted in Table 1.

Conclusion
This case series highlights the insidious nature of symptoms related to NRTI-associated mitochondrial toxicity including hyperlactatemia. Management strategies are not well defined for hyperlactatemia; however, NRTI-sparing regimens may offer improvement in quality of life. Despite improved tolerability of modern ART, clinicians should be aware of and monitor for symptoms of this potentially life-threatening side effect.

Disclosures
Carlos Malvestutto, MD MPH, Gilead Sciences: Advisor/Consultant|Viiv Healthcare: Advisor/Consultant.
490. Brain-derived neurotrophic factor (BDNF) is a prognostic biomarker and therapeutic target through AMP-activated protein kinase (AMPK) signal pathway for sepsis
Authors: Kim Jooyun , Jeon Ji Hoon , Jung Min Suk , Seok Hyeri , Song Juhyun , Choi Won Suk , Park Dae Won 
Published: December 2022

Abstract

Background
Brain-derived neurotrophic factor (BDNF) is a pleiotropic cytokine that not only acts on the central nervous system, but is also implicated in metabolic regulation, development of lung diseases, and support of hematopoiesis. Recently, a study report that the plasma levels of BDNF were independently associated with mortality in critically ill patients. We aimed to evaluate the role of BDNF in sepsis patients and animal sepsis model.

Methods
Prospectively enrolled adult sepsis patients (n=168) who visited the emergency room (ER) of Korea University Ansan Hospital from January 2017 to December 2018., and healthy volunteers (n=48) were included in the present study. Serum BDNF level was determined and analyzed in septic patients and healthy volunteers. The effects of BDNF on pro-inflammatory cytokines, AMP-activated protein kinase (AMPK) and NF-κB signaling in septic condition of RAW264.7 cells and mouse peritoneal macrophage, and mouse sepsis model by cecal ligation and puncture (CLP).

Results
Serum BDNF levels (mean) were significantly decreased in sepsis patients compared to healthy controls (11.78ng/ml vs 18.91ng/ml, p&lt; 0.001) and significantly decreased in non-survivors compared to survivors at discharge (3.16ng/ml vs 13.86ng/ml, p&lt; 0.05). BDNF treatment suppressed LPS-induced pro-inflammatory cytokine (TNF-α, iL-6, and iL-1β) in RAW264.7 cells. Although LPS stimulation diminished AMPK phosphorylation, BDNF was able to decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on down stream signaling events, particularly LPS-induced IκBα degradation in RAW cells and peritoneal macrophage. In CLP model, intra-muscular injection of BDNF after CLP significantly decreased serum levels of TNF-α which was increased compared to sham, and significantly improved survival of mouse (p&lt; 0.01).

Conclusion
Sepsis results in a decreased production of BDNF, which might be a potential prognostic biomarker and therapeutic target through AMPK signal pathway for sepsis.

Disclosures
All Authors: No reported disclosures.
594. An Open-Label Study in Healthy Volunteers to Determine the Absolute Bioavailability of, the Effect of Food and Dosing by Nasogastric Tube upon the Pharmacokinetics of a Single Oral Dose of Olorofim (OLO)
Authors: Cornelissen Karen , Newell Paul A , Rex John H , Galbraith Hal , Israel Samuel , Bush James , ChB M B 
Published: December 2022

Abstract

Background
OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. Information on absolute bioavailability and effect of food upon the pharmacokinetics (PK) of OLO when administered as a 30 mg tablet, including feasibility of alternative enteral delivery, is required for appropriate guidance on dosing.

Methods
Healthy male and female subjects in Cohorts A and B (6/cohort; high carbohydrate /low fat meals at 8 and 24 h for Cohort A and low carbohydrate/high fat meals for Cohort B ) participated in 3 treatment periods; single doses of 150 mg OLO as a 2-h IV infusion, a fasted PO dose (after overnight fast), and a fed single PO dose (30 min after starting a high fat breakfast). Healthy subjects in Cohort C participated in 2 treatment periods and received fasted single doses of 150 mg OLO either PO as intact tablets or via NG tube (tablets dispersed in water). PK sampling was performed for 120 h after each dose, with at least 10 days between dosing occasions per subject.

Results
The absolute bioavailability of a fasted single PO dose of OLO was found to be 67%. Administering OLO in the presence of food resulted in slight reduction in overall exposure, with an approximate 30% reduction in Cmax (Table 1). Multiple post-dose OLO peaks were observed for most subjects regardless of dose route or fed state; peaks typically coincided with meal times (Figure).
OLO systemic exposure was similar for intact tablets given PO and tablets dispersed in water given via NG tube (Table).
Statistical Analysis of Olorofim PK parameters for Cohorts A, B and C

Conclusion
OLO (30 mg tablet) has good oral bioavailability and based upon the minimal impact of a high-fat breakfast upon overall exposure, can be administered with or without food. No dose adjustment is needed if switching from oral dosing with intact tablets to dosing tablet in water via NG tube.

Disclosures
Karen Cornelissen, PhD, F2G: Employee Paul A. Newell, MB BS, AstraZeneca: Stocks/Bonds|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Samuel Israel, MBBS, Labcorp: Eemployee James Bush, MB ChB, PhD, Labcorp: Employee (Salaried)|Labcorp: Stocks/Bonds.