bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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 > 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 > 25 kg/m2). 75% had a CD4 lymphocyte count < 200 cells/mm3 at the time of human immunodeficiency virus (HIV) diagnosis and 50% had the diagnosis for >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 > 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

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< 0.001) and significantly decreased in non-survivors compared to survivors at discharge (3.16ng/ml vs 13.86ng/ml, p< 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< 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

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.
602. Clinical Outcomes of Ertapenem in Patients with Hypoalbuminemia
Authors: Gavaghan Victoria , Luu Tyler , Adams Jenna , Santarossa Maressa , Albarillo Fritzie S , Rech Megan A
Published: December 2022

Background

Infections caused by extended-spectrum ß-lactamase (ESBL) producing organisms pose a unique challenge for infection control. The preferred agents for treatment of infections due to ESBL-producing bacteria are carbapenems. Data from prior studies suggest that hypoalbuminemia may have a profound effect on the pharmacodynamic properties of ertapenem. Our hypothesis is that ertapenem usage in patients with hypoalbuminemia will lead to negative clinical outcomes such as infection recurrence, hospital readmission, and mortality when compared to subjects with higher albumin levels.

Methods

This was a retrospective, observational, single-centered, cohort study of hospitalized patients at Loyola University Medical Center between January 2010 and August 2020. Patients were divided into 2 groups to include those who received ertapenem with serum albumin >2.5 g/dL and those who received ertapenem with serum albumin < 2.5 g/dL. The primary outcome of interest was 30-day all-cause mortality. Baseline characteristics that were collected included age, sex, nutrition status, patient comorbidities. Data regarding predictors of mortality within 24 hours of initiation of ertapenem including the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Charlson Comorbidity Index (CCI) was also collected.

Study Criteria

Results

Of the 146 subjects that were included, 73 patients had serum albumin levels of < 2.5 g/dL during treatment with ertapenem. 30 day all-cause mortality was 19.7% for subjects with low albumin and 9.6% for subjects with normal albumin levels (p=0.09). Our study found that although not statistically significant, there is potentially a clinical significance between hypoalbuminemia and our primary endpoint, 30-day all-cause mortality, with higher rates of mortality in the low albumin group and a 9.6% between group difference. This data suggests that in subjects with hypoalbuminemia, treatment with once-daily ertapenem may lead to suboptimal outcomes regarding patient mortality.

Outcome Data

Conclusion

The present study data suggests that in subjects with hypoalbuminemia, treatment with ertapenem dosed as a once-daily intravenous infusion may be associated with suboptimal clinical outcomes that may include an increased mortality, hospital readmission, and length of stay.

Disclosures

All Authors: No reported disclosures.
659. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents against Enterobacterales Collected from Patients with Bloodstream Infections (BSI) as Part of the ATLAS (India) Surveillance Program, 2019-2020
Authors: Routray Abhisek , Mane Akshata
Published: December 2022

Background

Ceftazidime-avibactam (CAZ-AVI) is indicated for patients with bacteremia that occurs in association complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) and hospital-acquired pneumonia (HAP). The present report evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales clinical isolates collected from BSI as part of the ATLAS (The Antimicrobial Testing Leadership and Surveillance) surveillance program in 2019-2020 from India.

Methods

A total of 2126 Enterobacterales (493 from blood samples) non-duplicate clinically significant isolates, were collected from 2019-2020. In vitro activity of Ceftazidime-avibactam and its comparators were assessed against Enterobacterales blood isolates.

Results

Overall susceptibility to the β -lactam/β -lactamase inhibitor (BL-BLI) was 60 -76% for Enterobacterales. with highest susceptibility to Ceftazidime-avibactam. Overall highest susceptibility (97%) was noted for Tigecycline for Enterobacterales(n=476).The susceptibility to colistin was lower(83%) in Enterobacterales (n=409). Among 168 CR-Enterobacterales (CRE), Ceftazidime avibactam showed 29% susceptibility (n=49) while susceptibility to Tigecycline was 96%(n=161) followed by Colistin at 84%(n=141). Molecular analysis for CRE isolates showed 55 % (n=93) to be OXA-48 like producers (with or without NDM) ,68%(n=114)to be NDM producers (with or without OXA- 48) and 30%(n=51) to be co producers of OXA-48 like & NDM.

In vitro activity of commonly used antibiotics against Enterobacterales, blood isolates (2019-2020)

Conclusion

Caz-Avi showed overall good susceptibility against the blood isolates tested hence it may be a valuable therapeutic option for treating BSI caused by MBL-negative Enterobacterales. Tigecycline followed by Colistin showed the highest susceptibilities. Tigecycline attains very low plasma concentrations and is not licensed for use in blood stream infections, while the use of colistin may be limited by the lack of CLSI susceptibility breakpoints and safety concerns.

Disclosures

Abhisek Routray, PhD, Pfizer India Limited: Advisor/Consultant Akshata Mane, MD, Pfizer India Limited: Advisor/Consultant|Pfizer India Limited: Stocks/Bonds.
669. Real World Use of Ceftazidime/Avibactam for the Treatment of Multidrug Resistant Gram Negative Bacilli Infections: A Real World Experience from Two Centers in Mexico
Authors: Molina-Jaimes Aaron , Olmedo-Reneaum Alejandro , Sanabria-Trujillo Giovanni
Published: December 2022

Background

Ceftazidime-avibactam (C-A) is effective against many carbapenem resistant Enterobacteriaceae (CRE) and some carbapenem resistant Pseudomonas aeruginosa (CRPsa), indicated in complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and hospital-acquired pneumonia. To our knowledge, in Mexico, there is no data regarding the clinical efficacy (clinical cure) of its use in the treatment of cIAI, cUTI, hospital-acquired pneumonia, and the treatment of CRE and CRPsa.

Methods

this is a descriptive, observational, retrospective study, including infections in which ceftazidime avibactam was the definitive therapy for CRE and CRPsa, and empiric treatment of cUTI, cIAI, Hospital-acquired pneumonia. The study includes patients from 2 centers, between April 2019 and february 2020. Demographic, clinical and microbiological data were obtained. Clinical cure was defined as the absence of fever, leukocytosis, tachycardia, systolic pressure < 90mmHg or use of vasopressors, and lowering of C-reactive protein by at least 60% after 5 days of treatment.

Results

Seventy patients in which C-A was the definitive antimicrobial treatment were evaluated. UTI accounts for 24 cases (34.2%), followed by primary and secondary peritonitis (28.5%), soft tissue infection (12.8%), bacteremia (12.8%) and hospital-acquired pneumonia (11.4%). Of all infections 39.9% were secondary to CRPsa, and 60.1% were due to CRE (30.3% Klebsiella pneumoniae, 21.2% Escherichia coli and 6% for Klebsiella oxytoca, Enterobacter cloacae and Proteus mirabilis). Clinical cure was achieved in 64 patients (91.4%). Six patients died, but only one was associated to CRPsa infection.

Conclusion

To the best of our knowledge, this is the first study of Mexican experience with C-A. Our study brings relevant information on the treatment of carbapenem resistant GNB infections with C-A in our population. More studies, specifically RCTs are needed to prove the antibiotic efficacy in our media.

Disclosures

All Authors: No reported disclosures.
965. Prevalence and Drivers of Burnout Among Antimicrobial Stewardship Personnel in the United States: A Cross-Sectional Study
Authors: Szymczak Julia E , Elle Saine M , Chiotos Kathleen , Keller Sara C , Newland Jason , Lautenbach Ebbing , Heil Emily L
Published: December 2022

Background

Although antimicrobial stewardship (AS) personnel are faced with occupational stressors that may contribute to burnout, little is known about the degree to which they experience this work-related syndrome. Our objective was to characterize the prevalence of, and identify factors associated with, burnout among AS personnel practicing in United States (US) hospitals.

Methods

We conducted a cross-sectional survey in October-December 2021. AS personnel (physicians and pharmacists) were approached via email through four US-based professional organizations. Respondents self-administered a questionnaire measuring demographics, AS program structure, resources, and organizational climate. Burnout was measured using the Maslach Burnout Inventory, a 22-item validated instrument with three subscales. Burnout was defined as a dichotomous outcome based on the presence of high scores on the emotional exhaustion subscale along with either a high depersonalization score or low professional accomplishment score. Descriptive statistics and logistic regression analyses were performed.

Results

A total of 259 AS personnel completed the questionnaire. The majority of respondents were pharmacists (n=201; 78.2%), female (n=166; 64.3%) and worked in a teaching hospital (n=212, 84.1%). The median age was 36 (IQR, 32-41). Thirty-six percent (n=94 of 259) of respondents met the definition for burnout. There were no significant differences in burnout by respondent demographics or professional role. Significant drivers of burnout (P< 0.05) identified in univariable regression modeling included feeling as if AS is not an institutional priority, that hospital leadership is unsupportive of AS, prescriber resistance to AS recommendations is common, having unsupportive infectious diseases or pharmacy colleagues, the AS team does not work well together, and AS work is not intellectually stimulating.

Conclusion

Over one third of AS personnel in our sample met predefined standardized criteria for burnout. Contextual aspects of the work environment, including leadership, unsupportive peer climate and conflict were associated with burnout. There is a need to address factors that contribute to burnout in AS personnel to ensure an engaged workforce and to minimize turnover.

Disclosures

Jason Newland, MD, AHRQ: Grant/Research Support|Merck: Grant/Research Support|NIH: Grant/Research Support|PEW Charitable Trust: Grant/Research Support|Pfizer: Grant/Research Support.
1033. Management of Disseminated Nocardiosis in an Immunocompromised Patient Using Multi-Drug Therapy
Authors: Khan Abrar , Perwez Talha , Farooq Junaid , Gutierrez Ramiro , Zeineddine Nabil , Mahapatra Rahul
Published: December 2022

Background

Nocardiosis may cause fatal infections in immunocompromised and immunocompetent patients. While there are many different species, Nocardia farcinica, has been a clinically important cause but less frequently identified species. We present a case of an immunocompromised patient successfully treated with a multi-drug regimen for disseminated nocardiosis due to Nocardia farcinica.

Methods

The patient is a 65-year-old male with a history of Autoimmune Hemolytic Anemia (AIHA) who presented with fevers, chills, symptomatic anemia, and new left lower extremity weakness associated with spasms over several days prior to arrival.

Results

6 months prior, he had received treatment for AIHA with rituximab, cyclophosphamide, and high dose corticosteroids. Head CT revealed a 1.5cm right posterior frontal lobe mass with surrounding edema. CT thorax revealed innumerable spiculated pulmonary nodules and masses bilaterally. Lung biopsy as well as blood culture were positive for Nocardia farcinica, specimen was sent to reference laboratory for susceptibility testing. He was initially treated with imipenem and IV Bactrim. Subsequently, clinical exam findings were unchanged and repeat MRI brain showed enlarging frontal mass. Linezolid and IV amikacin were added to the regimen based on susceptibility results. Patient was discharged home but returned to hospital shortly after discharge with severe hemolytic anemia, suspected to be due to Bactrim administration. The patient was later discharged home on Imipenem, IV amikacin, oral Linezolid, and oral Moxifloxacin in stable condition without surgical intervention and with improved left lower extremity weakness.

Conclusion

Disseminated Nocardiosis is known to cause fatal pulmonary and CNS infections in immunocompromised patients and requires aggressive therapy usually with multiple antibiotics. Nocardia farcinica infections are particularly clinically complex given the organism’s multiple inherent resistance mechanisms, interpretation of in vitro susceptibility testing, and possible adverse effect profile of treatment regimen.

Disclosures

All Authors: No reported disclosures.
1118. COVID-19 Therapeutics: Real-World Experience in Flint, Michigan (MI)
Authors: Younas Mariam , Osterholzer Danielle , Rios-Bedoya Carlos , Flues Brandon R , Bachuwa Ghassan , Bachuwa Ghassan
Published: December 2022

Background

Data on the real-world effectiveness of Remdesivir (RDV) has yielded conflicting results. US Food and Drug Administration granted full approval for RDV on 10/22/20. On 11/20/20, the World Health Organization issued a conditional recommendation against its routine administration in hospitalized patients, regardless of disease severity. We aimed to examine the association between COVID-19 therapeutics and survival among the recipients.

Methods

Hurley Medical Center, is a 443-bed teaching hospital in Flint, MI. We retrospectively collected basic demographics, treatment data, and outcomes on adults (≥ 18 years of age) with confirmed SARS-CoV-2 infection, hospitalized at our facility from 03/2020 through 02/2022. Mortality predictors were identified using logistic regression.

Results

During the study period, overall crude 90-day mortality rate was 16% (269/1668). Supplemental oxygen was required by 1,213 patients and 378 needed ventilatory support. Early in the pandemic, 159/1668 patients received Hydroxychloroquine (HCQ). Based on institutional protocol, 51% (858/1668) of the patient received RDV (Figure 1, 2). After adjusting for age, gender, race and Body Mass Index, HCQ was associated with increased risk of mortality (Odds ratio (OR) 1.72, 95% Confidence Interval (CI) 1.14 – 2.59, p-value 0.010). Mortality in the RDV group was also noted to be higher (162/269) (adjusted OR for mortality 1.37, 95% CI 1.03 – 1.83, p-value 0.032). Supplemental oxygen use was associated with mortality regardless of RDV use (adjusted OR 3.39, 95% CI 2.15 – 5.36, p-value < 0.001). RDV showed no mortality benefit in the group requiring mechanical ventilation (MV) (adjusted OR 0.77, 95% CI 0.55 – 1.09, p-value 0.152) (adjusted OR for mortality with MV 18.62, 95% CI 13.02 – 26.63, p-value < 0.001). Figure 1:Institutional protocolFigure 2:Institutional protocol

Conclusion

This study adds to the growing evidence that more efficacious treatments against COVID-19 respiratory failure are needed once a patient is hospitalized and that antiviral therapies at this late stage may not have the desired effect. This study has several limitations including its retrospective nature and that the RDV group was likely sicker with higher disease severity. We also did not assess the effect of combination therapy such as RDV and steroids on mortality. A need for further studies remains.

Disclosures

All Authors: No reported disclosures.
1153. Safety and Potential Efficacy of Exosomes Overexpressing CD24 (EXO-CD24) for the Prevention of Clinical Deterioration in Patients with Moderate or Severe COVID-19: A Phase II, Randomized, Single-blinded Study.
Authors: Grigoropoulos Ioannis , Tsioulos Georgios , Kastrissianakis Artemis , Shapira Shiran , Arber Nadir , Poulakou Garyfallia , Syrigos Konstantinos , Rapti Vasiliki , Xynogalas Ioannis , Leontis Konstantinos , Ntousopoulos Vasileios , Sakka Vissaria , Gaga Mina , Sardelis Zafeiris , Fotiadis Andreas , Vlassi Lamprini , Kontogianni Chrysoula , Levounets Anastasia , Tsakona Maria , Savva Athina , Kavatha Dimitra , Boumpas Dimitrios , Antoniadou Anastasia , Tsiodras Sotirios
Published: December 2022

Background

EXO-CD24 is a novel inhaled drug of exosomes displaying CD24, a protein with anti-inflammatory properties. We evaluated the safety and potential efficacy of EXO-CD24, in a phase II, randomized, single-blinded clinical trial of EXO-CD24 in hospitalized patients with moderate or severe COVID-19, following the preliminary safety and efficacy results of a phase 1 study (ClinicalTrials.gov: NCT04747574).

Methods

Two tertiary care hospitals in Athens, Greece participated. Patients received either 109 or 1010 exosome particles per dose, once per day for 5 days and were followed for 28 days. Safety and efficacy measures (including respiratory rate < 23 b/min and pulse oximetry SpO2≥ 94% on room air, oxygen need and levels of inflammatory biomarkers i.e. CRP, LDH, ferritin, fibrinogen and d-dimers) were compared between groups at days 3, 5 and 7. A separate analysis was conducted comparing the clinical course of treated patients with that of a control cohort (n=70 patients) matched by propensity scoring out of a similar period hospitalized cohort (n=202) that did not participate in the study.

Results

Between June 9th and August 3rd 2021, 91 patients underwent randomization: 45 in group A and 46 in group B (109vs. 1010 exosome particles per dose). Mean age was 49.4 (± 13.2) years and 74.4% were male. Mean time from symptom onset to randomization was 8 days. Improvement in respiratory rate and pulse oximetry was noted in 72 out of 86 (83.7%) and 55 out of 86 (64%) analyzed patients. Day 7 inflammatory indices levels dropped at least 50% from baseline admission values in 72 out of 86 (82.8%) analyzed patients (p< 0.001). No treatment-related adverse events were reported. Comparison with the propensity score matched group showed statistically significant differences in the same parameters (p≤ 0.01 for all comparisons).

Conclusion

Our results suggest safety and potential efficacy of EXO-CD24 on clinical and laboratory parameters of moderate or severe COVID-19, that deserve further investigation in a phase 3 study. (Funded by Athens Medical Society. ClinicalTrials.gov: NCT04902183, EU Clinical Trials Register EudraCT Number 2021-002184-22).

Disclosures

All Authors: No reported disclosures.
Suicide and Self-Injury in Schools
Authors: Haag Granello Darcy , Granello Paul F. , Juhnke Gerald A.
Published: December 2022

Suicide and self-injury among students is a significant and growing concern. Students of all ages and grade levels are at risk, and the risk is disproportionately affecting certain students. Suicide rates are rising among Black students, for example, particularly among the very young. Other high-risk groups, such as transgender, LGBTQI+, and gender non-conforming students, Latinx, American Indian/Alaska Native, Asian/Pacific Islander students, and students with high ACEs scores are challenging our traditional perceptions about suicide risk. The pandemic, racism, social unrest, sleep disturbances, higher rates of substance use or mental illness, loneliness, bullying, and increased screen time all contribute to this increased risk. Schools must now use a whole school approach to suicide prevention where school mental health specialists develop and lead a comprehensive approach to creating a school-wide culture of care. In this approach, all staff, teachers, students, and parents have a role to play in saving lives, and suicide prevention truly becomes a shared responsibility. This book provides a research-informed, practical strategy for how schools can develop—and implement—a systemic and realistic school-wide approach. Readers will learn step-by-step approaches that will ultimately lead to the creation of Comprehensive School-Wide Suicide Prevention Program, grounded in 10 core components. Throughout the book, when a new concept, risk category, need, or application idea is presented, it is immediately followed by a concrete, practical strategy that can be implemented. There are more than 120 of these research-backed strategies, all of which have been tested in practice.
A Call to Action
Authors: Granello Darcy Haag , Granello Paul F. , Juhnke Gerald A.
Published: December 2022

Suicide is the third leading cause of death among young people ages 15–24, accounting for 17% of all deaths in this age group. Yet completed suicides are just the tip of the iceberg. More than 5,000 middle and high school students have a suicide attempt each day, and nearly one in five middle and high school students has seriously considered suicide in the past year. It is not fully understood how the pandemic has affected the long-term mental health and suicide rates of today’s young people, but all indications are that there will be multiple negative outcomes. It is within this context that readers are given information that underscores the importance of the topic and introduced to some of the key concepts and terminology regarding suicide.
Understanding Who Is at Risk
Authors: Granello Darcy Haag , Granello Paul F. , Juhnke Gerald A.
Published: December 2022

Understanding which students might be at elevated risk for suicide can help school personnel begin to create appropriate suicide prevention programming for their schools. Students in all demographic categories, of both sexes, as well as students who are transgender and gender fluid, of all sexual orientations, and of all races, ethnicities, and ages, can be at risk for suicide, although specific risk can vary. This chapter discusses these large-scale social and demographic risk categories. However, an important take-home message from this chapter is that school personnel must understand the students within their own schools and the risk factors for their specific school populations.
Understanding How the Online World and Social Media Affect Suicide Risk
Authors: Granello Darcy Haag , Granello Paul F. , Juhnke Gerald A.
Published: December 2022

Today’s students live in an online environment. Although the digital world, particularly social media, can seem overwhelming and frightening when it comes to suicide prevention, the reality is that this is the world in which students live. School-based mental health professionals must help students learn social media literacy. Students need help to make sense of what they see, hear, and participate in when they engage in these virtual relationships so that they are protected and safe. Ultimately, there is great potential in helping students use their engagement in these online platforms to help reduce mental health stigma, encourage help seeking, and lower suicidality. School-based mental health professionals can teach appropriate guidelines and then support and encourage students as they discover how to best, and safely, use these virtual platforms to help save lives.
Working With Suicidal Students in Schools
Authors: Granello Darcy Haag , Granello Paul F. , Juhnke Gerald A.
Published: December 2022

Schools are expected to help identify, perform the initial assessment of, contact parents of, help initiate the referral process for, and monitor students who have chronic suicidal thoughts; develop protocols for the re-entry of students who are returning after a suicide crisis; follow up with suicidal students; and document their efforts. Although most intervention work takes place with a community provider, school mental health professionals must work with parents, clinicians, and the suicidal student. Advanced training in suicide may be needed for staff to carry out these duties. Suicidal students fall into roughly three categories: chronically suicidal students, actively suicidal students, and students who return to school following a suicide crisis. Intervention for students who are suicidal generally follows a modified crisis counseling approach.
Causation
Authors: Boyle Deborah
Published: December 2022

This chapter examines Shepherd’s objections to Humean causation. After a brief overview of Hume’s account of causation, the chapter proceeds through the first four of six points Shepherd makes in opposition to Hume: that we know through reason, not “custom,” the causal principle that every object that begins to exist must have a cause other than itself; that we also know through reason, not custom, that causes that are similar to each other will necessarily have effects that are similar to each other; that Shepherd can offer a better definition of ‘cause’ than Hume; and that Hume’s definitions of ‘cause’ are flawed in several respects. In the course of surveying her objections, the chapter introduces Shepherd’s own novel theory of causation as synchronous necessary connection.