bluuebunny/crossref_metadata_2025_split huggingface dataset:
1470. Human monoclonal antibodies for the treatment and prevention of Crimean Congo Hemorrhagic Fever
Authors: Tehrani Zahra Rikhtegaran , Koksal Iftihar , Yilmaz Gürdal , Karaaslan Elif , Spengler Jessica , Welch Stephen R , Karakoc Hanife N , Hamidi Sanaz , Albay Cansu , Durie Ian A , Sorvillo Teresa E , McGuire Jack , Spiropoulou Christina F , Mousa Jarod J , Godzik Adam , Bergeron Eric , Pegan Scott D , Sajadi Mohammad M 
Published: December 2022

Abstract

Background
Crimean-Congo hemorrhagic fever (CCHF) is the most widely spread viral hemorrhagic disease, found in Europe, Asia, and Africa. The disease symptoms start and progress rapidly and can lead to bruising and bleeding, with high fatality rates of up to 50% in hospitalized patients. Currently there are no approved vaccines or therapeutics available, and treatment is supportive.
The CCHFV glycoprotein is made up of two major structural glycoproteins, GC and GN, which are required for the virus attachment and entry. An additional protein, GP38, is a secreted byproduct derived from a glycoproptein precursor of GN and whose role remains unknown. Recently, the non-neutralizing mouse mAb 13G8 (anti-GP38) has shown 60-90% protection prophylactically or post-challenge in a mouse model when challenged with various CCHFV strains. This is noteworthy because neutralizing mouse mAbs to GC have not shown consistent protection in mouse models. Because most of the work has been on mice up till now, we decided to isolate and study mAbs from human survivors of CCHF.

Methods
The antibody response to GC and GP38 were measured in CCHF patients from Turkey ∼ 6 months after infection, and one high titer sample was selected for mAb isolation. For this purpose, a combined proteomics/genomics approach was performed; plasma Abs were isolated using sequential affinity chromatography, peptides subjected to Mass spectrometry, and then matched to single cell VDJ sequence libraries constructed from PBMCs. mAbs were tested for binding and neutralization, and one candidate used for in-vivo evaluation with Ifnar1- mice (lacking IFN) challenged with CCHF virus.

Results
11 anti-GP38 and 8 anti-Gc antibodies were isolated. All anti-Gc (and none of the GP38) mAbs exhibited neutralization. Anti-GP38 antibodies were segregated into 6 epitope groups based on competition assays (including 3 not described before). CC5-17, the human mAb sharing the same epitope as 13G8, showed 50% protection two separate experiments in Ifnar1- mice (when given 30 minutes prior to challenge, or 1 and 4 days after challenge).

Conclusion
The non-neutralizing gp38 antibodies have proven to afford protection before or after exposure to CCHFV. Human mAbs have the potential for protection and/or prevention of CCHF.

Disclosures
All Authors: No reported disclosures.
1471. Treatment of Influenza with Baloxavir was Associated with Reduced Absenteeism Compared with Oseltamivir in a Patient-Generated Health Data Study
Authors: Benitez Alejandra , Xu Hao , Ukachukwu Vincent , Chawla Devika 
Published: December 2022

Abstract

Background
Lost productivity from workplace absenteeism is a significant component of the economic burden of influenza [1]. Antiviral treatment together with influenza vaccination may help reduce work time lost from influenza illness [2]. In clinical trials, baloxavir, an oral single dose treatment for influenza, demonstrated comparable symptom resolution to oseltamivir taken twice daily for 5 days [3]. We examined baloxavir real-world outcomes using patient generated health data (PGHD) to investigate the association between antiviral use and workplace absenteeism.

Methods
Using data from a participatory influenza-like illness (ILI) surveillance program (ISP), we identified participants who self-reported ILI using the online Evidation platform during the 2019-2020 influenza season in the United States. Participants who self-reported treatment with baloxavir or oseltamivir were included. We conducted an ordinal logistic regression to estimate the odds of missing work due to ILI, while adjusting for use of over-the-counter (OTC) medication, age, number of symptoms, US region, and comorbidities.

Results
Of 3658 participants eligible for inclusion in the analysis, 3285 (89.8%) were prescribed oseltamivir and 373 (10.2%) were prescribed baloxavir. A majority of participants (81.7%) reported missing at least one day of work. In the ordinal logistic regression, use of baloxavir was associated with lower odds of absenteeism, compared to oseltamivir (odds ratio [OR]: 0.748, 95% confidence interval [CI]: 0.616, 0.907). In addition, a higher number of symptoms (OR 2.922, 95% CI: 2.454, 3.481), older age (OR: 1.425, 95% CI: 1.162, 1.747), and use of OTC medication (OR: 1.242, 95% CI: 1.086, 1.420) were associated with higher odds of absenteeism. Due to a high rate of missing data on the timing of antiviral use (24.5% missing), its association with absenteeism could not be adequately assessed.

Conclusion
Treatment of patients with ILI with single dose baloxavir was associated with reduced workplace absenteeism compared to oseltamivir after adjusting for measured confounders. This study provides useful insight into factors associated with ILI-related workplace absenteeism and the potential real-world utility of baloxavir.

Disclosures
Hao Xu, MSc, Hoffmann-La Roche Limited: Employee Vincent Ukachukwu, n/a, Roche Products Ltd: Employee Devika Chawla, PhD, Genentech: Employee.
1664. Impact of a Midline Catheter Prioritization Project on Central Venous Access and Central Line Associated Bloodstream Infections at an Urban Safety-net Community Hospital
Authors: Mena Lora Alfredo J , Lindsey Brenna , Echeverria Stephanie , Ali Mirza , Krill Candice , Takhsh Eden , Bleasdale Susan C 
Published: December 2022

Abstract

Background
The use of peripherally inserted central catheters (PICCs) has increased in the past decade. PICCs are central lines (CLs) commonly used for venous access. Midline catheters (MLs) can provide access when the need for a CL, such as vasopressors, is no longer present. MLs have a lower rate of BSI compared to PICCs and CLs, while providing dwell times comparable to PICCs. We established a project prioritizing ML use.

Methods
This is a quasi-experimental study in a 151-bed safety net community hospital. The pre-intervention period was January-December 2018 and post period was January 2019-December 2021. MLs were prioritized when new PICCs are requested without CL indications, such as total parenteral nutrition, hyperosmolar solutions and vasopressors. PICCs and CLs are transitioned to a ML once indications are no longer met and peripheral IVs are not feasible. Data on utilization and complications, such as deep venous thrombus (DVT) and BSIs, were reviewed and compared.

Results
A total of 63 peripherally inserted lines occurred prior to the intervention, of which 55 (87%) were PICC and 8 (13%) were ML (Figure 1). Post-intervention, 76 lines were placed the first year, of which 48 were ML (63%). This upward trend was sustained throughout the pandemic, with 116 lines in 2020 (80% ML) and 96 in 2021 (88% ML). No BSIs occurred during the pre-intervention and first post-intervention year. During the pandemic, 8 BSIs in MLs and 3 in PICCs occurred. The most common organism was Candida (Figure 2). The majority had COVID-19 (72%) and all (100%) BSIs were in the setting of shock. Case review demonstrated suspected secondary sources other than central venous catheters (CVCs). All BSIs with ML would have met NHSN criteria if CL present. No upper extremity DVTs were found.

Conclusion
A midline prioritization project was successfully implemented and sustained during the COVID-19 pandemic. The decline of PICC use from 87% to 12% suggests use for access without CL needs. High acuity during the pandemic led to BSIs that were likely secondary to shock and complications of COVID-19. All cases would have met NHSN criteria for CLABSI. The cost of a CLABSI is estimated at $48,108. Thus, this midline prioritization project may have led to CLABSI avoidance and an estimated cost savings of $384,864.

Disclosures
All Authors: No reported disclosures.
1672. Antimicrobial Activity of Cefepime-Taniborbactam and Comparators Against Clinical Isolates from ICU and Non-ICU Patients; 2018-2020 Global Surveillance
Authors: Hackel Meredith , Wise Mark , Sahm Daniel F 
Published: December 2022

Abstract

Background
Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with selective direct inhibitory activity against both serine- and metallo-β-lactamases. Taniborbactam restores the activity of cefepime against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales (EB) and P. aeruginosa (PA). The activity of cefepime-taniborbactam (FTB) and comparator agents was evaluated against clinical isolates of EB and PA from a 2018-2020 global surveillance study.

Methods
16,742 isolates of EB and PA were collected from patients in wards designated ICU and non-ICU in 2018-2020. MICs of FTB and comparators were determined by the CLSI reference method. Resistant (R) phenotypes were based on 2022 CLSI breakpoints. Multidrug resistant (MDR) was defined as resistance to at least one agent from ≥3 drug classes. Provisional susceptible (S) breakpoints of ≤8 µg/mL and ≤16 µg/mL were applied for FTB for comparative purposes only.

Results
FTB had potent activity against EB, with MIC90s of 0.25 µg/mL for isolates from non-ICU patients and 0.5 µg/mL for isolates from ICU patients (Table). At least 99.2% of all EB from both wards were inhibited by ≤8 µg/mL FTB. FTB maintained activity against R phenotypes of EB in both ward types, with 90.3% to 98.1% of isolates inhibited at ≤8 µg/mL. FTB had potent activity against PA, with MIC90 values of 8 µg/mL and inhibiting ≥94.0% of isolates at ≤8 µg/mL for both ICU and non-ICU isolates. FTB maintained activity against R phenotypes of PA in both ward types, with 71.0% to 83.7% of isolates inhibited at ≤8 µg/mL and 84.7% to 92.5% inhibited at ≤16 µg/mL. %S to comparator agents against the R subsets ranged from 1.6% to 92.6% for EB, and 36.0% to 68.4% for PA. Against the particularly challenging subset of MDR PA from ICU patients, FTB was the most active agent tested as it inhibited 73.5/84.7% of isolates at ≤8/≤16 µg/mL compared to 43.1%S to CZA and 36.0%S to C/T.

Conclusion
Cefepime-taniborbactam demonstrated potent in vitro activity against EB and PA from ICU and non-ICU wards, including resistant subsets of isolates. This supports the continued development of FTB as a potential new treatment option for infections due to resistant Gram-negative pathogens.

Disclosures
All Authors: No reported disclosures.
1679. Susceptibility of Gram-Negative Clinical Isolates Collected from the USA in 2020 to Eravacycline and Comparators
Authors: Hawser Stephen , Kothari Nimmi , Lemos Bárbara , Monti Federica , Hodges Tony 
Published: December 2022

Abstract

Background
Eravacycline is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The activity of eravacycline has been surveyed annually since 2013. Here we present data on the in vitro activity of eravacycline and comparators against Gram-negative pathogens isolated in the USA during 2020.

Methods
Isolates were collected from patients from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using current CLSI breakpoints, except for eravacycline and tigecycline where FDA and EUCAST breakpoints were used due to a lack of CLSI breakpoints. Multi-drug resistant (MDR) was defined as resistance to ≥3 antibiotics including aztreonam, a carbapenem (meropenem or ertapenem), third or fourth generation cephalosporin (cefepime,cefotaxime,ceftazidime, or ceftriaxone), gentamicin, levofloxacin, piperacillin/tazobactam, tetracycline or tigecycline.

Results
Summary MIC and susceptibility data for eravacycline and select comparators are shown in the Table. Eravacycline MIC90 against Enterobacterales combined was 0.5 μg/mL (MDR Enterobacterales and individual species ranged from 0.25 to 1 μg/mL) and susceptibility was 93.9% using both FDA and EUCAST breakpoints. Tigecycline MIC90 against Enterobacterales was 1 μg/mL and susceptibility using FDA breakpoints (set in 2005) was 96.8%, whereas susceptibility by EUCAST breakpoints (set in 2019) was 87.8%. Eravacycline MIC50 and MIC90 against A. baumannii was 0.5 and 2 μg/mL, respectively; being at least 4-fold lower than that observed for tigecycline.

Conclusion
Eravacycline in vitro activity has remained unchanged since 2013, with comparable annual susceptibility rates observed against clinically important Gram-negative pathogens. These data also highlight that FDA breakpoints for tigecycline against Enterobacterales need urgent review to avoid potential false reporting of tigecycline susceptibility. In contrast, eravacycline FDA breakpoints are in keeping with those published by EUCAST and can be used to predict the clinical outcome of eravacycline treatment.

Disclosures
Tony Hodges, MD, LaJolla Pharmaceutical: Chief Medical Officer|LaJolla Pharmaceutical: Stocks/Bonds.
1680. Activity of the Novel Engineered Antimicrobial Peptide PLG0206 Against Enterobacterales isolates
Authors: Huang David , Sauer John Michael , Steckbeck Jonathan , Shinabarger Dean , Morrissey Ian , Hawser Stephen 
Published: December 2022

Abstract

Background
PLG0206 is an investigational, engineered cationic antimicrobial peptide designed to overcome the shortcomings of other natural AMPs, such as toxicity and limited activity. PLG0206 has recently been shown to be well tolerated and safe in a phase 1 study. This study evaluated the activity of PLG0206 and comparator antimicrobials against Enterobacterales isolates from the IHMA repository collected from various world-wide locations in 2019.

Methods
Isolates tested included Citrobacter spp. (151), Enterobacter cloacae (152), Escherichia coli (300), Klebsiella pneumoniae (300), Morganella morganii (43), Proteus spp. (152), Providencia spp. (61) and Serratia marcescens (45). Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution in cation-adjusted Mueller Hinton broth (CA-MHB), except for PLG0206 which was tested in RPMI medium due to plate-reading difficulties with CA-MHB. The susceptibility of comparators was determined using the 2022 CLSI breakpoints. MDR was defined as resistance to ≥ 3 antibacterial classes.

Results
Summary MIC and susceptibility data against Citrobacter spp., E. coli, E. cloacae, and K. pneumoniae are shown in the Table. PLG0206 retained activity against MDR isolates of Citrobacter spp. (26), E. coli (92), E. cloacae (45), and K. pneumoniae (132) with MIC50/90 values of 1/2, 1/2, 1/16 and 8/16 μg/mL, respectively. PLG0206 was essentially inactive against the Morganellaceae and Yersiniaceae isolates tested with MIC50 and MIC90 values of &gt; 32 μg/mL (data not shown).

Conclusion
PLG0206 was active against isolates from the family Enterobacteriaceae, including MDR strains. The spectrum of activity of PLG0206 ranged from being most active against Citrobacter spp. and least active against K. pneumoniae. These data suggest that the novel antimicrobial peptide PLG0206 could be a potential treatment option against infections caused by Enterobacteriaceae isolates.

Disclosures
David Huang, MD, PhD, Peptilogics: Employee Jonathan Steckbeck, PhD, Peptilogics: I am CEO of Peptilogics.
1681. Activity of the Novel Engineered Antimicrobial Peptide PLG0206 Against Staphylococci and Enterococci
Authors: Huang David , Michael Sauer John , Steckbeck Jonathan , Shinabarger Dean , Morrissey Ian , Hawser Stephen 
Published: December 2022

Abstract

Background
PLG0206 is an investigational, engineered cationic antimicrobial peptide designed to overcome the shortcomings of other natural AMPs, such as toxicity and limited activity. PLG0206 has recently been shown to be well tolerated and safe when administered i.v. in a Phase 1 study. The initial proposed indication for this peptide is the treatment of periprosthetic joint infections via irrigation due to a broad spectrum of activity and anti-biofilm properties. This study evaluated the activity of PLG0206 and comparator antimicrobials against staphylococci and enterococci, causes of periprosthetic joint infections, from the IHMA repository of isolates collected from various world-wide locations in 2019.

Methods
Isolates tested included Enterococcus faecalis (77), E. faecium (75), methicillin-resistant Staphylococcus aureus (MRSA, 180), methicillin-susceptible S. aureus (MSSA, 121) and 152 coagulase-negative staphylococci (CoNS) comprised of S. epidermidis (113), S. haemolyticus (31), S. hominis (4), S. lugdunensis (1), S. saprophyticus (2) and S. simulans (1). Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution in cation-adjusted Mueller Hinton broth (CA-MHB), except for PLG0206 which was tested in RPMI medium due to plate-reading difficulties with CA-MHB. The susceptibility of comparators was determined using the 2022 CLSI breakpoints. MDR was defined as resistance to ≥ 3 antibacterial classes.

Results
When tested in RPMI, 18 E. faecalis, 29 E. faecium, 9 S. aureus and 7 CoNS were unable to grow. Summary MIC and susceptibility data for PLG0206 and comparators just including those isolates able to grow in RPMI are shown in the Table. Identical MIC50 and MIC90 values were obtained for PLG0206 when tested against MDR E. faecium (38), MDR CoNS (63) and MDR MRSA (67). Insufficient numbers of MDR MSSA (7) and MDR E. faecalis (4) were tested to accurately evaluate.

Conclusion
PLG0206 was the most potent antimicrobial overall (based on MIC50 and MIC90) against enterococci and CoNS and compared well with the comparators against MRSA and MSSA. These data support the evaluation of this novel antimicrobial peptide as a treatment option for periprosthetic joint infections, including those caused by MDR strains.

Disclosures
David Huang, MD, PhD, Peptilogics: Employee Jonathan Steckbeck, PhD, Peptilogics: I am CEO of Peptilogics.
1691. Bacteriophage and Protein Synthesis Pathway Inhibitor Combinations: Antibiotic mechanism of action drives antagonistic interactions
Authors: Kunz Coyne Ashlan J , Bhutani Natasha , Holger Dana , Kebriaei Razieh , Stamper Kyle , Ghali Amer El , Ghali Amer El , Alexander Jose , Biswas Biswajit , Lehman Susan , Arias Cesar A , Rybak Michael J 
Published: December 2022

Abstract

Background
Bacteriophage (phage) to augment antibiotic efficacy is a possible therapeutic option in the era of antimicrobial resistance. Studies to date have assessed phage-antibiotic synergy (PAS), however, its efficacy may be dependent upon antibiotic mechanism of action. Here, we report our in-vitro evaluation of phage-antibiotic antagonism (PAA) among phage and protein synthesis inhibitor combinations in multidrug-resistant clinical strains of P. aeruginosa, S. aureus, and E. faecium.

Methods
The following bacteria (phage) regimens were evaluated: 10266 (EM) and R9010 (14207) (P. aeruginosa) against gentamicin (GEN), azithromycin (AZM), and ciprofloxacin (CIP); N315 and 494 (Intesti) (S. aureus), and R497 and HOU503 (NV-497) (E. faecium) against linezolid (LNZ), minocycline (MIN), and daptomycin (DAP). Modified checkerboard (CB) MIC assays were used for preliminary screening followed by 24h time kill analyses (TKA). For CB, synergy, additive activity, and antagonism were defined as an FIC index of ≤0.5, 1–4, and &gt;4, respectively. In 24h TKA, synergy and additivity were defined as a ≥2 and ≥1 log10 CFU/mL reduction from baseline, while antagonism was defined as phage-antibiotic combinations with CFU/mL higher than the most effective single treatment at 24h. Data were compared by one-way ANOVA and Tukey (HSD) test (P&lt; 0.05).

Results
In CB analyses and 24h TKA of S. aureus and E. faecium isolates, phage-LZD and phage-MIN combinations were antagonistic (FIC &gt;4) while phage-DAP was synergistic (FIC 0.5) (ANOVA range of mean differences 0.52 to 2.59 log10 CFU/mL; P&lt; 0.001). For P. aeruginosa, phage-AZM and phage-GEN were antagonistic (FIC &gt;4) and additive (FIC=1), respectively (ANOVA range of mean differences 1.04 to 1.95 log10 CFU/mL; P&lt; 0.001).

Conclusion
Our results suggest that antibiotics that act on the protein synthesis pathway may lead to PAA, however, PAA interactions may be highly dependent upon antibiotic mechanism of bacterial inhibition (i.e., location of ribosomal protein synthesis inhibition, bactericidal vs. bacteriostatic) protein synthesis inhibit. Studies assessing PAA in a wider array of phage-antibiotic combinations are warranted.

Disclosures
Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support.
1667. The Accuracy of Hospital-Onset Bacteremia and Candidemia Metric Variants Across Hospitals
Authors: Lewis Julia , Stevens Vanessa W , Ochoa Brennan , Malone Colin , Jones Makoto M 
Published: December 2022

Abstract

Background
Hospital-onset bloodstream (HOB) infection metrics are automatable alternatives to metrics based on chart review and may have comparable accuracy. Our group explored and evaluated variants of these measures.

Methods
Multiple electronic rules for HOB infection were developed, ranging from simple to moderately complex (Table 1).
To assess diagnostic accuracy overall and its stability over time and between facilities, we gathered electronic health record data between October, 2015 and December, 2019. Acute care admissions where the first positive blood culture was greater than 3 days after admission were included. We block-randomized 10 facilities across regions (North Atlantic, Southeast, Midwest, Continental, and Pacific) and whether above and below the median number of operating acute care beds. We restricted analysis to facilities &gt; 30 acute care beds. Four reviewers reviewed approximately 50 charts randomly selected from the 10 facilities, with 10 charts overlapping with 2 other reviewers. A 5th reviewer, adjudicated in the case of disagreement or uncertainty. Accuracy statistics were generated by comparing algorithm outputs to the adjudicated standard.

Results
Compared to the 140 chart standard, sensitivity was low for all algorithms investigated (Table 2), except where common skin commensals were excluded. Specificity dropped when antimicrobial-based criteria were used. Using definition F from Table 1 as representative of consistency of accuracy across facilities, the median facility sensitivity and specificity were 80.1% [IQR 72.1-95] and 85.4% [73.3-100], respectively.

Conclusion
HOB metrics may need to exclude common skin commensals for simplicity and accuracy. Addition of antimicrobial use criteria did not seem to improve accuracy. Although sample sizes were small, accuracy metrics appeared relatively stable across facilities.

Disclosures
All Authors: No reported disclosures.