bluuebunny/crossref_metadata_2025 huggingface dataset:
P-1800. Antimicrobial Stewardship Compliance with Accreditation Requirements within a Hospital Pharmacy Organization
Authors: Shea Katherine M , Hobbs Athena L V , Lundquist Steve , Sun Jessica
Published: January 2025

Background

Between 2022 and 2023 the Center for Medicare and Medicaid Services and The Joint Commission updated requirements and/or guidance related to antibiotic stewardship programs (ASPs). In June 2023, an antimicrobial stewardship gap analysis survey was required within all Cardinal Health pharmacy managed facilities to assess for compliance with accreditation requirements and identify areas for improvement.

Methods

This was a 55 question multi-site survey assessing compliance with accreditation requirements for hospital ASPs. Participants responded to questions as yes, no, or not applicable. Compliance was defined as a “yes” or “not applicable” response. A chi-square was used to assess responses between hospital types and average daily census (ADC).

Results

122 hospitals completed the survey (41 hospitals, 17 critical access, 27 long-term acute care (LTAC), 29 rehabilitation, 8 LTAC/rehabilitation). Most facilities had an ADC of < 50 (< 26: 46, 26-50: 44, 51-100: 17, 101-200: 7, 201-500: 8). The mean (+ STD) compliance within all hospitals was 81.7% (+ 5.1%). A significant difference in compliance with accreditation requirements was found based on hospital type (p< 0.001) and ADC (p< 0.001). Rehabilitation and LTAC hospitals had the highest compliance rates of 89% and 83%, respectively. When assessed by ADC, the lowest compliance rates were found in hospitals with less than 26 beds (78.8%).

The top five needs with < 75% compliance included documentation of program outcomes, documentation of evidence-based use of antibiotics in all departments and services of the hospital, reporting progress towards antibiotic stewardship goals and initiatives to hospital leadership, evaluating adherence to an evidence-based guideline, and providing competency-based education to hospital staff.

Conclusion

This standardized survey identified ASP gaps based on accreditation requirements and identified key areas for improvement. Interestingly, LTACs and rehabilitation hospitals had the highest compliance rates of all facility types; however, the largest post-acute system within the pharmacy managed hospitals, which accounted for 84.4% of all LTAC and rehabilitation hospitals, has a system-level antimicrobial stewardship committee as well as a dedicated infectious diseases pharmacist.

Disclosures

Katherine M. Shea, PharmD, BCIDP, T2 Biosystems: Advisor/Consultant
P-1801. Optimizing Antimicrobial Therapy in Gram-Negative Bloodstream Infections: Insights from a Pharmacist-Driven Intervention Leveraging Molecular Rapid Diagnostic Testing
Authors: Caniff Kaylee E , Coyne Ashlan Kunz , Judd Chloe , Orzol Carolina , Al Musawa Mohammed , Bleick Callan , Scipione Marco R , Rybak Michael J
Published: January 2025

Background

Molecular rapid diagnostic tests (mRDT) expedite pathogen and antimicrobial resistance gene detection in bloodstream infections (BSI), facilitating the prompt initiation of targeted therapy. However, mRDT has the greatest benefit to patients and public health when integrated with antimicrobial stewardship. This study describes a pharmacist-driven mRDT antimicrobial stewardship intervention in Gram-negative BSI, its associated outcomes and its applicability to public health partners.Table 1.Patient demographics, infection and management characteristics.

Methods

At an urban medical center in Detroit, Michigan, USA, trained pharmacists received an alert page for positive mRDT results. Subsequently, they conducted chart review and provided antimicrobial recommendations to the medical team per site protocol. This is a retrospective, descriptive analysis of patients ≥ 18 years old with Gram-negative BSI who received a pharmacist intervention from 5/2023-4/2024. Patient characteristics and intervention outcomes, including time to pharmacist review and recommendation type, are described.Table 2.Pharmacist intervention and clinical outcomes.

Results

Sixty-six patients were included; mean (SD) age was 63 (16) years and patients were predominantly Black (68.2%). The most common primary infection source was urinary (40.9%). Escherichia coli and Klebsiella pneumoniae were most frequently identified in blood culture; 31.8% of isolates possessed CTX-M. Pharmacists reviewed mRDT results at a median (IQR) of 20 (6-97) minutes post-alert. There was no difference in time to effective therapy when mRDT alerts occurred afterhours vs. daytime hours (9 [IQR 0-22] vs. 17 [IQR 0-20] hours, p = 0.66). Sixteen patients were on ineffective empiric therapy; a pharmacist successfully adjusted therapy in 13 of these patients; two patients did not have a resistance marker identified on the initial mRDT report and the pharmacist recommendation was rejected in one patient. Twenty-two patients received empiric anti-Pseudomonal therapy who could have potentially been de-escalated upon mRDT result.Figure 1.Pharmacist workflow for mRDT alert.

Conclusion

Pharmacists facilitated the attainment of effective therapy in those with Gram-negative BSI with mRDT resistance marker detection. Opportunities for de-escalation highlight the potential for pharmacists to further impact patient care and public health broadly through antimicrobial stewardship.Figure 2.Institutional Gram-negative therapy protocol.

Disclosures

Kaylee E. Caniff, PharmD, BCIDP, T2Biosystems: Honoraria Michael J. Rybak, PharmD, PhD, MPH, Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Advisor/Consultant|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Grant/Research Support|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Speaker
P-1808. Strategies for Antimicrobial Stewardship Program Resiliency During the COVID-19 Pandemic
Authors: Schwei Rebecca , Griffin Meggie , Ikenberry Helena , Kaur Ashleen , Scalzo Sarah , Pop-Vicas Aurora E , Schulz Lucas , Werner Nicole , Pulia Michael
Published: January 2025

Background

The COVID-19 pandemic was an unprecedented stress test for hospital-based antimicrobial stewardship (AMS) programs. The purpose of this study was to characterize strategies for AMS program resiliency during the COVID-19 pandemic.

Methods

Using a national dataset, we identified hospitals according to three criteria: 1.) significant COVID-19 burden; 2.) appropriate antibiotic prescribing patterns before the pandemic; and 3.) maintenance of appropriate antibiotic prescribing patterns during the pandemic. We conducted semi-structured interviews with pharmacists, physicians and quality leaders involved in AMS during the pandemic from identified hospitals. Interview guides were developed using the Systems Engineering Initiative for Patient Safety (SEIPS) framework. Transcribed interviews were analyzed iteratively using content analysis directed by the SEIPS model.

Results

We conducted 30 interviews from 19 unique high-performing health care systems across the country. We interviewed 17 pharmacists, 12 physicians and 1 infection prevention nurse. Resilient AMS strategies in place pre-pandemic included positive hospital wide AMS culture (organization); system-wide AMS programs (organization); decentralized antimicrobial stewardship (organization); strong interprofessional relationships (organization & person); infectious disease involvement (person); protocols to facilitate pharmacist autonomy (organization & tools and technology) and automated tools to facilitate AMS program activities (tools and technology). Additionally, the following strategies were implemented during the pandemic to withstand increased workload and the rapidly evolving pandemic: prioritization of highest yield stewardship interventions (organization & task); and organizational flexibility (organization).

Conclusion

Using a systems engineering informed qualitative approach, we characterized work system strategies to promote resiliency among AMS programs during the COVID-19 pandemic which should inform future efforts to promote AMS program resiliency during periods of health system stress.

Disclosures

All Authors: No reported disclosures
P-1810. Implementation of the Core Elements of Hospital Antibiotic Stewardship Programs and the Priorities for Hospital Core Element Implementation in Long-term Acute Care Hospitals Reporting to the National Healthcare Safety Network, 2014 and 2023
Authors: Gouin Katryna , Kabbani Sarah , O’Leary Erin , Srinivasan Arjun , Neuhauser Melinda M
Published: January 2025

Background

The Centers for Disease Control and Prevention (CDC) defines the 7 Core Elements of Hospital Antibiotic Stewardship Programs as a framework for antibiotic stewardship implementation. In 2022, CDC released 6 Priorities for Hospital Core Element Implementation to enhance the quality and impact of existing antibiotic stewardship programs. Acute care hospitals reported 97% uptake of the 7 Core Elements and 10% uptake of the 6 Priorities in 2022 as per reporting to the National Healthcare Safety Network (NHSN) Annual Hospital Survey. However, stewardship implementation in long-term acute care (LTAC) hospitals has not been widely assessed. The objective of this analysis was to assess the uptake of the 7 Core Elements and 6 Priorities in LTAC facilities in 2023 and compare Core Elements uptake to 2014.Table 1.Facility Characteristics of Long-Term Acute Care (LTAC) Hospitals Reporting to the National Healthcare Safety Network Annual Facility Survey for LTAC, 2014 and 2023

Methods

We used the NHSN Annual Facility Surveys for LTAC hospitals (4/1/2024 data pull) for survey years 2014 and 2023 to characterize facility characteristics and self-reported responses to antibiotic stewardship program survey questions. We mapped stewardship survey questions to corresponding Core Elements and Priorities to describe the reported uptake of the 7 Core Elements and 6 Priorities.Figure 1.Reported Implementation of the Priorities for Hospital Core Element Implementation by Priority in Long-Term Acute Care (LTAC) Hospitals (N=337), 2023

Results

In 2014 and 2023, 489 and 337 LTAC hospitals completed the annual survey. In 2023, most LTAC facilities were for-profit (79%), free-standing (58%), part of multi-facility organizations (47%), and in the South (50%) (Table 1). From 2014 to 2023, the number of facilities reporting uptake of all 7 Core Elements in LTAC hospitals increased from 60% to 98%. In 2023, 2% of LTAC hospitals reported meeting the 6 Priorities and 44% reported meeting 4-5 Priorities. The highest reported uptake of Priorities across LTAC hospitals was Pharmacy Expertise (81%) and Leadership (77%). The lowest reported uptake of Priorities was Tracking (7%) and Reporting (42%) (Figure 1).

Conclusion

LTAC hospitals reported uptake of the Core Elements of Antibiotic Stewardship increased from 2014 to 2023, on par with the increase acute care hospitals reported for Core Elements implementation. Engagement with LTAC hospital leadership and leveraging pharmacy expertise are important to support antibiotic stewardship Priorities, especially tracking & reporting of antibiotic use.

Disclosures

All Authors: No reported disclosures
P-1814. Say it Ain't Steno - Impact of a Microbiology Nudge Comment on Treatment of Respiratory Colonization
Authors: Boettcher Stormmy , Kenney Rachel M , Arena Christen J , Beaulac-Harris Amy , Tibbetts Robert , Shallal Anita , Suleyman Geehan , Veve Michael
Published: January 2025

Background

Stenotrophomonas maltophilia (SM) is a known colonizer of the respiratory tract, in which treatment is not required. Microbiological comment “nudges” have been successful as passive stewardship interventions. The study objective was to describe the effect of a targeted SM respiratory culture nudge on antibiotic use in patients with colonization.

Methods

IRB approved quasi-experiment of adult patients with a SM respiratory culture between 01/01/2022-01/27/2023 (pre-nudge) and 03/27/2023-12/31/2023 (post-nudge). Patients with criteria for active community/hospital/ventilator-acquired pneumonia or on targeted antibiotics prior to culture were excluded. Nudge comment implemented 2/2023: “S. maltophilia is a frequent colonizer of the respiratory tract. Clinical correlation for infection is required. Colonizers do not require antibiotic treatment.” The primary outcome was absence of SM therapy; secondary outcomes were SM therapy > 72 hours, hospital and ICU length of stay (LOS), and in-hospital all-cause mortality. Safety outcomes included antibiotic-related adverse events.

Results

94 patients were included: 53 (56.4%) pre- and 41 (43.6%) post-nudge. Most patients were men (53, 56.4%), had underlying lung disease (61, 64.8%), and required invasive ventilatory support (70, 74.5%). 11 (11.7%) patients were admitted from a long-term care facility. The absence of SM therapy was observed in 13 (23.1%) pre- vs 32 (78.0%) post-nudge patients (P< 0.001). There were no differences in SM therapy > 72 hours (36/40 [90%] vs. 8/9 [88.9%], P=1.0), mortality (11 [20.8%] vs. 7 [17.5%], P=0.69), median (IQR) hospital LOS (24 [10-49] vs. 16 [8-29]), P=0.37), and median (IQR) ICU LOS [15 [2-35] vs. 11 [3-25], P=0.40) between pre- and post-nudge groups, respectively. Safety outcomes of patients treated > 72 hours (n=41); elevated SCr 12 (29.3%), fluid overload 18 (43.9%), hyponatremia 17 (41.5%), and hyperkalemia 5 (12.2%). After adjustment for confounders, post-nudge was associated with 11-fold increased odds of the absence of SM therapy (Table 1).

Conclusion

A targeted SM nudge was associated with a reduction in treatment of SM colonization. Patient outcomes, including length of stay and all-cause mortality, were comparable between the two groups.

Disclosures

Rachel M. Kenney, PharmD, BCIDP, Medtronic Inc: Spouse is an employee, stockholder
P-1816. Stepwise Implementation of an Antimicrobial Stewardship Prospective Audit and Feedback Intervention at a Large Academic Center in Canada
Authors: Zeggil Teagan , Cervera Carlos , Smith Stephanie W , Kabbani Dima , Bains Serena , Lau Cecilia , Fong Karen G , Stewart Jackson J , Doucette Karen , Chen Justin
Published: January 2025

Background

Effective implementation strategies for establishing antimicrobial stewardship (AMS) program inpatient interventions are not well described. We describe a methodology for prospective audit and feedback (PAF) implementation at a large Canadian hospital and report its outcomes.

Methods

A PAF intervention targeting restricted antibiotics (carbapenems, daptomycin, linezolid, and tigecycline) was launched in March 2018. Stepwise implementation by inpatient programs was prioritized by collaboration readiness as immediate site-wide implementation was deemed unfeasible. New prescriptions were assessed by the antimicrobial stewardship team. Prescription, prescriber, intervention type, and acceptance data were collected through March 2024.

Results

Over a 2-year period, site wide stepwise implementation occurred in 16 discrete phases. Over the study period, 5185 prescriptions were evaluated; 3789 (73%) were empiric, and 1396 (27%) culture directed from which 3604 (70%) were optimally prescribed (evaluated by agent, regimen, and duration). Of empiric prescriptions, 636 (17%) were not guideline-concordant by indication, 1102 (29%) did not follow guidelines but was reasonable by expert opinion, and 2051 (54%) were guideline-concordant.

ASP recommendations included: 3604 no change (70%), 864 change agent (17%), 535 change regimen (10%), 172 discontinue antibiotic (3%), and 10 other (0.2%). The recommendation acceptance rate was 91% (1581 cases evaluable).

Infectious diseases (ID) were involved in 1466 (28%) prescriptions. With ID involvement, higher guideline-concordant empiric prescribing (64% vs 51%, p< 0.001) and regimen appropriateness (85% vs 65%, p< 0.001) was observed. ASP suggested no changes more often with ID involvement (84% versus 62%, p< 0.001).

Conclusion

Stepwise implementation allowed evolution and implementation of ASP processes and workflow. 30% of prescriptions audited resulted in intervention, suggesting a possible role for further education, guidelines, or restriction. ID involvement was associated with more optimal prescribing. A stepwise implementation of an antimicrobial stewardship PAF intervention is a viable strategy.

Disclosures

All Authors: No reported disclosures
P-1820. Can a Tele-Mentoring Program for Antimicrobial Stewardship Contribute to Program Satisfaction and Staff Retention?
Authors: Kassamali-Escobar Zahra , Chan Jeannie D , Hartlage Whitney , Bajenov Maria , Martinez-Paz Natalia , Jain Rupali , Lynch John B , Bryson-Cahn Chloe
Published: January 2025

Background

Rural and critical access hospitals (CAHs) serve 20% of the United States population. Fewer than 10% of US physicians practice in rural areas and workforce shortages and staff turnover are a constant threat. The University of Washington Center for Stewardship in Medicine (UW CSiM) supports a tele-antimicrobial stewardship (AMS) program (UW TASP ECHO) in small, rural, and CAHs, primarily in the western U.S. with education, mentoring, organizational capacity building, and a community of peers.

Methods

UW CSiM distributes an annual program evaluation survey to participating hospitals. In 2022, 2 questions were added to the survey and measured with a Likert scale from 1 (strongly disagree) to 5 (strongly agree): 1) Participation in UW-TASP increased my job satisfaction; 2). Participation has increased the likelihood that I will continue working in my institution. Respondents had the option to add free-text comments. Results were summarized descriptively.

Results

In 2023, 53/80 (66%) of hospitals responded, 44 (83%) met the definition of CAH. Response rate was 60% in 2022. In 2022 and 2023, 85% and 83% agreed or strongly agreed that participation in UW-TASP increased their job satisfaction. Seventy three percent (2022) and 64% (2023) agreed or strongly agreed that participating in UW-TASP increased the likelihood of continuing to work with their current institution. Comments included:

“It's easy to feel "alone" out here in a rural area. Having TASP makes me feel very much a part of a community that I can share my barriers/struggles with and get ideas for how I can do more with my program.”

“Knowledge is power, TASP provides knowledge to make us effective leaders and give the best patient care. That is what gives me job satisfaction, knowing I am helping patients with best practice.”

Conclusion

UW-TASP’s impact expands beyond checking a box that mandates AMS in every acute care hospital. We found establishing and maintaining a relationship with participants allowed us to build a community with and among rural and critical access hospital partners. This study is limited by self-reported survey data but demonstrates that engagement within UW-TASP is associated with increased job satisfaction and rural healthcare worker retention. Further qualitative studies are needed to further explore this.

Disclosures

All Authors: No reported disclosures
P-1824. AI-Powered Differential Diagnosis: Distinguishing MIS-C from Kawasaki Disease
Authors: Basu Aditya , Basu Surupa
Published: January 2025

Background

Distinguishing Multisystem Inflammatory Syndrome in Children from COVID-19 (MIS-C) from Kawasaki Disease (KD) can be challenging due to several overlapping clinical presentations. Clinical management of these conditions can vary. Hence, timely and accurate diagnosis is essential. We evaluated the potential of laboratory findings in the differentiation using machine learning (ML) models.

Methods

Patient demographics (Age, Sex) and laboratory data were compared between MIS-C and KD. Simultaneous CBC and routine biochemistry tests were evaluated. ML models were created using PyTorch, scikit-learn, Pandas, NumPy, and Matplotlib libraries. Specifically, Naive Bayes Classifier, KNN, Logistic Regression, SVC, Random Forest Classifier, XGBoost, GBM and LightGBM models were created and the model performances of the classifiers were evaluated with accuracy percentages. The confusion matrix of every learning model was also generated. K-fold CrossValidation was also performed to evaluate the predictive models. ROC and feature importance analysis were also performed. Identification of the disease as MIS-C or KD based on both regressive (Eg: Total Protein) and binary features (Eg: Sex) is posed as a binary classification ML problem. Train and test datasets were created using a couple of train-test splits (0.2 and 0.25).

Results

209 paediatric patients with MIS-C (n=140), and KD (n=69) were included.

• The accuracy performances of the models in the test set were determined as 67.8, 73.8, 75.9, 76.8, 79.9, 80.4, 81.0, 81.1%, respectively.

• The area under curve (AUC) values of the LightGBM, GBM, XGBoost, were determined as 79.1, 79.5 and 78%, respectively.

• Permutation importance analysis of the LightGBM model showed that elevated platelets, neutrophil count, SGPT, WBC levels, Creatinine, and NT ProBNP had influenced the model’s explainability.

Conclusion

Although four years have passed since the onset of COVID-19, the early diagnosis of MIS-C is still crucial. In addition to clinical findings, laboratory tests may contribute to the fight against the disease by providing early diagnosis of MIS-C and KD. Explainable ML models can help determine the appropriate markers for this purpose.

Disclosures

Aditya Basu, Bachelor of Technology, Triomics Healthcare: Stocks/Bonds (Private Company)
P-1825. Investigating the Impact of Immunomodulatory Drugs on Severe COVID-19 Through Transcriptomic Analysis
Authors: Kim Jeong Yeon , Sung Yoo Jin , Hong Eujin , Kim Hyun Uk , Yoon Young Kyung
Published: January 2025

Background

The Coronavirus disease (COVID-19) has highlighted the role of hyperinflammatory states and cytokine storms in severe SARS-CoV-2 infections, leading to extensive research into immunomodulatory drugs previously used for autoimmune diseases. Despite their promising effects, the mechanisms underlying their efficacy remain unclear. This study aims to elucidate these mechanisms through RNA-sequence data analysis.Table 1.Clinical characteristics of 30 COVID-19 patient cohort

Methods

Bulk RNA sequencing data from PBMC samples of COVID-19 patients was used to identify two sets of differentially expressed genes (DEGs). The first set was made by comparing COVID-19 patient data to healthy individuals using public datasets, while the second set involved DEGs from samples treated with immunomodulatory drugs versus untreated samples. Comparative analysis focused on genes with opposite expression changes, particularly those showing contrasting fold changes between COVID-19 and drug-treated samples.Figure 1.DEG array

Results

All COVID-19 patients met the criteria for severe or critical illness, requiring at least a high-flow nasal cannula. The median age was 66.5 years. Clinically, 46.7% underwent mechanical ventilation and the mortality rate stood at 46.7%. By arraying the table with all the samples combined from COVID-19 patient samples and immunomodulatory drug samples, DEGs that show opposite fold change signs were selected as having potential significance in COVID-19 pathways and being affected by immunomodulatory drugs. Specifically, 18 genes were upregulated in response to COVID-19 yet downregulated in immunomodulatory drug use, including key inflammatory and immune response genes such as FAP, RGS16, and IDO1. Conversely, 39 genes showed downregulation in response to COVID-19 but were upregulated in immunomodulatory drug use, featuring genes like DUSP1, TOB1, and RGMA.Table 2.List of genes found in DEG array

Conclusion

Through transcriptomic analysis and differential expression screening between COVID-19 and medication-treated samples, 57 were found to exhibit reversed fold changes in expression. Further investigation of these genes is expected. This research aims to uncover the shared biological mechanisms between autoimmune diseases and COVID-19, which could lead to effective drug repurposing strategies for treating COVID-19.

Disclosures

All Authors: No reported disclosures
P-1837. Development and Validation of a Novel Multiplex Immunoassay for the Measurement of the Antibodies against Pneumococcal Vaccine Serotypes
Authors: Hayashi Yumiko , Kato Kentaro , Morimoto Konosuke , Ariyoshi Koya , Dhoubhadel Bhim G
Published: January 2025

Background

Enzyme-linked immunosorbent assay (ELISA) is a traditional WHO recommended method to measure antibody levels against pneumococcal vaccines. However, ELISA is limited in its capacity to assess all 24 pneumococcal vaccine serotypes simultaneously, which is time-consuming, labor-intensive, and it requires a large amount of serum samples. Therefore, we require a high-throughput assay to assess all vaccine serotypes simultaneously and efficiently to assess pneumococcal vaccine impact at a population level.

Methods

Twenty-four pneumococcal polysaccharide antigens were coupled with 24 distinct colored microspheres by employing the carboxyl method. These conjugated microspheres were exposed to the WHO reference serum in a well of a 96-well plate. The WHO reference serum contained 24 serotype-specific pneumococcal antibodies whose concentrations were known. After washing, a mouse anti-human IgG monoclonal antibody (a secondary antibody tagged with phycoerythrin) interacted with the antigen-antibody complex, and then the final reaction was read on the Bio-Plex 200 System (BioRad). We performed assay validation parameters, such as sensitivity, specificity, linearity, and reproducibility according to the WHO recommendation.

Results

A 4.0 log10 of dynamic range was observed in all standard curves specific for 24 serotypes. Depending on specific serotypes, a lower limit of quantitation (sensitivity) varied from 0.40 ng/mL to 10.05 ng/mL. The assays were highly specific for individual serotypes, except for 6A and 6B, and 19F and 19A (some cross-reactivity was observed, which was known and expected among these serotypes). Specificity was >90% in all serotypes, except serotypes 8 (87%) and 14 (59%). Reproducibility trials showed that the coefficient of variation for all serotypes was < 20% (desired limit), except serotype 19A (29.7%) and 23F (25.4%).

Conclusion

We have developed and validated the novel microsphere-based assay. As this assay enables the simultaneous measurement of 24 vaccine serotype-specific antibodies in a single well, it will reduce workload, the need for the amount of serum, and the overall cost. We expect to use this assay in pneumococcal vaccine immunogenicity studies among an elderly population in Japan and among young children in Nepal.

Disclosures

Konosuke Morimoto, MD, PhD, Pfizer: Grant/Research Support Koya Ariyoshi, MD, PhD, Pfizer: Grant/Research Support
P-1838. The human Herpesvirus dUTPases of EBV and HSV-1 may contribute to neurological disorders by altering the integrity of the blood brain barrier and promoting a pro-inflammatory microenvironment
Authors: Mena-Palomo Irene , Martinez Victor , Perdersen Irene Munk , Ariza Maria
Published: January 2025

Background

The global prevalence of Herpes Simplex Virus 1 (HSV-1) and Epstein-Barr Virus (EBV) ranges from 60% to >90%. Some herpesviruses have been linked to neurological diseases including Alzheimer’s disease (AD) and one common feature to these pathologies is disruption of the blood-brain barrier (BBB). The BBB is a key structure responsible for protecting the brain from toxic substances due to its high impermeability and providing energy which is critical for proper brain function. While disruption of the BBB is a hallmark of numerous neurological disorders, the mechanisms underlying herpesvirus-induced BBB dysfunction remain elusive.

Herpesvirus dUTPases encoded by EBV and HSV-1 alter blood brain barrier integrity

Stress, aging as well as other environmental and genetic factors can reactivate human herpesviruses to undergo lytic or abortive-lytic replication, which results in the release of viral dUTPases as a free protein or in exosomes. dUTPase-containing exosomes can travel to the brain via the bloodstream and target cells at the blood brain barrier, triggering the release of pro-inflammatory cytokines and disturbing the structural and functional properties of cell-cell contact molecules. Altogether, the herpesviruses dUTPases can contribute to neurological disorders by increasing blood brain barrier permeability and promoting neuroinflammation.

Methods

In this study we investigated whether a viral protein of EBV and HSV-1 called dUTPase can alter BBB integrity using AD clinical samples, in vitro and 3D perfused hiPSC-derived BBB/NVU models, in combination with a multi-system analysis approach that included, trans-endothelial electrical resistance (TEER), confocal imaging, ELISA, proteome array and qRT-PCR/RNAseq.

Results

Exposure of 3D BBB to HSV-1 or EBV dUTPases resulted in significant BBB permeability, reduced TEER, and loss of functional tight junction protein (TJP; ZO-1 and Claudin-5) structural and functional properties. Both dUTPases significantly increased the expression and/or secretion of IL-1β, IL-6 and TNF-α in immortalized human cerebral microvascular endothelial cells, astrocytes and pericytes. A modest but significant increase in IL-1β and IL-6 mRNA was also observed in dUTPase-treated astrocytes. These cytokines are elevated in patients with AD and are known to disrupt BBB integrity and induce neuroinflammation.

Conclusion

In conclusion, this study provides compelling evidence that EBV/HSV-1 dUTPases have the potential to disrupt the BBB and foster a pro-inflammatory environment in the brain. Thus, it highlights a novel mechanism linking common herpesviruses to brain pathologies.

Disclosures

All Authors: No reported disclosures
P-1845. Evaluation of the immunogenicity and protective efficacy of a fusion vaccine based on the class 5a fimbrial tip of Enterotoxigenic Escherichia coli (ETEC) in an Aotus nancymaae CS14+ and CFA/I+ challenge model
Authors: Gaspar Juan Carlos , Moeller Tyler , Prouty Michael , Nunez Rosa , Espinoza Nereyda , Nieto Monica
Published: January 2025

Background

Enterotoxigenic Escherichia coli (ETEC) colonizes intestinal epithelial cells via colonization factors (CFs), fimbrial, non-fimbrial, and helical adhesins. Once attached, ETEC can release enterotoxins including heat-stable toxin (ST) and/or heat-labile toxin (LT) which cause hypersecretion of fluid in the intestinal lumen resulting in watery diarrhea. Currently, there are no effective countermeasures against ETEC, and antibiotic treatments are losing effectiveness due to increasing antimicrobial resistance. Passive or active immunization against CFs are alluring targets to prevent adhesion, colonization, and ultimately, diarrhea. However, ETEC which infects humans exhibits remarkable heterogeneity and expresses at least 29 immunologically different CFs, making it difficult to create a broadly targeting vaccine that is effective in preventing diarrhea caused by multiple ETEC strains. One third of the CFs that have been described belong to one of three phylogenetic families: CFA/I-like family, which is defined as Class 5 fimbriae divided into three subclasses, 5a, 5b and 5c that are highly related in structure and function.

Methods

In this work, we evaluated the efficacy of a vaccine based on the CFA/I adhesin-pilin fusion (CfaEB) fused to the pilins of colonization factor CS14 (CsuA2) and CS4 (CsfA) to generate broad cross-protection against members of subclass 5a. We previously established a non-human primate challenge model for CS14+ ETEC (strain WS3294A) and found that a 5x1012 CFU dose was needed to achieve a sufficiently high (70%) attack rate. Therefore, the same challenge dose was used to evaluate the effectiveness of the vaccine candidate CfaEp3 (CfaEB-CsuA2-CsfA) against ETEC H10407 (CFA/I; n=10) and WS3294A (CS14; n=10).

Results

Animals that received four vaccine doses with dmLT adjuvant, administered intradermally, were protected from challenge with WS3294A (91% efficacy; p=0.05). However, only 20% protection against ETEC H10407 was achieved.

Conclusion

Although the vaccine candidate did not present cross-protection against members of subclass 5a, the model opens the possibility of future testing of combined vaccines to combat infection with the main pathogenic strains of ETEC encountered by travelers, the military, and civilian populations.

Disclosures

All Authors: No reported disclosures
P-1846. Differences in Type 6 Secretion System Composition among Serogroups of Neonatal Meningitis Escherichia coli
Authors: Ienes-Lima Julia , Álvarez-Narváez Sonsiray , Barbieri Nicolle , Nolan Lisa , Logue Catherine
Published: January 2025

Background

Neonatal meningitis is a public health challenge for pediatricians. Neonatal meningitis Escherichia coli (NMEC) is the most common Gram-negative bacterial cause of sepsis and meningitis in newborns in the United States. NMEC strains can replicate in macrophages, survive in the bloodstream and traverse the blood-brain barrier, resulting in meningitis. Most NMEC cases are associated with serogroups O18, O83, O7, O12, O1, and O45 (Logue et al., 2012). Two clusters of the Type 6 Secretion System (T6SS-I and T6SS-II) were identified in an NMEC O18:K1 strain, and studies have demonstrated that T6SS plays an essential role in the pathogenesis of several bacterial species. However, there is still a lack of knowledge regarding the function of some T6SS genes. Here, we investigated the role of T6SS in different NMEC serogroups to identify specific genes that may be used as a potential target for an efficacious prevention strategy.

Characteristics of NMEC strainsFigure 1.Characteristics of NMEC strains used in this study. A) Percentage of serogroups; B) Prevalence of T6SS among the NMEC isolates.

Methods

A total of 120 NMEC genomes were used in this study (n=78 from the Logue Lab collection; n=42 publicly databases). The T6SS clusters were identified through BLAST analysis using NMEC RS218 and O18 as reference genomes. To establish the presence of a specific cluster, a query cover and percentage identity threshold of 60% and 70% were set. The sequence comparisons were performed using the Artemis Comparison Tool (ACT).

Results

The serogroup O18 was the most abundant (23%; n=28), followed by O1 (22%; n=26), and O83 (12%; n=14). Analysis examined the prevalence of both T6SS clusters in the NMEC genomes and identified that they were present in 69% (n=83) of the genomes, while 12% (n=14) have only one of the clusters, and 19% (n=23) have no clusters. The presence of both T6SS clusters was observed in the serogroups O18, O14, and O2/O50. In contrast, no gene of any cluster was identified in serogroup O7. To understand the role of variation among the serogroups, in vitro analyses were performed. The results indicate differences in survival within THP-1 macrophages-like among distinct serogroups.

Conclusion

Our results support the hypothesis that T6SS components differ among the NMEC serogroups, potentially impacting their pathogenicity and ability to cause meningitis. These findings have significant implications for development of a prevention strategy for neonatal meningitis.

Disclosures

All Authors: No reported disclosures
P-1847. Exploring the correlation between time to positivity and positive culture bottle count in Staphylococcus aureus bacteremia: implications for metastatic lesion development
Authors: Ishikawa Kazuhiro , Sekiya Satoru , Mori Nobuyoshi
Published: January 2025

Background

While numerous studies have investigated the correlations among time to positivity (TTP) in blood cultures, the number of positive bottles, and mortality rates, the association with metastatic lesion formation in Staphylococcus aureus (S. aureus) bacteremia remains poorly understood. This investigation aims to assess the impact on the severity of the, mortality, and the frequency of metastatic lesions.

Study Population Flowchart

Flowchart illustrating categorization of S. aureus-positive blood culture cases for assessing TTP, bottle count, severity, mortality, and metastatic lesions.

Methods

A retrospective analysis was conducted on patients over 15 years old, admitted to St. Luke's International Hospital between 2015 and 2023, who tested positive for S. aureus in blood cultures. Patients with polymicrobial patterns or transferred within a week were excluded. Metastatic lesions were identified through chart reviews and imaging.

Baseline Characteristics of Study Participants

Results

From 398 initial cases, 317 patients were included after exclusions (Figure 1). The patient cohort had an average age of 70.3 years (Standard deviation, SD: 17.0), with 62.5% being male, and 22.4% with MRSA infections. The average TTP was 19.9 hours (SD: 11.9) (Table 1). No significant differences were observed in TTP or bottle count in relation to mortality or severity. Further investigation into the relationship with metastatic lesions shown in Table 2 revealed that TTP for patients with intravascular infections was significantly shorter, averaging 16.81 hours (SD: 5.68), compared to 23.45 hours (SD: 13.84) in bacteremia without metastatic lesions. TTP for bone and joint infections was significantly shorter, averaging 17.88 hours (SD: 8.26), compared to bacteremia without metastatic lesions. SSTI did not show a significant difference in TTP. A weak correlation was found between TTP and metastatic lesion counts (r=0.203) (Figure 2). Additionally, TTP and positive set count showed a weak correlation (r=0.544). When TTP cannot be determined, bottle counts may offer an alternative indicator.

number of complications due to S. aureus

Conclusion

While TTP and bottle count were weakly correlated, they failed to predict severity or mortality in S. aureus bacteremia. Positivity within 24 hours warrants further examination for metastatic conditions like intravascular and bone infections. Yet, TTP and bottle counts' predictive value for metastatic lesion quantity is minimal, highlighting the need for thorough physical exams and imaging.

Correlation between number of disseminated lesions and positive time

Disclosures

All Authors: No reported disclosures
P-1860. Staphylococcus aureus nasal colonization and transmission is enhanced by concurrent influenza A virus upper respiratory infection in an infant mouse model
Authors: Ulrich Robert J , Bartlett Stacey , Morales Sabrina M , Rocha Hedy , Ortigoza Mila B
Published: January 2025

Background

Staphylococcus aureus asymptomatically colonizes the anterior nares of 20-30% of the population, and nasal carriage is a major risk factor for invasive S. aureus disease. Furthermore, rates of S. aureus nasal colonization are higher (40-50%) during the first eight weeks of life and colonizing strains can be transmitted among household contacts. Affecting the same niche, influenza A virus (IAV) is a common cause of viral upper respiratory infection (URI), and IAV predisposes the host to post-URI secondary S. aureus pneumonia. Despite the frequency of S. aureus and IAV in a shared anatomic site, the effects of IAV on S. aureus nasal colonization and transmission are understudied, and infant animal models that may better represent the younger high-colonization age group are not reported.

Infant mouse model

Two index pups from each litter were inoculated with S. aureus, and on day three the entire litter was either infected with IAV or mock (PBS) solution. S. aureus shedding is monitored daily and nasal lavage was performed.

Methods

We established nasal colonization in infant B6 mice by inoculating 106 colony forming units (CFU) of S. aureus MRSA strain JE2 and quantified nasal shedding for seven days on S. aureus chromogenic agar plates. For transmission experiments, we colonized two index pups per cage with S. aureus and infected the groups of pups with Influenza A virus (IAV) or mock (PBS) control on day three after S. aureus colonization. Nasal shedding of S. aureus was quantified daily and nasal lavage was performed at day seven.

Results

Infant mice maintain S. aureus nasal colonization at seven days post-inoculation and they can transmit the colonizing strain to naive co-housed pups. IAV infection increases the S. aureus colonization burden 1000-fold by day 5 and the transmission to co-housed naïve pups by 63%.

Conclusion

Influenza A virus infection increases nasal colonization burden of S. aureus and transmission to S. aureus-naive close contacts in an infant mouse model. We anticipate the model to be a starting point for the study of bacteria-virus interactions that contribute to S. aureus colonization in a high-risk population. Moreover, our work will allow for the study of both S. aureus and IAV mechanisms that contribute to S. aureus transmission amongst close contacts.

Disclosures

All Authors: No reported disclosures
P-1863. Maternal Mycobacterial-Specific T-cell Signatures and Infant Risk of Mycobacterium tuberculosis Infection
Authors: Himmelfarb Talia , Warr Alex , Kinuthia John , Matemo Daniel , Mecha Jerphason O , LaCourse Sylvia M , John-Stewart Grace , Harrington Whitney , Hawn Thomas
Published: January 2025

Background

Tuberculosis disease (TB) caused 214,000 pediatric deaths in 2022. A growing body of evidence suggests that HIV exposed uninfected infants (iHEU) are at increased risk for Mycobacterium tuberculosis (Mtb) infection. Harnessing the power of the maternal immune system to protect infants has shown promise in other infections. Yet no well powered study has evaluated the association between maternal mycobacterial-specific T cell memory and infant protection from Mtb infection. To address this knowledge gap, we examined the hypothesis that previously undescribed maternal factors modulate infant immunity to bacillus Calmette-Guèrin (BCG) and Mtb.Fig 1.Mothers of infants negative for Mtb infection had higher proportions of CD8 T cells expressing IL2 in response to mycobacterial antigens.ESAT-6/CFP-10 negative median 0.004710 (95% CI 0.00096000-0.01103), positive median 0.0 (95% CI 0-0.009410). TBWCL negative median 0.01172 (95% CI 0.005340-0.01860), positive median 0.003710 (95% CI 0-0.008467).

Methods

This study was nested within a randomized controlled trial of isoniazid to prevent Mtb infection in 300 iHEU (iTIPS) who were vaccinated with BCG at birth, randomized to isoniazid or placebo at 6-10 weeks, and had Quantiferon-Plus (with IFNγ, IL2, IP10, TNF measured in supernatant) (QFT-4) at 14 months, and/or tuberculin skin testing (TST) at 14 and 24 months. Paired maternal peripheral blood mononuclear cells were collected at the 6-10 week visit. The majority (73%) of mothers started antiretroviral therapy before pregnancy, 26.3% during pregnancy, and 0.7% after pregnancy. Frequency of self-reported history of TB disease was 10.7%. We assessed the response of maternal T cells to Mtb whole cell lysate (TBWCL), a proxy for BCG, and ESAT-6/CFP-10 (E6C10), an Mtb specific peptide pool, by flow cytometry with a T cell panel including surface, memory, and activation markers and IL2, IL17A, IFNγ, and TNF.

Results

Our preliminary analysis of 166 of 235 maternal samples with flow cytometry revealed that mothers of infants with positive TST or QFT-4 had significantly fewer CD8+IL2+ cells in response to TBWCL (median 0.0037% vs 0.0117%, p=0.032) (Fig 1). Conversely mothers of these infants had significantly higher CD4+TNFa+ responses to E6C10 (median 0.0458% vs 0%, p=0.0014) and CD4+IFNγ+ responses to TBWCL (median 0.0533% vs 0.0302%, p=0.0395).

Conclusion

These results establish that maternal mycobacterial-specific immune signatures are associated with infant outcomes, which we plan to further investigate by comparing these maternal signatures with infant T cell response to TBWCL and determining the role of maternal microchimeric cells.

Disclosures

Sylvia M. LaCourse, MD, MPH, Merck: Grant/Research Support|UpToDate: Royalties
P-1880. An Innovative Infectious Diseases Hospitalist Model - Supporting Lean ID Teams
Authors: Ue Frances V , Banerji Debjani , Bruno-Murtha Lou Ann
Published: January 2025

Background

Two-thirds of the US population live in counties with no or below-average ID physician (ID/P) coverage. This workforce shortage is exacerbated by emerging ID threats and an inadequate fellowship match. In response to these demands, we developed an innovative ID hospitalist (ID/H) model. Subspecialty hospitalists have been increasing since the early 2000s, and ID/Hs may provide support to a stretched ID workforce and mitigate burnout.

Methods

Setting: Cambridge Health Alliance (CHA) is an academic, community, safety-net healthcare system in Massachusetts with two hospitals and multiple outpatient clinics. It serves >140,000 patients in Boston’s metro-north region.

Intervention: CHA’s ID Division is composed of 4 attending physicians (2 FTE total in ID), 1 physician’s assistant (PA), and 1 ID pharmacist. Inpatient consultations are usually performed by 2 ID/Ps (1 at each hospital campus) with partial PA support. During high volume and low staffing weeks from 7/2021 to 4/2023 with only 1 ID/P available, a new staffing model was created. An ID/H provided in-person consultations at one campus (with over-the-phone discussion with the ID/P), while the ID/P provided in-person consultations at the other campus. Outcomes were evaluated via surveys to the ID/Ps, chart review analyzing recommendations, and financial modeling of compensation rates at CHA and locum agencies.

Results

An ID/H completed 59 clinical encounters during 21 shifts over 9 weeks in the study period. All ID/Ps had high/highest satisfaction working with an ID/H when ranked on a Likert scale. ID/Ps characterized the impact of the ID/H in Table 1. Qualitative themes included an increase in staffing flexibility and timely patient care.

There was a high adoption rate of consult recommendations (58/59= 98.3%). The majority of consults were sought by the Medicine service (49/59= 83.1%). ID Consults are characterized in Table 2.

This model was cost-effective for department finances compared to utilization of ID moonlighters or locums. Locums are compensated at a much higher hourly rate and due to delays with insurance processing, the institution may not receive reimbursement for their work.

Conclusion

An ID/H model is a novel way to support lean ID teams. Future research is needed to explore if this will attract more physicians to ID.

Disclosures

All Authors: No reported disclosures