bluuebunny/crossref_metadata_2025_split huggingface dataset:
541. In Silico Modeling by Causal Inference for Identifying Biomarkers of Sepsis
Authors: Carvalho Walisson , Silvério-Machado Rita , Couto Bráulio R G M , Zarate Luis Enrique 
Published: December 2022

Abstract

Background
“Every 3 seconds, someone in the world dies of sepsis” (https://sepsistrust.org/about/). We used causal inference theory as a in silico method to identify biomarkers of sepsis. Causal Inference is a theory in Machine Learning that seeks for the root causes of an event.

Methods
In the study it was used transcription profile data downloaded from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE12624. This dataset has 70 samples, being 34 sepsis and 36 non-sepsis samples. Data set contains 8,519 attributes: 7,672 genes obtained after preprocessing of the mRNA expression profile data. The method applied in the dataset was a modification in the HEISA, a local learner of two stages algorithm (Figure 1). In the first stage HEISA identifies variables that compounds the set of parents, children, parents of parents and children of children of a target. During the second stage is calculated the causal effect using do-calculus method, of the selected variables of the first stage in the target. At end of the second stage, features with causal effect greater than 0.2 is selected. After selecting the features mRNA expression, it was applied two algorithms of classification, Random Forest and K-means, in order to evaluate the ability of the selected variables of identifying the occurrence of sepsis. Figure 1- Causal inference HEISA algorithm.

Results
As shown in Table I, after applying the algorithm, it was select six mRNA expressions that better explains whether sepsis occurs, or not. Analyzing these genes it was possible to observe that three of them are known biomarkers, they are related to sepsis: NM_017526, NM_004649 and NM_006099. It is important to stress that the second one, Homo sapiens leptin receptor overlapping transcript (LEPROT) transcript variant 1 mRNA, is known to be inversely proportional to sepsis (its causal effect is negative). The other three biomarkers, NM_017526, NM_001274, and NM_001071 also are inversely proportional to sepsis. Their relationship with sepsis is still unknown. Regarding the classification task, using only those six mRNA expressions, the accuracy of the task of classification was 100%. Table I- Sepsis biomarkers candidates.

Conclusion
In a big set of 7,672 genes, only six were returned as sepsis biomarkers candidates. This is a very promising in silico discovery, made by a novel mathematical method, the Causal Inference theory.

Disclosures
All Authors: No reported disclosures.
553. Designing and evaluating a facilitation workshop for antimicrobial stewardship teams to de-implement inappropriate perioperative antibiotic use in pediatric hospitals
Authors: Malone Sara , McKay Virginia , Saito Jacqueline M , Rangel Shawn , Bono Kelly , Newland Jason 
Published: December 2022

Abstract

Background
In pediatric hospitals, approximately 20% of inappropriate antibiotic use results from unnecessary postoperative antibiotic prophylaxis (POP). Facilitation, an implementation strategy focused on using individuals as change agents, may be an effective strategy. No standard facilitation training has been provided for individuals leading antimicrobial stewardship programs (ASP). We describe the development and evaluation of a virtual facilitation workshop to increase antimicrobial stewards’ ability to reduce POP.

Methods
This work was conducted in the Optimizing Perioperative Antibiotic in Children (OPERATIC) trial, a stepped wedge randomized controlled trial with 9 pediatric hospitals to test strategies with ASPs to reduce POP. After comprehensive literature review, we developed a theoretically supported facilitation training workshop. Four modules were presented weekly that targeted evidence against POP use, data visualization, understanding local context, and enhancing interpersonal skills. After workshop completion, participants completed an electronic survey consisting of 13 Likert questions (scale 1-5; 1=very poor) questions adapted from a published measure for practice facilitation and four open ended questions. Responses were analyzed descriptively.

Results
A total of 10 physicians, 7 pharmacists, and 1 other staff affiliated with ASPs completed the survey for a 75% response rate. Participants rated the overall workshop as a 4.5 on average. Participants stated they were likely to use workshop information in the future. Individuals stated they gained skills regarding communication/conflict style (4.45), implementation science principles (4.3), and data visualization (4.1). Three individuals believed the workshop could be shorter. In free text responses, participants highlighted the usefulness of examples and role play as well as the conceptual shift in viewing the ASP as an active facilitator in the surgical setting.

Conclusion
Virtual facilitation training is feasible and useful for ASP teams. This workshop method could enable skill development within the context of a clinician’s schedule, while still promoting evidence-based strategies for better de-implementation of unnecessary prescribing.

Disclosures
Sara Malone, PhD, LCSW, AHRQ: Grant/Research Support|NIH: Grant/Research Support 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.
558. Increasing Safety Net Antibiotic Prescriptions (SNAP) for Acute Otitis Media Treatment in Pediatric Urgent Care Clinics
Authors: McKinsey Jennifer , Nedved Amanda , Wyly Donna , Austin Holly B , Dosdos Dinah , Murdock Emily , Lee Brian R , Patel Aimy T , El Feghaly Rana E 
Published: December 2022

Abstract

Background
Acute otitis media (AOM) is the most common diagnosis for which antibiotics are prescribed in pediatrics. National guidelines recommend offering a safety net antibiotic prescription (SNAP) to select patients, to be filled if symptoms worsen or do not improve within 48-72 hours. However, clinicians continue to prescribe immediate antibiotics for most cases of AOM. Our goal was to increase the percentage of eligible patients diagnosed with AOM in our pediatric urgent care (PUC) clinics who are offered a SNAP from our baseline of 7.7% to 40% within nine months.

Methods
A multidisciplinary team of PUC clinicians, an Infectious Diseases physician, and a data analyst, used quality improvement (QI) methodology to identify barriers to offering SNAP (Figure 1). Patients without chronic ear conditions were considered eligible for SNAP if they had no or mild otalgia for &lt; 48 hours, fever &lt; 39oC, no otorrhea, and for patients ≤ 24 months old, if they had only unilateral AOM. We analyzed all encounters of patients ≥ 6 months old with a discharge diagnosis of AOM from three PUC clinics during baseline (October 2020 – September 2021) and study (October 2021 – March 2022) periods. Interventions included clinician education, standardized discharge instructions, electronic health record updates to improve documentation, and educational flyers for clinicians and families. Our outcome measure was the percentage of eligible encounters during which SNAP was offered. Our process measure was the percentage of AOM encounters in which SNAP eligibility was documented. Our balancing measure was the percentage of patients returning with AOM symptoms within 14 days.

Results
We reviewed 12,502 encounters from October 2020 through March 2022. At baseline, clinicians documented SNAP eligibility in 5.5% of AOM encounters and offered SNAP to 7.7% of eligible patients. By March 2022, clinicians documented SNAP eligibility in 58.9% of AOM encounters and offered SNAP to 40.7% of eligible patients (Figure 2). There was no change in our balancing measure.
UCL: Upper control limit. LCL: Lower control limit.

Conclusion
Using QI methodology, we increased the percentage of eligible patients with AOM who were offered SNAP, reducing antibiotic exposure in PUC clinics. Efforts are ongoing to further improve this process.

Disclosures
Brian R. Lee, PhD, MPH, CDC: Grant/Research Support|Merck: Grant/Research Support.
561. Methicillin-Resistant Staphylococcus aureus is Decreasing in Community-Onset Pediatric Infections Treated at a Mid-Atlantic Health System
Authors: Prochaska Erica , Milstone Aaron , Sick-Samuels Anna , Xiao Shaoming , Schumacher Christina , Tamma Pranita , Carroll Karen C , Gadala Avi 
Published: December 2022

Abstract

Background
Hospitalizations due to soft tissue methicillin resistant S. aureus (MRSA) infections are decreasing nationally. Analyzing trends in pediatric community-onset (CO) S. aureus infections is needed to inform empiric antibiotic selection in the Emergency Department and outpatient settings.

Methods
We identified all cultures growing S. aureus between January 1, 2014 and December 31, 2020 in the Johns Hopkins Hospital microbiology laboratory that services an academic medical center, a mid-level teaching hospital, and a community hospital. Patients were included if they were ≤18 years of age or treated in a pediatric location. Cultures that likely represented colonization, such as nasal swabs, throat swabs, or sputum were excluded. Patients hospitalized within 2 calendar days of culture collection were defined as treated in-hospital. All others were defined as treated outpatient. CO infection was defined as a culture obtained within 3 days of hospitalization or from children not hospitalized. Only the first culture per patient per quarter was included. Cochran Armitage test was used to analyze trends in antibiotic susceptibilities.

Results
3517 cultures obtained from 3078 patients were included. 3208 cultures (91%) were CO. Of CO cultures, 2517 (78.5%) were treated in an outpatient setting and 691 (21.5%) were treated in-hospital. There was a 74% decrease in the number of CO S. aureus cultures during the study period: 751 in 2014 to 191 in 2020. Comparing CO cultures from 2014 and 2020, methicillin susceptibility increased from 59.5% to 67% overall (p = 0.007), 59.4% to 63.8% in outpatient treated cultures (p = 0.07), and 60% to 76% among in-hospital treated cultures (p =0.02). Methicillin susceptibility from CO soft tissue sources remained about 60% during the study period with no significant change in trend. When soft tissue sources were excluded from CO cultures, methicillin susceptibility increased from 61.7% in 2014 to 84.1% in 2020 (p = 0.01). Within CO blood cultures, methicillin susceptibility increased from 86.7% to 92.3% (p = 0.4).

Conclusion
In a regional health system, CO pediatric MRSA incidence is decreasing. Although the majority of CO bloodstream S. aureus infections are methicillin susceptible, MRSA continues to cause up to 40% of S. aureus soft tissue infections.

Disclosures
Aaron Milstone, MD, Merck: Grant/Research Support Karen C. Carroll, MD, Abbott Diagnostics: Advisor/Consultant|BD Diagnostics: Advisor/Consultant|BD Diagnostics: Grant/Research Support|BioRad, Inc: Grant/Research Support|Meridian Biosciences: Grant/Research Support|Roche Diagnostics: Advisor/Consultant|Scanogen, Inc: Advisor/Consultant|Scanogen, Inc: Grant/Research Support|Thermo Fisher, Inc: Advisor/Consultant.
574. Antibodies Targeting Candida albicans Als3 and Hyr1 Antigens Protect Neonatal Mice from Candidiasis
Authors: Singh Shakti , Nabeela Sunna , Barbarino Ashley M , Ibrahim Ashraf S , Uppuliri Priya 
Published: December 2022

Abstract

Background
Pre-term infants in neonatal intensive care units are vulnerable to fungal sepsis. In this patient population, C. albicans remains the predominant fungal pathogen causing high morbidity and mortality, despite antifungal therapy. Thus, new therapeutic strategies against neonatal candidiasis are needed. We have reported that vaccination with C. albicans cell wall N-termini recombinant proteins Als3 (rAls3p-N) and Hyr1 (rHyr1p-N) protected adult mice from disseminated candidiasis. Further, NDV-3A (rAls3p-N+alum) protected women from recurrent vulvovaginal candidiasis, which was correlated with anti-Als3p IgG2 isotype titer. Here, we evaluated the efficacy of Als3p and Hyr1p based vaccine in a neonatal candidiasis mouse model.

Methods
Inbred BALB/c mice strain was used for both active and passive vaccination studies. Female 4-6 weeks old mice were vaccinated with rAls3p-N or rHyr1p-N antigens mixed with complete Freund’s adjuvant (CFA, priming)/incomplete Freund’s adjuvant (IFA, boosting). Mice were mated after the boost and pups (3 days old) born to vaccinated mice were infected intraperitoneally (IP) with C. albicans. For passive vaccination, 3 days old naive pups were IP infected with C. albicans and treated with serum obtained from vaccinated adult mice. Fungal burdens were determined in the kidneys of infected neonate mice at 3 days post-infection. Antibody titers were determined by ELISA.

Results
CFA/IFA formulated Als3 and Hyr1 vaccines induced a robust antibody response with a ten-fold higher titer of IgG2, than attained by either antigen formulated with alum. Transplacental transfer of these antibodies significantly reduced the fungal burden in the kidneys of mice pups, and adoptive transfer of vaccinated mothers’ sera into pups displayed similar levels of protection. Neutrophils were found important for this efficacy. Anti-Hyr1 antisera potentiated the activity of fluconazole in protecting from C. albicans infection.

Conclusion
Our current studies are the first to emphasize the importance of anti-Als3 and anti-Hyr1 antibodies in preventing neonatal candidiasis. Considering that Candida infections in low birth weight infants is a lethal infection, active and passive vaccination strategies using these antigens could have profound clinical significance.

Disclosures
All Authors: No reported disclosures.
610. Low Rates of Acute Kidney Injury (AKI) in Outpatient Vancomycin Managed by Pharmacists using Precision Dosing Software
Authors: Schroeder Claudia P , Couch Kimberly A , Gee Joyce F , Van Anglen Lucinda J 
Published: December 2022

Abstract

Background
AKI is a complication of intravenous vancomycin (VAN) occurring in up to 43% of patients (pts) during hospitalization. Data on AKI in pts receiving VAN through outpatient parenteral antimicrobial therapy (OPAT) are limited. There is suggestion that VAN managed through precision dosing pharmacokinetic (PK) software may limit this occurrence. We evaluated the AKI rate of pts receiving VAN as OPAT through Physician Office Infusion Centers (POICs) over a 12-month period.

Methods
A review was conducted of OPAT VAN pts treated in 2021 with therapeutic drug monitoring (TDM) performed (InsightRX) and ≥2 VAN serum levels. These pts were then evaluated for AKI, defined as increase in serum creatinine (SCr) ≥1.5 times baseline. Pts on dialysis were excluded. Data included comorbidities, diagnosis, VAN regimen, concomitant medications, SCr, and VAN serum levels. PK parameters were collected with trough values and estimated 24-hr area under the curve (AUC24). Outcome of therapy was assessed following identification of AKI.

Results
A total of 330 pts from 51 POICs had TDM performed. Of these, 27 (8.2%) developed AKI. Median age was 61 years, 67% were male, and baseline SCr was 0.8 mg/dL (IQR, 0.7-1.0). Most pts (89%) were on concomitant nephrotoxic medications. Median duration of OPAT was 34 days (IQR, 18-41) with onset of AKI after 16 days (IQR, 10-21). At time of AKI, the median SCr increase was 1.7 times baseline (IQR, 1.5-2.0) with a corresponding VAN trough of 21 mg/mL (IQR, 15-28) and AUC24 of 572 mg*h/L (IQR, 495-660). As a result, VAN was discontinued in 14 (52%), dose or frequency modified in 10 (37%) with completion of VAN, and no modifications performed in 3 (11%). One pt who discontinued VAN required hospitalization due to AKI with resolution.

Conclusion
VAN managed by pharmacists in an OPAT setting using precision dosing software resulted in a low rate of AKI. Median rise in SCr was &lt; 2 times baseline for those with AKI. Rapid identification of early AKI by the pharmacist resulted in changes to the regimen or VAN discontinuation, preventing serious patient sequelae. This supports the need for pharmacist-led monitoring in an outpatient setting with long VAN therapy durations.

Disclosures
Lucinda J. Van Anglen, PharmD, Merck & Co.: Grant/Research Support|Paratek: Grant/Research Support.
615. Pharmacodynamics (PD) of the Beta-Lactamase Inhibitor Xeruborbactam When Administered in Combination with Meropenem
Authors: Tarazi Ziad , Roos Niki , Page Ted , Griffith David 
Published: December 2022

Abstract

Background
Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. The purpose of these studies was to determine the pharmacodynamic parameter that best described the activity of XERU against Enterobacterales and A. baumannii when administered in combination with a fixed dosage regimen of meropenem in the neutropenic mouse thigh infection model.
24h Free Xeruborbactam AUC vs CRE
24h Free Xeruborbactam AUC vs CRAB

Methods
Seven carbapenem resistant Enterobacterales (CRE) and six carbapenem-resistant A. baumannii (CRAB) isolates were used in these studies. Mice were rendered neutropenic, infected with ∼107 CFU/thigh and were treated with various doses of XERU in combination with meropenem (300 mg/kg q2h) by the IP route starting 2 hours post infection for 24 hours. The meropenem dosage regimen was fixed and designed to simulate 2 g every 8 hours by 3-hour infusion in humans. Plasma exposures (PK) were measured in neutropenic, infected mice. The relationship between XERU PK-PD indices and the reduction in the log number of CFU per thigh were analyzed by using the sigmoid Emax PD model.

Results
The activity of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free xeru plasma AUC.
Xeru PK-PD Parameters in Combination with Meropenem against CRE
Xeru PK-PD Parameters in Combination with Meropenem against CRAB

Conclusion
The PK-PD of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free XERU plasma AUC. The PK-PD of XERU in combination with meropenem and the clinical PK of both drugs support further clinical development for the treatment of carbapenem-resistant isolates of Enterobacterales and A. baumannii.

Disclosures
Ziad Tarazi, Qpex Biopharma: Employee Niki Roos, n/a, Qpex Biopharma: Employee Ted Page, n/a, Qpex Biopharma: Employee David Griffith, n/a, Qpex Biopharma: Employee.
618. Pharmacokinetic/pharmacodynamic analysis of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating documented carbapenem-resistant Gram-negative bloodstream infections and/or hospital-acquired pneumonia: a case series
Authors: Gatti Milo , Rinaldi Matteo , Cojutti Pier Giorgio , Horna Clara Solera , Fornaro Giacomo , Viale Pierluigi , Giannella Maddalena , Pea Federico 
Published: December 2022

Abstract

Background
To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour and the microbiological outcome of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating severe carbapenem-resistant Gram-negative (CR-GN) infections.

Methods
Single-center retrospective study of patients who were treated with CI fosfomycin plus EI or CI beta-lactams for severe CR-GN infections and who underwent therapeutic drug monitoring (TDM), from 01 April 2021 to 31 January 2022. Concentrations of CI fosfomycin, meropenem and ceftazidime-avibactam were determined at steady-state (Css), while those of EI cefiderocol were measured at trough (Cmin). The desired joint PK/PD targets of combination therapy were considered as optimal when simultaneously the area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio for fosfomycin was &gt; 83 and the Css/MIC for meropenem or for ceftazidime-avibactam or the Cmin/MIC ratio for cefiderocol was &gt; 4 (quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). Relationship between the joint PK/PD targets and microbiological failure (MF) defined as isolation of the same pathogens from follow-up blood cultures or BAL and assessed within 30 days of treatment onset, was investigated.

Results
Among the 16 retrieved patients with documented CR-GN infections, 12 underwent TDM of both fosfomycin and beta-lactams, and seven out of these (3 HAP, 3 BSI+HAP, and one BSI) had determination of fosfomycin MIC determined by agar-dilution (see Table). The joint PK/PD targets were optimal in 4 cases and quasi-optimal in the other 3y. MF occurred in two patients (29%) who were affected by HAP, received combination therapy with ceftazidime-avibactam, and achieved only quasi-optimal joint PK/PD targets (with fosfomycin AUC/MIC &lt; 83). No MF occurred in patients with optimal joint PK/PD targets.
Summary of the relationship between PK/PD targets and microbiological failure in patients receiving combination therapy with CI fosfomycin plus EI/CI beta-lactams

Conclusion
CI fosfomycin in combination with EI/CI beta-lactams may allow for the achievement of optimal joint PK/PD targets in most patients with CR-GN infections, and may represent a potential strategy for minimizing the risk of MF.

Disclosures
All Authors: No reported disclosures.
627. Too Much of a Good Thing? The Clinical Effects of Very High Serum Posaconazole Levels
Authors: Jensen Kelsey L , Mara Kristin , Jannetto Paul J , Chesdachai Supavit , Yetmar Zachary A , Abu Saleh Omar M , Rivera Christina G 
Published: December 2022

Abstract

Background
Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety (i.e., hepatotoxicity, QTc prolongation); however, little is known about clinical effects of very high serum posaconazole serum levels (i.e., ≥ 5000 mg/mL). Reported incidence rate of adverse drug reactions (ADRs) with posaconazole per most recent clinical trial was ∼30%. The primary objective was to compare the ADR incidence in patients with serum posaconazole levels of 3000-4999 ng/mL to ≥5000 ng/mL.

Methods
This retrospective cohort study included adult patients with a posaconazole serum level ≥3000 ng/mL from 1/1/2019 to 04/30/2021. The primary outcome was symptomatic ADR at time of first serum level ≥3000 ng/mL. Secondary outcomes were laboratory defined hepatoxicity, electrolyte and adrenal laboratory abnormalities, QTc changes, and dose changes in response to TDM. Patient outcomes were censored after the first serum level and were compared between groups using Fisher’s exact tests.

Results
Ninety patients met inclusion criteria, 80 with a level of 3000-4999 ng/mL and 10 with a level of ≥ 5000 ng/mL occurring at a median of 91 days (26-443) and 27 days (12-45) from posaconazole initiation, respectively. Majority of patients were immunocompromised (55.6% transplant recipients, 28.9% active malignancy, 5.6% other) with a split of treatment (50%) and prophylaxis (42.2%) indication. Symptomatic ADRs were very common in patients with posaconazole levels of ≥5000 ng/mL and 3000-4999 ng/mL (80% vs. 58.8%; p=0.31), primarily neurologic (49.1% overall) followed by gastrointestinal (32.7% overall). Hepatotoxicity was also common (≥5000 ng/mL 40% vs 3000-4999 ng/mL 23.4%, p=0.26). Fifty percent of patients had the posaconazole dose continued without change. Electrolytes and QTc results were similar between groups, but median overall QTc was borderline high (456 [IQR 435, 479]).

Conclusion
There are safety concerns for patients with serum posaconazole levels ≥3000 ng/mL. Posaconazole levels should be monitored and, importantly, dose adjusted according to serum level and patient symptoms for both treatment and prophylaxis indications.

Disclosures
Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.