bluuebunny/crossref_metadata_2025_split huggingface dataset:
140. Symptoms and Situations Predispose Patients to Use Antibiotics Without Medical Advice
Authors: Hansen Michael , Trautner Barbara , Zoorob Roger , Germanos George , Alquicira Osvaldo , Salinas juanita , Barning Kenneth , Mahmood Hammad , Gonzalez Malissa A , Fowler Michele , Grigoryan Larissa 
Published: January 2021

Abstract

Background
Use of antibiotics without a prescription (non-prescription use) contributes to antimicrobial resistance. Non-prescription use includes obtaining and taking antibiotics without a prescription, taking another person’s antibiotics, or taking one’s own stored antibiotics. We conducted a quantitative survey focusing on the factors that impact patients’ decisions to use non-prescription antibiotics.

Methods
We surveyed patients visiting public safety net primary care clinics and private emergency departments in a racially/ethnically diverse urban area. Surveys were read aloud to patients in Spanish and English. Survey domains included patients’ perspectives on which syndromes require antibiotic treatment, their perceptions of health care, and their access to antibiotics without a prescription.

Results
We interviewed 190 patients, 122 from emergency departments (64%), and 68 from primary care clinics (36%). Overall, 44% reported non-prescription antibiotic use within the past 12 months. Non-prescription use was higher among primary care clinic patients (63%) than the emergency department patients (39%, p = 0.002). The majority felt that antibiotics would be needed for bronchitis (78%) while few felt antibiotics would be needed for diarrhea (30%) (Figure 1).
The most common situation identified “in which respondents would consider taking antibiotics without contacting a healthcare provider was “got better by taking this antibiotic before” (Figure 2). Primary care patients were more likely to obtain antibiotics without prescription from another country than emergency department patients (27% vs. 13%, P=0.03). Also, primary care patients were more likely to report obstacles to seeking a doctor’s care, such as the inability to take time off from work or transportation difficulties, but these comparisons were not statistically significant.
Figure 1. Patients’ agreement that antibiotics would be needed varied by symptom/syndrome.

Figure 2. Situations that lead to non-prescription antibiotic use impacted the two clinical populations differently

Conclusion
Non-prescription antibiotic use is a widespread problem in the two very different healthcare systems we included in this study, although factors underlying this practice differ by patient population. Better understanding of the factors driving non-prescription antibiotic use is essential to designing patient-focused interventions to decrease this unsafe practice.

Disclosures
All Authors: No reported disclosures
148. Fungal Disease Mortality Trends, United States, 1999–2017
Authors: Toda Mitsuru , Jackson Brendan R , Deng Li , Derado Gordana , Chiller Tom M , Benedict Kaitlin 
Published: January 2021

Abstract

Background
Fungal diseases can lead to substantial morbidity and mortality, although research funding has been disproportionately low compared with other infectious diseases. Despite dramatic changes in immunosuppressive therapy over the past two decades, the U.S. mortality burden of fungal diseases has not been recently assessed.

Methods
We analyzed fungal disease-associated mortality trends during 1999–2017 using multiple cause-of-death mortality records from the National Vital Statistics System. We calculated age-standardized rates for aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, unspecified mycoses, and other mycoses based on the age distribution of the 2000 U.S. population.

Results
Among over 47 million deaths, 86,058 (0.2%) people had one or more fungal diseases listed on the death certificate as an underlying or contributing cause of death (median 4,431 annually) (Figure 1). The age-standardized mortality rate was 2.2/100,000 population in 1999. By 2017, rates declined by 47% to 1.2. The largest declines occurred for pneumocystosis and cryptococcosis, diseases particularly associated with HIV, by 66–70% from 1999 to 2007 and by 3–6% from 2008 to 2017. During 1999–2017, rates for aspergillosis, candidiasis, and other mycoses declined by 46–56%, although rates for candidiasis and other mycoses increased (10% and 31%, respectively) from 2013 to 2017. Overall, the steepest declines were seen in infants and younger adults (Figure 2).
Age-standardized mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and fungal disease type, United States, 1999–2017

Age-specific mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and age group, United States, 1999–2017

Conclusion
Fungal disease-associated mortality rates declined by half from 1999 to 2017. Improved treatment of HIV and availability of new antifungals likely influenced the decline. However, fungal diseases are still documented in thousands of deaths annually, and rates differed substantially by disease. Better prevention, diagnosis, and treatment are needed to reduce mortality from fungal diseases.

Disclosures
All Authors: No reported disclosures
168. Efficacy of the Novel gwt1 Inhibitor APX2039 in a Rabbit Model of cryptococcus Meningitis
Authors: Shaw Karen J , Giamberardino Charles D , Soltow Quinlyn A , Tenor Jennifer , Toffaletti Dena , Boua Jane-Valeriane , Marius Choiselle , Palmucci Julia R , Perfect John R 
Published: January 2021

Abstract

Background
Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. New oral treatment options are needed that demonstrate rapid reductions in CFU in CSF and brain tissue.
APX2039 is a novel inhibitor of the fungal Gwt1 enzyme, which catalyzes an early step in glycosylphosphatidyl inositol (GPI) anchor biosynthesis. It is highly active against both C. neoformans and C. gattii and has previously demonstrated significant efficacy in a mouse delayed-treatment model of CM.
CSF Fungal Burden in Rabbits

Methods
Male New Zealand White rabbits were inoculated with C. neoformans H99 (1.4 ×106 CFU) directly into the cisterna magna. Rabbits were immunosuppressed with cortisone acetate at 7.5 mg/kg (i.m.), starting on Day -1 relative to inoculation and then administered drug daily throughout the 14-day experimental period. Treatment was initiated on Day 2 postinfection and continued through Day 14 consisting of: 50 mg/kg APX2039 PO (BID), 80 mg/kg fluconazole (FLU) PO (QD), c) 1 mg/kg amphotericin B deoxycholate (AMB) IV (QD); and vehicle control. CSF was removed via an intracisternal tap on Days 2, 7, 10 and 14 post-infection and CFU/ml was assessed. Animals were sacrificed on Day 14 and CFU/g brain tissue was assessed.

Results
APX2039 demonstrated rapid reduction in CFU in both CSF and brain tissue. The range in CFU values in rabbit CSF is shown (Figure). Reductions in CFU were statistically different from the control group for all treatment groups. APX2039 was also different from both FLU and AMB and resulted in sterilization in CSF by Day 10. Brain harvested on Day 14 demonstrated a reduction in CFU/g tissue vs control of 1.8 log10 and 3.4 log10 for FLU and AMB, respectively, while a &gt; 6 log10 reduction (tissue sterilization) was observed for APX2039.

Conclusion
APX2039 demonstrated potent efficacy in a rabbit model of CM. The more rapid clearance in CSF than either AMB or FLU, as well as &gt; 6 log10 reduction in brain CFU highlights the unique properties of this drug, warranting further investigation of this molecule for the treatment of CM.

Disclosures
Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Charles D. Giamberardino, Jr., MR, Box (Shareholder) John R. Perfect, MD, amplyx (Grant/Research Support)astellas (Grant/Research Support)astellas (Grant/Research Support)
171. Short-course Antimicrobial Therapy for Paediatric Respiratory Infections (SAFER): a multicentre, Randomized, Controlled, Blinded, Noninferiority Trial
Authors: Pernica Jeffrey , Harman Stuart , Kam April J , Carciumaru Redjana , Vanniyasingam Thuva , Crawford Tyrus , Dalgleish Dale , Khan Sarah , Fulford Martha , Main Cheryl L , Slinger Robert , Smieja Marek , Thabane Lehana , Loeb Mark 
Published: January 2021

Abstract

Background
Community-acquired pneumonia (CAP) is a common occurrence in childhood; consequently, evidence-based recommendations for its treatment are required. The study objective was to determine if, in previously healthy children presenting to the emergency department (ED), 5 days of high-dose amoxicillin led to noninferior rates of clinical cure at 14–21 days post-enrolment compared with 10 days of high-dose amoxicillin.

Methods
The SAFER study was a multicentre, randomized, parallel-group, multiple-blinded, controlled, noninferiority study, enrolling between 2012–2014 (single centre pilot) and then 2016–2019 (follow-up main study). Children aged 6 months – 10 years with all of the following were eligible: fever within 48h; a respiratory symptom/sign; a chest radiograph consistent with pneumonia as per the emergency MD; and a primary diagnosis of CAP. Children were excluded if they required hospitalization, had any medical comorbidities, or if they were already receiving beta-lactam antibiotic therapy. The intervention of interest was 5 days of high-dose amoxicillin followed by 5 days placebo. The control (standard care) arm received 5 days of high-dose amoxicillin followed by a different formulation of 5 days of high-dose amoxicillin. The primary outcome was clinical cure at 14–21 days post-enrolment. The pre-set noninferiority margin was 0.075 less than the clinical cure risk difference (1-sided 97.5% CI).

Results
Of the 281 participants, 119 (42%) were female; the median age was 2.6 y (25–75%ile 1.6–4.9 y). There were 140 randomized to short-course treatment and 141 to standard care. Clinical cure at 14–21 days was observed in 108/126 (86%) in the short-course arm and in 106/126 (84%) in the standard-care arm (risk difference 0.023, lower limit of 1-sided 97.5%CI -0.061). There were no participants who, after finishing amoxicillin, later deteriorated and required hospitalization for progressive CAP.

Conclusion
Short-course antibiotic therapy was noninferior to standard care for the treatment of previously healthy children with non-severe CAP diagnosed in Canadian EDs. Clinical practice guidelines should recommend no more than 5 days of amoxicillin for paediatric pneumonia management, in accordance with antimicrobial stewardship principles.

Disclosures
All Authors: No reported disclosures
173. HSV-2 Isolates from Neonates with Different Clinical Outcomes Exhibit Different in Vitro and in Vivo phenotypes
Authors: Akhtar Lisa N , Choi Sue , Hayes Cooper , Awasthi Sita , Koyuncu Orkide , Szpara Moriah , Enquist Lynn , Friedman Harvey , Longnecker Richard , Weitzman Matthew 
Published: January 2021

Abstract

Background
Herpes simplex virus (HSV) infection of the neonatal brain causes severe meningoencephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow different clinical courses. Some infants develop only external infection of the skin, eyes, or mouth (SEM disease), while others develop invasive infection of the central nervous system resulting in encephalitis (CNS disease). The factors that explain this clinical divergence are not well understood. While adults can be predisposed to HSV CNS infection by an innate immune defect, no such host susceptibility has been identified in neonates. Therefore, we have taken a novel approach to determine whether variations in the HSV genome contribute to infection of the neonatal brain. We recently defined the viral genetic diversity among HSV-2 isolates cultured from neonates with a range of clinical presentations. Isolates collected from neonates with CNS disease contained several unique amino acid variations in HSV proteins known to contribute to cell-to-cell spread and neurovirulence in mouse models.

Methods
To understand the relevance of these findings to neonatal CNS disease, we evaluated CNS disease- and SEM disease-associated neonatal HSV-2 isolates in neurologically-relevant in vitro and in vivo models.

Results
We found that HSV-2 isolates from neonates with CNS disease, as compared to those collected from neonates with SEM disease, displayed enhanced spread in human neuronally-differentiated SH-SY5Y or LUHMES cells and enhanced retrograde transport in rat neurons cultured in modified Campenot chambers. CNS disease-associated isolates also resulted in increased hind limb paralysis and zosteriform disease in a mouse flank scratch infection model, and increased death in a mouse direct intracerebral injection model of encephalitis. Notably, CNS disease and SEM disease-associated isolates resulted in equivalent outcomes following mouse intraperitoneal injection, suggesting similar systemic virulence.

Conclusion
These data suggest that virus-mediated differences in neuronal spread and transport may contribute to neurovirulence in neonatal HSV disease.

Disclosures
All Authors: No reported disclosures
174. Shotgun Metagenomics and Colonization by Antibiotic-resistant Bacteria in Pediatric Hematopoietic Stem Cell Transplant Recipients
Authors: Heston Sarah M , Young Rebecca R , Arshad Mehreen , Jenkins Kirsten , Martin Paul L , Ward Doyle V , Bhattarai Shakti , Bucci Vanni , Seed Patrick C , Kelly Matthew S 
Published: January 2021

Abstract

Background
Bacteremia in hematopoietic stem cell transplant (HSCT) recipients most frequently arises from gut bacterial translocation and is associated with a higher mortality if the organism is antibiotic-resistant. We sought to determine the impact of prior antibiotic exposure on antibiotic resistance genes (ARGs) in the gut metagenomes of HSCT recipients to inform future infection prevention strategies.

Methods
We performed shotgun metagenomic sequencing of fecal samples collected during the transplant hospitalization from children (&lt; 18 years of age) undergoing HSCT at Duke University between 2015 and 2018. Host-decontaminated sequencing reads were aligned to the Comprehensive Antibiotic Resistance Database. We used a negative binomial regression model to determine the impact of recent therapeutic antibiotic exposure on the number of ARGs prior to HSCT.

Results
Median age of the 77 children included in these analyses was 4.8 years, and 58% were male. Hematological malignancy was the transplant indication for 42% of children, and 87% of transplants were allogeneic. In the 654 longitudinal samples, we identified 926 unique ARGs, conferring resistance to 31 classes of antibiotics. The median number of ARGs per sample was 24 (interquartile range: 13, 49). The most common ARGs detected were dfrF (conferring resistance to trimethoprim), tetO (tetracyclines), and tetW (tetracyclines), each detected in &gt;65% of samples. Of the 66 children with fecal samples collected prior to HSCT, 70% of children received therapeutic antibiotics in the 2 weeks prior to enrollment. Accounting for transplant indication, sex, and age, the incidence of ARGs was 47% higher in children who received recent therapeutic antibiotics (incidence rate ratio 1.47; 95% CI (1.03–2.13); p=0.04).

Conclusion
ARGs are commonly found in the gut metagenomes of pediatric HSCT recipients prior to HSCT and are associated with recent receipt of therapeutic antibiotics. Future directions for this dataset include determining the ability of ARGs in the metagenome to predict clinical outcomes, including mortality and infections. Understanding the colonization and acquisition of ARGs could inform infection prevention strategies and empiric therapies and lead to improved infectious outcomes in these high-risk patients.

Disclosures
All Authors: No reported disclosures
180. Impact of Pneumococcal Conjugative Vaccine on Antibiotic Resistant Invasive Pneumococcal Disease in the United States
Authors: Bajema Kristina , Gierke Ryan , Farley Monica M , Schaffner William , Thomas Ann , Reingold Art , Harrison Lee , Lynfield Ruth , Burzlaff Kari , Petit Susan , Barnes Meghan , Torres Salina , Beall Bernard , Pilishvili Tamara 
Published: January 2021

Abstract

Background
Antibiotic-nonsusceptible invasive pneumococcal disease (NS-IPD) in the United States declined dramatically following the introduction of pneumococcal conjugative vaccines (7-valent, PCV7 in 2000, replaced by the 13-valent, PCV13 in 2010). We evaluated the long-term impact of PCV13 on NS-IPD.

Methods
IPD cases were identified through CDC’s Active Bacterial Core surveillance during 2005−2018. We applied 2012 Clinical and Laboratory Standards Institute breakpoints to minimum inhibitory concentrations determined by broth microdilution (2005−2014) or whole genome sequencing (2015−2018) and classified non-susceptible isolates as those intermediate or resistant to ≥1 antibiotic class. Isolates were serotyped and classified as PCV13 or non-vaccine type (NVT). Incidence rates (cases per 100,000) were calculated using United States Census Bureau population denominators.

Results
From 2005 to 2018, NS IPD incidence decreased from 8.5 to 3.2 among children &lt; 5 years old and from 13.0 to 9.4 among adults ≥ 65 years old. Incidence of vaccine-type NS-IPD decreased in all age groups (Figure 1), while incidence of NVT NS-IPD increased in all age groups (Figure 2). The greatest absolute increase in NVT NS-IPD occurred among adults ≥ 65 years from 4.7 in 2005 to 7.2 in 2018. PCV13 serotypes contributed to 62% of NS-IPD (36% of NS-IPD caused by serotype 19A alone) in 2005−2009, and 27% of NS-IPD in 2014−18 (8% of NS-IPD caused by 19A). During 2014–18, NVTs 35B (11%), 33F (9%), 22F (9%), and 15A (9%) were the most common NS-IPD serotypes.
Figure 1. Incidence of vaccine type antibiotic non-susceptible invasive pneumococcal disease by age group, 2005−2018.

Figure 2. Incidence of non-vaccine type antibiotic non-susceptible invasive pneumococcal disease by age group, 2005−2018.

Conclusion
NS-IPD incidence decreased following PCV13 use in the United States, driven by reductions in PCV13 serotypes. Recent increases in NVT NS-IPD, most pronounced among older adults, have started to erode PCV impact on NS-IPD. PCVs in development that contain serotypes 22F and 33F could help to further reduce NS-IPD.

Disclosures
Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)
181. Antimicrobial Use in the Time of COVID-19 – Data from 84 VA Facilities
Authors: Goetz Matthew B , Graber Christopher J , Jones Makoto M , Stevens Vanessa W , Glassman Peter A , Rubin Michael 
Published: January 2021

Abstract

Background
The VA initiated an antimicrobial stewardship program in 2011, which includes participation in the Center for Disease Control (CDC) Antimicrobial Use Option, educational webinars, training programs for antimicrobial stewards, required staffing & reporting, and quality improvement initiatives, that has led to ongoing decreases in antimicrobial therapy nationwide. With the onset of the COVID-19 pandemic, however, there are several factors that may contribute increases in antimicrobial use (increased presentations of lower respiratory tract infection, concern for bacterial co-infection with SARS-CoV-2, etc.). We sought to compare patterns of antibacterial use in the VA from January – May 2020 with corresponding time periods in prior years.

Methods
Data on antibacterial use from 2015 – 2020 were extracted from the VA Corporate Data Warehouse for acute inpatient care units in 84 VA facilities (facilities which provide limited acute inpatient services were excluded). To control for seasonal effects, only data from January to May for each year were included in the analysis. Days of therapy (DOT) per 1000 days-present (DP) were calculated and stratified by CDC-defined antibiotic classes.

Results
From 2015 – 2019, total antibiotic use from January to May decreased by a mean of 9.1 DOT/1000 DP per year. In contrast, from 2019 to 2020, antibiotic use over the same months increased by 26.4 DOT/1000 DP (Table). Increases were observed in all drug classes except for a decrease in narrow spectrum ß-lactam antibiotics. Total antibiotic DOT in 2020 increased by 27.9 and 7.3 DOT/1000 DP in facilities in the highest and lowest terciles of use in 2019 (Figure).
Table – Trends in Yearly Antibiotic Use by CDC Drug Class, 2015 to 2019 versus 2019 to 2020

Figure – Facility Specific Total Antibiotic Use in 2019 and Change in Use from 2019 to 2020

Conclusion
We observed a broad increase in antibacterial use during the initial surge of COVID-19 cases in VA facilities that abruptly reversed steady reductions in use over the prior 4 years. The degree to which this increase reflects potentially appropriate use in the setting of increased patient vulnerability and provider uncertainty, inappropriately decreased provider thresholds for initiating or continuing therapy, or stresses on the structure and staffing of antimicrobial stewardship programs requires further study.

Disclosures
All Authors: No reported disclosures
182. increasing Odds of Resistance for Subsequent Urinary e. Coli Isolates
Authors: Frisbie Lauren , Weissman Scott , Kapoor Hema , D’Angeli Marisa A , Salm Ann , Rabinowitz Peter M 
Published: January 2021

Abstract

Background
Annual cumulative antibiograms are routinely used by clinicians to guide selection of empirical antibiotic therapies. CLSI guidelines recommend that these antibiograms to analyze data yearly, include only final, verified results, include bacterial species with &gt; 30 isolates and to include only the first isolate for each species/patient instance per analysis period. Handling multiple isolates from individual patients in cumulative antibiograms is a controversial topic within the antimicrobial stewardship community. Current practice favors removing subsequent isolates, thereby discarding data reflecting impact of selective antibiotic pressure on resistance patterns in recurring urinary tract infection (UTI).
In this study we analyzed a five-year data set of deidentified outpatient antibiotic results from a commercial laboratory to determine whether there were significant differences in resistance patterns between first and subsequent isolates from the same patient.

Methods
The 5-year antibiotic susceptibility data was restricted to urinary Escherichia coli (EC) isolates. Patient occurrence(s) of urinary EC were categorized by frequency: 1st occurrence, 2nd occurrence, 3rd occurrence, and 4th or greater occurrence. A logistic regression analysis using a binary outcome for resistance and independent variable of patient isolate occurrence was run for amoxicillin-clavulanate, ampicillin, ceftriaxone, ciprofloxacin, gentamicin, levofloxacin, nitrofurantoin, and trimethoprim-sulfa.

Results
From a logistic regression analysis, we estimate that for each occurrence in the data, an isolate’s odds of resistance were higher for every increase in a patient’s number of occurrences in the data for all antibiotics reported with p values &lt; 0.0001.
Table 1: Odds ratios (OR) of resistance for each subsequent urinary EC isolate occurrence over 5 years

Conclusion
Our findings suggest that individuals with higher numbers of urinary EC occurrences have more resistant EC than the first EC occurrence, with effects that vary by antibiotic class. Although traditional antibiograms include only the first occurrence of urinary EC from a single patient, this approach may underestimate levels of reservoir resistance in a community. Such an underestimation likely impacts efficacy of empiric therapeutic choice, healthcare outcomes, and cost.

Disclosures
All Authors: No reported disclosures