bluuebunny/crossref_metadata_2025 huggingface dataset:
11. Evaluation of the Bact/alert® VIRTUO™ in Terms of Time to Detection, Performance, Workflow Efficiency and Impact on Patient Management, Compared to the BACTEC™ FX Automated Blood Culture System
Authors: Halperin Ana V , Cuevas José Luis Cortés , Del Castillo Polo Juan Antonio , Cuesta Miriam , Talens Sergio , Birch Robert , Sánchez Díaz Ana María , Cantón Rafael
Published: January 2021

Background

Bloodstream infections are associated with high rates of morbidity and mortality, therefore prompt identification and antimicrobial susceptibility testing of the causative organism(s) are critical. We compared the microbiological/clinical performance of BacT/ALERT®-VIRTUO™-(BioMerieux) to that of the BACTEC™FX-(BD) instrument, with time-to-detection (TTD, from loading into system until positivity) as the primary outcome. Secondary microbiological outcomes were positivity and contamination rates, hands-on-time, turn-around-time (TAT) and time-to-identification.

Methods

We performed a prospective cross-over study using blood cultures from patients (>18 years) suspected of bacteremia/fungemia, localized in different wards into two strata (Stratum-1: Emergency Department-ED-; Stratum-2: in-hospital patients). Testing was performed in BACTEC™-PlusAerobic/F and BACTEC-Lytic/10-Anaerobic/F bottles and incubated in BACTEC™FX, or BacT/ALERT®FA-Plus and FN-Plus bottles and incubated in VIRTUO™. Initially, each strata was randomly assigned to one of the incubators and then alternated every 2-weeks for 6 months (October-16th-2018 to April-16th-2019). All samples were processed in parallel with the same work-flow from the moment they were flagged positive. Maximum incubation time was 5 days.

Results

We included a total of 4782 extractions (9510 bottles) in VIRTUO and 5139 (10193 bottles) in BACTEC. The median age was 67 years for both groups and the samples were equally distributed for each ward (ED: VIRTUO 80.9%, BD 76.4%). The number of blood cultures with at least one positive extraction was 873(18.3%) for VIRTUO and 802(15.6%) for BACTEC (p=0.0003). TTD and proportion of aerobic/anaerobic bottles is shown in Table.

Hands-on-time was reduced by 15 minutes/day when using VIRTUO.

Table

Conclusion

We have compared on a large scale and in a “real world” setting the performance of two automatic blood culture incubators. TTD was significantly lower for the VIRTUO incubated samples, with differences in both systems depending on the type of bottle (aerobic vs. anaerobic). The number of positive results was significantly higher for the VIRTUO incubated samples, which might impact antimicrobial prescription and clinical outcomes.

Disclosures

Ana V. Halperin, MD, Biomérieux (Grant/Research Support) José Luis Cortés Cuevas, MD, biomerieux (Research Grant or Support)biomerieux (Research Grant or Support) Juan Antonio Del Castillo Polo, MD, Biomérieux (Research Grant or Support) Sergio Talens, n/a, Biomerieux (Research Grant or Support) Robert Birch, n/a, bioMerieux Inc. (Employee) Rafael Cantón, PharmD PhD, Biomérieux (Grant/Research Support)
14. Outcomes from the AHRQ Safety Program for Improving Antibiotic Use Across 439 Long-term Care Facilities
Authors: Katz Morgan , Rowe Theresa A , Cosgrove Sara E , Tamma Pranita D , Miller Melissa A , Dullabh Prashila , Speck Kathleen , Ahn Roy , Gao Yue , Scherpf Erik , Jump Robin , Jump Robin
Published: January 2021

Background

Implementing effective antibiotic stewardship programs (ASPs) in long-term care (LTC) settings is challenging. We present the results of an intervention intended to change the culture of antibiotic prescribing in 439 United States LTC facilities (LTCF).

Methods

The LTC Safety Program assisted LTCFs with establishing and implementing ASPs from 12/2018 to 11/2019. Through webinars held 1–2 times per month and other educational content, the Safety Program emphasized 1) the science of safety to improve teamwork and identify antibiotic-associated harm and 2) clinical best practices in making antibiotic treatment decisions. Content was organized using the Four Moments of Antibiotic Decision Making Framework (Figure 1). All staff (e.g., physicians, nurses, nurse assistants) were encouraged to participate. LTCFs submitted monthly antibiotic days of therapy (DOT), numbers of new antibiotic starts, urine cultures (UCX) ordered, Clostridioides difficile LabID events, and census data. Generalized linear mixed effects models were used to calculate pre-post intervention changes at bi-monthly intervals for antibiotic DOT, antibiotic starts and UCX, each per 1,000 resident-days (RD), and C. difficile LabID events per 10,000 RD, comparing the beginning (1/2019 and 2/2019) and end (11/2019 and 12/2019) of the Safety Program.

Figure 1. Four Moments of Antibiotic Decision Making in the Long-Term Care Setting

Results

Of 439 LTCFs who completed the Safety program, the majority were mid-sized (75–149 beds; 229, 52.2%), most were non-hospital based and owned by a larger system (246, 56.0%), with similar distributions between urban and rural settings. Of these, 348 (79%) submitted both baseline and end-of-intervention data. Antibiotic starts decreased from 7.89 to 7.48 starts/1000 RD; P = 0.02). Days of therapy for all antibiotics decreased from 64.1 to 61.0 DOT/1,000 RD; P = 0.068) and for fluoroquinolones (an antibiotic targeted in the Safety Program) from 1.49 to 1.28 DOT/1,000RD; P=0.002. UCX decreased from 3.01 to 2.63 orders/1000 RD; P = 0.001). There were no significant differences in C. difficile LabID events Table 1.

Table 1. Changes from baseline (Jan-Feb, 2019) to the end (Nov-Dec, 2019) of the AHRQ Safety Program

Conclusion

By targeting both antibiotic prescribing culture and knowledge of best practices, the AHRQ Safety Program led to significant reductions in antibiotic use across a large cohort of LTCFs.

Disclosures

Morgan Katz, MD, MHS, AHRQ (Research Grant or Support)FutureCare Health Systems (Consultant)Roche (Advisor or Review Panel member) Robin Jump, MD, PhD, Accelerate (Grant/Research Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)
16. SCORE-UC: Antibiotic Stewardship in Urgent Care
Authors: Hersh Adam , Stenehjem Eddie , Fino Nora , Willis Park , Srivastava Rajendu , Buckel Whitney R , Brunisholz Kim , Wallin Anthony , Kumar Naresh , Samore Matthew H
Published: January 2021

Background

Urgent care (UC) is a rapidly growing site of healthcare delivery. The CDC developed Core Elements for Outpatient Antibiotic Stewardship to guide development of outpatient stewardship but little experience exists in applying Core Elements to UC settings. Our objective was to evaluate the effectiveness of a UC stewardship program in a health system.

Figure

Methods

We designed a UC stewardship program for Intermountain Healthcare’s 39 UC sites based on CDC Core Elements. The pre-intervention period was Aug 2017-June 2019. The intervention period was 12 months from Jul 2019 -June 2020. The program consisted of education for patients/providers about appropriate diagnosis and prescribing for respiratory conditions; media campaigns; EHR tools; and a prescribing dashboard for clinicians. The primary outcome was the percentage of respiratory visits where an antibiotic was prescribed. Secondary outcomes included the percentage of encounters receiving antibiotics for conditions where no antibiotics are indicated (e.g. bronchitis) and the percentage of encounters receiving first-line recommended therapy for conditions in which antibiotics may be warrented (otitis media, sinusitis, and pharyngitis). We used a binomial mixed effects hierarchical model to calculate the odds of antibiotic prescribing associated with the intervention period accounting for pre-intervention trends. Models account for clustering within providers and clinics. We present the results of an interim analysis after 7 months of the intervention.

Results

The overall number of UC encounters during the study period was 1,559,403 and 41.5% were for respiratory conditions. The percentage of patients with respiratory conditions that received an antibiotic prescription declined from 49.9% pre-intervention to 35.3% during the intervention (OR 0.73, 95% CI: 0.71, 0.76), reaching a low of 30% during February 2020 (Figure). Prescribing for conditions where antibiotics are not indicated decreased (OR 0.31, 95% CI 0.26–0.36) and first line recommended therapy increased (OR 1.28, 95% CI 1.20–1.26) during the intervention.

Conclusion

After 7 months of a planned 12 month intervention, the UC stewardship program was associated with improved antibiotic prescribing.

Disclosures

Rajendu Srivastava, MD, AHRQ, NIH, CDC (Grant/Research Support, I hold grants from AHRQ, NIH and CDC for a variety of clinical research and implementation studies)IPASS Patient Safety Institute (Other Financial or Material Support, I am a physician founder of this company to spread handoff best practices and reduce adverse events. My employer holds my equity in this company.)
20. Fluoroquinolone and Overall Outpatient Antibiotic Prescribing Trends in Adults, 2011 to 2018
Authors: Gouin Katryna A , King Laura M , Bartoces Monina , Roberts Sarah Kabbani; Rebecca M , Tsay Sharon , Hicks Lauri
Published: January 2021

Background

Fluoroquinolones (FQs) are the third most commonly prescribed antibiotics among U.S. outpatients, and the second most commonly prescribed class among adults ≥ 65 years of age. However, FQ use has been associated with severe adverse events, especially among older adults. As a result, in 2016 the U.S. Food and Drug Administration (FDA) issued warnings against FQ use when other agents may be effective. We assessed changes in outpatient FQ prescribing relative to overall antibiotic prescribing from 2011 to 2018.

Methods

We estimated annual antibiotic prescription rates in adults ≥ 20 years of age for all classes and FQs using national prescription dispensing count data from IQVIA Xponent (numerator) and census estimates (denominator) for 2011 to 2018. We used Poisson models to estimate prevalence rate ratios (PRR) and 95% confidence intervals (CIs) comparing antibiotic prescription rates overall and stratified by age group from 2011 to 2018. The Chi-square test was used to compare the percent decrease in rates between age groups.

Results

From 2011 to 2018, prescription rates in adults for all antibiotics decreased by 2% (PRR 0.98, 95% CI: 0.98-0.98); FQ prescription rates decreased by 30% (PRR 0.70, 95% CI: 0.69–0.70), with the largest decline from 2015–2018 (Figure 1). Adults ≥ 65 years had the highest FQ prescription rates for 2011 to 2018, at a rate 2.37 (95% CI: 2.32,2.42) times that of adults 20–64 years (Figure 2). The FQ prescribing rate in adults 20–64 experienced a greater decrease from 2011 to 2018 than the rate in adults ≥ 65 years (p< 0.0001), with a 35% decrease (PRR 0.65, 95% CI: 0.65, 0.65) in adults 20–64 years compared to a 29% (PRR 0.71, 95% CI: 0.71-0.71) decrease in adults ≥ 65 years (Figure 2).

Decreases in total outpatient antibiotic and fluoroquinolone prescribing rates among adults in the United States from 2011 to 2018

Decreases in outpatient fluoroquinolone prescriptions per 1,000 persons by age group in the United States from 2011 to 2018

Conclusion

FQ prescribing decreased markedly compared to overall antibiotic prescribing from 2011 to 2018, which was likely due in part to FDA warnings on FQ-associated adverse events. However, FQ prescribing among older adults remained high during this period and did not decrease as much as in younger adults. Further evaluation of the diagnoses associated with prescribing may provide additional opportunities to optimize FQ prescribing practices, especially among older adults.

Disclosures

All Authors: No reported disclosures
21. Association of MRSA Prevalence and Hospital-level Antibiotic Use: A Retrospective Study Across 122 Acute-care Hospitals
Authors: Livorsi Daniel J , Nair Rajeshwari , Lund Brian , Alexander Bruce , Beck Brice , Goto Michihiko , Perencevich Eli N
Published: January 2021

Background

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA), varies across geographic regions, which could contribute to regional variation in antibiotic use. In this study, we evaluated whether local MRSA prevalence rates were associated with hospital-level antibiotic use across the Veterans Health Administration (VHA).

Methods

This retrospective cohort included all acute-care patients admitted in VHA hospitals during 2016. Anti-MRSA antibiotics were identified per National Healthcare Safety Network definitions and use was quantified as days-of-therapy (DOT) per 1000 days-present. Hospital-level MRSA prevalence (colonization and/or infection) was determined by calculating the proportion of admissions with a positive MRSA nasal swab and/or a MRSA-positive clinical culture obtained ≤1 day before or ≤2 days after admission. Negative binomial regression models were used to determine the association between a hospital’s MRSA prevalence and its antibiotic use, after accounting for intra-hospital clustering, patient case-mix, month of admission, and use of hospital-based stewardship strategies.

Results

There were 548,476 admissions across 122 hospitals. The median rate of MRSA prevalence at admission was 8.0% (IQR 6.7–9.7%). Hospital level median use of anti-MRSA and total antibiotics was 96.5 (interquartile range [IQR] 81.1–116.9) and 562.1 (IQR 505.9–631.6) DOT per 1,000 days-present, respectively. In a hospital-level risk adjusted analysis, a hospital’s MRSA prevalance was significantly associated with its monthly use of both anti-MRSA and total antibiotics (IRR=1.05, 95% 1.02–1.07; IRR=1.02, 95% CI, 1.01–1.03). A 5% increase in the hospital’s MRSA prevalence was associated with an increase in the monthly use of anti-MRSA antibiotics and total antibiotics by 23.6 and 8.3 DOT per 1,000 days-present, respectively.

Conclusion

Higher hospital-level MRSA prevalence was associated with significantly higher rates of antibiotic utilization, even after adjusting for case-mix and reported antibiotic stewardship strategies. Future benchmarking of anti-MRSA antibiotic use across hospitals may need to risk-adjust using baseline rates of MRSA prevalence.

Disclosures

Daniel J. Livorsi, MD, MSc, Merck and Company, Inc (Research Grant or Support) Rajeshwari Nair, PhD, Merck and Company, Inc. (Research Grant or Support)
24. Antibiotic Use in Hospital Emergency Departments and Observation Settings from 2012–2018 in a Large Cohort of U.S. Hospitals
Authors: Preston Leigh Ellyn , Baggs James , Kabbani Sarah , Neuhauser Melinda M , King Laura M , Reddy Sujan , Hatfield Kelly M , Wolford Hannah , Kazakova Sophia , McCarthy Natalie , McDonald Clifford
Published: January 2021

Background

While discharge antibiotic prescriptions from emergency department (ED) visits have been reported, systemic antibiotic use during ED and hospital observation (OBS) visits have not been well assessed. We conducted a descriptive analysis of antibiotic use in these settings.

Methods

We identified ED and OBS visits not resulting in hospitalization, and systemic antibiotics administration charges during these visits from January 2012-December 2018 using the Premier Healthcare Database, representing at least 600 hospitals annually. Antibiotics prescribed after discharge were excluded. We reported the proportion of visits with antibiotic use, and described antibiotic use by class, agent and route stratified by location. We also examined trends in antibiotic use over time using a multivariable logistic model.

Results

We assessed 161,291,011 ED visits and 15,660,062 OBS visits from 2012–2018. Systemic antibiotics were identified in 9.0% of ED visits and 25.2% of OBS visits. Parenteral (IV) antibiotics were received in a high proportion of ED and OBS visits in which a systemic antibiotic was received (52.6% and 87.6% respectively). In the ED, 3rd/4th generation cephalosporins were the most commonly identified (32.7%) while in the OBS, 1st/2nd generation cephalosporins were most commonly identified (38.9%), Fig. 1. The most common agents in the ED were ceftriaxone, azithromycin, and cephalexin while the most common agents in the OBS were cefazolin, ceftriaxone, and levofloxacin. Any systemic antibiotic use in EDs declined slightly from 2012–2018 (9.2%-8.9%, p< 0.0001) while use in OBS settings saw the largest increase from 2017- 2018 (25.4%-30.4%, p< 0.0001), Fig. 2. Fluoroquinolone use decreased in both ED (41.3%) and OBS (31.2%) (both p< 0.0001) beginning in years 2012 and 2016 respectively.

Figure 1: Antibiotic use in emergency departments and observation settings by antibiotic class, Premier Healthcare Database Hospitals, 2012–2018

Figure 2: Overall antibiotic use in emergency departments and observation settings by year, Premier Healthcare Database Hospitals, 2012–2018

Conclusion

Hospital ED and OBS settings are uniquely positioned to improve appropriate antibiotic use across the spectrum of healthcare. Frequent use of IV antibiotics and recent increases in antibiotic use in observation settings call for evaluation of appropriateness of their use and presence of transition-of-care process. Further evaluation of diagnoses to evaluate the appropriateness of IV administration may highlight additional opportunities for optimizing prescribing practices.

Disclosures

All Authors: No reported disclosures
32. Risk Factors for Vertical Transmission of t. Cruzi infection in an Endemic Setting
Authors: Klein Melissa D , Tinajeros Freddy , Malaga Edith , Verástegui Manuela , Condori Beth J , Urquizu Federico , Gilman Robert , Bowman Natalie M
Published: January 2021

Members of the Chagas Disease Working Group in Peru and Bolivia include

Edith Hinojosa, Clariza Chavez, Jean Karla Velarde, Carla Chavarria, Victoria Serrudo, Roberto Araya, Alcides Buitron, Rita Mendieta, Holger Mayta, Maritza Calderon, Holger Mayta and Yagahira Castro.

Background

Vertical transmission of Trypanosoma cruzi infection accounts for a growing proportion of new cases of Chagas disease. Congenital infection is curable if treated promptly, but the majority of infected infants do not receive timely diagnosis or treatment. Better risk stratification is needed to predict which women are more likely to transmit the infection.

Methods

This study enrolled women who presented for delivery and their infants at the Percy Boland Women’s Hospital in Santa Cruz, Bolivia. Pregnant women were screened for Chagas disease by rapid test. The infants of seropositive mothers underwent diagnostic testing with microscopy (“micromethod”) and quantitative polymerase chain reaction (qPCR) as newborns and at one- and nine-month follow-up. Mothers completed surveys about demographics and medical history.

Results

Among 5,828 enrolled women, 1,271 (21.8%) screened positive for Chagas disease. Of the 1,325 infants of seropositive mothers, 113 (8.5%) were diagnosed with congenital Chagas disease by microscopy or qPCR. Cesarean delivery was significantly associated with lower odds of vertical transmission (adjusted OR: 0.63, 95% CI: 0.41–0.98, p=0.040). Congenital infection was more common in twins (adjusted OR: 3.30, 95% CI: 1.97–5.54, p< 0.001) and male infants (adjusted OR: 1.50, 95% CI: 1.01–1.22, p=0.045).

Conclusion

Our findings suggest that Cesarean delivery may be protective against vertical transmission of T. cruzi, while twins and male infants may have an increased risk. A better understanding of risk stratification for congenital Chagas disease may help improve regional initiatives to reduce disease burden.

Disclosures

All Authors: No reported disclosures
35. Missed and Unrecorded Drug Use Among Infective Endocarditis Cases Is Associated with Underestimated Burden of Disease and Fragmented Care: Evidence from Six States
Authors: Christine Paul , Usher Michael , Pham Cuong , Kelly Ryan , Winkelman Tyler
Published: January 2021

Background

Studies using national administrative data suggest that hospitalizations for drug use-associated infective endocarditis (DUA-IE) have increased over the last ten years. However, drug use as a contributing factor to IE hospitalizations is often missed or not included in coding documentation, resulting in undercount of DUA-IE. We assessed whether missed drug use during IE hospitalizations was associated with higher levels of fragmented care and underestimation of DUA-IE burden.

Methods

We analyzed data from State Inpatient Databases and State Emergency Department Databases from six states (FL, GA, IA, NY, UT, VT) from 2011–2015. Patients older than 16 with ICD-9/10 codes for admissions with IE were included. IE was categorized as DUA using ICD-9/10 codes for drugs/conditions associated with injection drug use. We labeled IE cases as a “missed” DUA-IE case if they had no diagnosis of drug use during their index hospitalization but received a drug use diagnosis during an ED visit or inpatient stay in the calendar year of their index IE hospitalization. We compared “missed” DUA-IE cases to DUA-IE cases where drug use was identified in the index hospitalization and non-DUE-IE cases with respect to demographics, length of stay (LOS) and total charges. To assess care fragmentation, we stratified IE groups by whether the patient was admitted to 1 or >1 hospital within 90-days of the index IE admission.

Results

There were 52147 non-DUA-IE cases, 6872 DUA-IE cases, and 2676 “missed” DUA-IE cases identified by linking drug use across multiple encounters. Missed cases represented a 39% increase in total DUA-IE cases. Compared to DUA-IE cases identified at index hospitalizations, missed cases were more likely to be older, Black, insured by Medicare, and from rural areas. They also had higher 30-day readmission rate (23.2% vs 14.5%, p< 0.001) and higher charges (p< 0.001), with similar LOS. Fragmented care was most common among patients with missed DUA-IE (33.3%), followed by DUA-IE cases identified during index hospitalization (20.5%) and non-DUA-IE cases (13.7%).

Table 1

Table 2

Conclusion

Missed and/or unrecorded drug use and fragmented care are common features of DUA-IE. This results in underestimation of both DUA-IE prevalence and hospital utilization due to DUA-IE.

Disclosures

All Authors: No reported disclosures
40. The Impact of Medically Assisted Therapy for Opiate Use Disorder in staphylococcus Aureus Bacteremia Patients Within a Large Hospital System - A Retrospective Cohort Study
Authors: Keene Brooks A , Saboori Shadi , Meredith Jacqueline , King Deanna , Polk Christopher , Leonard Michael
Published: January 2021

Background

Intravenous drug use (IVDU) is a risk factor for development of S. aureus bacteremia (SAB) and prevalent in opiate use disorder (OUD). While the standard of care involves treating the underlying OUD with medically assisted therapy (MAT), it is unknown how much impact this has on clinical endpoints.

Methods

We conducted a retrospective cohort study of patients with IVDU with hospitalizations for SAB during a 28-month period from 9/2016 through 12/2018 in 10 urban and rural North Carolina hospitals in a single large health system. We compared outcomes for patients receiving prescription for MAT at discharge versus no MAT at discharge. MAT was defined as receiving methadone, buprenorphine, or naltrexone. Patients who expired inpatient were excluded from analysis. Clinical endpoints were 30- and 90-day mortality and 30-day SAB-related readmissions.

Results

Of the 174 patients, 28% received a prescription for MAT at discharge. The majority of the patients were Caucasian (88%), female (57%), with mean age of 37 years. Factors that significantly increased likelihood of MAT at discharge were female gender (34% vs 20%, p=0.04), having a complicated SAB (33% vs 28%, p=0.01), presence of a spinal/epidural abscess (57% vs 43%, p=0.002), and increased length of stay (LOS) (37 days vs 24 days, p=< 0.001). No difference in 30- and 90-day mortality was observed; only one patient in each group died within 90 days. Prescription for any MAT at discharge was associated with a significant decrease in the risk of SAB-related 30-day readmission (0% vs 17%, p=0.002).

Table 1: Baseline Characteristics

Table 2: MAT & Clinical Outcomes in S. aureus Bacteremia

Figure 1: Medically Assisted Therapy Prescribed at Discharge

Conclusion

Gender, more complicated infections, and prolonged LOS may increase the likelihood of receiving a prescription for MAT at discharge. MAT prescription at discharge may decrease the risk of 30-day SAB related readmission (NNT 5.9). The results suggest that provision of MAT to patients with SAB and history of IVDU should be incorporated into standardized treatment guidelines.

Disclosures

All Authors: No reported disclosures
41. Impact of Gut Microbiome Changes on Hematopoietic Stem Cell Transplantation Outcomes in Children
Authors: Teherani Mehgan , Pratte Zoe , Banskota Samridhi , Gulick Dalia , Djeddar Naima , Gillespie Scott , Gibson Gregory , Qayed Muna
Published: January 2021

Background

In adults undergoing allogeneic hematopoietic cell transplantation (HCT), higher gut microbiome diversity is associated with reduced bloodstream infections (BSI) and improved overall survival (OS). Rifaximin prophylaxis in adult HCT helps to maintain microbiome diversity. We examine changes in microbiome in a cohort of pediatric patients undergoing HCT.

Methods

Patients were enrolled in an institutional biorepository (n=82) with a subset enrolled in an ongoing trial using rifaximin (n=21) between 2013–2020. All patients had HCT for a hematologic malignancy, using myeloablative conditioning. Patients in the rifaximin trial received rifaximin starting 7 days before HCT (D-7) through D+28, otherwise, no prophylactic antibiotics were used. Systemic antibiotic timing was categorized as none, early (≤ Day 0, day of HCT), and late (> D0). We performed 16s rRNA sequencing from stool for 73 subjects, at baseline (D-7), and weekly through D+28 (engraftment). Microbiome diversity was assessed by Shannon index.

Results

Median age was 9 years (range 1–20), 59% male, 41% Caucasian and 29% Black. There were no differences in BSI or mortality by age, sex, or race.

Microbiome diversity changed significantly over time (p=0.008). Drop in diversity was most notable in patients who had early antibiotics (Mean=1.4, CI -0.15, 2.94, p=0.077). Higher diversity was seen when patients received none or late versus early antibiotics, but this was not statistically significant (Figure 1, p=0.23). Piperacillin-tazobactam was used empirically in 91% of patients. OS at 1 year was 88.5% (CI 68.4%, 96.1%) for patients with high (≥ median) D+28 diversity compared to 60% (CI 38.4%, 76.1%) for patients with low diversity (Figure 2, p=0.018) Only 1 of 21 (4.8%) in the rifaximin group developed a BSI with a gut bacterium compared to 8 of 61 (13.1%) not on rifaximin within the first 30 days (trial enrollment ongoing).

Figure 1. Effect of systemic antibiotic timing on microbiome diversity over time.

Figure 2. One-year overall survival of patients with high (>2.77) versus low (<2.77) diversity defined by median Shannon-Index.

Conclusion

We have shown a significant correlation between engraftment microbiome diversity and 1-year OS. Early antibiotic exposure was detrimental to microbiome diversity. Approaches to preserve microbiome diversity and prevent BSI are likely to improve HCT outcomes. Our ongoing trial using rifaximin will provide preliminary data regarding this approach.

Disclosures

All Authors: No reported disclosures
42. Common Population Variants Cause Susceptibility to Disseminated Coccidioidomycosis
Authors: Hsu Amy P , Davis Joie , Chaput Alexandria L , Powell Daniel A , Pouladi Nima , Lussier Yves , Fierer Joshua , Frelinger Jeffrey A , Galgiani John N , Lionakis Michail , Holland Steven M
Published: January 2021

Background

Coccidioides are endemic, dimorphic fungi found in soils of southwestern United States, Mexico and Central America. Infection occurs via inhalation of arthroconidia which swell, differentiate into spherules and rupture releasing endospores. While the majority of infected individuals will never report illness, roughly 1/3 seek medical attention for fungal pneumonia and ~1% of those present with disseminated coccidioidomycosis (DCM). IL12-IFNγ pathway mutations have been reported in DCM but are exceedingly rare and cannot account for the ~500–600 cases of DCM/year.

Methods

We performed whole exome sequencing on 66 individuals with DCM, retaining variants predicted damaging (CADD >15) with a population frequency < 10%.

Results

Homozygous CLEC7A c.714T >G; p.Y238* causing a truncated Dectin-1 receptor was overrepresented (OR=9.8449, 95% CI 3.0841 to 31.4260, P=0.0001). Dectin-1 signaling pathway variants included 3 homozygous and 11 heterozygous CLEC7A p.Y238* individuals, one each CLEC7A p.I223S and MALT1 p.R149Q and five PLCG2 p.R268W. Since Dectin-1 is the receptor for b-glucan, a major Coccidioides cell-wall component, we hypothesized that Dectin-1 pathway variants could affect fungal recognition and cellular response. Healthy control PBMCs stimulated with purified β-glucan or heat-killed Candida albicans induced 6-fold more TNFα than patients with homozygous or heterozygous CLEC7A, PLCG2 or MALT1 variants (P=0.0022, Ordinary one-way ANOVA). Additionally, one patient with a family history of DCM but lacking a defined mutation also failed to up-regulate TNFα after stimulation.

Normalized TNF production from healthy control and DCM patient’s peripheral blood mononuclear cells

Conclusion

These data are consonant with increased dissemination in Clec7a-/- mice as well as in patients receiving anti-TNF biologics. These gene variants accounted for 31% of our DCM cohort (21/66 patients). This is the first demonstration of variants outside the IL12-IFNg pathway impairing fungal recognition and cellular response in coccidioidomycosis. Common heterozygous variants may be sufficient for disease susceptibility to highly pathogenic organisms.

Disclosures

Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)
44. In-host Infection Dynamics Of Pseudomonas Aeruginosa Pneumonia
Authors: Bachta Kelly E R , Allen Jonathan P , Hauser Alan R
Published: January 2021

Background

Pseudomonas aeruginosa (PA) is an important cause of healthcare-associated infections including pneumonia and bloodstream infections (bacteremia). PA pneumonia is a significant cause of morbidity and mortality, especially in immunocompromised patients and those on prolonged mechanical ventilation; However, little is known about the in-host infection dynamics of PA pneumonia and its relationship to transmission.

Methods

We utilized a mouse model in conjunction with sequencing technology to dissect the infection dynamics of PA pneumonia. BALB/c mice were challenged intranasally with a clinical isolate, PABL012. At various time points post infection, organs were harvested and the surviving PA enumerated. STAMP (sequence tag-based analysis of microbial populations) analysis was applied to define the in-host infection dynamics.

Results

Bacterial enumeration revealed that PA disseminates early and widely in intranasally infected animals. Infected mice shed significant amounts of PA in their gastrointestinal tract (GI). Finally, STAMP analysis revealed that compared to bloodstream infections where PA experiences a severe in vivo bottleneck when trafficking to GI tract, PA disseminates freely from the lungs to the GI tract with little bottleneck effect.

Conclusion

Our research, using murine models, sheds light on the infection dynamics of PA pneumonia. Our results suggest that the lungs are a unique environment in which PA replicates unchecked and experiences little bottleneck effect. This unchecked replication likely seeds the gastrointestinal tract and promotes significant fecal excretion. Fecal excretion of PA from hospitalized patients is observed, but the direct link between pneumonia, GI shedding, and transmission remains unclear. Our observations have significant implications for infection control and shed light on how PA might exit the human host into the healthcare environment setting the stage for a transmission event.

Disclosures

All Authors: No reported disclosures
45. In Silico Identification of Virulence Factors That May Contribute to Enhanced Gut Colonization of ESBL e. Coli
Authors: Diaz Alondra , Whitmer Grant R , Arshad Mehreen
Published: January 2021

Background

The rapid global spread of extended spectrum beta lactamase-producing Escherichia coli (ESBL-E) strains threatens our ability to the treat many common infections and have become a major threat to public health. Some ESBL-E have a fitness advantage allowing them a competitive edge in gut colonization contributing to their global spread. We aimed to conduct in silico molecular characterization of virulence factors that may contribute to this fitness advantage.

Methods

For this observational study, we report data from fifteen whole-genome sequenced ESBL-E isolates found in the stool of a cohort of otherwise healthy infants. These strains were compared to MG1655 (commensal E. coli) and UTI89 (pan-sensitive uropathogenic E. coli). Phenotypic growth curves were done in minimal media with glucose as the only carbohydrate source. The genome sequences were assembled and annotated using Pathosystems Resource Integration Center (PATRIC) database and used to predict antibiotic resistance genes (ARGs) as well as virulence factors that may be driving the competitive advantage of these strains.

Results

All ESBL E. coli strains encoded multiple ARGs including those that target beta-lactams, aminoglycosides, fluoroquinolones, tetracyclines and macrolides. Growth curves in minimal media showed enhanced growth of some ESBL E. coli compared to control strains (Figure 1). ESBL-E strains 7 and 8 were also shown to have a higher copy number of carbohydrate metabolism genes. Proteome comparison of ESBL-E to MG1655 or UTI89 identified 93 and 321 proteins, respectively, with < 50% homology to the corresponding protein in the comparator strains (Figure 2). However, only 29 proteins across all ESBL-E were showed non-homology to both MG1655 and UTI89. These included both fimbrial and phosphotransferase system proteins.

Figure 1

Figure 2A

Figure 2B

Conclusion

ESBL-E strains may use a combination of attributes to out-compete commensal or non-resistant E. coli. These may include enhanced carbohydrate metabolism, increased adherence to the epithelial cells (via fimbrial proteins) or greater efficiency of carbohydrate uptake from the environment (via the phosphotransferase system). Further in vitro and in vivo studies are in progress to verify these in silico observations.

Disclosures

All Authors: No reported disclosures
1. The Impact of Behavioral Nudges, Communication Training and Assessment and Feedback on Adolescent Vaccination Rates and Parent Satisfaction
Authors: Bradley-Ewing Andrea , Goggin Kathy , Meredith Georgann , Lee Brian R , Li Susan , Doctor Jason , Myers Angela
Published: January 2021

Background

Effective prevention of HPV is possible, but < 50% of adolescents in the Midwest complete the recommended vaccine series. Strategies to increase HPV vaccination rates have demonstrated efficacy, however widespread implementation of these interventions has not been realized. Behavioral nudges have demonstrated efficacy in increasing uptake of desired heath behaviors among providers (e.g. hand hygiene, judicious antibiotic prescribing). This trial assessed the impact of an assessment and feedback, communication training, and behavioral nudge (i.e. poster-sized vaccine commitment statements) intervention (T3) on adolescent vaccination rates and parental satisfaction at four Midwestern pediatric practices.

Methods

Practices were randomly assigned to receive either 1) assessment and feedback or 2) T3 intervention. Providers (n=16) completed surveys regarding vaccine polices and parents of vaccine eligible adolescents (n=230) reported their child’s vaccine history and satisfaction with the consultation. Practice- level vaccination rates for Tdap, Meningococcal, and HPV were calculated through billing data queries from an integrated pediatric health network. Vaccination rates and provider/ parental responses were compared by intervention arm.

Results

All practices evidenced increased adolescent vaccine rates, ranging from 0.8% to 3.4% for Meningococcal and 1.3% to 12.1% for Tdap. Three of the four practices had increased HPV vaccination rates (1% to 10%), however there was no statistically significant difference by study arm. Most parents (M age 41.34; SD 8.05; 85% female, 68% White) indicated their child had previously initiated the HPV vaccine series (61%) and 72% indicated receipt of an HPV vaccine during the study visit. Concerns among HPV vaccine hesitant parents (n=60) included concerns about vaccine safety and necessity. Most (97%) of parents were satisfied with their consultation.

Conclusion

Practices in both intervention groups evidenced an increase in adolescent vaccination rates. While some parents had concerns about HPV vaccine safety and necessity, parents welcomed discussions about HPV vaccine and were satisfied with their provider’s communication regardless of their vaccine decisions.

Disclosures

Brian R. Lee, MPH, PhD, Merck (Grant/Research Support)
2. Understanding Patient Preferences for Meningococcal Serogroup B Vaccines in the United States
Authors: Johnson Reed , Fairchild Angelyn , Whittington Dale , Presa Jessica , Srivastava Amit , Huang Liping
Published: January 2021

Background

Among US adolescents, meningococcal disease serogroup B (MenB) causes more cases (62% in 2018) than other 4 serogroups (A, C, W, Y). ACIP’s recommendation for shared clinical decision-making calls for individuals to be given the choice of vaccination after consultation with their health care provider. No data are available to-date that formally quantify values and preferences for MenB vaccines. Our objective is to quantify such values.

Methods

Following best-practice standards for stated-preference research, a survey employed a discrete choice experiment (DCE) and contingent-valuation (CV) questions to quantify respondents’ trade-off preferences for vaccines that protect against diseases with various levels of severity and incidence, and to estimate the monetary value of receiving additional consultation regarding MenB vaccination with healthcare providers. A total of 2162 respondents (1203 young adults and 1185 parents) completed on-line surveys between August - October 2019.

Results

DCE analysis identified 3 classes of respondents for parents (table 1) and young adults, respectively. Overall, half of the respondents considered vaccines for low-incidence, high-severity diseases such as MenB to be at least as important as vaccines for high-incidence, low- severity diseases.

Respondents were asked to react to a hypothetical situation in which the health care provider did not discuss MenB vaccines with them and found out later. Approximately 70% of respondents expressed reactions ranging from ‘Concerned’ to ‘Angry or Disgusted’ (Figure 1). The majority of young adults and parents wanted physician-provided information about protection against low-incidence but serious diseases such as MenB.

The CV analysis estimated that willingness to pay for the MenB vaccine was about US$300 for young adults and over US$400 for parents. However, they often felt entitled to the consultation with their health care provider about the MenB vaccines and were not willing to pay much for it (Figure 2).

Table 1. Parent Class Results (n=1185)

Figure 1. Respondents’ Reactions to Health Care Provider Choosing Not to Discuss the MenB Vaccine with Them

Figure 2. Mean Willingness to Pay for Additional Time with Doctor for Discussing MenB Vaccine and Willingness to Pay for MenB Vaccine

Conclusion

The study found that parents of adolescents and young adults placed significant value on obtaining information about and protection against low-incidence diseases such as MenB that can result in severe long-term disabilities and death.

Disclosures

Reed Johnson, PhD, Pfizer (Research Grant or Support) Angelyn Fairchild, BA, Pfizer (Research Grant or Support) Dale Whittington, PhD, Pfizer (Research Grant or Support) Jessica Presa, MD, Pfizer (Employee) Amit Srivastava, PhD, Pfizer (Employee) Liping Huang, MD, MA, MS, Pfizer (Employee)
4. MenACWY-TT Long-Term Antibody Persistence Following Adolescent Vaccination and Evaluation of a Booster Dose: A Review of Clinical Data
Authors: Peyrani Paula , Webber Chris , Burman Cindy , Balmer Paul , Perez John L
Published: January 2021

Background

A peak in meningococcal carriage and invasive meningococcal disease (IMD) occurs during adolescence and young adulthood. In the United States, preventive vaccination with a quadrivalent meningococcal (MenACWY) conjugate vaccine is recommended at age 11–12 years, with a booster dose given at age 16 years. MenACWY-TT (Nimenrix®), a MenACWY tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in the European Union and 50 other countries. Immune responses to other MenACWY conjugate vaccines decline over several years following vaccination. Here, we review 2 recent studies evaluating the long-term persistence of MenACWY-TT immune responses in adolescents as well as safety and immunogenicity of a booster dose given 10 years after primary vaccination.

Methods

Both studies (ClinicalTrials.gov NCT01934140, NCT03189745) were extensions of phase 2 or 3 studies of subjects 11–17 years of age given a single dose of MenACWY-TT or MenACWY polysaccharide vaccine (MenACWY-PS). Immune responses through 10 years after primary vaccination and after a Year 10 MenACWY-TT booster dose were measured by serum bactericidal antibody assays using baby rabbit complement (rSBA). Specific endpoints included percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs). Booster dose safety and tolerability were also evaluated.

Results

In both studies, the percentages of subjects with rSBA titers ≥1:8 through 10 years postvaccination were generally higher or similar among MenACWY-TT (69.3%–91.2% at Year 10; n=137–163) compared with MenACWY-PS (24.4%–88.9%; n=45–53) recipients for all 4 serogroups (Figure); similar results were observed for GMTs (146.0–446.9 vs 12.9–191.0 at Year 10). One month after a MenACWY-TT booster dose, 97.7%–100% of subjects across groups had titers ≥1:8 (Figure), and GMTs were markedly higher than prebooster values. No new safety signals were identified following the booster dose.

Figure 1. Subjects in each of the 2 studies with rSBA titers ≥1:8 before and at 1 month, 5 years, and 10 years after primary vaccination with MenACWY-TT or MenACWY-PS at 11–17 years of age and 1 month after booster vaccination with MenACWY-TT at 10 years following primary vaccination.

Conclusion

Functional antibodies for all 4 serogroups persisted through 10 years after MenACWY-TT adolescent vaccination, suggesting that this vaccine may help prevent IMD throughout the lengthy risk period in this group. A MenACWY-TT booster dose may further extend protection regardless of the primary vaccine received.

Funded by Pfizer.

Disclosures

Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)
10. Kinetics of Post-Vaccination Seroprotection to S. Pneumonia for the Immune-Compromised and Vaccine-Naïve Populations
Authors: Gruenglas Jeffrey , Mond James , Scobie Micaela , Tolman Cynthia , Martinez Joseph
Published: January 2021

Background

S. pneumonia infection presents a significant challenge, accounting for 20–38% of hospital-acquired pneumonia, and the leading cause of community-acquired pneumonia despite availability of effective vaccines. Incidence is highest in children under 2 years, the immunocompromised, and elderly. CDC has reported the emergence of antibiotic resistance in ~30% of cases, adding to risk of morbidity and mortality. Fewer than half of the elderly are vaccinated and vulnerable to infection on admission. Passive immunotherapy as an adjunct to vaccines may improve outcomes in such populations. The objective of this study was to evaluate whether seroprotective response induced with a pneumococcal conjugate vaccine could rapidly yield protective opsonic levels of antibody within anticipated duration of hospitalization.

Methods

Healthy donors (n=30) were immunized with Prevnar. Blood was drawn on days 0, 3, 7, 10, 14, 21, and 28. Samples were pooled and tested for presence of functional opsonic antibodies recognizing capsular polysaccharides. Clearance mechanism of S. pneumonia was based on antibody recognition to pneumococcal capsular polysaccharide and opsonic titers used as an in vitro surrogate to evaluate the efficacy of vaccine.

Results

There was little to no opsonic activity against most serotypes on day 0, except for low antibody activity with serotypes 1, 3, 4, and 5. Titers increased, with protective levels achieved by day 10 for most serotypes (except 14 and 18C), peaking at day 14 or after across serotypes (Figures 1 and 2). Average titers rose from log2 titer 2 on day 0 to log2 titer 8 on days 21 and 28. Titers against most serotypes reached log2 10 (titer 1024) or higher. Patients remained susceptible to nosocomial infection for at least 10 days post admission until protective titers are reached.

OPK titers (log2 scale) for serum samples on day 0 (pre), day 3, 7, 10, 14, 21, 28, and control for S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V. N=2.

OPK titers (log2 scale) for serum samples on day 0 (pre), day 3, 7, 10, 14, 21, 28, and control for S. pneumoniae serotypes 14, 18C, 19A, 19F, and 23F. N=2.

Conclusion

Patients with no prior history of vaccination (or inability to mount response) with Prevnar or pneumovax remain vulnerable to S. pneumonia infection even if vaccinated on entry, due to delayed kinetics in reaching protective titers. These patients may require prophylactic intervention of hyperimmune Ig with high opsonic titers to S. pneumonia, providing protection until vaccine response elicits protective antibodies.

Disclosures

All Authors: No reported disclosures