bluuebunny/crossref_metadata_2025_split huggingface dataset:
2235. Discordance of Clinical and Microbiological Endpoints in Clinical Trials for Complicated Urinary Tract Infection (cUTI)
Authors: Kadry Nadia A , Natarajan Mukil , Bein Edward , Kim Peter , Farley John 
Published: December 2022

Abstract

Background
Complicated urinary tract infections (cUTI) are a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine or blood culture, accompanied by local and systemic signs and symptoms, in the presence of urinary tract abnormalities or acute pyelonephritis. Current FDA guidance recommends that the primary endpoint for cUTI clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed time after therapy. In recent trials, it has been noted that while some patients have clinical resolution of symptoms, they are considered failures due to positive urine cultures. These discordant outcomes have raised questions about the utility of the microbiological endpoint.

Methods
We analyzed patient data from 13 phase 3 clinical trials submitted to the FDA. We focused on the microbiological modified intent-to-treat (m-MITT) population, including patients who have at least 1 bacterial pathogen known to cause cUTI and received at least one dose of study drug (N=4842). Outcomes were determined at the Test of Cure (TOC) visit 7-10 days after therapy, and the Late Follow Up (LFU) visit 3-4 weeks after therapy. Clinical and microbiological success were defined as the resolution of cUTI symptoms present at entry, with no new symptoms (clinical cure), and reduction of the pathogen at entry to ≤ 103 CFU/mL on urine culture (microbiological eradication).

Results
Among all included patients, 70.7% were overall successes at the TOC, exhibiting clinical and microbiological success. 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). In a multivariate logistic regression model, discordance was associated with obesity, lithiasis, use of analgesics, and receipt of carbapenem antibiotics. Discordant patients were at an increased risk for clinical failure at the LFU visit, and the risk of late clinical failure increased with longer time between the TOC and LFU visits.

Conclusion
Microbiological persistence at the TOC visit despite resolution of symptoms was associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component in the composite endpoint.

Disclosures
All Authors: No reported disclosures.
2242. Nitrofurantoin Use and Resistance in Urinary Tract Infections Across a Large, Integrated Health System
Authors: Voyer Kira , Shihadeh Katherine C , Jenkins Timothy C 
Published: December 2022

Abstract

Background
Nitrofurantoin is a preferred empiric antibiotic for the treatment of acute cystitis; however, there are limited data on nitrofurantoin utilization patterns and bacterial resistance in the outpatient setting. The objectives of this study were to describe nitrofurantoin use in an integrated health system and evaluate nitrofurantoin resistance.

Methods
A retrospective review of patients prescribed nitrofurantoin at Denver Health from January 1, 2017 to December 31, 2021 in 9 community health centers, 2 urgent cares, and the emergency department was completed. Patients were included if they received nitrofurantoin within 72 hours of a positive urine culture, defined as &gt; 100,000 cfu/mL of a single organism (Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, or Klebsiella oxytoca) and excluded if they were less than 18 years old.

Results
A total of 634 unique patients were included. Of 934 positive urine cultures, the organism was resistant to nitrofurantoin in 16 (1.7%). Mean patient age was 42.7 years, 99% were women, and nearly 75% were of Hispanic, Latinx, or Spanish ethnicity. The most common comorbid conditions were pregnancy (40.5%) and diabetes (24.6%). Over 90% of organisms identified were Escherichia coli. Despite institutional guidance for 5-day nitrofurantoin courses, prescribed durations were discordant in 46% of cases. Of the 16 cases associated with a nitrofurantoin-resistant pathogen, 9 (56.3%) had recent exposure to nitrofurantoin: 3 were taking nitrofurantoin suppressive therapy for recurrent UTIs and 6 received a treatment course within the last 90 days. Nitrofurantoin-resistant pathogens included E. coli (12), Klebsiella pneumoniae (3), and Enterobacter cloacae (1). A new antibiotic was prescribed for 15 of the 16 patients. 3 patients presented to an outpatient location within 30 days of the index nitrofurantoin prescription for ongoing urinary symptoms.

Conclusion
Increasing guideline-concordant durations of nitrofurantoin is an important antibiotic stewardship opportunity. Despite widespread use, resistance among urinary pathogens remains uncommon and may be associated with recent nitrofurantoin exposure.

Disclosures
All Authors: No reported disclosures.
16. Evaluation of a Monkeypox virus PCR assay and suggestions for future improvement
Authors: Zhang Fan , Murnane Courtney , Joseph Ansamma , Duong Scott , Lemon Jamie , Juretschko Stefan , Streva Vincent 
Published: December 2022

Abstract

Background
Monkeypox virus is an Orthopoxvirus in the Poxviridae family currently responsible for an ongoing global epidemic including active transmission in all 50 US states. To date, nearly 12,000 US cases have been confirmed, with the largest case count in New York State, where over 2,500 cases have been confirmed. Of these, the vast majority (greater than 90%) of cases are residents of New York City (NYC). Nearly all described cases have been identified in men, predominantly in men who have sex with men. Until recently, laboratory testing for Monkeypox virus was limited to state and local public health laboratories or the US Centers for Disease Control (CDC). Northwell Health is the largest healthcare provider in the NYC region and is responsible for molecular PCR testing for over 25 hospitals in the area.

Methods
We describe the evaluation of two real-time PCR assays developed by the CDC: one specific for Monkeypox virus and the other a generic Orthopoxvirus assay. We describe performance characteristics in a high-prevalence patient population, identify room for improvement in future assay iterations, and discuss potential scalability of the assay and portability to an ultra high-throughput platform.

Results
We evaluated the CDC Orthopoxvirus and Monkeypox virus PCR assays using 50 clinical specimens collected from patients presenting with lesions. We determined the limit of detection for both assays is 250 copies/mL. Additionally the assays are highly specific with no cross-reactivity with other viruses tested, including HSV-1, HSV-2, and VZV. One significant limitation is the high rate of indeterminate results due to the use of an RNase P specimen control. Indeterminate results were not the result of assay inhibition and may be from inadequate specimen collection. However, since RNase P signal was often absent in positive specimens, the clinical impact of the RNase P result is questionable.

Conclusion
The CDC Orthopoxvirus and Monkeypox virus PCR assays were useful tools for clinical laboratories to launch rapid testing capacity for these viruses early in the course of the outbreak. However, limitations of the assays prevent them from being expanded to more high-throughput testing platforms. Moving forward, additional work is needed to optimize these PCR assays for more widespread clinical use.

Disclosures
All Authors: No reported disclosures.
LB1534. Cord blood and maternal cytokine levels following SARS-CoV-2 infection during pregnancy
Authors: Sunderraj Ashwin , Otero Sebastian , Miller Emily , Shanes Elisheva D , Goldstein Jeffery A , Mithal Leena B 
Published: December 2022

Abstract

Background
Pregnant people and fetuses are uniquely vulnerable to SARS-CoV-2, a driver of inflammation and immune dysregulation. Prior investigations have shown that pregnant people with SARS-CoV-2 are at higher risk of severe illness, mortality, and obstetric complications. We investigated the impact of SARS-CoV-2 infection severity and latency on maternal and infant cytokine levels.

Methods
We collected maternal blood and cord blood at delivery from mother-infant dyads (Chicago, IL; 3/2020-1/2022). A multiplex cytokine panel (IsoPlexis) was run on plasma from 93 SARS-CoV-2 infected dyads and 32 matched controls. Clinical data was abstracted by chart review, including latency (acute being ≤14 days and distant &gt;14 days from SARS-CoV-2 infection to delivery) and severity (NIH criteria: asymptomatic, mild, moderate, severe/critical). Kruskal-Wallis tests with post-hoc pairwise Dunn Tests were used (α=0.05).

Results
SARS-CoV-2 exposed infants had lower levels of MIP-1b (p=0.037) and PDGF (p=0.008) than controls [Fig 1]. There were no differences in maternal blood cytokines at time of delivery following SARS-CoV-2 infection during pregnancy (pooled analysis of all SARS-CoV-2).
Stratifying by latency, acutely exposed infants showed higher levels of MCP-1 than controls or those with distant maternal SARS-CoV-2 (p=0.016). There were no significant differences in maternal cytokines between control, acute, and distant SARS-CoV-2.
In mothers with acute SARS-CoV-2, differences in levels of IL-1B (p=0.011) and IL-10 (p=0.046) were observed across severity groups, with a significant linear trend for each among severity groups (p for trend &lt; 0.001, respectively). Severe/critical acute infection resulted in higher maternal granzyme and IL-8 than mild infection (p=0.037 and 0.047) [Fig 2]. There were no differences across severity groups in 1) mothers with distant infection, 2) infants with acute maternal infection, or 3) infants with distant maternal infection.
Maternal and infant cytokine levels in acute SARS-CoV-2 infection across severity

Conclusion
Cytokine levels in SARS-CoV-2 positive dyads were altered only in the setting of acute or more severe infection and demonstrated anti-inflammatory, anti-viral, and anti-angiogenic responses. In acute infection, greater severity drives higher levels of both a pro- and anti-inflammatory cytokine in pregnant people.

Disclosures
All Authors: No reported disclosures.
LB1579. A single and a two-dose regimen of MVA-BN elicit similar memory responses to a boost vaccination two years after the initial regimen, indicating potential flexibility for a delayed second dose of MVA-BN in the ongoing monkeypox emergency
Authors: Weidenthaler Heinz , Lienert Florian , Reichhardt Daniela , Schmidt Darja , Silbernagl Günter , Meyer Thomas , Chaplin Paul 
Published: December 2022

Abstract

Background
The ongoing monkeypox outbreak, a WHO-declared PHEIC, requires fast and broad rollout of MVA-BN vaccinations among risk groups. An initial single-dose strategy, followed by a delayed second dose beyond the approved 4-week interval, could help managing tight vaccine resources.

Methods
Bavarian Nordic has run a study in vaccinia-naïve participants, randomized to receive either 1 MVA-BN vaccination (N = 181) or 2 MVA-BN vaccinations 4 weeks apart (N = 183). Of note, this study also evaluated participants with prior smallpox vaccination, who received 1 MVA-BN boost (N = 200). Subsets of approximately 75 participants of the vaccinia-naïve subjects having received either 1 or 2 doses of the vaccine were administered an MVA-BN boost 2 years later. Neutralizing antibodies (nAb) were measured using Vaccinia PRNT.

Results
The 1xMVA-BN and 2xMVA-BN groups responded as expected to the primary regimen, with modest increases in nAb GMTs at Week 2 (5.1 and 4.8, respectively) that further increased at Week 4 (7.2 and 7.5). Two weeks after the second primary vaccination (at Week 6) (2xMVA-BN) nAb GMTs peaked (45.6) before stabilizing at Week 8 (34.0). In both the 1x and 2xMVA-BN groups, the nAb levels were near baseline 2 years after primary vaccination. After the MVA-BN boost at 2 years, both groups exhibited rapid anamnestic responses with nAb GMTs that peaked 2 weeks post-boost (80.7 and 125.3), at higher levels than those observed at any timepoint following primary vaccination, remaining elevated at 6 months post-boost (25.6 and 49.3). These anamnestic responses support the presence of durable immunological memory in both groups. No safety concerns were identified and the most common adverse event following a 2-year MVA-BN boost was injection site erythema in 82.2% of participants.

Conclusion
A single dose of MVA-BN elicits a durable memory immune response for at least 2 years. Similarly, high nAb responses following a boost dose among subjects in the initial 1xMVA-BN or 2xMVA-BN groups indicate that the approved 4-week interval of the two-dose regimen could optionally be extended up to at least 2 years.
NCT00316524 and NCT00686582

Disclosures
Heinz Weidenthaler, MD, Bavarian Nordic GmbH: Employee and received warrants Florian Lienert, PhD, Bavarian Nordic GmbH: employee Employee and received warrants Daniela Reichhardt, PhD, Bavarian Nordic A/S: employee Employee and received warrants Darja Schmidt, Dr, Bavarian Nordic GmbH: Employee and received warrants Günter Silbernagl, MSc, Bavarian Nordic: Employed|Bavarian Nordic GmbH: employee Employee and received warrants Paul Chaplin, PhD, Bavarian Nordic A/S: employee (CEO)|Bavarian Nordic A/S: Stocks/Bonds.
LB1581. Exhalation Delivery System with Fluticasone (EDS-FLU) Significantly Reduces Acute Exacerbations and Associated Antibiotic Use in Chronic Rhinosinusitis
Authors: Mahmoud Ramy 
Published: December 2022

Abstract

Background
Data suggest chronic rhinosinusitis (CRS) may be the top reason for adult outpatient antibiotic use; of ≈10 million office visits per year for CRS, ≈70% result in antibiotic use. Acute exacerbations of CRS (AECRS) are common, possibly due to persistently impaired mucociliary clearance, and drive use of antibiotics. No drugs have been shown effective for reducing AECRS. ReOpen1 and 2 are randomized controlled trials that evaluated prevention of AECRS with the exhalation delivery system with fluticasone (EDS-FLU; XHANCE®), a novel device delivering topical steroid into chronically inflamed sinonasal regions not typically accessible with standard nasal sprays (eg, past the nasal valve and above the inferior turbinate).

Methods
CRS patients were randomized to EDS-FLU one or two sprays per nostril or placebo twice daily (BID) for 24 weeks. Frequency of AECRS, defined as worsening of at least 1 cardinal symptom of CRS (nasal congestion/obstruction, rhinorrhea, facial pain/pressure, hyposmia/anosmia) for ≥ 3 days requiring escalation of medical care (eg, doctor visit, antibiotic or steroid prescription), was analyzed using pooled data from both trials.

Results
Among 555 patients enrolled, 39.4% were using standard nasal steroids at study entry and 38.8% reported prior sinus surgery. There were 76 AECRS over 24 weeks, almost all (71) resulting in antibiotic use. Patients receiving EDS-FLU had a large reduction in AECRS versus placebo (incidence rate ratio [IRR]=0.39, P=0.001, vs placebo). Reduction was greater at the higher dose (2 sprays/nostril BID) than the lower dose (1 spray/nostril BID): IRR=0.34, P=0.002; IRR=0.44, P=0.012, respectively. 9.9% of low-dose patients and 7.8% of high-dose patients had ≥ 1 AECRS (20 and 15 events, respectively) vs 15.7% receiving placebo (41 events; P=0.012 and P=0.002 vs placebo, respectively). Treatment was well tolerated: adverse events in ≥ 3% of patients and more common in one active group than placebo were epistaxis, COVID-19, headache, and nasopharyngitis.

Conclusion
EDS-FLU is the first and only medication shown in randomized controlled trials to significantly reduce acute exacerbations of CRS, offering potential to improve antibiotic stewardship by substantially reducing one of the most common drivers of outpatient antibiotic use.

Disclosures
Ramy Mahmoud, MD, MPH, OptiNose Inc.: Employee of OptiNose Inc.
121. Safety, Tolerability, and Pertussis Immunogenicity Findings From a Randomized, Participant-Blinded, Active-Controlled, Dose-Escalating, Phase 1 Trial of a Tetanus/Diphtheria/Pertussis Booster Vaccine (Tdap-1018 CpG Adjuvanted) Compared With Boostrix in Healthy Adults Aged 18 to 22 Years
Authors: Janssen Robert , McGirr Anthony , Napier-Flood Fiona , Leah Amber , Nolan Terry , Richmond Peter , Boyce Tammy , Xie Fang , Godeaux Olivier 
Published: December 2022

Abstract

Background
Bordetella pertussis is a gram-negative bacterium causing the highly contagious respiratory infection pertussis in over 151 000 individuals annually worldwide. A tetanus/diphtheria/pertussis (Tdap) vaccine combined with CpG 1018 adjuvant (Tdap-1018) may induce higher antibody titers than existing aluminum-adjuvanted Tdap vaccines used as a booster in adults.

Methods
In this randomized, active-controlled, participant-blinded, phase 1 trial, healthy adults aged 18 to 22 years received 1 booster injection of Tdap-1018 (with same Tdap composition as in Boostrix and escalating CpG 1018 dose of 1500 µg and 3000 µg) or Boostrix on Day 1. Pertussis immunogenicity evaluations assessed booster response rates (BRRs) for anti-pertussis toxin (anti-PT), anti-filamentous hemagglutinin (anti-FHA), and anti-pertactin (anti-PRN) antibodies, and systems serology at Week 4 post-vaccination. Safety and tolerability were assessed for solicited local and systemic post-injection reactions for 7 days and unsolicited adverse events for 12 weeks after vaccination.

Results
Of the 87 enrolled adult participants, 84 had post-vaccination immunogenicity results. The median age was 19.0 years, 35% were men, and 83% were white. At Week 4, BRRs in the Tdap-1018 3000 µg group were statistically significantly higher (based on lower 95% confidence interval [CI] &gt;0%) than the Boostrix group for anti-PT (difference in BRRs 22.2% [95% CI: 1.5%–42.8%]) and anti-PRN (22.2% [95% CI: 8.2%–40.9%]) antibodies, and similar for anti-FHA (14.8% [95% CI: -2.6%–33.9%]) antibodies (Table). Tdap-1018 1500 µg, Tdap-1018 3000 µg, and Boostrix were generally well tolerated with no observed safety concerns.

Conclusion
In this phase 1 trial, both dose levels of Tdap-1018 were generally well tolerated. Tdap-1018 3000 µg induced statistically significantly higher BRRs than Boostrix for anti-PT and anti-PRN, and a similar response for anti-FHA antibodies.

Disclosures
Robert Janssen, MD, Dynavax Technologies Corporation: employee|Dynavax Technologies Corporation: Stocks/Bonds Tammy Boyce, MEd, Dynavax Technologies Corporation: Employee|Dynavax Technologies Corporation: Stocks/Bonds Fang Xie, PhD, Dynavax Technologies Corporation: Employee|Dynavax Technologies Corporation: Stocks/Bonds Olivier Godeaux, MD, MPH, Dynavax: Advisor/Consultant.
143. Genomics analysis of Carbapenem resistance in BCC Identify PenR E151V substitution and novel Burkholderia cepacia complex specific OXA-1043 subgroup
Authors: Liao Ya-Chun , University Chung Shan Medical , Liu Po-Yu , Huang Yao-Ting 
Published: December 2022

Abstract

Background
Treatment options for Burkholderia cepacia complex (Bcc) remain limited, and previous study revealed 26% of strains was susceptible to meropenem.
In B. cenocepacia and many Bcc species, ampC and its regulator, ampR, named penR in Burkholderia genomes are not associated, sharing a divergent promoter, as in other previously studied species. Recently, Josselin Bodilis et el (2018) found that there was no different in genetic organization between imipenem-sensitive and imipenem-resistant strains.
Our study is to provide an answer to the different of genetic expression pattern between imipenem resistance and imipenem sensitive Burkholderia cepacia complex species.

Methods
The Bcc species genome was deeply sequenced using Nanopore technology. Protein-coding genes, and coding and non-coding RNAs in the chromosomes and plasmids were annotated via the NCBI PGAP pipeline. Antibiotic-resistant genes (ARGs) were predicted by aligning protein-coding genes against the Comprehensive Antibiotic Resistance Database (CARD) using Diamond.

Results
In our study, drug susceptibility test of different antibiotic showed only Burkholderia cenocepacia strain MC0-3 revealed sensitive to imipenem (Table 1). Further genetic organization between imipenem-resistance and imipenem-sensitive strains showed similar β-lactamase-encoding genes (Figure 1). In the multiple sequence alignment of PenR, nine imipenem-resistance Bcc stains, which amino acid sequence at position 151 is glutamic acid, however, in imipenem-sensitive strain amino acid substitute glutamic acid with valine (Figure 2b). PROVEAN also showed amino acid substitutions at position E151 in PenR is deleterious (Table 2). We also analyzed 95 strains of Burkholderia, and drew the phylogenetic tree which showed PenR E151V subsititution consisted in other imipenem-sensitive strains of Burkholderia. In addition, a novel Burkholderia cepacia complex specific OXA-1043 subgroup is found in stain toggle 2, toggle 3 and toggle 4 (Figure 3). Figure 1.Genetic organization of imipenem resistance and imipenem sensitive in different strain of Burkholderia cepacia complex.

Conclusion
The results of this study indicate that antibiotic resistance related to the amino acid substitutions, which may explain the imipenem-sensitive strain of Burkholderia cenocepacia. Bedsides, a new OXA family is found in Burkholderia cenocepacia strain, and is named OXA 1403. Figure 2.Multiple sequence alignment PenR in different strains of Burkholderia cepacia complex and phylogenetic tree of Burkholderia spp.

Disclosures
All Authors: No reported disclosures.