bluuebunny/crossref_metadata_2025_split huggingface dataset:
447. Improvement of Anal Pap Collection Documentation and Adequacy in PLWHIV in Infectious Diseases Clinic
Authors: Villa-Chan Frederico , Pryor Zachary , Wark Kellie , Kubat Ryan C , Newman Jessica 
Published: December 2022

Abstract

Background
Anal Pap smear is an essential screening tool for high-risk human papillomavirus (hrHPV)-associated anal squamous cell carcinoma (ASCC), particularly in people living with HIV (PLWHIV). Currently, there is no consensus regarding time interval or protocols for screening of anal hrHPV-associated cancer. Limited reports suggest self-collected specimens have similar cytology sensitivity compared to physician-collected samples.

Methods
We utilized a Quality Improvement project (QIP) to assess validity of self-collected anal swab specimens (SCS) for screening of hrHPV-related anal lesions versus physician-collected specimens (PCS) over 3 months. The protocol was implemented in an Infectious Diseases clinic by patients and physicians during routine visits. Patients learned about the QIP via educational handout and were offered self- or physician-collection.

Results
A total of 60 patients participated. Seventy-five percent opted for self-collection and 35/45 (78%) SCS were adequate for interpretation, compared to 10/15 (67%) PCS. Fisher exact test value was 0.49, indicating no significant difference between groups (at p&lt; .05). In total, 77% of patients completed the satisfaction survey. Only 13% reported preference for physician-performed procedure, while 63% felt that a self-collection option made them more likely to complete the Pap. A limitation to this project is the Hawthorne effect, as participants were aware of the QIP and that validity of the samples depended on appropriate sample collection. There was also a relatively small sample size of self-collected specimens (n=45).
Survey results
Final result from surveys answered by patients that participated in the project.

Conclusion
Survey analysis showed increased patient satisfaction and similar adequacy of samples collected. While the project was not powered to demonstrate an increase in acceptance of anal Paps, increased satisfaction could lead to improvement over time with a simple and inexpensive workflow adjustment. Additionally, with expansion of telehealth, self-collected anal Paps may increase opportunities to complete screening at times physicians are not available. Studies with larger populations, in multiple institutions and with varying educational handouts/instruction methods may provide better data to corroborate recommendations regarding best practices for screening for ASCC.

Disclosures
All Authors: No reported disclosures.
466. All-Cause Mortality in Patients with Invasive Candidiasis or Candidemia from an Interim Analysis of a Phase 3 Open-label Study (FURI)
Authors: Prattes Juergen , King Thomas , Azie Nkechi , Angulo David A 
Published: December 2022

Abstract

Background
There are limited oral antifungal treatment options for patients with high-mortality fungal infections such as candidemia or invasive candidiasis who fail available antifungals or have infection caused by resistant fungi. Ibrexafungerp is a broad-spectrum glucan synthase inhibitor with activity against Candida spp., including azole- and echinocandin-resistant strains. A Phase 3 open-label study of ibrexafungerp (FURI; NCT03059992) is ongoing for patients intolerant of, or invasive fungal disease refractory to, standard antifungal therapy. We present an interim analysis of all-cause mortality (ACM) through 30 d post-treatment for patients with candidemia or invasive candidiasis (IC) who completed therapy up until Oct 2020.

Methods
FURI patients are eligible for enrollment with proven/probable severe mucocutaneous candidiasis or IC, or candidemia, with documented evidence of failure, intolerance, or toxicity related to an approved standard-of-care antifungal treatment; or patients who cannot receive oral antifungals (e.g., due to susceptibility), and continued IV antifungal therapy is clinically undesirable/unfeasible. Patients were followed through 30 d post-treatment for ACM.

Results
Out of the 74 patients who completed therapy in the FURI study through October 2020, 39 (52.7%) had IC or candidemia and received ibrexafungerp. The most common infections in this group were candidemia (28.2%), intra-abdominal infection (28.2%), and bone infection (20.5%).
Survival at ≥ 30 d post-treatment was 92.3%. Three patients (7.7%) died within 30 d post ibrexafungerp, a 4th died at 31 d, and a 5th died at 56 d. The mean age of the expired patients was 54 yr. Three patients had candidemia (2 with C. parapsilosis and 1 with C. albicans), and 2 had intra-abdominal candidiasis, (both with C. glabrata). The average time on ibrexafungerp was 16.6 d. The mean time to death post-treatment for these patients was 22 d (median 8 d). In each case, the deaths were due to causes other than the underlying fungal disease.

Conclusion
Analysis of all-cause mortality in these patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options.

Disclosures
Thomas King, MS MPH, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds Nkechi Azie, MD MBA FIDSA, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds David A. Angulo, MD, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds.
471. Comparison of Outcomes for Obese and Non-Obese Patients Receiving Micafungin 100 mg Daily for Candidemia
Authors: Diaz Jonathan , Denzer Rose , Hand Elizabeth O , Foster Dana , Yap Alexander , Hughes Darrel W 
Published: December 2022

Abstract

Background
Echinocandins, such as micafungin, are first-line agents for the treatment of candidemia. Researchers have questioned the adequacy of the standard 100 mg dose for all patients, as certain characteristics such as obesity can significantly alter the pharmacokinetics of this agent. Prior data have shown obese patients may be less likely to achieve the pharmacodynamic targets shown to be associated with clinical success. The purpose of this study is to compare clinical outcomes for obese and non-obese patients receiving standard dosing of micafungin.

Methods
This is a multi-center, retrospective study conducted at two large academic hospitals. All adults admitted with a positive blood culture for Candida spp. between January 1st 2017 and December 31st 2021 were reviewed for inclusion. Patients who received &gt; 1 dose of micafungin were designated as either obese (BMI ≥ 30 kg/m2) or non-obese (BMI &lt; 30 kg/m2). Patients who received combination antifungal therapy or had subsequent episodes of candidemia were excluded.

Results
One hundred and eighty-five of 248 patients were included. Fifty-six (30.3%) patients were obese and 129 (69.7%) were non-obese. Most were critically ill (55.1%), middle-aged (median 60 years), Hispanic or Latino (52.7%) and male (57.8%). Patients received micafungin 100 mg IV daily for a median of 6 (IQR 3-11.5) days. Obese patients had a higher Charlson Comorbidity Index of 4.5 (IQR 3-6.8) compared to 4 (IQR 2-6) in non-obese patients. Critically ill obese and non-obese patients had median Sequential Organ Failure Assessment scores of 10 (IQR 6.75-11.5) and 9 (IQR 4-12), respectively. Clinical and microbiologic failure at day 14 were numerically higher in obese patients ([44.6% vs 32.3%; p = 0.13] and [19.6% vs 10.1%; p = 0.10], respectively), while in-hospital and 30-day mortality were significantly higher in the obese population ([39.3% vs 22.5%; p = 0.03] and [44.6% vs 27.1%; p = 0.03], respectively).

Conclusion
Obese patients treated for candidemia with micafungin 100 mg IV daily had a significantly higher in-hospital and 30-day mortality. Clinical and microbiological failure followed a similar trend, without meeting statistical significance. Additional studies are warranted to determine whether higher doses of micafungin may improve outcomes in obese patients.

Disclosures
All Authors: No reported disclosures.
472. Corticosteroid Exposure as a Risk Factor for Pneumocystis jirovecii Pneumonia Mortality in HIV-Negative Patients: A Multicenter Retrospective Case-Control Study with a Global Research Network Validation
Authors: Vargas Barahona Lilian , Molina Kyle C , Pedraza-Arévalo Laura C , Sillau Stefan , Tagawa Alex , Scherger Sias , Chastain Daniel B , Shapiro Leland , Franco-Paredes Carlos , Hawkins Kellie , Henao-Martínez Andrés F 
Published: December 2022

Abstract

Background
HIV-negative patients have higher mortality from PJP compared to patients with HIV, however, we lack data on predictors of PJP-associated mortality in HIV-negative patients. We aim to characterize the role of previous corticosteroid exposure in PJP-related mortality.

Methods
A multicenter retrospective case-control study was performed on HIV-negative patients tested for PJP within the UCHealth system from 2000 to 2021. Cox proportional-hazards model was used for survival analysis. We queried TrinetX, a global research network, to validate mortality risk differences among HIV-negative patients with PJP with prior corticosteroid exposure versus those without. We used propensity score matching to assess independent corticosteroid risk of 1-year mortality.

Results
We identified 105 cases of PJP and 71 controls without PJP. HIV-negative patients with steroid exposure in the previous 6 months were more likely to have a history of malignancy (26.5% vs 11.9%, p=0.026), solid organ transplant (14.8% vs 3.4%, p=0.023), inflammatory disease (27.6% vs 8.5%, p=0.03), or use of other immunosuppressive drugs (83.8% vs 13.6%, p&lt; 0.0001). The median prednisone equivalent dose was higher in patients who died at 7 weeks (33.7 vs. 21.5 mg/d) and 1 year (33.7 vs. 20 mg/d). Adjusted Cox proportional-hazard model found an increased rate of death at 10 weeks (HR: 3.8, CI: 1.6-9.26, p=0.003)(Figure 1) and 1 year (HR: 4.8, CI: 2.2-10.7, p&lt; 0.0001) among patients previously on steroids. A TrinetX-based propensity score matching of 2176 HIV-negative patients found a significantly increased 1-year mortality (OR: 1.9 CI: 1.6-2.2, p&lt; 0.0001) after PJP diagnoses in the group with corticosteroid exposure in the previous year compared to those with PJP without corticosteroid exposure. The mean β-d-glucan (203±154 vs. 82± 35.8 pg/mL, p=0.025) and ferritin levels (1591±5576 vs. 1041± 1300 mcg/L, p=0.02) were higher in those with prior steroid use. Figure 1.Adjusted 70-days mortality among HIV negative patients with PJP by corticosteroid exposure

Conclusion
HIV-negative patients with PJP and corticosteroid use preceding diagnosis have higher mortality than those without corticosteroid use. A higher fungal burden may influence corticosteroid mediated mortality.

Disclosures
All Authors: No reported disclosures.
475. Does Metabolite Matter? Defining Target Itraconazole and Hydroxy-itraconazole Serum Levels for Blastomycosis
Authors: Hess Danielle , Abu Saleh Omar M , Enzler Mark , Jannetto Paul J , Mara Kristin , Stevens Ryan W , Vergidis Paschalis , Rivera Christina G 
Published: December 2022

Abstract

Background
Itraconazole is first-line treatment for mild-moderate blastomycosis and consolidation of moderate-severe disease. Itraconazole is metabolized to 3 metabolites, including an active metabolite hydroxy-itraconazole. The sum of itraconazole and hydroxy-itraconazole levels &gt; 1.0 mcg/mL is guideline recommended for treatment of invasive fungal infections; conversely, some experts suggest targeting a parent compound level alone &gt; 1.0 mcg/mL. This study aims to compare clinical outcomes and adverse drug reactions (ADRs) of combined itraconazole and hydroxy-itraconazole levels &gt; 1.0 mcg/mL versus itraconazole parent compound alone &gt; 1.0 mcg/mL in patients with blastomycosis.

Methods
This study is a single-center, retrospective chart review of patients ≥ 18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole level. The primary outcome was rate of partial or complete treatment response in patients with a combined itraconazole and hydroxy-itraconazole level &gt; 1.0 mcg/mL versus itraconazole parent compound &gt; 1.0 mcg/mL for &gt; 75% of measured levels. ADRs attributable to itraconazole were compared between the groups. Treatment response rates and ADRs were compared between groups using two proportion z-tests.

Results
Total of 80 patients were included: 36 = combined itraconazole and hydroxy-itraconazole &gt; 1.0, 32 = itraconazole parent alone &gt; 1.0, 12 = 75% of all levels &lt; 1.0. No statistically significant difference was observed between groups for blastomycosis rate of partial or complete treatment response (94.3% combined vs 96.6% parent, p=0.99). Significantly higher mortality was observed in patients failing to achieve itraconazole or itraconazole/hydroxy-itraconazole &gt; 1.0 (2.8% combined vs 0% parent vs 25% neither, p=0.01). There was no significant difference in total ADRs between the three groups (p=0.56).

Conclusion
This limited evidence supports an itraconazole therapeutic target combining itraconazole and hydroxy-itraconazole &gt; 1.0 for blastomycosis treatment.

Disclosures
Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.
494. Enteric bacteria are immune-reactive in patients with Crohn's disease with extraintestinal manifestations
Authors: Maldarelli Grace A , Metz Maeva , Funez-dePagnier Gabriela , Lavergne Alexa , Lai Daniel , Chang Adrienne , Malik Fardina , de Vlaminck Iwijn , Longman Randy S 
Published: December 2022

Abstract

Background
Bacterial constituents of the intestinal microbiota can contribute to local and systemic inflammatory diseases. Crohn's disease (CD), a type of inflammatory bowel disease, can result in extraintestinal manifestations (EIM) including peripheral (CD-SpA) and axial spondyloarthritis (CD-AxSpA). Microbial contributors to CD pathogenesis can be identified by flow cytometric sorting and 16S sequencing of bacteria recognized by mucosal IgA. We expand this technique by incubating fecal samples with autologous sera, capturing bacterial species recognized by circulating IgG in a process called IgG-seq. We hypothesize that these systemically-recognized enteric bacteria are linked to development of CD-EIM.

Methods
Fecal samples from individuals with CD were sorted into IgG-positive and negative populations. DNA was extracted from each population, 16S sequencing performed, and sequences processed with QIIME2. Intestinal coating index (ICI) was calculated at the genus level. Serum cell-free DNA sequencing (cfDNA) was performed for a subset of samples.

Results
IgG-seq was conducted on 86 CD, 41 CD-SpA, and 16 CD-AxSpA samples. PCoA analysis demonstrates significant differences in microbiome composition in the three groups (P = 0.013, PERMANOVA). Relative abundances of Escherichia-Shigella and Ruminococcus are positively correlated with joint disease activity. Analysis of IgG ICI for genera present in &gt; 10% of patients demonstrates overrepresentation of Ruminococcus, Escherichia-Shigella, and Bacteroides in IgG-recognized fractions. IgG recognition of bacteria does not cluster specifically by CD or EIM severity. cfDNA sequencing demonstrates no Ruminococcus DNA in serum, whereas E. coli DNA was detected in multiple patient sera.

Conclusion
IgG-seq is a robust method for identifying immune-reactive enteric bacteria; our results highlight the link between immune response to enteric bacterial genera, such as Escherichia-Shigella and Ruminococcus, and joint disease activity in CD-SpA and CD-AxSpA. While Escherichia-Shigella may induce immunity by breaching the mucosal barrier, the absence of Ruminococcus in serum cfDNA suggests immune activation at barrier sites. Further studies are needed to characterize the strain-specific features that underlie our findings.

Disclosures
Fardina Malik, MD, Pfizer: Advisor/Consultant Iwijn de Vlaminck, PhD, GenDX: Advisor/Consultant|GenDX: Board Member|Kanvas Biosciences: Board Member|Kanvas Biosciences: Ownership Interest|Karius Inc.: Board Member|Karius Inc.: Ownership Interest|Viracor Eurofins: Advisor/Consultant Randy S. Longman, MD, PhD, Pfizer: Advisor/Consultant.
496. Epidemiology, virulence and antimicrobial resistance of hypervirulent Klebsiella pneumoniae and K. pneumoniae complex member in western New York, 2017-2020
Authors: Tesini Brenda L , Taffner Samantha , Cameron Andrew , Pecora Nicole 
Published: December 2022

Abstract

Background
Klebsiella pneumoniae is a leading cause of nosocomial infections, and hypervirulent K. pneumoniae (hvKp) is an increasingly recognized community-associated pathogen. However, the epidemiology and pathogenicity of hvKp and K. pneumoniae complex infections in the US remains poorly understood. We characterized the tissue tropism, antimicrobial resistance, and virulence factors associated with K. pneumoniae complex members and hvKp using whole genome sequencing.

Methods
We analyzed all Klebsiella pneumoniae isolates from liver sources from 2017-2020 and isolates from other sterile tissue sites from 2018-2019 in a western New York regional academic microbiology laboratory by whole genome sequencing. Only one isolate per patient was included. Basic clinical and demographic data was obtained from the medical chart. Virulence factors and antibitoic resistance genes were identified using Kleborate version 2.0. Hypervirulence was defined as the presence of rmpA or rmpA2 and the aerobactin gene cluster (iuc).

Results
We sequenced 25 Klebsiella pneumoniae isolates from liver sources from 2017-2020 and an additional 29 isolates from other non-blood sterile sites from 2018-2019. 80% of the hepatic K. pneumoniae complex isolates were K. pneumoniae sensu stricto (n=20). The remaining isolates were identified as K. quasipneumoniae (n=3) and K. variicola (n=2). Non-hepatic tissue isolates contained only one K. variicola; the remainder were K. pneumoniae sensu stricto. Seven isolates met criteria for hypervirulence; all were K. pneumoniae sensu stricto isolated from liver abscesses (28% of such isolates). All were community onset infections, and only 2 patients with hvKp had prior international travel identified. None had additional sites of infection documented. Four isolates were identified as ESBL phenotypically and all had blaCTX-M-15 detected; one of which was K. quasipneumoniae.

Conclusion
This study suggests that hypervirulent K. pneumoniae hepatic abscesses may be more prevalent in the US than previously appreciated. Non-sensu stricto K. pneumoniae complex members were infrequently isolated from bodily tissues, less likely to carry hypervirulence genes but may harbor extended antibiotic resistance.

Disclosures
All Authors: No reported disclosures.
497. Fecal cytokine profiling and markers of intestinal inflammation in Aotus nancymaae diarrhea model for enteropathogens
Authors: Lizewski Rhonda A , Carlos Gaspar Juan , Nuñez Roza , Nieto Monica , Espinoza Nereyda 
Published: December 2022

Abstract

Background
Naval Medical Research Unit 6 (NAMRU-6) established an animal model that closely resembles diarrheal diseases caused by Shigella, Campylobacter, and enterotoxigenic Escherichia coli (ETEC) in humans. These enteropathogens cause considerable mortality due to diarrhea in children and morbidity in travelers and military personnel deployed to regions of high prevalence. The successful oral challenge model developed in Aotus nancymaae, a New World monkey species, for Shigella, Campylobacter, and ETEC results in reproducible diarrhea attack rates of ≥70%. This model has been fundamental for the development and evaluation of new vaccine candidates. Many new approaches in vaccine development focus on stimulating antibodies against specific antigens expressed by these enteropathogens. Recent studies use the Aotus diarrhea model to evaluate new passive therapeutic and prophylactic treatments to prevent infection, inflammation, or diarrhea. However, the immune response and intestinal inflammation by the main enteropathogens are not clearly defined.

Methods
This study investigates how the cytokines and fecal markers of intestinal inflammation respond to gastroenteritis caused by Shigella, Campylobacter and ETEC in Aotus. Twenty-nine fecal cytokines (FC) were measured during diarrhea induced by Shigella flexneri (N = 8), Campylobacter jejuni (N=8), and ETEC (N = 8).

Results
Of note, both IL-1β and IL-15 were significantly increased at 24 hours after ETEC challenge. In contrast, when an infection with Shigella flexneri occurs, a significant increase in cytokines and chemokines such as MIF, MIP-1α and MIP-1β are observed 24 hours after challenge. While animals challenged with Campylobacter jejuni produce an increase in IL-1β 24 hours after challenge and an increase in cytokines MIF, MIP-1α and MIP-1β 4 days after challenge.

Conclusion
There is nonspecific upregulation of TH1/TH17 effector cytokines and those known to mediate intestinal barrier damage. The FC profiles have a different behavior between the three enteropathogens. This provides new insights into gut-specific immune alterations in the Aotus diarrhea model, which will help improve the design of new prophylactic and therapeutic treatments against diarrhea.

Disclosures
All Authors: No reported disclosures.