bluuebunny/crossref_metadata_2025_split huggingface dataset:
146. antifungal Susceptibility Patterns of candida Parapsilosis Bloodstream Isolates in the US, 2008–2018
Authors: Tesini Brenda L , Lyman Meghan , Jackson Brendan R , Gellert Anita , Schaffner William , Farley Monica M , Shrum Sarah , Phipps Erin C , Zhang Alexia Y , Pattee Brittany , Fischer Jill , Johnston Helen , Barter Devra , Harrison Lee , Marceaux Kaytlynn , Nadle Joelle 
Published: January 2021

Abstract

Background
Multidrug resistant Candida is an increasing concern. C. parapsilosis in particular has decreased in vitro susceptibility to echinocandins. As a result, fluconazole had been favored for C. parapsilosis treatment. However, there is growing concern about increasing azole resistance among Candida species. We report on antifungal susceptibility patterns of C. parapsilosis in the US from 2008 through 2018.

Methods
Active, population-based surveillance for candidemia through the Centers for Disease Control and Prevention’s (CDC) Emerging Infections Program was conducted between 2008–2018, eventually encompassing 9 states (GA, MD,OR, TN, NY, CA, CO, MN, NM). Each incident isolate was sent to the CDC for species confirmation and antifungal susceptibility testing (AFST). Frequency of resistance was calculated and stratified by year and state using SAS 9.4

Results
Of the 8,704 incident candidemia isolates identified, 1,471 (15%) were C. parapsilosis; the third most common species after C. albicans and C. glabrata. AFST results were available for 1,340 C. parapsilosis isolates. No resistance was detected to caspofungin (MIC50 0.25) or micafungin (MIC50 1.00) with only one (&lt; 1%) isolate resistant to anidulafungin (MIC50 1.00). In contrast, 84 (6.3%) isolates were resistant to fluconazole and another 44 (3.3%) isolates had dose-dependent susceptibility to fluconazole (MIC50 1.00). Fluconazole resistance increased sharply from an average of 4% during 2008–2014 to a peak of 14% in 2016 with a subsequent decline to 6% in 2018 (see figure). Regional variation is also observed with fluconazole resistance ranging from 0% (CO, MN, NM) to 42% (NY) of isolates by site.

Conclusion
The recent marked increase in fluconazole resistance among C. parapsilosis highlights this pathogen as an emerging drug resistant pathogen of concern and the need for ongoing antifungal resistance surveillance among Candida species. Our data support the empiric use of echinocandins for C. parapsilosis bloodstream infections and underscore the need to obtain AFST prior to fluconazole treatment. Furthermore, regional variation in fluconazole resistance emphasizes the importance of understanding local Candida susceptibility patterns.

Disclosures
Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)
149. Efficacy of Cochleated Amphotericin B (CAMB) in Mouse and Human Mucocutaneous Candidiasis
Authors: Desai Jigar V , Urban Amanda , Swaim Doris Z , Ferre Elise , Colton Benjamin , Lu Ruying , Matkovits Theresa , Mannino Raphael J , Tramont Edmund , Lionakis Michail , Freeman Alexandra 
Published: January 2021

Abstract

Background
Candida albicans causes debilitating mucosal infections in patients with inherited susceptibility to chronic mucocutaneous candidiasis (CMC), often requiring long-term azole-based treatment. Due to increasing azole resistance, alternative treatments are desirable. Acquired resistance to amphotericin B (AMB) is rare but AMB use is limited by parenteral administration and nephrotoxicity. Cochleated AMB (CAMB) is a new oral formulation of AMB and thus an attractive option for oropharyngeal candidiasis (OPC), esophageal candidiasis (EC) and vulvovaginal candidiasis (VVC). We assessed the efficacy of CAMB in mouse models of OPC and VVC and in 4 patients with azole resistant CMC manifesting as OPC, EC or VVC.

Methods
Act1 -/- mice were infected with C. albicans in models of OPC and VVC and were treated once daily via oral gavage with CAMB or vehicle or intraperitoneal AMB-deoxycholate (AMBd) from day 1 through 4 post-infection (pi). At day 5 pi, the tongue or vaginal tissue was harvested to quantify fungal burden. Patients with azole resistant CMC enrolled in a phase 2A CAMB dose escalation study. The primary endpoint was clinical improvement at 2 weeks based on an efficacy scale, followed by optional extension for long-term suppression of CMC to assess safety and efficacy.

Results
CAMB-treated mice had significantly reduced tongue and vaginal tissue fungal burden compared to vehicle-treated mice, while they exhibited comparable fungal control relative to AMBd-treated mice. Among 4 CAMB-treated patients, 3 reached clinical efficacy by 2 weeks at a dose of 400 mg twice daily and one reached clinical efficacy at 200 mg twice daily. Three of 4 patients continued on the extension phase past 48 months with sustained clinical improvement of OPC and EC; patient #3 had relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical response was not seen for onychomycosis or VVC. CAMB was safe and well-tolerated without renal toxicity.

Conclusion
Oral administration of CAMB in IL-17-signaling deficient mice resulted in reduced tongue and vaginal tissue fungal burden during mucosal C. albicans infections. A proof-of-concept clinical trial in humans with inherited CMC showed efficacy in OPC and EC with good tolerability and safety.

Disclosures
Benjamin Colton, PharmD, Merck (Shareholder)Pfizer (Shareholder) Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Theresa Matkovits, PhD, Matinas BioPharma (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder) Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)
150. the RAPID trial: randomized Controlled Trial assessing point-of-care influenza and Other Respiratory Virus diagnostics in the Pediatric ED Setting
Authors: Rao Suchitra , Lamb Molly , Moss Angela , Mistry Rakesh , Dominguez Samuel 
Published: January 2021

Abstract

Background
Respiratory illnesses represent one of the commonest reasons for pediatric visits to the ED, and over 50% of these children are prescribed antibiotics despite a viral etiology in most cases. Our objectives were to determine whether rapid respiratory pathogen (RRP) testing decreases antibiotic and health care utilization among children evaluated in the ED with a respiratory illness.

Methods
We conducted a randomized controlled trial among children 1 mo-18 yrs of age attending an ED with influenza like illness (ILI). All children received a nasopharyngeal swab for RRP testing, and were randomized to the intervention group (result given to providers and parents) or control group (result not given, routine clinical care). Families were interviewed on enrollment, 1 and 10 days later. The primary outcome was antibiotic use. Secondary outcomes included antiviral use, hospitalization and recurrent medical visits. Intention to treat (ITT) (assigned group) and pragmatic (provider knows test results) analyses were conducted using SAS v 9.4. Pragmatic analyses were adjusted using multivariable Poisson regression.

Results
Among 920 visits (890 children) with ILI, 795 (85%) were RRP positive. Sociodemographic characteristics between groups were similar; 37% of children in the intervention group were discharged before results were available and 12% of children in the control group underwent clinical testing. The median age was 2.1 yrs (IQR 0.88–5.6); 35% had high-risk comorbidities. In the ITT intervention group, children were more likely to receive antibiotics (RR 1.3, 95% CI 1.0–1.7) (Table 1). In adjusted pragmatic analyses, children with known results were more likely to receive antivirals (RR 2.6 95% CI 1.5–4.3) and be hospitalized (RR 2.0, 95% CI 1.5–2.7); antibiotic use was not significant (Table 2). Children testing negative for a virus were more likely to receive antibiotics than those with a virus (35% vs 23%, p = 0.01).
Table 1. Clinical Outcomes by Study Arm, Intention to Treat Analyses

Table 2. Clinical Outcomes by Study Arm, Pragmatic Analyses

Conclusion
Knowledge of testing led to a paradoxical increase in antibiotic prescribing, as well as an increase in appropriate antiviral prescribing, ED length of stay and hospitalization. Further studies are needed to assess whether RRP testing with faster turn around times or coupled with stewardship interventions may impact outcomes.

Disclosures
Suchitra Rao, MD, BioFire (Grant/Research Support) Molly Lamb, PhD, BioFire (Grant/Research Support) Rakesh Mistry, MD, MSCE, BioFire (Grant/Research Support) Samuel Dominguez, MD, PhD, BioFire (Consultant, Research Grant or Support)
154. comparative Genomics Reveals Extra-hospital Transmission Networks of Carbapenem-resistant acinetobacter Baumannii sustained over Multiple Years in a US Midwest City
Authors: Calix Juan J , de Almeida Maria Claudia Stockler , Potter Robert , Wallace Meghan , Burnham Carey-Ann , Dantas Gautam 
Published: January 2021

Abstract

Background
The transmission dynamics of Acinetobacter baumannii (Ab) outside the setting of hospital outbreaks is underinvestigated. The BJC Healthcare System in St. Louis, MO has not experienced an Ab hospital outbreak since 2012. Despite this, nearly 60% of all BJC Ab isolates are carbapenem-resistant Ab (CrAb).

Methods
We acquired whole genome sequences (WGSs) of 110 Ab isolates identified in five BJC hospitals from July 2017 to May 2019. We performed multilocus sequence typing, core genome alignment and pairwise average nucleotide identity analysis to compare WGSs from BJC isolates and GenBank-available WGSs of Ab isolates from other US hospitals. Further epidemiologic characterization was performed using BJC electronic medical records and detailed chart review.

Results
Though the majority of CrAb isolates in other US studies belonged to globally-prevalent sequence type 2 (ST2 [Pasteur scheme]), 62% and 26% of BJC CrAb index isolates belonged to the unrelated ST499 and ST406, respectively. BJC ST499 and ST406 isolates were phylogenetically distinct compared to corresponding isolates from other US hospitals. Under the assumption that Ab transmission occurs primarily through nosocomial spread, we expected BJC isolates from the same hospital and timespan to share the highest degree of homogeneity. However, geotemporal proximity between ST499 or ST406 BJC isolates was a poor predictor of their genetic relatedness, according to multiple comparative methods. Review of patient metadata did not identify epidemiological links between BJC isolates within phylogenetic subgroups.

Conclusion
We combined comparative genomics and detailed clinical chart review to characterize the transmission dynamics of two emerging US CrAb sequence types, ST499 and ST406. Though these highly homogeneous Ab isolates were identified over two years in multiple BJC hospitals, we found no evidence of robust intra-hospital transmission networks. Instead, it appears that these CrAb isolates independently emerged from yet-to-be-identified regional, extra-hospital Ab populations. To neutralize the threat of drug-resistant infections in the US, it is essential to identify, characterize and disrupt emergent CrAb transmission networks that exist outside of hospital environments.

Disclosures
All Authors: No reported disclosures
155. Public Health Action-based System for Tracking and Responding to U.S. candida Drug Resistance: AR Lab Network, 2016–2019
Authors: Forsberg Kaitlin , Lyman Meghan , Chaturvedi Sudha , Schneider Emily C , Fischer Jill , Baynham Dorothy F , Dunbar Denise F , Plehn Michele , Podzorski Diane , Gumbis Stephanie , Sievert Dawn , Jackson Brendan R , Lockhart Shawn R , Berkow Elizabeth L 
Published: January 2021

Abstract

Background
Many U.S. clinical laboratories lack capacity to definitively identify fungi or perform antifungal susceptibility testing (AFST). To expand testing access, CDC’s Antibiotic Resistance Laboratory Network (AR Lab Network) provides Candida species identification and AFST to U.S. facilities for clinical and public health purposes. We describe the first three years of Candida AR Lab Network resistance data.

Methods
Isolates from any body site with species identification and AFST performed July 2016–June 2019 are included. Submissions were based on clinical and public health need. Patients may have multiple isolates. The 7 AR Lab Network regional laboratories used matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) or DNA sequencing for species identification. AFST was performed using broth microdilution for azoles and echinocandins (anidulafungin and micafungin) and Etest for amphotericin B. This analysis focuses on non-albicans Candida species with Clinical and Laboratory Standards Institute M60 minimum inhibitory concentration breakpoints and C. auris, which has CDC-proposed tentative breakpoints.

Results
Participation increased from healthcare facilities from 2 states submitting in 2016 to 35 states in 2019. Species identification was performed on 5,234 non-albicans isolates. AFST was performed on 4,222 (81%) isolates, including 2,395 C. glabrata, 815 C. auris, 267 C. parapsilosis, 125 C. tropicalis, 35 C. guilliermondii, and 32 C. krusei. Of isolates with AFST and body site indicated, 22% (900/4,102) were from blood. We found 85% of C. auris, 8% of C. glabrata, and 5% of C. parapsilosis isolates were resistant to azoles; 33% of C. auris isolates were resistant to amphotericin B; and 2% of C. glabrata, 1% of C. auris, and 1% of C. parapsilosis isolates were resistant to echinocandins. Although intrinsically resistant to fluconazole, C. krusei isolates were not resistant to voriconazole. Multidrug resistance was present in 32% of C. auris and 1% of C. glabrata isolates.

Conclusion
AR Lab Network has expanded access to rapid Candida testing, including AFST, and provides real-time surveillance. Results can be used to detect emerging species and resistance and guide public health action and healthcare practices.

Disclosures
All Authors: No reported disclosures
156. How Does Exposure to C. Diffogenic Antibiotics Impact Multidrug-resistant Organism Colonization and Environment Contamination in Nursing Homes?
Authors: Gontjes Kyle J , Gibson Kristen , Lansing Bonnie , Mantey Julia , Jones Karen , Cassone Marco , Wang Joyce , Mills John , Mody Lona , Patel Payal K 
Published: January 2021

Abstract

Background
Antimicrobial stewardship program (ASP) outcomes are often measured in the acute care setting, less is known about the effect of acute care antibiotic exposures on multidrug-resistant organism (MDROs) colonization of nursing home (NH) patients. We assessed exposure to antibiotics commonly associated with Clostridioides difficile (C. diffogenic agents) on post-acute care patient colonization and room environment contamination (Figure 1).
Figure 1. Conceptual Diagram of Hospital Antibiotic Exposure’s Influence on Patient Colonization and Room Environment Contamination with Multidrug-Resistant Organisms

Methods
MDRO surveillance of post-acute care patients in 6 NHs between 2013–16. We screened patient hands, nares, oropharynx, groin, perianal area, and high-touch room environment surfaces for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and resistant Gram-negative bacilli (rGNB). C. diffogenic agents were defined as fluoroquinolones, 3rd/4th generation cephalosporins, penicillin combinations, lincosamides, and carbapenems. Multivariable logistic regression was used to assess whether hospital antibiotic exposure is an independent risk factor for MDRO colonization and room environment contamination on study enrollment.

Results
We enrolled 618 patients: average age was 74.4 years; 57.4% female; 62.3% white; 9.9% had indwelling devices (Table 1). Three hundred-fifty patients (56.6%) were MDRO colonized on enrollment: 98 (15.9%), MRSA; 208 (33.7%); VRE; 196 (31.7%), rGNB. Sixty-eight percent of patient rooms were MDRO contaminated: 166 (26.9%), MRSA; 293, (47.4%). VRE; 182 (29.5%), rGNB.
A majority (59.4%) of patients were exposed to an antibiotic before admission. Of which, 239 (65.1%) were exposed to a C. diffogenic antibiotic. In multivariable analysis, C. diffogenic antibiotic exposure was an independent risk factor for MDRO colonization (OR, 1.94; 95% CI, 1.35–2.79), MDRO room environment contamination (OR, 1.94; 95% CI, 1.43–2.63), VRE colonization (OR, 4.23; 95% CI, 2.59–6.90), and VRE room environment contamination (OR, 2.58; 95% CI, 2.00–3.33).
Table 1. Clinical Characteristics and MDRO Burden on Study Enrollment, Stratified by Hospital Antibiotic Exposure Status

Multivariable Analysis of Hospital Antibiotic Exposure Status as Risk Factor for Proximal and Distal MDRO Outcomes

Conclusion
Hospital exposure to antibiotics is associated with an increased risk of VRE colonization and room environment contamination on NH study enrollment. These observations highlight the potential influence of hospital-based ASPs on MDRO prevalence and transmission in NHs.

Disclosures
All Authors: No reported disclosures
159. efficacy of CD377, a Novel Antiviral Fc-conjugate, Against Seasonal Influenza in Lethal Mouse Infection Models
Authors: Levin James , Amundson Karin , Shathia Kim , Borchardt Allen , Lam Thanh , Brady Tom , Noncovich Alain , Tari Les 
Published: January 2021

Abstract

Background
Cidara’s AVCs (antiviral Fc-conjugates) are novel conjugates of potent, antiviral agents with the Fc domain of human IgG1. CD377 is an AVC development candidate for prevention and treatment of influenza that has broad anti-neuraminidase activity in both enzymatic and cell-based assays and the potential to engage the immune system, as well as a long half-life.

Methods
Efficacy studies were conducted in BALB/c mice lethally challenged intranasally at 3x the LD95 with influenza A (H1N1, H3N2) and influenza B (both lineages). CD377 was administered as a single dose subcutaneously (SC) 2 hours after viral challenge. Body weights (BW) and health scores were monitored daily, with 20% BW loss recorded as a mortality.

Results
In mice challenged with a lethal dose of an H1N1 strain (A/California/12/2012), a single 0.3 mg/kg dose of CD377 administered 2 hours post-challenge was fully protective (P=0.0015 relative to vehicle) (Fig 1A). In a similar study against a mouse-adapted H3N2 subtype (A/Hong Kong/1/1968), a single dose of CD377 at 0.1 mg/kg was fully protective (P=0.0025) (Fig 1B). In both studies, only a transient loss of BW was observed before mice began recovering weight.
The activity of CD377 was also evaluated against both lineages of influenza B (Fig 1C, 1D). Against influenza B/Colorado/06/2017 (Victoria), a single CD377 dose of 0.3 mg/kg was fully protective (P=0.0035) while the Fc-only control dosed at 1 mg/kg was not, as expected. Against the Yamagata lineage (B/Florida/4/2006), CD377 demonstrated full protection at a dose of only 0.03 mg/kg (P=0.0023).

Conclusion
A single dose of CD377 (0.3 mg/kg or less) was protective against lethal challenge with several seasonal influenza A/B subtypes. The exceptional PK profile of CD377 combined with potent broad-spectrum activity highlight its potential for use as a long-term preventative against seasonal influenza.
Seasonal influenza efficacy

Disclosures
James Levin, PhD, Cidara Therapeutics (Shareholder) Karin Amundson, BSc, Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Tom Brady, PhD, Cidara Therapeutics (Shareholder) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)
161. impact of State Childcare and School Hepatitis a Vaccination Requirements on Coverage of Hepatitis a Vaccines in the United States
Authors: Choi Yoonyoung , Bhatti Alexandra , Liu Zhiwen , Goveia Michelle , Simon Jakub 
Published: January 2021

Abstract

Background
Widespread Hepatitis A (Hep A) outbreaks in the United States (US) have raised the importance of vaccination. Vaccination requirements for childcare and school entry could be an effective strategy to ensure compliance to recommended vaccination schedule. We assessed the association between state childcare and school entry requirements for Hep A vaccination and vaccine coverage rate among children and adolescents in the US.

Methods
We conducted a cross-sectional cohort study using National Immunization Survey-Child and Teen dataset between 2008 and 2017. We included children aged 19–35 months and adolescents aged 13–17 years residing in states with childcare entry requirement only (C); school entry requirement only (S); childcare AND school entry requirement (C+S); and neither of requirements in place in the survey year (Control). We developed a multivariate logistic regression model adjusting for demographics, survey year, state’s CDC vaccination recommendation status, stringency of requirement, and history of Hep A outbreak, accounting for the survey design.

Results
We included 150,653 children and 119,265 adolescents in the analysis. Vaccination initiation rate was 53.9% and 72.6% (C), 48.3% and 74.9% (S), 48.2% and 83.9% (C+S) in pre- and post-requirement periods, respectively. In multivariate analysis, all state requirements were associated with higher Hep A vaccination initiation compared to control states (C: odds ratio 1.51, 95% confidence interval 1.37–1.66; S: 1.82, 1.49–2.23; and C+S: 1.49, 1.38, 1.62). Predictors for high vaccination initiation included vaccine recommendation since 1999 vs 2006 (2.87, 2.63–3.13); exemption of enforcement (most restrictive vs lenient: 2.10, 1.68–2.63). In addition, non-White, Hispanic children aged between 19–35 months with insurance, &gt;$75,000 family income household, mothers having college degree were more likely to initiate Hep A vaccination. The associations were similar for Hep A vaccination completion.
Figure 1. Hep A vaccination initiation and completion rates between pre- and post-requirement periods (C=childcare entry requirement only; S=school entry requirement only; and C+S=childcare AND school entry requirement)

Table 1. Multivariate association between state policy and vaccination initiation and completion rate

Conclusion
States with childcare and school entry requirements are more likely to initiate and complete Hep A vaccine compared to those without such policy. This interventional policy may help to control and prevent Hep A outbreaks in states where it is applied.

Disclosures
Yoonyoung Choi, PhD, MS, RPh, Merck (Employee) Alexandra Bhatti, JD, MPH, Merck (Employee) Zhiwen Liu, PhD, Merck & Co., Inc., (Employee) Michelle Goveia, MD, Merck & Co., Inc (Employee, Shareholder) Jakub Simon, MD, MS, Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder)