bluuebunny/crossref_metadata_2025_split huggingface dataset:
2841. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate (TZD) and Linezolid (LZD) for Treatment of Ventilated Gram-Positive (G+) Nosocomial Pneumonia
Authors: Wunderink Richard G , Roquilly Antoine , Croce Martin , Rodriguez Gonzalez Daniel , Fujimi Satoshi , Butterton Joan R , Broyde Natasha , Popejoy Myra W , Kim Jason Y , De Anda Carisa S 
Published: October 2019

Abstract

Background
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are frequently caused by G+ cocci; TZD has potent in vitro activity against these pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The VITAL study compared the efficacy and safety of TZD vs. LZD for the treatment of ventilated patients with G+ HAP/VAP.

Methods
Randomized, double-blind, double-dummy, global, phase 3 study in mechanically ventilated adult patients with presumed G+ HAP/VAP (clinicaltrials.gov NCT02019420). Patients were stratified by region, age, and trauma/nontrauma, then randomized 1:1 to intravenous (IV) TZD 200 mg once daily for 7 days or IV LZD 600 mg every 12 h for 10 d (patients with concurrent G+ bacteremia received 14 d of treatment). The primary efficacy endpoint was day 28 all-cause mortality (ACM) in the intent to treat (ITT) population (all randomized patients; noninferiority [NI] margin, 10%). Secondary endpoints included investigator-assessed clinical response at test of cure (TOC; NI margin, 12.5%).

Results
In total, 726 patients were randomized (TZD n = 366; LZD n = 360). Baseline characteristics were well balanced between arms. TZD was noninferior to LZD for day 28 ACM in the ITT (table). Noninferiority was not demonstrated for TZD vs. LZD for investigator-assessed clinical success at TOC in the ITT. Stratification factors, analysis population, baseline clinical/laboratory signs of HAP/VAP, G+ only vs. mixed G+/gram-negative (G–) HAP/VAP, adjunctive G– therapy, MRSA vs. methicillin-susceptible S. aureus, and HAP vs. VAP were evaluated, and no single factor accounted for the observed imbalance in clinical response between treatment arms. Greater than 90% of patients experienced treatment-emergent adverse events (TEAEs). Anemia, hypokalemia, and diarrhea were the most frequently reported (TEAEs) in both arms. Types and incidence rates of TEAEs overall, and of drug-related TEAEs specifically, were comparable between TZD and LZD.

Conclusion
TZD was noninferior to LZD for day 28 ACM in the treatment of ventilated G+ HAP/VAP. However, TZD was not noninferior to LZD based on the investigator-assessed clinical response at TOC. Both drugs were similarly well tolerated and TEAEs were well balanced between groups, with no new safety signals identified.

Disclosures
All Authors: No reported Disclosures.
2842. Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naïve Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies
Authors: van Wyk Jean A , Man Choy Y , Sievers Jörg , Urbaityte Rimgaile , Underwood Mark , Tenorio Allan R , Pappa Keith , Wynne Brian , Smith Kimberly , Gartland Martin 
Published: October 2019

Abstract

Background
At Weeks 48 and 96 in the GEMINI-1 and GEMINI-2 studies (Clinicaltrials.gov: NCT02831673 and NCT02831764), the 2DR of DTG+3TC was noninferior to the three-drug regimen of DTG + tenofovir/emtricitabine (TDF/FTC) in achieving plasma HIV-1 RNA < 50 c/mL in treatment-naïve adults.

Methods
GEMINI-1 and 2 are identical, global, double-blind, multicenter Phase III studies. Participants with screening HIV-1 RNA ≤ 500.00 c/mL were randomized to once-daily DTG+3TC or DTG+TDF/FTC, stratified by plasma HIV-1 RNA and CD4+ cell count. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). We present a secondary endpoint analysis of efficacy at Week 96 by baseline disease and demographic characteristics. For the overall population, estimates and confidence intervals were based on a stratified analysis using Cochran–Mantel–Haenszel weights.

Results
In total, 714 and 719 adults were randomized and treated in GEMINI-1 and -2, respectively. Based on a 10% noninferiority margin, DTG+3TC was noninferior to DTG+TDF/FTC at Week 96 in both GEMINI-1 and -2 and in the pooled analysis. Response rates across baseline HIV-1 RNA subgroups were high and similar in both arms in the pooled analysis, including in participants with baseline HIV-1 RNA >100,000 c/mL (Table 1). Results were also generally consistent regardless of age, gender, or race. In the CD4+ ≤ 200 cells/mm3 subgroup, response rates were lower in the DTG+3TC group compared with DTG+TDF/FTC; most reasons for nonresponse were unrelated to virologic efficacy or treatment regimen. Across both studies, 11 participants on DTG+3TC and 7 on DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 96; none had treatment emergent integrase-strand-transfer-inhibitor or NRTI resistance mutations.

Conclusion
In GEMINI-1 and 2, DTG+3TC was noninferior to DTG+TDF/FTC in treatment-naïve adults at Week 96, demonstrating durable efficacy. The results of subgroup analyses of efficacy at Week 96 were generally consistent with overall study results, and further demonstrate that DTG+3TC is an effective initial treatment for HIV-infected patients across a spectrum of disease characteristics and patient populations. The studies are ongoing.

Disclosures
All Authors: No reported Disclosures.
2847. Comparative Genomics and Clonal Tracking of Multi-drug-Resistant Uropathogens Implicates the Fecal Microbiome as a Potential Reservoir for Recurrent Urinary Tract Infections
Authors: Thanert Robert , Reske Kimberly , Hink Tiffany , Wallace Meghan , Wang Bin , Schwartz Drew , Burnham Carey-Ann , Seiler Sondra , Cass Candice , Dubberke Erik R , Dantas Gautam , Kwon Jennie H 
Published: October 2019

Abstract

Background
Multi-drug-resistant organisms (MDRO) have complicated the treatment of urinary tract infections (UTIs), especially in patients with recurrent UTIs (rUTI). The objective of this pilot prospective cohort study is to determine the role of the fecal microbiome in rUTIs.

Methods
Stool and urine specimens were prospectively collected from patients with MDRO UTIs at 6 time points during and after the UTI, and with any rUTI. Specimens underwent semi-quantitative culture on differential and selective media for MDROs, and isolates underwent phenotypic susceptibility testing and whole-genome sequencing. Comparative genomics and clonal tracking were used to detect clonal uropathogen strains in the urinary and gastrointestinal tracts. Resistance genes, resistance-plasmids, and virulence genes of MDROs were characterized in silico.

Results
A total of 110 isolates (95 Escherichia coli, 2 Klebsiella pneumoniae, 13 Proteus mirabilis) were cultured from the urine and stool of 15 patients (7 non-rUTI, 8 rUTI). Clonal uropathogens were isolated between the urinary tract and their intestinal reservoir (Figure 1). Integration of clonality information with semiquantitative culturing implicated three potential routes for recurrence of UTIs: (i) bladder colonization following an intestinal bloom of uropathogens, (ii) reinfection from an external source, and (III) bacterial persistence within the urinary tract (Figures 2 and 3). Antibiotic susceptibility testing and genomic profiling indicated that antibiotic-resistant uropathogen populations colonizing the urinary tract and intestinal reservoir at symptomatic and asymptomatic timepoints have similar resistance profiles that are largely determined via a pool of shared resistance plasmids (Figure 3).

Conclusion
This study provides the first time-resolved analysis of uropathogen persistence following UTIs, showing that clonal antibiotic-resistant uropathogens can be detected in both the urine and stool at varying time points post-initial infection. The study implicates 3 potential routes of rUTI, including uropathogen persistence within the gut microbiota, reinfection from an external source, and persistent bacteriuria. Study findings could be utilized to inform future diagnostics and therapies for treatment of rUTIs.

Disclosures
Carey-Ann Burnham, PhD, BioFire: Research Grant; bioMerieux: Research Grant; Cepheid: Research Grant; Luminex: Research Grant.
2852. Epidemiology of Emerging Carbapenemase-Producing Organisms (CPO) in Chicago, Illinois, 2013–2018
Authors: Pacilli Massimo , Adil Hira , Walblay Kelly , Xydis Shannon N , Clegg Whitney , Lin Michael Y , Valley Ann M , Tang Angela , Fealy Amy E , Kemble Sarah K , Black Stephanie R 
Published: October 2019

Abstract

Background
Emerging CPO in the Chicago area poses clinical and infection control challenges across the spectrum of care. Since November 2013, CPO are reportable to the Illinois’ Extensively Drug-resistant Organism (XDRO) registry. We examined trends in mechanism of resistance (MOR) among CPO reported through December 2018.

Methods
MOR reported into the XDRO registry were identified by clinical laboratories performing molecular methods on routine clinical cultures, by public health laboratories during point prevalence surveys (PPS) in response to clusters and as part of a project to assess CPO prevalence in high-risk Chicago area healthcare settings. Chicago patients with known MOR other than Klebsiella pneumoniae carbapenemase (KPC) are investigated by Chicago Department of Public Health (CDPH) to implement containment strategies and identify risk factors within 6 months of culture date.

Results
MOR was identified in 40% (1,216/3,587) of CPO-positive specimens collected from unique Chicago patients; 87% were KPC, 7% New Delhi metallo-β-lactamase (NDM), 5% Verona integron-mediated metallo-β-lactamase (VIM), 0.6% OXA-48-type carbapenemases, and 0.01% Imipenemase metallo-β-lactamase (IMP) (figure). Since 2017, 15 patients with CPO expressed more than one MOR; 14 were identified during PPS at ventilator capable skilled nursing facilities (vSNF) or long-term acute care hospitals (LTACH), and one was hospitalized in India. Among 156 patients with non-KPC CPO, the median age was 64 years (range, 20–97), 107 (69%) were identified from rectal screening and 49 (31%) were from clinical specimens, most of which were urine 23 (47%) or blood 6 (12%). Among 134 patients with risk factor history, 64% had history of tracheostomy (Table 1). Among 113 patients without documented travel outside of the United States, all stayed overnight at an Illinois healthcare facility; 62% stayed in a vSNF and 24% in an LTACH within 6 months of identification (Table 2).

Conclusion
We have increasingly detected non-KPC CPO in Chicago; however, estimates of prevalence are limited by lack of systematic surveillance and molecular testing. The high proportion of CPO patients without travel who stayed in vSNF or LTACH underscores the need for infection control training and surveillance in these settings.

Disclosures
All Authors: No reported Disclosures.
2856. Salvaging High-Value Catheters: Antifungal Lock Therapy for Candidal Central Catheter Infections in a Pediatric Cohort
Authors: Walker Lorne W , Nowalk Andrew J 
Published: October 2019

Abstract

Background
By IDSA guidelines, therapy for central line-associated bloodstream infections (CLABSI) due to Candida species requires catheter removal and administration of systemic antifungals. Despite this, in selected cases catheter salvage is desirable. The addition of antifungal lock therapy (ALT) has been proposed in these cases, but evidence for efficacy of this approach is limited. Here we report a retrospective analysis of ALT use for CLABSI due to Candida species at a single pediatric center.

Methods
All events of candidal CLABSI with ALT use were identified by retrospective record review between January 1, 2008 and December 31, 2018. CLABSI was defined by the growth of Candida from at least one central blood culture. Clearance was defined as a period of 48 hours with no positive cultures. Recurrence was defined as a subsequent positive blood culture with the same fungal organism either before or after line removal. Events were classified as “early removal” vs. “retained 7 days” depending on whether the line remained in place on day 7 after the first positive culture.

Results
Overall, 122 qualifying CLABSI were identified, 64 (52%) were retained 7 days or more (Table 1). Overall, 59% of CLABSI met criteria for clearance prior to line removal. Lines retained 7 days were likely to also remain in place at 28 days (72%) and had a low rate of relapse (8%) within 28 days. Lines in the early removal group had lower recurrence rates within 1 year (17% vs. 42%, P = 0.005), but this difference narrowed when considering recurrence at any time (31% vs. 47%, P = 0.1) or by Kaplan–Meier analysis (Figure 1) Additional microbiological and outcome data can be found in Tables 2 and 3.

Conclusion
This retrospective analysis is the largest described cohort of antifungal locks for line salvage in a pediatric population to our knowledge. These findings highlight the advantages of line removal, with lower recurrence at 1 year. However, when line salvage with antifungal locks is attempted, retention and recurrence rates in the first month are favorable, and recurrence rates converge in the long-term, presumably because the underlying risk factors remain. While line removal remains the standard therapy for candidal CLABSI, we find that ALT-based line salvage may be a viable alternative.

Disclosures
All Authors: No reported Disclosures.
2885. A Host Transcriptional Signature for Accurate Diagnosis of Candidemia in the Hospital Setting
Authors: Steinbrink Julie M , Hua Kaiyuan , Myers Rachel , Johnson Melissa D , Seidelman Jessica , Tsalik Ephraim L , Tsalik Ephraim L , Alexander Barbara D , McClain Micah T 
Published: October 2019

Abstract

Background
Candidemia is one of the most common nosocomial bloodstream infections in the United States and causes significant morbidity and mortality in hospitalized patients. Improved rapid diagnostics capable of differentiating candidemia from other causes of febrile illness in the hospitalized patient are of paramount importance. Pathogen class-specific biomarker-based diagnostics such as those focusing on host gene expression patterns in circulating leukocytes may offer a promising alternative.

Methods
RNA sequencing was performed on peripheral blood samples from 27 hospitalized patients with blood culture positive invasive candidiasis. Samples from healthy controls as well as at-risk subjects with acute febrile illness and similar clinical backgrounds but other infectious or noninfectious etiologies were used as comparator phenotypes (35 subjects with culture-proven bacterial infection, 49 with confirmed viral infection, and 17 with acute noninfectious illness). Bayesian techniques were utilized to develop infection-specific classifiers and leave one out cross-validation was used to estimate the predictive probability of each pathogen class.

Results
Candidemia triggers a unique, robust and conserved transcriptomic response in human hosts with 1,170 genes differentially upregulated compared with healthy controls. Based on this strength of signal, we developed a transcriptomic classifier that was capable of identifying candidemia, viral, or bacterial infection with a high degree of accuracy (auROC for Candida 0.93, Bacterial 0.98, Viral 0.99). The Candida component of this classifier (29-genes) was able to diagnose candidemia with a sensitivity of 88% and specificity of 100%.

Conclusion
The host transcriptomic response during candidemia in hospitalized adults is highly conserved and unique from the genomic responses to acute viral and bacterial infection. This approach shows promise for the development of host response-based classifiers capable of differentiating multiple types of clinical illnesses at once in at-risk febrile patients.

Disclosures
Ephraim L. Tsalik, MD MHS PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.
2889. Skin Niche Conditions Trigger C. auris to Form Robust Biofilms That Resist Desiccation
Authors: Nett Jeniel E , Patel Tarika , Johnson Chad , Kernien John 
Published: October 2019

Abstract

Background
Emerging pathogen Candida auris, the first fungus to be labeled as a public health threat, causes nosocomial outbreaks of invasive candidiasis with mortality as high as 60%. Little is known about the pathogenesis of this species that has newly arisen in the last 10 years. It is unclear why this species readily colonizes the skin and transmits efficiently in healthcare settings. We considered the possibility that C. auris may proliferate in conditions of the skin niche.

Methods
We analyzed the growth of C. auris (B11203) in synthetic sweat media that was designed to mimic human axillary sweat. We included C. albicans SC5314 as a comparison. To simulate sweat evaporation, we examined fungal growth in sweat media that had been concentrated up to 2.5-fold. We utilized OD600 readings to quantify planktonic and biofilm growth. Biofilm architecture was assessed by scanning electron microscopy. To determine the resilience of biofilms, biofilm viability was assessed by viable burden following desiccation.

Results
In the various concentrations of sweat media, C. auris formed biofilms that were 3.5- to 5-fold greater that those observed for C. albicans (A). In contrast, C. auris biofilms formed in RPMI-MOPS were approximately half the density of the C. albicans biofilms. During planktonic growth in synthetic sweat media, C. auris and C. albicans replicated similarly, including in media that had been concentrated 2.5-fold. This suggests that the various media conditions differently trigger biofilm formation for the two species. The C. auris biofilm formed in sweat media was approximately 100-fold more resistant to 1 week of desiccation (B).

Conclusion
Skin niche conditions trigger C. auris to form resilient biofilms that resist desiccation. We propose that this unique characteristic may account for the propensity of this species to colonize the skin and for its capacity to persist on the surface of contaminated medical devices.

Disclosures
All Authors: No reported Disclosures.
2904. Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice
Authors: Jagger Brett W , Dowd Kimberly A , Chen Rita , Desai Pritesh , Himansu Sunny , Graham Barney S , Pierson Theodore C , Diamond Michael S 
Published: October 2019

Abstract

Background
Zika virus (ZIKV) caused an epidemic of microcephaly and congenital malformations in 2015–2016, prompting the development of ZIKV vaccines. Plasmid DNA and modified mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccines were among the first to reach human clinical trials, where their evaluation is ongoing. Few studies have evaluated vaccine efficacy in the setting of infection during pregnancy, and there is an open question around antibody-dependent enhancement (ADE) of flaviviral disease due to cross-reactive fusion loop epitope (FLE) antibodies.

Methods
Female C57BL/6J mice and human STAT2 knock-in (hSTAT2-KI) mice were immunized with plasmid DNA (VRC5283) or mRNA-LNP (Moderna Inc.) vaccines encoding the ZIKV prM-E genes. Antibody responses were assayed, and immunized mice were mated and WT mice were transiently immunocompromised by administration of interferon blocking antibody, followed by ZIKV challenge. 1 week post-infection, ZIKV burden was measured via qRT-PCR. ZIKV-specific memory B cell (MBC), long-lived plasma cell (LLPC), and CD8+ T cell vaccine responses were also assayed.

Results
VRC5283 and mRNA-LNP vaccines were highly immunogenic, eliciting serum neutralizing EC50 responses >1:10,000, and markedly reduced placental ZIKV burden and fetal transmission. An improved mRNA-LNP construct with higher immunogenicity correlated with reduced placental viral burden. Significantly, an FLE-mutant mRNA-LNP vaccine yielded comparable EC50 responses without compromising vaccine efficacy; sera from these mice did not enhance dengue virus infection in vitro. Both VRC5283 and mRNA-LNP vaccines elicited MBC, LLPC, and CD8+ T cell responses, although MBC and LLPC responses were greater after mRNA-LNP immunization. Surprisingly, low-level ZIKV infection of the placenta and a minority of fetal heads were observed despite robust neutralizing antibody responses, which was not seen in the immunocompetent hSTAT2-KI model.

Conclusion
Nucleic acid vaccines were highly immunogenic and protective against vertical ZIKV transmission during pregnancy in mice. These data support and inform the ongoing clinical development of these vaccines in humans.

Disclosures
All Authors: No reported Disclosures.
2905. Long-term Immunological Persistence of the Adjuvanted Recombinant Zoster Vaccine: Clinical Data and Mathematical Modeling
Authors: Bastidas Adriana , Catteau Grégory , Volpe Stéphanie , Mrkvan Tomas , Enemuo Adaora , Smetana Jan , Schwarz Tino , Rombo Lars , Pauksens Karlis , Berengier Estelle , Hervé Caroline , Oostvogels Lidia , Schuind Anne 
Published: October 2019

Abstract

Background
The adjuvanted recombinant zoster vaccine (RZV, GSK), administered to adults ≥ 50 years of age (YOA) demonstrated ≥ 90% efficacy against herpes zoster across all age cohorts. Vaccine-specific immune responses elicited by two RZV doses in adults ≥ 60 YOA have been shown to persist above pre-vaccination levels at least up to 9 years after initial vaccination. Here we present persistence of the humoral and cellular immunity and safety up to 10 years after initial vaccination as well as data from mathematical modeling, performed to predict immune persistence up to 15 years.

Methods
This phase IIIB, open-label extension trial (NCT02735915) included 70 participants who had received two RZV doses in the initial trial (NCT00434577) and builds on a previous extension trial (NCT01295320). Cellular and humoral immune responses up to year 10 after an initial 2-dose vaccination schedule are presented here. Additionally, prediction of immunological persistence at year 15 was assessed by mathematical modeling (Piecewise, Power-law, Fraser), using the individual subject values for available data up to year 10.

Results
The median frequency of varicella-zoster virus glycoprotein E (gE)-specific CD4+ T-cells expressing ≥ 2 activation markers plateaued at 3.3-fold above pre-vaccination levels starting around year 4 up to year 10 post-initial vaccination. Anti-gE antibody concentrations plateaued starting around year 3 up to year 10 post-initial vaccination.Ten years after initial vaccination, humoral responses remained 5.9-fold higher as compared with pre-initial vaccination levels (Figure 1). No relevant safety events were identified during the study (year 9–10 post-initial vaccination). In line with previous modeling data, the year 10 analysis predicts that both cellular and humoral immune responses will remain above pre-vaccination levels for at least 15 years after initial vaccination (Figures 2 and 3).

Conclusion
In adults vaccinated when ≥ 60 YOA, humoral and cellular immune responses induced by two RZV doses persist above pre-vaccination levels for at least 10 years post-initial vaccination. Mathematical modeling predicts a maintained vaccine-related immune response for at least 15 years after initial vaccination.
Funding. GlaxoSmithKline Biologicals SA.

Disclosures
All Authors: No reported Disclosures.