bluuebunny/crossref_metadata_2025_split huggingface dataset:
SYN-004 (ribaxamase) prevents New Onset Clostridium difficile Infection by Protecting the Integrity Gut Microbiome in a Phase 2b Study
Authors: Kokai-Kun John , Roberts Tracey , Coughlin Olivia , Whalen Heidi , Le Charles , Da Costa Christopher , Sliman Joseph 
Published: October 2017

Abstract

Background
Clostridium difficile infections (CDI) are an “urgent threat,” but there are no approved drugs or vaccines to prevent new onset CDI. SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered with IV β-lactam antibiotics and remain localized in the intestine to degrade antibiotics excreted into the intestine. This is expected to protect the gut microbiome from disruption thus preventing deleterious effects including CDI, colonization by opportunistic pathogens, and emergence of antibiotic resistance in the gut microbiome. Ribaxamase was well tolerated and not systemically absorbed in Phase 1 studies and efficiently degraded ceftriaxone excreted into the human intestine while not altering the plasma pharmacokinetics of ceftriaxone in Phase 2a studies.

Methods
A multinational Phase 2b, double-blind, placebo-controlled, study was conducted to determine whether ribaxamase could prevent new onset CDI with additional endpoints for non-CDI antibiotic-associated diarrhea, colonization by opportunistic pathogens, changes in the gut microbiome and emergence of antibiotic resistance. The 412 patient mITT population, enriched for higher risk for CDI, were admitted to the hospital for ≥5 days of IV ceftriaxone for the treatment of a lower respiratory tract infection. Patients were randomized 1:1 to receive ribaxamase or placebo during treatment and for 72h after. Fecal samples were collected at prespecified points for determination of colonization by opportunistic pathogens and to examine changes in the gut microbiome. Patients were monitored for 6 weeks for CDI (diarrhea plus the presence of C. difficile toxin). The study was powered at 80% for the reduction in CDI with 1-sided α = 0.05.

Results
The study met its primary endpoint with a 71% relative risk reduction in CDI (1-sided p = 0.045) and had a statistically significant 44% relative risk reduction in new colonization by vancomycin-resistant enterococci (1-sided p = 0.0002). Ribaxamase also protected the diversity of the gut microbiome and reduced the emergence of antibiotic resistance in ceftriaxone-treated patients.

Conclusion
These data support that ribaxamase can maintain the balance of the gut microbiome and thereby prevent opportunistic infections like CDI during IV β-lactam treatment.

Disclosures
J. Kokai-Kun, Synthetic Biologics, Inc.: Employee, Salary; T. Roberts, Synthetic Biologics, Inc.: Employee, Salary; O. Coughlin, Synthetic Biologics, Inc.: Employee, Salary; H. Whalen, Synthetic Biologics, Inc.: Employee, Salary; C. Le, Synthetic Biologics, Inc.: Employee, Salary; C. Da Costa, Synthetic Biologics, Inc.: Employee, Salary; J. Sliman, Synthetic Biologics, Inc.: Employee, Salary.
Comparison of Respiratory Pathogen Detections from Routine Hospital Testing and Expanded Systematic Testing from the Minnesota Severe Acute Respiratory Illness Surveillance Program, 2015–2016
Authors: Steffens Andrea , Friedlander Hannah , Como-Sabetti Kathryn , Boxrud Dave , Bistodeau Sarah , Strain Anna , Reed Carrie , Lynfield Ruth , Fowlkes Ashley 
Published: October 2017

Abstract

Background
Hospital testing for respiratory pathogens is nonsystematic, leading to potential missed detection of clinically relevant pathogens. The Minnesota Severe Acute Respiratory Illness (SARI) surveillance program monitors hospitalizations due to acute respiratory illness and conducts systematic testing for several respiratory pathogens. We assessed viruses detected by the hospital and additional detections identified by expanded testing.

Methods
Residual upper respiratory specimens collected from patients hospitalized for suspected respiratory illness for routine diagnostic testing at three hospitals, including one children’s hospital, were submitted to the Minnesota Department of Health (MDH). Specimens were tested for 18 respiratory viruses by RT-PCR. Clinical and hospital test data were collected through medical record review.

Results
From September 2015 to August 2016, 2,351 hospitalized SARI patients were reported, with the following age distribution: 57% &lt;5 years, 13% 5–17 years, 30% ≥18 years. Among all SARI patients, 97% (2,273) had hospital-based, clinician-directed testing for viral pathogens. Viruses were detected among 47% (1,077) of tested patients, among which testing methods included PCR (85%), rapid antigen (13%), and culture (2%); 74% were tested on the day of admission. Most common viruses detected by clinical testing included respiratory syncytial virus (41%), rhinovirus/enterovirus (31%), and influenza (15%) (Figure 1). Systematic RT–PCR testing at MDH identified 1,600 (68%) patients positive for ≥1 respiratory virus, identifying previously unknown detections among 35% (820) of SARI patients (Figure 2). Of 1,272 patients with no virus identified at the hospital, 46% (586) had a viral detection at MDH. Patients aged &lt;18 years were significantly more likely to have an additional pathogen detected by MDH testing than those aged ≥18 years (P &lt; 0.01), including rhinovirus/enterovirus, adenovirus, human metapneumovirus, and coronaviruses.

Conclusion
Systematic, expanded testing at MDH identified a higher proportion of respiratory pathogens among SARI patients compared with clinical laboratory testing. Additional testing for clinically relevant respiratory pathogens may inform medical decision-making.

Disclosures
All authors: No reported disclosures.
Pneumococcal Urinary Antigen Testing in US Hospitals: Underutilized and Rarely Acted Upon
Authors: Haessler Sarah , Schimmel Jennifer , Yu Pei-Chun , Rothberg Michael 
Published: October 2017

Abstract

Background
The IDSA guideline for CAP recommends Pneumococcal urinary antigen testing (UAT) in addition to blood and sputum cultures for patients with severe CAP. In controlled settings, UAT is 50–80% sensitive and &gt;90% specific; however, its utility and performance on a large-scale in real-world use has not been assessed. It is unclear whether UAT is clinically useful or whether the results impact prescribing behavior.

Methods
Retrospective cohort study of adult patients admitted with CAP or HCAP from 2010 to 2015 at 170 US hospitals that submit data to Premier. Date and time-stamped administrative and microbiologic data were assessed. Patients with a principal diagnosis of pneumonia, or sepsis with a secondary diagnosis of pneumonia plus a CXR and antibiotics within the first 24 hours, were included if they had a UAT plus either a blood or respiratory culture within the first 48 hours of admission.

Results
Of 159,894 eligible pneumonia patients, 24,757 (15.5%) had UAT plus either blood or respiratory cultures performed. Of 1,797 (7%) who had a positive UAT, 457 (25%) also grew S. pneumoniae (SP) from blood or respiratory cultures, 1,240 (69%) had negative cultures, and 100 (6%) an organism other than SP, with S. aureus, Pseudomonas spp., and E.coli being the most common pathogens, predominantly from respiratory cultures. Among 22,960 patients with a negative UAT, 429 (2%) had a positive blood or respiratory culture for SP and 2,653 (12%) had a culture positive for another organism. UAT was performed among 18.4% of patients admitted to the ICU, and 15.3% of those admitted to wards. Among patients empirically started on broad-spectrum antibiotics, 35% who had a positive UAT were de-escalated by Day 5, compared with 49% who grew SP in blood cultures and 24% in respiratory cultures.

Conclusion
In a large representative US inpatient database, there was poor concordance between UAT and cultures for SP. A positive UAT decreased the probability of having a non-SP pathogen. Antibiotic de-escalation occurred more often in association with a positive blood culture for SP than for UAT or positive respiratory culture, but occurred in less than half the patients with these markers of pneumococcal pneumonia. Overall, UAT is underutilized and does not appear to have a substantial impact on clinical care.

Disclosures
S. Haessler, AHRQ: Investigator, Research grant; P. C. Yu, AHRQ: Investigator, Research grant; M. Rothberg, AHRQ: Investigator, Research grant
Comparing the Outcomes of Adults with Enterobacteriaceae Bacteremia Receiving Short-Course vs Prolonged-Course Antibiotic Therapy
Authors: Chotiprasitsakul Darunee , Han Jennifer H , Conley Anna T , Cosgrove Sara E , Harris Anthony D , Lautenbach Ebbing , Tamma Pranita D 
Published: October 2017

Abstract

Background
The recommended duration of antibiotic treatment for Enterobacteriaceae bacteremia is between 7 and 14 days. We compared the clinical outcomes of patients receiving short-course (6–10 days) vs prolonged-course (11–15 days) antibiotic therapy for Enterobacteriaceae bacteremia.

Methods
A retrospective cohort study was conducted at The Johns Hopkins Hospital, The University of Maryland Medical Center, and The Hospital of the University of Pennsylvania including patients with monomicrobial Enterobacteriaceae bacteremia treated with in vitro active antibiotic therapy in the range of 6–15 days between 2008 and 2014. 1:1 nearest neighbor propensity score matching without replacement was performed, prior to regression analysis, to estimate the risk of all-cause mortality within 30 days after the end of antibiotic treatment for patients receiving short vs. prolonged durations of antibiotic therapy. Secondary outcomes included Clostridium difficile infection (CDI) and the emergence of multidrug-resistant Gram-negative (MDRGN) bacteria within 30 days after the end of antibiotic therapy.

Results
A total of 1,769 patients met eligibility criteria. There were 385 matched pairs who were well-balanced on baseline characteristics. The median duration of therapy in the short-course group and prolonged-course group was 8 days (interquartile range (IQR) 7–9 days) and 15 days (IQR 13–15 days), respectively. No difference in all-cause mortality between short- and prolonged-course treatment groups was observed (adjusted hazard ratio [aHR] 1.00; 95% CI 0.62–1.63). Rates of CDI were similar between the treatment groups (OR 1.17; 95% CI 0.39–3.51). There was a non-significant protective effect of short-course antibiotic therapy on the emergence of MDRGN bacteria (OR 0.59; 95% CI 0.32–1.09 P = 0.09).

Conclusion
Short courses of antibiotic therapy yields similar clinical outcomes to prolonged courses of antibiotic therapy for Enterobacteriaceae bacteremia, and may protect against subsequent MDRGN emergence.

Disclosures
All authors: No reported disclosures.
Rapid Phenotypic Antibiotic Susceptibility Testing Through RNA Detection
Authors: Bhattacharyya Roby , Liu Jamin , Ma Peijun , Bandyopadhyay Nirmalya , Livny Jonathan , Hung Deborah 
Published: October 2017

Abstract

Background
Culture-based antibiotic susceptibility testing, the gold standard, is too slow to guide early antibiotic selection, while newer genotypic methods require comprehensive knowledge of resistance mechanisms to predict phenotype. Quantitative measurement of key antibiotic-responsive transcripts offers a rapid, phenotypic assay for assessing antibiotic susceptibility, agnostic to the genetic basis for resistance.

Methods
We performed RNA-Seq on Klebsiella pneumoniae and Acinetobacter baumanii treated with ciprofloxacin, gentamicin, or meropenem for 0, 10, 30, and 60 minutes. For each, we identified 50 responsive transcripts whose expression levels differ most between susceptible and resistant organisms upon antibiotic exposure. We measured their expression using a multiplexed fluorescent RNA hybridization assay (NanoString) in 69 clinical isolates, including a “test set” of multidrug-resistant strains from the CDC, in an 8-hour assay. Gene expression data from test strains were compared against known susceptible and resistant isolates to generate a transcriptional susceptibility metric. We also designed NanoString probes to detect 5 carbapenemase genes (KPC-2, KPC-3, NDM-1, OXA-48, and CTX-M15).

Results
Across all bacteria-antibiotic pairs tested, a susceptibility metric derived from these transcriptional assays correctly grouped isolates in 167 of 173 tests (Table 1), with only 1 of 88 resistant isolates misclassified as susceptible. Five of six incorrectly grouped isolates were within one dilution of the breakpoint MIC, including the misclassified resistant isolate.

Conclusion
We demonstrate phenotypic antibiotic resistance detection based on fluorescent RNA detection in an 8-hour assay. We have previously published proof-of-concept studies that this assay may be run on a positive blood culture bottle with minimal sample processing. By coupling this phenotypic assay with detection of genetic resistance determinants (demonstrated for carbapenemases) in a single assay, strains with unexplained resistance can be prioritized for further study.

Disclosures
All authors: No reported disclosures.
Defining Aerosol Generating Procedures and Pathogen Transmission Risks in Healthcare Settings
Authors: Li Jiayu , Leavey Anna , Yang Wang , O’Neil Caroline , Wallace Meghan , Boon Adrianus , Biswas Pratim , Burnham Carey-Ann D , Babcock Hilary M 
Published: October 2017

Abstract

Background
Questions remain about the degree to which small particle aerosols are generated during patient care activities and whether such aerosols could transmit viable pathogens to healthcare personnel. This project measured aerosol production during common medical procedures and collected samples for pathogen recovery.

Methods
Six procedures were targeted for aerosol sampling: extubation, bronchoscopy, mechanical ventilation, noninvasive ventilation, suctioning (open or tracheostomy), and nebulized medication administration. Any patient undergoing one of these procedures was eligible for sampling, with a preference for patients with a respiratory viral infection. Baseline samples were collected when possible. Four real-time aerosol characterization instruments were used to detect small particle aerosols generated during procedures. SKC Biosamplers, placed at 3 feet and 6 feet from the patient, were used for pathogen recovery. All samples were subjected to bacterial culture; viral PCR, and viral culture were added depending on the patient’s respiratory disease profile.

Results
Samples were collected during extubation (n = 1), bronchoscopy (n = 3), mechanical ventilation (n = 13), noninvasive ventilation (n = 6), suctioning (n = 6), and nebulized medication administration (n = 9). Only nebulized medication administration exhibited differences in particle mass concentration between baseline and procedure aerosol measurements. None of the Biosampler samples were PCR positive for a respiratory virus and none had a positive influenza culture. Five samples had positive bacterial cultures, mainly with common environmental or skin contaminants such as Micrococcus luteus, Staphylococcus pasturei, and Bacillus flexus.

Conclusion
Significant small particle aerosol generation was only seen with nebulized medication administration. No viruses were recovered and minimal viable bacteria were recovered. Additional study is needed to confirm these findings and examine aerosol generation during other procedures commonly considered to be aerosol-generating.

Disclosures
C. A. D. Burnham, bioMerieux: Grant Investigator, Research grant; ThermoFisher: Consultant, Salary; Cepheid: Grant Investigator, Research grant
Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1
Authors: Emu Brinda , Fessel W Jeffery , Schrader Shannon , Kumar Princy N , Richmond Gary , Win Sandra , Weinheimer Steven , Marsolais Christian , Lewis Stanley 
Published: October 2017

Abstract

Background
Management of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment.

Methods
TMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks.

Results
A total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL &lt;50 copies/ml and 17 (63%) patients had VL &lt; 200 copies/ml. All 15 patients with VL &lt; 50 copies/ml at Week 24 maintained viral suppression to Week 48.

Conclusion
IBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients.

Disclosures
B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner
Association Between Patient Portal Access and Viral Suppression Among People Living with HIV in a Large Southeastern Clinical Cohort
Authors: Scott Sarah , Jenkins Cathy , Rebeiro Peter , Turner Megan , Bebawy Sally , Bofill Carmen , Yan Zhou (Ellen) , Jackson Gretchen , Pettit April 
Published: October 2017

Abstract

Background
Viral suppression (VS) among people living with HIV (PLWH), the goal of the HIV care continuum, leads to improved patient outcomes and decreased HIV transmission. Patient portals are online tools that enable patient interaction with healthcare systems and may increase patient engagement and improve health outcomes. We examined whether portal access was associated with VS among PLWH.

Methods
We conducted an observational cohort study among PLWH aged ≥18 years who had ≥1 HIV healthcare provider visit at the Vanderbilt Comprehensive Care Clinic (Nashville, Tennessee) from January 1, 2011–December 31, 2015. Patient portal access was defined as being registered for a portal account at any point in the year prior. VS was defined as having ≥1 viral load (VL) measured and the last VL ≤200 copies/ml within a given year. The adjusted relative risk (aRR) of VS was estimated with modified Poisson regression and robust standard errors for multiple outcomes per individual. Models were adjusted for all covariates in the Figure and for year since first kept appointment. Missing data were multiply imputed.

Results
The study population included 4,237 PLWH; median age was 43 years (IQR 33–50), 78% were male, 41% were black, and 60% reported male–male sexual contact (MSM). Of the 57% who had portal access during the study period, median age was 42 years (IQR 31–49), 86% were male, 30% were black, and 75% were MSM. In adjusted analysis, portal access was independently associated with improved VS (aRR = 1.19, 95% CI 1.16–1.21 vs. no portal access) (Figure). Increasing age and sexual contact (vs. injection drug use) remained associated with improved VS; black race (vs. white race), lower socioeconomic status, and higher baseline VL remained associated with poor VS after accounting for portal access (Figure).

Conclusion
Portal access was independently associated with improved VS, although sociodemographic disparities in VS persisted. Additionally, there were sociodemographic disparities in patient portal access. There may be important unmeasured confounders such as health literacy and educational attainment. Additional prospective studies are needed to determine whether patient portal access leads to improved VS among PLWH.

Disclosures
P. Rebeiro, NIH: Grant Investigator, Research grant; G. Jackson, Vanderbilt Center for Effective Health Communication: Grant Investigator, Research grant; Agency for Healthcare Research and Quality: Grant Investigator, Research grant; American Medical Informatics Association: Board Member, Research support; A. Pettit, NIH/NIAID - K08AI104352: Grant Investigator, Research grant