bluuebunny/crossref_metadata_2025_split huggingface dataset:
811. A Randomized Controlled Trial of Prednisolone vs. Interleukin 17 A Inhibitor Secuinumab in the Management of Type 1 Lepra Reaction in Leprosy Patients
Authors: Mitra Debdeep 
Published: November 2018

Abstract

Background
Leprosy is a chronic granulomatous infectious disease caused by Mycobacterium leprae. Type 1 lepra reactions (T1R) are delayed hypersensitivity (Type IV) reactions which if not treated promptly leads to disability affecting eyes, hands and feet. IL-17 A which is produced mainly by inflammatory T helper 17 cells is up regulated in patients of Lepra reaction. Conventionally oral corticosteroids steroids have been the main stay in the management of Type 1 lepra reactions. This novel biologic drug is a targeted therapy which blocks the offending interleukin molecule without any serious adverse effects. We report the results of this randomized control study wherein an immuno-modulator biologic molecule has been safely used to treat an inflammatory reaction in a chronic infectious disease. Outcomes were measured using recurrence rate, a clinical severity score, quality of life, and adverse events.

Methods
Seventy-four patients with new T1R were randomized to receive Secukinumab (a human IgG1κ monoclonal antibody that binds to the protein interleukin (IL)-17A) or Prednisolone for 20 weeks. IL-17 A levels were correlated before and after the intervention.

Results
Recovery rates in skin signs was similar in both groups (92% vs. 87%). Improvements in nerve function both, new and old, sensory (67% vs. 48%) and motor (73% vs. 76%) loss were higher (but not significantly so) in the patients on Secukinumab. Recurrences rates of lepra reaction (25%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients on Secukinumab, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were much lesser with Secukinumab as compared with Prednisolone alone. Both groups had a significant improvement in their quality of life after the study, measured by the Short form survey SF-36.

Conclusion
This is the first double-blind randomized control trial assessing Secukinumab, in the management of lepra reaction. It could be a safe alternative second-line drug for patients with leprosy reactions who are not improving with prednisolone or are experiencing adverse events related to prednisolone. IL-17A levels could be an important diagnostic marker to diagnose and prognosticate cases of Type 1 Lepra reaction, which if not treated in time can lead to irreversible nerve damage.

Disclosures
All authors: No reported disclosures.
994. AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Peripheral Blood Mononuclear Cells
Authors: Howard Leigh , Goll Johannes , Jensen Travis , Hill Heather , Gelber Casey , Creech C Buddy , Edwards Kathryn 
Published: November 2018

Abstract

Background
Influenza A/H5N1 vaccines have been poorly immunogenic. Addition of Adjuvant System 03 (AS03) markedly enhances immune responses, but the mechanisms of this enhancement are unclear.

Methods
We compared gene expression in peripheral blood mononuclear cells (PBMCs) between recipients of AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 vaccine on days 1, 3, 7, and 28 postvaccination. We used a systems vaccinology approach to assess functional classifications of differentially expressed (DE) genes between the two vaccine groups, identify DE genes that correlate with serologic responses, and compare these findings with previous cell-specific assessments.

Results
AS03-adjuvanted vaccine induced the strongest differential gene expression signals on day 1 after vaccination (Figure 1). Multiple innate immune signaling pathways were activated, including the interferon, JAK-STAT, and TNF pathways, and FC gamma receptor (Fc_R) mediated phagocytosis. Immune pathways specific for antigen processing and presentation and influenza A responses were also enriched. Early differential expression of several signal transduction (day 1) and immunoglobulin (day 7) genes were predictive of peak HAI titer (Figure 2). Compared with cell-specific responses, DE gene, and immunologic pathways of PBMCs were most similar to innate immune cell subsets. However, several pathways were unique to PBMCs, and several cell-type-specific pathways, particularly from neutrophils, were absent in PBMCs (Figure 3).

Conclusion
Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early differential regulation of multiple innate immune signaling pathways and enrichment of pathways involved in antigen presentation and influenza immune responses. Early expression of several genes was associated with peak HAI responses, suggesting a potential role for application of these signatures in earlier determination of vaccine responses. While PBMC and immune cell-specific results shared key innate immune signals, unique signals were identified by either approach.

Disclosures
L. Howard, Pfizer: Grant Investigator, Grant recipient. C. B. Creech, Pfizer: Grant Investigator, Research grant. Novartis: Grant Investigator, Research grant. K. Edwards, Novartis: Grant Investigator, Research grant. Novartis: Scientific Advisor, Consulting fee.
999. Ongoing Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjuguate Vaccines
Authors: Asner Sandra 
Published: November 2018

Abstract

Background
Recent population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on the burden of pneumococcal sepsis in children are lacking. We aimed to define the burden of pneumococcal sepsis in children and assess predictors for severe outcomes following the introduction of PCV-13 in 2011 in a nationwide cohort study.

Methods
The Swiss Paediatric Sepsis Study prospectively recruited children &lt;17 years of age with blood culture-proven sepsis between September 2011 and December 2015 in Switzerland. We report on patients with Streptococcus pneumoniae sepsis stratified by the presence of meningitis vs. any other clinical focus. Admission to the paediatric intensive care unit (PICU) and length ofhospital stay (LOS) were defined as outcomes.

Results
From all 1,181 sepsis episodes recorded during the 4.3-year period, children with pneumococcal sepsis (n = 117) accounted for 10% of all sepsis episodes, and 25% of community-acquired sepsis episodes. Forty-two (36%) patients required PICU admission resulting in a mortality of 8%. Children presenting with meningitis (29; 25%) were more frequently admitted to PICU (69% vs. 25%; P &lt; 0.001) and more likely infected by serotypes not included in vaccines (69% vs. 31%; P &lt; 0.001) than those without meningitis. Pneumococcal serotypes 3, 19A, and 7F accounted for 49 (44%) pneumococcal sepsis episodes. From 62 children completely immunised with PCV, of whom 32 were infected with vaccine serotypes, 16 (50%) presented with vaccine failure, of whom 11 were infected with serotype 3. In multivariable analyses, children with meningitis (OR 6.8; 95% C.I 2.4–19.3; P &lt; 0.001) and those infected with serotype 3 (OR 2.8; 95% C.I 1.1- 7.3; P = 0.04) were more likely admitted to PICU, and those infected with serotype 3 had a longer hospital stay (β-coefficient 0.2, 95% CI 0.1–1.1; P = 0.01).

Conclusion
The burden of pneumococcal sepsis in swiss children shortly after the introduction of PCV-13 remains important. Meningitis and serotype 3 were significant predictors of severity.

Disclosures
All authors: No reported disclosures.
1000. Antimicrobial Susceptibility of Gram-Positive Bacteria Isolated From Patients Hospitalized With Bacteremia in United States and European Medical Centers: Results From the International Dalbavancin Evaluation of Activity (IDEA) Program
Authors: Sader Helio S , Flamm Robert K , Rappo Urania , Debabov Dmitri , Castanheira Mariana , Mendes Rodrigo E 
Published: November 2018

Abstract

Background
Gram-positive bacteria (GP), mainly S. aureus (SA), coagulase-negative staphylococci (CoNS), and Enterococcus spp., represent major causes of bacteremia in hospitalized patients. We evaluated the activity of dalbavancin (DALBA) and comparator agents against contemporary GP from patients with bacteremia.

Methods
A total of 8,296 GP unique isolates were consecutively collected from 33 United States (n = 4,409) and 39 European (EUR; n = 3,887) medical centers in 2015–2017 and susceptibility tested by reference broth microdilution methods.

Results
The most common organisms were SA (48.3% in United States, 44.3% in EUR), CoNS (14.3% in United States, 15.6% in EUR), and E. faecalis (EF; 11.5% in United States, 13.1% in EUR). All SA isolates were susceptible (S) to DALBA (MIC50/90, 0.03/0.03 mg/L), linezolid (LZD; MIC50/90, 1/2 mg/L), vancomycin (VAN; MIC50/90, 1/1 mg/L), and teicoplanin (TEI; MIC50/90, ≤0.5/≤0.5 mg/L); &gt;99.9% were S to daptomycin (DAPTO; MIC50/90, 0.25/0.5 mg/L). Based on MIC50, DALBA was 8-fold more active than DAPTO and 32-fold more active than VAN against SA, and DALBA activity was not adversely affected by oxacillin (OXA) resistance (R). Among CoNS, 99.9% of isolates were inhibited at a DALBA MIC of ≤0.25 mg/L (MIC50/90, 0.03/0.06 mg/L); S to DAPTO (MIC50/90, 0.5/0.5 mg/L), LZD (MIC50/90, 0.5/1 mg/L), VAN (MIC50/90, 1/2 mg/L), and TEI (MIC50/90, 2/4 mg/L) were 99.9%, 97.6%, 100.0%, and 98.5%, respectively. Among EF, 97.7% were DALBA-S (96.4% in USA, 99.0% in EUR; MIC50/90, 0.03/0.06 mg/L), 97.5% were VAN-S (96.1% in United States, 99.0% in EUR; MIC50/90, 1/2 mg/L), and all isolates were S to ampicillin (MIC50/90, 1/1 mg/L), DAPTO (MIC50/90, 0.5/1 mg/L) and LZD (MIC50/90,1/2 mg/L). Among E. faecium isolates (n = 656; 7.9% overall), 63.9% were inhibited at ≤0.25 mg/L of DALBA (33.4% in United States, 87.5% in EUR) and 61.6% were VAN-S (32.8% in United States, 84.0% in EUR). DALBA was highly active against β-hemolytic streptococci (BHS; n = 686 [8.3%]; MIC50/90, 0.015/0.03 mg/L) and viridans group streptococci (VGS; n = 432 [5.2%]; MIC50/90, 0.015/0.03 mg/L).

Conclusion
DALBA was very active against SA, CoNS, VAN-S enterococci, BHS, and VGS isolated from patients with bacteremia. Based on MIC50, DALBA was generally 8- to 32-fold more active than DAPTO and VAN against these organisms.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research support. R. K. Flamm, Allergan: Research Contractor, Research support. U. Rappo, Allergan: Employee, Salary. D. Debabov, Allergan: Employee, Salary. M. Castanheira, Allergan: Research Contractor, Research support. R. E. Mendes, Allergan: Research Contractor, Research support.
1001. Evaluation of the Clinical Efficacy and Safety of Oral Antibiotic Therapy for Streptococcus spp. Bloodstream Infections
Authors: Kang Amy , Bor Cynthia , Chen Jamie , Gandawidjaja Michelle , Minejima Emi 
Published: November 2018

Abstract

Background
Despite the severity and frequency of bloodstream infections (BSI), the effectiveness of oral definitive therapy remains unknown. The objective of this study was to evaluate the efficacy and safety of step down oral antibiotics for the treatment of Streptococcus spp. BSI.

Methods
This was a retrospective cohort study of adult, hospitalized patients with Streptococcus spp. BSI between June 2015 and June 2017. Patients were excluded if received &lt;48 hours of antibiotic therapy or therapy was started &gt;48 hours from first positive culture. Patients were grouped by receipt of step down oral antibiotic therapy (PO group) vs. full course IV therapy (IV group) and compared for demographics, clinical course, and outcomes. The primary outcome was 30-day mortality and hospital length of stay (LOS). The secondary outcomes included 30-day recurrence of BSI and adverse events (AEs).

Results
One hundred ninety-five patients met inclusion criteria; median age was 51 year old, 68% were male, 57% were Hispanic, and 71% had community-onset BSI. Sixty-four (33%) were treated with step down oral therapy. The most common source of bacteremia was pneumonia (21%); 8% had endocarditis. Comorbidities were similar between the groups, with diabetes being most common (IV 22% vs. PO 19%, P = 0.29). Severity of illness measured by need for ICU admission, initial lactate level, and SOFA score was similar between the two groups. S. viridans was the most frequent pathogen isolated (IV 28% vs. PO 27%, P = 0.87). Ceftriaxone (39%) for the IV group and levofloxacin (30%) for the PO group were the most common definitive therapy prescribed. PO group received 4 days of IV therapy prior to transition to orals. The IV group had significantly higher mortality rate (11% vs. 2%, P = 0.02) and longer LOS (median 9 days [IQR 5–18] vs. 5 days [4–7.75], P ≤ 0.01) compared with the PO group. 30-day recurrence (IV 2% vs. PO 5%, P = 0.40) and AEs (IV 2% vs. PO 3%, P = 0.60) were similar between the two groups.

Conclusion
In Streptococcus spp. BSI, step down oral antibiotic therapy was associated with a significantly shorter LOS compared with IV only therapy without compromise of clinical outcomes. Larger prospective trials evaluating step down oral therapy are warranted to confirm our results.

Disclosures
All authors: No reported disclosures.
1003. Clinical Implications of Emerging Nonvaccine-Serotype Invasive Pneumococcal Disease Among Adults in the Republic of Korea in the Era of Protein-Conjugated Pneumococcal Vaccine
Authors: Kim Jong Hun , Baik Seung Hee , Song Joon Young , Bae In-Gyu , Kim Hyo Youl , Kim Dong-Min , Choi Young Hwa , Choi Won Suk , Jeong Y H , Kwon Hyun Hee , Jeong Hye Won , Kim Yeon-Sook , Kim Jeong Yeon , Lee Jacob , Kee Sae Yoon , Chung Jin-Won , Nahm Moon H , Kim Min-Ja 
Published: November 2018

Abstract

Background
In the Republic of Korea (ROK), protein conjugated vaccines (PCV13 and PCV10) in replacement of PCV7 have been used in children since 2010, and then included in the childhood national immunization program (NIP) in 2014. This study investigated indirect effect of PVCs on serotypes in PCV-naïve adult invasive pneumococcal disease (IPD) and its clinical implications.

Methods
A prospective observational cohort study was conducted, through the serotype surveillance program following the NIP implementation of 23-valent pneumococcal polysaccharide vaccine (PPV23) for elderly population (≥65 years) from 2013 to 2015. Clinical data and pneumococcal isolates from adult IPD patients (≥18 years) were collected from 20 hospitals. Clinical characteristics were compared between vaccine-serotype (VT) and nonvaccine-serotype (NVT) groups.

Results
Of a total of 319 IPD patients enrolled, 189 cases (59.2%) were available for serotypes. Among them, the proportion of PCV-naïve cases was 99.5% (188/189) and 189 patients consisted of NVT (n = 64, 33.9%) and VT group (n = 125, 66.1%). Compared with the previous study in the ROK (2004–2010), the proportion of PCV13 serotypes was decreased (61.4% vs. 37.0%, P &lt; 0.001) and PPV23 serotypes were stationary (71.5% vs. 65.6%), but NVT serotypes were increased (23.4% vs. 33.9%, P = 0.033) in our study. The most common serotype was 3 (20.8%) and 34 (23.4%) in VT and NVT group, respectively. VT group had more bacteremic pneumonia (72.0% vs. 48.4%, P = 0.002). There was no difference of the case fatality rate between NVT and VT groups (29.7% vs. 35.2%, P = 0.447). Multiple logistic regression analysis showed that chronic kidney disease (odds ratio [OR] 10.26, 95% confidence interval [CI] 1.94–54.44, P = 0.006), younger age of 18–49 years (OR 4.04, 95% CI 1.29–12.71, P = 0.017), deep-seated infection (OR 3.73, 95% CI 1.34–10.39, P = 0.012), meropenem resistance (OR 3.21, 95% CI 1.49–6.91, P = 0.003) were significantly associated with NVT-IPD cases.

Conclusion
Our study indicates that emerging and expanding NVT-IPD among adults, probably due to indirect herd effect of widespread use of pediatric PCV. Further changes of IPD serotypes might occur and IPD serotypes should be monitored for developing better pneumococcal vaccination policy.

Disclosures
All authors: No reported disclosures.
1004. Frequency of Occurrence and Antimicrobial Susceptibility of Bacteria Isolated From Patients Hospitalized With Bloodstream Infections in United States Medical Centers (2015–2017)
Authors: Sader Helio S , Flamm Robert K , Pfaller Michael A , Castanheira Mariana 
Published: November 2018

Abstract

Background
Bloodstream infections (BSIs) cause significant morbidity and mortality. We evaluated the frequency and antimicrobial susceptibility of bacteria causing BSIs in the United States.

Methods
A total of 9,210 bacterial isolates were consecutively collected (1/patient) from 33 US medical centers in 2015–2017 and tested for susceptibility by reference broth microdilution methods in a central laboratory (JMI Laboratories) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Whole-genome sequencing was performed on carbapenem-resistant Enterobacteriaceae (CRE).

Results
The most common organisms were S. aureus (SA; 24.3%), E. coli (EC; 20.8%), K. pneumoniae (KPN; 9.1%), coagulase-negative staphylococci (7.3%), E. faecalis (5.5%), P. aeruginosa (PSA; 4.7%), and β-hemolytic streptococci (4.7%). Overall, 50.0% of isolates were Gram-negative bacilli (GNB) and 41.4% were Enterobacteriaceae (ENT). All SA were susceptible (S) to dalbavancin (MIC90, 0.03 μg/mL), linezolid, tigecycline (TGC), and vancomycin; &gt;99.9% S to daptomycin, 97.6% S to ceftaroline, and 57.8% S to oxacillin. The most active agents against ENT were CAZ-AVI (99.9% S; table), amikacin (AMK; 99.7% S), and the carbapenems meropenem (MEM) and doripenem (99.1% S). Ceftolozane-tazobactam (C-T; tested in 2017 only) was active against 96.9% of ENT. Ceftriaxone (CRO)-S rates were 83.0% and 86.5% among EC and KPN, respectively. CRO-non-S KPN exhibited low S rates to most agents, except CAZ-AVI (99.1% S), TGC (93.6%), AMK (93.8%), and colistin (COL; 93.4%). Among 28 CRE isolates (0.7% of ENT), 21 produced a KPC-like, 2 an NMD-like, and 1 a KPC-17 and an NDM-1. COL (100.0% S), C-T (98.7%S), CAZ-AVI (98.2% S), AMK (97.9% S), and tobramycin (95.6% S) were very active against PSA. CAZ-AVI and C-T remained active against most PSA isolates non-S to MEM (93.0 and 95.0% S, respectively) and/or piperacillin–tazobactam (P-T; 88.9 and 91.3% S) and/or CAZ (86.9 and 88.2% S).

Conclusion
GNB represented 50.0% of bacteria isolated from patients with BSIs and the most active agents against these organisms were CAZ-AVI and AMK. Various agents exhibited excellent overall coverage against Gram-positives, including dalbavancin, daptomycin, linezolid, and TGC.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research support. R. K. Flamm, Allergan: Research Contractor, Research support. M. A. Pfaller, Allergan: Research Contractor, Research support. M. Castanheira, Allergan: Research Contractor, Research support.
1043. Evaluation of Early Clinical Failure Criteria for Gram-Negative Bloodstream Infections
Authors: Rac Hana , Gould Alyssa , Bookstaver P Brandon , Justo Julie Ann , Kohn Joseph , Al-Hasan Majdi N 
Published: November 2018

Abstract

Background
Early identification of patients at high risk of morbidity and mortality following Gram-negative bloodstream infections (GN-BSI) based on initial clinical course may prompt adjustments to optimize diagnostic and treatment plans. This retrospective cohort study aims to develop early clinical failure criteria (ECFC) to predict unfavorable outcomes in patients with GN-BSI.

Methods
Adults with community-onset GN-BSI who survived hospitalization for at least 96 hours at Palmetto Health hospitals in Columbia, SC, USA from January 1, 2010 to June 30, 2015 were identified. Multivariate logistic regression was used to examine association between clinical variables within 72–96 hours of BSI and unfavorable outcomes (28-day mortality or hospital length of stay &gt;14 days).

Results
Among 766 patients with GN-BSI, 225 (29%) had unfavorable outcomes. After adjustments for Charlson Comorbidity Index and appropriateness of empirical antimicrobial therapy in multivariate model, predictors of unfavorable outcomes included systolic blood pressure &lt;100 mmHg or vasopressor use (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.1–2.5), heart rate &gt;100/minute (aOR 1.7, 95% CI 1.1–2.5), respiratory rate ≥22/minute or mechanical ventilation (aOR 2.1, 95% CI 1.4–3.3), altered mental status (aOR 4.5, 95% CI 2.8–7.1), and peripheral WBC count &gt;12 × 103/mm3 (aOR 2.7, 95% CI 1.8–4.1) at 72–96 hours from index BSI. Area under receiver operating characteristic curve of ECFC model in predicting unfavorable outcomes was 0.77 (0.84 and 0.71 in predicting 28-day mortality and prolonged hospitalization separately, respectively). Predicted 28-day mortality increased from 1% in patients with no ECFC to 3%, 7%, 16%, 32%, and 54% in presence of each additional criterion (P &lt; 0.001). Predicted hospital length of stay was 7.5 days in patients without any ECFC and increased by 4.0 days (95% CI 3.1–4.9, P &lt; 0.001) in presence of each additional criterion.

Conclusion
Risk of 28-day mortality or prolonged hospitalization can be estimated within 72–96 hours of GN-BSI using ECFC. These criteria may have utility in future clinical research in assessing response to antimicrobial therapy based on a standard evidence-based definition of early clinical failure.

Disclosures
P. B. Bookstaver, CutisPharma: Scientific Advisor, &lt;$1,000. Melinta Therapeutics: Speaker’s Bureau, &lt;$1,000.