bluuebunny/crossref_metadata_2025_split huggingface dataset:
886. Pregnancy Outcomes Following Raltegravir Exposure
Authors: Shamsuddin Hala , Raudenbush Casey , Sciba Brittany , Gooch Erica N , Greaves Wayne , Leong Ronald W , Straus Walter 
Published: October 2019

Abstract

Background
Safety data are needed regarding HIV treatment in women of reproductive potential and during pregnancy. This review is to evaluate pregnancy outcomes following prospective exposures (exposure report prior to knowledge of pregnancy outcome) to raltegravir during pregnancy.

Methods
Exposures to raltegravir during pregnancy reported cumulatively through March 26, 2019 to the internal safety database at Merck & Co., Inc. were reviewed. This database includes all reports of pregnancy from clinical trials sponsored by the company, spontaneous post-marketing reports, and noninterventional data sources. Prospective pregnancy reports were evaluated to determine rates of spontaneous abortion, stillbirth, and congenital anomalies, including neural tube defects. Data from two ongoing cohorts of pregnant women with HIV-1 infection, not included in the internal safety database, were also reviewed.

Results
A total of 2,508 prospective pregnancy reports with reported outcomes were identified among women exposed to raltegravir: 919 from the internal safety database (Table 1) and 1,589 from the UK/Ireland and French pregnancy cohorts. Among the 2,508 prospective pregnancy exposures, 945 were in the first trimester, of which 757 were within the periconception period (within 28 days of conception). Of the 471 documented first trimester exposures identified in the internal safety database, the rates of spontaneous abortion (6.9%), stillbirth (1%), and congenital anomalies (1.5% per live births) were similar to the rates observed in the background populations of the United States Among outcomes following any exposure, the rate of congenital anomalies was 3.4% per live births. There were no reports of neural tube defects identified within the internal safety database or among the cohort data.

Conclusion
Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure and spontaneous abortion, stillbirth, or congenital anomalies, including neural tube defects. These data support the current HIV treatment recommendations for the use of raltegravir 400 mg twice daily in women of reproductive potential and during pregnancy.

Disclosures
All Authors: No reported Disclosures.
901. MEDI8897 Prevents Serious RSV Disease in Healthy Preterm Infants
Authors: Pamela Griffin Mary , Yuan Yuan , Takas Therese , DeVincenzo John , Domachowske Joseph B , Simoes Eric A , Khan Anis , Esser Mark T , Dubovsky Filip , Villafana Tonya L 
Published: October 2019

Abstract

Background
RSV is the principal cause of lower respiratory tract infection (LRTI) among infants, and a significant unmet need exists for RSV prevention in healthy infants. We have developed a highly potent, extended half-life monoclonal antibody (mAb), to protect infants for an entire RSV season using a single IM dose. Here we report the efficacy, safety, pharmacokinetics, and anti-drug antibody (ADA) responses for MEDI8897 in palivizumab-ineligible preterm infants born between 29 and 35 weeks gestation.

Methods
A total of 1,453 Infants were randomized 2:1 to receive a single 50 mg IM injection of MEDI8897 (n = 969) or placebo (n = 484) and followed for 360 days. Enrollment occurred just prior to the 2016 and 2017 RSV seasons in 23 northern and southern hemisphere countries. Blood was collected periodically. Infants with a medically attended (MA) LRTI (outpatient or inpatient) had nasal swabs obtained for central RSV testing by RT-PCR. Predefined clinical criteria were used for the case definition.

Results
A total of 1,417 (97.5%) subjects completed the 150-day efficacy follow-up period and 1,367 (94.1%) completed the study. In the MEDI8897 group, a 70.1% (95% CI: 52.3%, 81.2%; P < 0.0001) reduction in the incidence of medically attended RSV LRTI and a 78.4% (95% CI: 51.9%, 90.3%; P = 0.0002) reduction in the incidence of RSV LRTI hospitalization was achieved. These efficacy results were consistent when analyzed by hemisphere, RSV subtype, and subject demographics. Similar proportions of adverse events (86.8% placebo; 86.2% MEDI8897) and serious adverse events (16.9% placebo; 11.2% MEDI8897) were reported in study subjects. There were no significant hypersensitivity reactions with similar proportions reported for both groups (0.6% placebo; 0.5% MEDI8897). The incidence of ADA detected any time post baseline was low (3.8% placebo; 5.6% MEDI8897) with no impact on PK or safety. The occurrence of non-RSV LRTIs was similar for both groups indicating no replacement by other pathogens.

Conclusion
In this large randomized study of RSV prophylaxis in healthy preterm infants, MEDI8897 immunoprophylaxis provided a significant reduction in RSV MA-LRTI and hospitalization. These results have promising implications for the future of RSV prophylaxis for all infants.
This study was funded by AstraZeneca and sanofi pasteur.

Disclosures
All Authors: No reported Disclosures.
975. Roles of Type I and III Interferon in Severe Pathogenesis of Human Metapneumovirus
Authors: Williams John V , Zhang Yu , Xu Jiuyang , Miranda-Katz Margot , Rich Helen , Manni Michelle , Tollefson Sharon , Sarkar Saumendra , Alcorn John 
Published: October 2019

Abstract

Background
Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood.

Methods
We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry.

Results
HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4).

Conclusion
These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target.

Disclosures
All Authors: No reported Disclosures.
1836. Genomic Epidemiology of Methicillin-Susceptible Staphylococcus aureus Colonization and Infection among US Army Trainees at Fort Benning, Georgia
Authors: Millar Eugene V , McGann Patrick , Ellis Michael , Tribble David , Jones Anthony , Bennett Jason 
Published: October 2019

Abstract

Background
Methicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of skin and soft-tissue infection (SSTI). MSSA genomic epidemiology data are limited. We used whole-genome sequencing (WGS) to examine MSSA strain diversity among military trainees, a group known to be at high risk for S. aureus infection and carriage.

Methods
From July 2012 to December 2014, we conducted a prospective SSTI case–control study among US Army trainees at Fort Benning, GA. Thereafter, we identified MSSA SSTI clusters within select military training classes and performed WGS on clinical and colonizing isolates. We analyzed epidemiologic, clinical, genomic, and phylogenetic data in order to evaluate MSSA strain diversity and patterns of disease transmission.

Results
A total of 67 SSTI cases from 15 training classes were identified. The median (range) number of cases per class was 4 (3–10). Cases presented for care after a median of 39 (6–101) days of training. Of the 67 cases, 42 (63%) were colonized with MSSA at ≥1 anatomic site. A total of 78 MSSA colonizing isolates were identified at the time trainees presented for clinical care; colonizing isolates were found in the nares (37%), throat (31%), inguinal region (21%), and perianal region (12%). Multilocus sequence typing (MLST) assigned 128 (88%) isolates to 20 known types and 17 isolates to novel types. Among clinical isolates, 60 (90%) were assigned to known types. Sequence Type (ST) 8 was the most frequent type, accounting for 45% and 35% of clinical and colonizing isolates, respectively. The phylogenetic tree of isolates revealed seven major clusters, some of which were composed of a diversity of training classes, specimen types, and STs. These major clusters were further segregated into 15 sub-clusters where there was considerable diversity in intrahost variation.

Conclusion
Genomic characterization of MSSA infection and colonization isolates among congregate military trainees revealed a broad diversity of strains. There was a clear clonal origin and dissemination of MSSA isolates among close contacts within the ST-8 cluster but this transmission pattern was less apparent for MSSAs from other STs.

Disclosures
All Authors: No reported Disclosures.
1878. Title: Impact of Antibiotic Stewardship Rounds in the Intensive Care Setting: A Prospective Cluster-Randomized Crossover Study
Authors: Seidelman Jessica , Turner Nicholas A , Wrenn Rebekah , Sarubbi Christina , Anderson Deverick J , Sexton Daniel J , Moehring Rebekah W 
Published: October 2019

Abstract

Background
The impact of formalized, interdisciplinary antimicrobial stewardship program (ASP) rounds in the intensive care unit (ICU) setting has not been well described.

Methods
We performed a two-arm, cluster-randomized, crossover quality improvement study over 8 months to compare the impact of weekly ICU rounds with an ASP team vs. usual care. The primary outcome was antibiotic use (AU) in days of therapy (DOT) per 1,000 days present during and following ICU exposure. Our cohort consisted of ICU patients in 5 ICUs in Duke University Hospital. The unit of randomization was rounding team, which corresponded to half of the ICU beds in each unit. Each team was randomized to the intervention for 4 months followed by usual care for 4 months (or vice versa). The intervention involved multidisciplinary review of eligible patients to discuss antibiotic optimization. Patients not on antibiotics, followed by infectious diseases, post-transplant, on ECMO, or with a ventricular assist device were excluded from review. Intervention impact was assessed with multivariable negative binomial regression rate ratios (RR). AU was assessed over time before and after the study period to assess global and unit-level trends.

Results
We had 4,683 ICU-exposed patients. Intervention effect was not significant for the primary outcome (table). The intervention order was not significant in the model. Eligible patients were lower in the cardiothoracic ICU (CTICU) compared with other units (table); the intervention led to a significant decrease in AU when the CTICU was removed (RR = 0.93 [0.89–0.98], P = 0.0025). Intervention impact was differential among ICUs, with the greatest effect in surgical and least in CTICU (table). nit-level AU decreased in all ICUs, driven by 4 of the 5 ICUs (table, figure).

Conclusion
The effect of ASP rounds on AU was mixed for different types of ICUs. The direct effect on AU (intervention vs. control) was small because the analysis addressed the whole ICU population and thus was subject to biases from exposures after an ICU stay, ineligible patients, and lack of blinding. However, we observed an overall decline in AU during the study period, which we believe represents indirect effects of increased ASP activity and awareness. Additional ASP resources to round more than weekly may result in greater effect.

Disclosures
All Authors: No reported Disclosures.
1888. A Nationwide Outbreak of Invasive Pneumococcal Disease (IPD) Caused by a Novel Streptococcus Pneumoniae Serotype 2 (SP2) Clone in the PCV13 Era, in Israel
Authors: Dagan Ron , Ben-Shimol Shalom , Benisty Rachel , Regev-Yochay Gili , Ron Merav , Givon-Lavi Noga , Rokney Assaf 
Published: October 2019

Abstract

Background
IPD caused by Sp2 (non-PCV13 serotype) is relatively rare. However, Sp2 has a high potential for causing IPD including meningitis. Large-scale outbreaks of Sp2 IPD are rare and were not reported post-PCV implementation. We describe Sp2 IPD outbreak in Israel, in the PCV13 era, caused by a novel clone. Additionally, we analyzed the population structure and evolutionary dynamics of Sp2 during 2006–2018.

Methods
An ongoing, population-based, nationwide active surveillance, conducted since July 2009. PCV7/PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All isolates were tested for antimicrobial susceptibility, PFGE, MLST and whole-genome sequencing (WGS). Results. Overall, 173 Sp2 IPD cases were identified; all isolates were analyzed by MLST (Figure 1). During 2016–2017, Sp2 caused 7.6% of all-IPD, a 7-fold increase compared with 2006–2015, and ranked second (after serotype 12F causing 12%) among IPD isolates. During 2006–2015, 98% (40/41) Sp2 IPD were caused by the previously reported global ST-1504 clone. The outbreak was caused by a novel clone ST-13578, not previously reported (Figure 2). WGS analysis confirmed that ST-13578 was related, but genetically distinct from ST-1504, observed exclusively before the outbreak. A single strain of clone ST-74 previously globally reported was identified in 2017–2018. An additional case was identified in an adult in the UK, following a family visit from Israel. The ST-13578 clone was identified only in the Jewish population and was mainly distributed in 3 of the 7 Israeli districts. All tested strains were penicillin-susceptible (MIC < 0.06 μg/mL).

Conclusion
To the best of our knowledge, this is the first widespread Sp2 outbreak since PCV13 introduction worldwide, caused by a novel clone ST-13578. The outbreak is still ongoing, although a declining trend was noted since 2017.

Disclosures
All Authors: No reported Disclosures.
1956. Reduction in Endotracheal Aspirate Cultures after Implementation of a Diagnostic Stewardship Intervention in a Pediatric Intensive Care Unit
Authors: Sick-Samuels Anna , Bergmann Jules , Linz Matthew , Fackler James , Berenholtz Sean , Dwyer Joe , Hoops Katherine , Colantuoni Elizabeth , Milstone Aaron 
Published: October 2019

Abstract

Background
Clinicians obtain endotracheal aspirate (ETA) cultures from mechanically ventilated patients in the pediatric intensive care unit (PICU) for the evaluation of ventilator-associated infection (i.e., tracheitis or pneumonia). Positive cultures prompt clinicians to treat with antibiotics even though ETA cultures cannot distinguish bacterial colonization from infection. We undertook a quality improvement initiative to standardize the use of endotracheal cultures in the evaluation of ventilator-associated infections among hospitalized children.

Methods
A multidisciplinary team developed a clinical decision support algorithm to guide when to obtain ETA cultures from patients admitted to the PICU and ventilated for >1 day. We disseminated the algorithm to all bedside providers in the PICU in April 2018 and compared the rate of cultures one year before and after the intervention using Poisson regression and a quasi-experimental interrupted time-series models. Charge savings were estimated based on $220 average charge for one ETA culture.

Results
In the pre-intervention period, there was an average of 46 ETA cultures per month, a total of 557 cultures over 5,092 ventilator-days; after introduction of the algorithm, there were 19 cultures obtained per month, a total of 231 cultures over 3,554 ventilator-days (incident rate 10.9 vs. 6.5 per 100 ventilator-days, Figure 1). There was a 43% decrease in the monthly rate of cultures (IRR 0.57, 95% CI 0.50–0.67, P < 0.001). The ITSA revealed a pre-existing 2% decline in the monthly culture rate (IRR 0.98, 95% CI 0.97–1.00, P = 0.01), an immediate 44% drop (IRR 0.56, 95% CI 0.45–0.69, P = 0.02) and a stable rate in the post-intervention period (IRR 1.03, 95% CI 0.99–1.07, P = 0.09). The intervention led to an estimated $6000 in monthly charge savings.

Conclusion
Introduction of a clinical decision support algorithm to standardize the obtainment of ETA cultures from ventilated children was associated with a significant decline in the rate of ETA cultures. Additional investigation will assess the impact on balancing measures and secondary outcomes including mortality, duration of ventilation, duration of admission, readmissions, and antibiotic prescribing.

Disclosures
All Authors: No reported Disclosures.
1965. PrEP On the Go! Implementation Mobile PrEP, STI, and HIV Prevention Services in South Florida
Authors: Doblecki-Lewis Susanne , Kobetz Erin , Byrne2; Stefani Butts John , Torrealba Marco , Klose Katie , McGaugh Angela , Shatz Connor , Scaramutti Carolina , Baez Leon Brian , Narcisse Gilianne , Morel Jessica , Whiteside Patrick , Cardenas Gabriel , Feaster Daniel , Stevenson Mario 
Published: October 2019

Abstract

Background
Pre-Exposure Prophylaxis (PrEP) can reduce HIV incidence when implemented effectively for people who are at highest risk of HIV infection. However, access to and uptake of PrEP remains suboptimal among priority populations such as black and Hispanic/Latino men who have sex with men (MSM). We established mobile HIV prevention/PrEP services delivered with cancer screening services through the Sylvester Gamechanger vehicle. We describe demographics, utilization, and early retention in PrEP care delivered through this model.

Methods
We selected four local HIV high-incidence areas where PrEP services were lacking, to locate the clinic. The vehicle, staffed by a medical provider, HIV/PrEP counselor, and cancer educator, returned to each site regularly. In addition to self-referrals, Prevention305, a community-based organization, developed focused patient recruitment through social media. Services were provided at no cost. Normative demographics, risk behavior, sexually transmitted infections (STIs), and early-maintenance-in-care data were collected. Descriptive statistics were compiled using SPSS.

Results
From October 2018 to April 2019 services were provided to 229 clients. Of these, 168 (73.7%) sought PrEP. Of PrEP clients, 125 (74.4%) identified as White/Hispanic, 6 (3.5%) as Black/Hispanic, 6 (3.5%) as White/non-Hispanic, 11 (6.5%) as Black/non-Hispanic, and 19 (11.3%) as other; 124 (73.8%) were foreign-born; 159 (94.9%) of PrEP clients identified as MSM. Six (3.5%) PrEP-seeking clients were HIV positive at baseline. Of these, 2 were identified as acute/early infections. An initial PrEP prescription was filled by 166 (98.8%). Of the 77 clients seen within the initial 3 months of operation and due for follow-up assessment, 55 (71.4%) completed a follow-up visit. Overall, 45 (26.6%) PrEP clients had positive STI results (gonorrhea, chlamydia, or syphilis) at baseline. Nine (16.3%) clients returned positive STI results at their follow-up visit.

Conclusion
Implementation of mobile HIV prevention services including PrEP is feasible and is effective in engaging Hispanic/Latino immigrant MSM. High demand for services is noted and plans are underway to increase capacity and outreach to other highly affected groups.

Disclosures
All Authors: No reported Disclosures.
2840. Long-term Efficacy, Safety, and Durability of CAB and RPV as Two Drug Oral Maintenance Therapy: LATTE Week 312 Results
Authors: Margolis David , Sutton Kenneth , De Vente Jerome , LeBlanc Roger , DeJesus Edwin , Smith Graham , Mills Anthony , Baril Jean-Guy , St. Clair Marty , Stancil Britt , Williams Peter , Spreen William 
Published: October 2019

Abstract

Background
Cabotegravir (CAB), an INI, is under development in both oral and long-acting (LA) injectable formulations. LATTE (NCT01641809) was designed to select a daily oral dose of CAB and evaluate a two-drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy. Results enabled the LATTE-2 (NCT02120352) study to evaluate CAB LA + RPV LA dosed once every 1 or 2 months.

Methods
Phase 2b, multicentre, partially blinded dose-ranging study in ART-naïve HIV infected adults, randomized 1:1:1:1 to the induction regimen of once-daily oral CAB 10, 30, or 60 mg or efavirenz (EFV) 600 mg with TDF/FTC or ABC/3TC through W24. CAB patients with VL <50 c/mL immediately prior to W24 discontinued NRTIs and began RPV 25 mg as a two-drug oral maintenance regimen through W96. No change was made to the EFV arm. After W96, at the start of the open-label (OL) phase, all patients randomized to CAB were given the option to continue and switch to the sponsor-selected dose of oral CAB 30 mg. EFV patients completed the study at W96. The OL phase was completed at W312 (288 weeks on CAB + RPV). Successful CAB + RPV patients transitioned to the POLAR study (NCT03639311).

Results
A total of 243 patients were randomized and initiated treatment (ITT-E). Of those randomized to CAB (n = 181), 160 patients began CAB + RPV (W24) and 138 continued into OL phase (W96). One hundred and ten patients successfully completed the study (W312). Among patients who began CAB + RPV at W24, 66% maintained <50 c/mL, 9% had HIV-1 RNA ≥ 50 c/mL, and 25% were categorized as “No Virologic Data” by Snapshot at W312 (ITT-ME). There were 11 protocol-defined virologic failures (PDVF) on CAB; only 2 occurring after W144. Six patients developed treatment emergent (TE) resistance to one or both agents during the study; of which 4 patients developed TE major INI resistance mutations, 3 after W96. The median increase in CD4+ cell count from Baseline was 393 cells/mm3 (−174 to 1118). During the maintenance and OL phases, 4% of CAB patients reported drug-related AEs ≥ Grade 2; SAEs occurred in 9% of CAB patients (none drug related); 3% of CAB patients withdrew due to AEs. 43% of CAB patients who entered maintenance phase reported TE lab abnormalities ≥ Grade 3.

Conclusion
As maintenance therapy in virologically suppressed patients, the 2DR CAB + RPV provided durable viral suppression through W312. Through 7 years of study, CAB + RPV continues to be generally safe and well tolerated.

Disclosures
All Authors: No reported Disclosures.