bluuebunny/crossref_metadata_2025_split huggingface dataset:
1396. Predictions of Isavuconazonium Sulfate Dosage in Patients Aged 6 Months: &lt;18 Years by Physiologically Based Pharmacokinetic Modeling
Authors: Desai Amit , Kovanda Laura , Lademacher Christopher , Hope William , Neely Michael , Bonate Peter , Edginton Andrea 
Published: November 2018

Abstract

Background
Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults.

Methods
Pediatric equivalent doses were predicted for patients aged 6 months and &lt;18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared with predictions by allometric scaling. All simulations were completed using PK-Sim®, which implements a whole-body PBPK model with 15 organs and appropriate maturation of anatomical and physiological parameters for children. The adult PBPK model was built using knowledge of drug physico-chemistry and clearance partitioning (CYP3A4, CYP3A5, glomerular filtration). PK data following IV (40, 80, 160 mg 60-minute infusion) and oral (100, 200, 400 mg capsule) doses in adults were used for initial model development. This model was validated by matching observed adult concentrations after multiple oral 200 mg doses. From this adult model, a virtual pediatric population (n = 4,600) from 6 months to &lt;18 years was created. Simulations with the pediatric model assessed optimal doses of isavuconazonium sulfate based on age and weight to achieve at least a median steady-state daily area under the curve (AUCss) of 100 mg hour/L, and the majority below 230 mg hour/L. These targets were derived from efficacy and safety data in clinical trials with adults.

Results
As shown in the figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients &gt;1 year old, in agreement with that predicted by allometry for patients aged 2–17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures.

Conclusion
A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 hours for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 1–17 years, similar to predictions from allometric scaling for patients aged 2–17 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm.

Disclosures
A. Desai, Astellas Pharma, Inc.: Employee, Salary. L. Kovanda, Astellas Pharma, Inc.: Employee, Salary. C. Lademacher, Astellas Pharma, Inc.: Employee, Salary. W. Hope, F2G: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Astellas: Grant Investigator and Investigator, Grant recipient and Research grant. Pfizer: Grant Investigator, Research support. Gilead: Consultant and Scientific Advisor, Consulting fee. P. Bonate, Astellas Pharma, Inc.: Employee, Salary. A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor, Consulting fee.
1583. The Utility of the Immunodeficiency Scoring Index (ISI) to Predict Outcomes of Coronavirus (HCoV) Infections in Hematopietic Cell Transplant (HCT) Recipients
Authors: Khawaja Fareed , Shigle Terri Lynn , Ghantoji Shashank S , Batista Marjorie , Ariza-Heredia Ella , Chemaly Roy F 
Published: November 2018

Abstract

Background
Respiratory viral infections in HCT recipients are associated with high morbidity and mortality, especially after progression from upper respiratory tract infection (URI) to lower respiratory tract infections (LRI). Data on risk factors (RF) for LRI and mortality is lacking for HCoV infections after HCT. We aimed to validate our ISI in HCoV infections.

Methods
All adult HCT recipients with HCoV infection from 2015 to 2017 were evaluated. An ISI based on RF was used to classify patients as low (0–2), moderate (3–6), or high (7 or higher) risk for progression to LRI or death. We defined LRI as HCoV detected in nasal wash and/or bronchoalveolar lavage and new lung infiltrates on diagnostic imaging. Clinical parameters were collected and ISI were calculated for comparison.

Results
A total of 144 adult HCT recipients with 166 episodes of HCoV infections were analyzed. The most common HCoV serotype for LRI and URI was 229E (42.4%) and OC43 (37.6%), respectively, and most patients were infected between November and March each year (Figures 1 and 2). When compared with URI, patients with LRI were more likely in the pre-engraftment period, had multiple respiratory viruses infections, had nosocomially acquired HCoV, required hospitalization, ICU transfer, and mechanical ventilation (all, P &lt; 0.05). Overall mortality rate was 4% at Day 30 from diagnosis and all patients who died had LRI with an 18% mortality. Among those who died, 33% had nosocomial infection, 67% were co-infected with another respiratory virus and 67% required mechanical ventilation. Using an ISI cut off of &lt;4, the negative predictive value (NPV) for progression to LRI was 86% with a specificity of 76%.

Conclusion
HCT recipients with HCoV LRI were more likely to have a fatal outcome. The NPV of the ISI for progression to LRI was high and could be used as a prognostic tool for future studies and for therapeutic clinical trials.

Disclosures
All authors: No reported disclosures.
662. Tick Borne-Associated Thrombocytopenia Among United States Veterans in Long Island New York
Authors: Kaplun Olga , Lemaitre Beth , Lobo Zeena , Psevdos George 
Published: November 2018

Abstract

Background
Long Island, New York, is highly endemic for tick borne illnesses (TBI) with rising numbers of cases in the past years. Thrombocytopenia is a known complication of babesiosis caused by Babesia microti, anaplasmosis caused by Anaplasma phagocytophilum, and ehrlichiosis caused by Ehrlichia chaffeensis. We identified cases of thrombocytopenia attributed to TBI in our institution.

Methods
Retrospective chart review of patients diagnosed with babesiosis, anaplasmosis, and ehrlichiosis from 2000 to 2017 at Northport Veterans Affairs Medical Center. Demographics, method of diagnosis (PCR/serologies), CBC/chemistries, treatment choices, and outcomes were analyzed.

Results
Thirty-two veterans (VETS) were identified with the following TBI: Babesiosis 22, Ehrlichiosis 6, Anaplasmosis 4. The majority of cases (19) were from Suffolk County, Long Island. The median (MED) age of this group was 62 years (range 31–89). Ninety-one percent were Caucasian, 9% Black. 37.5% had history of tick bite. The MED temperature on presentation was 101.9°F (range 97.6–105.2°F). 56% had HTN, 6% DM, 37% HLD, 9% hepatitis C, 3% HIV. Laboratory studies: MED platelet count 88,000/µL (36,000–161,000); MED hemoglobin 12 gm/dL (5.6–15.6); MED ALT 41 IU/L (6–330); MED LDH 335 IU/L (193–1,322). Twelve VETS had positive C6 peptide. The peak MED B. microti parasitemia was 1.4% (0.1–3%). PCR tests were available in the later years of the study period: three were positive for E. chaffeensis, two for A. phagocytophilum, and 14 for B. microti. The majority of the cases (19) were observed after year 2010. Morulae were seen in only one case. Haptoglobin in eight VETS was undetectable. One veteran with history of splenectomy and babesiosis with 3% parasitemia required exchange transfusion with 12 units of PRBCs. Two other babesiosis cases required regular transfusion of PRBCs. 20 babesiosis cases were treated with azithromycin-atovaquone and two with clindamycin-primaquine. Doxycycline was used in the other cases. One patient developed NSTEMI and required coronary stent placement. Platelet counts returned to baseline levels with treatment. No deaths occurred.

Conclusion
The incidence of TBI in Long Island, New York is rising. PCR testing for TBI can be utilized in our VETS presenting with febrile illness and thrombocytopenia to help identify the possible tick borne pathogen during the months of high tick activity.

Disclosures
All authors: No reported disclosures.
663. Characteristics, Treatment Patterns, and Outcomes of Outpatients With Rickettsial Diseases in a Large, Commercially Insured Population: United States, 2005–2016
Authors: Binder Alison , Peterson Amy E , Armstrong Paige 
Published: November 2018

Abstract

Background
Rickettsial diseases (RD) include Spotted Fever Group (SFG) Rickettsiosis, Ehrlichiosis, Anaplasmosis, Typhus Group (TG) and Rickettsialpox, among others. Doxycycline is the treatment of choice in all age groups; early treatment based on clinical diagnosis is important to prevent severe and fatal outcomes. SFG, Ehrlichiosis, and Anaplasmosis are nationally notifiable in the United States, but data on treatment patterns are not collected.

Methods
We conducted a retrospective analysis using Truven Health MarketScan® Commercial Claims and Encounters databases. We included any individual with an outpatient claim using an ICD-9/10-CM code for RD, who had one-year continuous pre- and 3 months post-diagnosis enrollment and pharmaceutical claim data. The first outpatient record with RD was considered the incident diagnosis, and those with an RD hospitalization in the prior 1 year were excluded. Epidemiologic characteristics, treatment patterns, and outcomes were summarized.

Results
13,353 individuals were included; median age was 45 years (IQR: 28–55 years), 2,045 (15%) were under 18 years of age, and 51% were male. The most common diagnosis was SFG (7,133; 50%), followed by Ehrlichiosis (3,920; 30%), and Typhus (1,281; 10%); 36 individuals had &gt;1 diagnosis. Over half (7,075; 53%) received doxycycline within 30 of the index date; of these, 3,634 (51%) received it within 14 days. The majority (5,369; 86%) were treated for at least 10 days at the recommended dose. The proportion with a pharmaceutical claim for doxycycline varied considerably across diagnoses and ranged from 24% for TG to 60% for SFG Rickettsiosis. Among the 6,278 (47%) without a claim for doxycycline, 2,185 (35%) were prescribed another antibiotic; 4,093 (28%) were not prescribed any antibiotic. Hospitalization within 30 days of the incident diagnosis was infrequent (149, 1.1%), and the majority were due to either SFR (40%) or ehrlichiosis (37%). No in-hospital deaths were recorded.

Conclusion
RD continues to be an important cause of disease in the outpatient population, but providers are still only prescribing the recommended treatment to about half of those in whom they suspect the disease. Continued education and increased awareness is critical to prevent severe outcomes from RD.

Disclosures
All authors: No reported disclosures.
669. Changing Epidemiology of Murine Typhus in Texas
Authors: Shuford Jennifer , Hunt Patrick , Mayes Bonny 
Published: November 2018

Abstract

Background
Murine (also known as flea-borne) typhus is uncommon in the United States, but it is considered endemic in certain parts of Texas, especially the southernmost region. It is caused by Rickettsia typhi, which is transmitted to humans by rat and cat fleas. Murine typhus is often a mild illness with nonspecific clinical findings, though delayed treatment may result in severe disease and increased risk of complications. Diagnostic tests have low sensitivity in early disease. Therefore, correctly diagnosing patients with murine typhus is challenging unless clinical suspicion is high. In endemic regions, physicians are aware of the disease and diagnose it readily. However, in areas that have not historically been affected, physicians may be less familiar with the presentation of this rickettsial infection, impacting their ability to diagnose and treat it effectively.

Methods
Probable and confirmed murine typhus cases reported in Texas were collected for 1944–2017. Cases were mapped by county for each of the last 5 years. Cases reported over the last 5 years were also geocoded by residence for spatial cluster analysis by year.

Results
There has been an overall rise in the number of murine typhus cases reported per year over the last 13 years (Figure 1). The distribution of reported cases throughout Texas has changed over the last 5 years. There continues to be a high number of reported cases in South Texas and Central Texas, while reported cases are increasing in the Harris County/Houston area, Tarrant County/Ft. Worth area, and Dallas County/Dallas area. Spatial cluster (hot spot) analysis of typhus cases in Texas over the last 5 years shows areas of increased risk of murine typhus in South Texas that have persisted over time, while other areas of increased risk have appeared more recently in North Texas and Central Texas (Figures 2 and 3).

Conclusion
Murine typhus can be a difficult diagnosis to make based on clinical presentation, and physician awareness of its epidemiology is important. The gradual increase in case counts and the changing distribution of cases within Texas may put patients at risk of missed diagnoses. Recognizing the changing epidemiology of typhus in Texas may help inform public health education and control efforts.

Disclosures
All authors: No reported disclosures.
672. The Impact on Humans of Treating Dogs with Amoxicillin/Clavulanate
Authors: Beaulac Kirthana R , Doron Shira , Fellman Claire , Wayne Annie , McDermott Laura A , Snydman David 
Published: November 2018

Abstract

Background
It has been shown that the use of antibiotics promotes resistance to that antibiotic, and that colonization with resistant pathogens can be transmitted from companion animals to their human owners. There is an evolving concern that use of medically important antibiotics in pets can confer colonization by resistant organisms in their human owners.

Methods
In dogs receiving amoxicillin/clavulanate for 14 days for a diagnosed infection, we screened stool both at the time of antibiotic initiation and at the end of the course for the dog taking antibiotics and their human owner. Owners had to meet a closeness score of 3 or 4, meaning living in same household with frequent contact, with or without oral contact, and have no recent antibiotic exposure. Stool samples were quantitatively cultured for enteric flora and incubated on selective media for ampicillin/sulbactam resistance (A/S-r), ciprofloxacin resistance (CIP-r), ESBL, MRSA, and VRE.

Results
We enrolled eight dog–human pairs. All had enteric flora present at the time of antibiotic initiation (Day 1), whereas two of the seven dog samples that could be analyzed had no detectable enteric flora by the end of antibiotics (Day 14). No humans or dogs acquired MRSA or VRE. One human lost colonization with CIP-r flora, whereas two dogs acquired CIP-r during antibiotic treatment that did not transmit to their owners. One dog and one unrelated human acquired ESBL colonization by day 14 that was not present at Day 1. There were three humans colonized with A/S-r on Day 1 which persisted through the treatment period. Of their three dogs, one had no A/S-r at either time point, one newly acquired high counts of A/S-r flora, and one did not provide enough stool at Day 14 for A/S-r testing. There was one other dog that acquired A/S-r flora and one dog that had increasing counts of A/S-r, both of which had human owners with no A/S-r on Day 1 or 14.

Conclusion
In this pilot study, we identified that use of amoxicillin-clavulanate, a common antibiotic prescribed to both humans and dogs, can lead to resistant colonization in the dog taking antibiotics, and may have some impact on their close human owners who may share or transmit colonization. Further study is under way to better understand this relationship.

Disclosures
L. A. McDermott, CutisPharma Inc.: Research Contractor, Contractual agreement with Tufts Medical Center.
673. Syphilis Outbreak in Women Who Have Sex with Men in Japan: A Case–Control Study in Tokyo, 2017–2018
Authors: Nishiki Shingo , Arima Yuzo , Yamagishi Takuya , Hamada Takashi , Takahashi Takuri , Sunagawa Tomimasa , Matsui Tamano , Oishi Kazunori , Ohnishi Makoto 
Published: November 2018

Abstract

Background
In Japan, syphilis notifications have increased sharply, with Tokyo accounting for a third of all cases. Importantly, the increase in women has been remarkable, with the majority being women who have sex with men. We therefore conducted a prospective case–control study to evaluate correlates of recent syphilis infection among women in Tokyo.

Methods
We employed a test-negative design case–control study among women who sought a syphilis test at a women’s health clinic in Tokyo, comparing socioeconomic status, medical history, and recent sexual behaviors/partnerships, between those who were diagnosed with recent syphilis infection based on clinical signs and serological test results (cases) vs. those who were nonreactive for the nontreponemal test (controls). Participants aged ≥20 years and sexually active in the past 6 months were recruited from June 2017 to March 2018 and completed a self-administered questionnaire. We described cases and assessed for correlates of recent syphilis infection based on odds ratios (ORs) and 95% confidence intervals (CIs).

Results
A total of 524 women, composed of 60 cases and 464 controls, were enrolled. The median age was 23 years (range = 20–54) among cases and 26 years (range = 20–59) among controls. Of the 60 cases, 10 (17%) were current students and three (5%) had a history of syphilis; in the past 6 months, while 35 (58%) had engaged in commercial exchange of sexual practices, 14 (23%) had only one sex partner. Having lower educational attainment (OR = 4.1; 95% CI = 2.1–8.1), not being employed full-time (OR = 3.1; 95% CI = 1.8–5.5), and commercial exchange of sexual practices (OR = 3.4; 95% CI = 2.0–5.9) were associated with case status in univariate analysis. The association between case status and inconsistent condom use (relative to consistent condom use) during vaginal/anal sex in the past 6 months (OR = 2.0; 95% CI = 0.9–4.3) became stronger when restricted to women engaged in commercial exchange of sexual practices (OR = 4.0; 95% CI = 1.4–10.9).

Conclusion
This was the first study to evaluate potential risk factors for recent syphilis infection among women in Japan. In light of these findings, we may need a multi-pronged approach to prevent and control syphilis, for both those engaged in commercial exchange of sexual practices and the general population.

Disclosures
All authors: No reported disclosures.
688. Impact of Expanded Influenza Post-exposure Prophylaxis on Healthcare Worker Absenteeism at a Tertiary Care Center During the 2017–2018 Season
Authors: Puig-Asensio Mireia , Douglas Margaret , Holley Stephanie , Kukla Mary Beth , Abosi Oluchi , Mascardo Lisa , Carmody Brenda , Gent Courtney , Diekema Daniel , Hartley Patrick , Edmond Michael , Salinas Jorge L 
Published: November 2018

Abstract

Background
A severe 2017–2018 influenza season was expected for the United States. We hypothesized that a surge in influenza cases paired with decreased vaccine effectiveness could increase healthcare worker (HCW) absenteeism. Because of a potential public health emergency during the 2017–2018 season, we offered oseltamivir post-exposure prophylaxis (PEP) to exposed HCWs regardless of vaccination status. We describe PEP uptake, cost, and impact on absenteeism at the University of Iowa Hospital and Clinics (UIHC).

Methods
UIHC serves as a referral and safety net health system for Eastern Iowa. Influenza seasons were defined as the period between Week 40 from 1 year to Week 13 of the following year. During the 2016–2017 season, PEP (75 mg/day for 7 days) was offered free of charge to unvaccinated exposed HCWs. Exposure was defined as proximity within 3 ft of a confirmed influenza-infected person for ≥10 minutes without mask protection, or direct contact with respiratory secretions. During the 2017–2018 season, PEP was expanded to all exposed HCWs regardless of vaccination status. We reviewed surveillance, employee health, pharmacy, and human resources records for the 2016–2017 and 2017–2018 seasons. We defined PEP uptake as prescriptions picked up/all referrals and absenteeism rate as sick-leave requests/scheduled hours.

Results
During the 2016–2017 and 2017–2018 seasons, we detected 373 and 427 confirmed influenza cases among patients at UIHC. HCW vaccination rates were similar: 89.7% and 90.9%. PEP was recommended in 49 exposures during 2016–2017 and 280 exposures during 2017–2018. A total of 22 (44.9%) and 133 (47.5%) HCWs picked up oseltamivir from the pharmacy during the 2016–2017 and 2017–2018 seasons. The estimated cost of oseltamivir was $1,791 and $10,828, respectively. Overall, 6,187 sick-leave requests (median = 12 hours, absenteeism rate = 3.2%), and 6,174 sick-leave requests (median = 12 hours, absenteeism rate = 3.4%) were reported during the 2016–2017 and 2017–2018 seasons.

Conclusion
Influenza case counts mildly increased from the 2016–2017 to the 2017–2018 season. Expanding PEP to all exposed HCWs, regardless of vaccination status, had moderate uptake and was costly. Absenteeism rates remained similar during both seasons.

Disclosures
All authors: No reported disclosures.
697. Pseudomonas aeruginosa PcrV and Psl, the Molecular Targets of Bispecific Monoclonal Antibody MEDI3902, Are Conserved Among Diverse Hospital Isolates Collected From an International Surveillance Study
Authors: Tabor David E 
Published: November 2018

Abstract

Background
Pseudomonas aeruginosa is a frequent cause of life-threatening infections in mechanically ventilated patients and is associated with high mortality rates. Bispecific monoclonal antibody MEDI3902 targeting Pa type-3-secretion system (PcrV) and the Psl exopolysaccharide is currently under phase 2b development for the prevention of pneumonia in mechanically ventilated subjects with Pa colonization in the lower respiratory tract. In this study, we sought to survey a vast collection of global Pa clinical isolates for presence of pcrV and psl loci and MEDI3902 epitope conservation to evaluate the magnitude of Pa strain coverage by MEDI3902.

Methods
913 Pa clinical isolates were collected from diverse patients and geographical locations in 2004–2014. Whole genome sequencing of the full collection was performed via MiSeq 2 × 250 runs (Illumina®). PcrV and Psl expression was detected by immunoblotting and ELISA, respectively. The crystal structure of anti-PcrV fab and PcrV fragment complex-crystals was solved at 2.8 Å resolution. MEDI3902 activity against representative isolates was tested in cytotoxicity and opsonophagocytosis assays and in a murine pneumonia model.

Results
Whole-genome sequencing revealed intact pcrV and psl genetic elements in 99% and 94% of isolates, respectively. We identified 46 variants of PcrV that were all bound by the anti-PcrV moiety of MEDI3902 and confirmed through crystal structure analysis that antibody-antigen contact residues were preserved in all variants. Similarly, anti-Psl binding was confirmed for selected isolates containing the complete Psl operon and strains lacking non-essential psl genes. Importantly, 99.9% of isolates contained the full complement of either genetic element. Consistent with these results, we observed potent MEDI3902 activity against diverse strain types, including strains that expressed only a single target.

Conclusion
Our results indicate PcrV and Psl are highly prevalent in recent clinical isolates from around the world, suggesting that MEDI3902 can mediate broad coverage against Pa.

Disclosures
D. E. Tabor, Astra Zeneca: employee, Salary.