bluuebunny/crossref_metadata_2025_split huggingface dataset:
1395. Defining the Magnitude of AUC:MIC Driver for Efficacy of the β-Lactamase Inhibitor VNRX-5133 When Combined with Cefepime Against KPC- and VIM/NDM-Producing Enterobacteriaceae and P. aeruginosa
Authors: Daigle Denis , Vernacchio Salvador , Xerri Luigi , Pevear Daniel 
Published: November 2018

Abstract

Background
VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) in clinical development with cefepime for treatment of infections caused by ESBL- and carbapenemase producing Enterobacteriaceae and P. aeruginosa. It is a new generation broad-spectrum BLI with direct inhibitory activity against serine-active site and emerging metallo-β-lactamases (e.g., VIM/NDM). In previous in vivo and in vitro studies, the PK-PD driver of efficacy of VNRX-5133 was defined as AUC:MIC. Described herein are in vitro studies to assess the magnitude of VNRX-5133 exposure (AUC:MIC) required to restore efficacy of cefepime against a broad collection of KPC- and VIM/NDM-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA) clinical isolates.

Methods
Dose-fractionation studies, consisting of four VNRX-5133 exposures fractionated into regimens administered every 4, 8, 12 and 24 hours, were performed in an in vitro infection model with simulated 2 g q8h dosing of cefepime against NDM-1 producing E. coli. A Hill-type model described the relationship between change in log10 CFU at 24 hours and VNRX-5133 exposure (AUC:MIC), where cefepime MIC was determined with 4 µg/mL VNRX-5133. To evaluate variability of efficacy enabled by VNRX-5133 between isolates as well as between Serine-BL and Metallo-BL producers, dose-ranging studies were completed for eight isolates (seven ENT and one PSA) producing KPC or VIM/NDM metallo-β-lactamases.

Results
The PK-PD exposure parameter AUC:MIC accurately described the efficacy of VNRX-5133 in rescuing cefepime activity against KPC and VIM/NDM carbapenemase-producing isolates of ENT and PSA. The AUC:MIC ratios associated with net bacterial stasis, 1-, and 2-log10 reductions in bacterial burden from baseline were 6.1, 18.4 and 45, respectively, for a collection of five VIM/NDM- and three KPC-producing isolates with cefepime MICs ranging from 4–8 µg/mL with no significant differences observed between Ser-BL and MBL producers.

Conclusion
These data confirm the equivalent in vitro activity of cefepime/VNRX-5133 against organisms producing serine- and metallo-β-lactamases and provides an initial PK-PD target for VNRX-5133 efficacy when used in combination with cefepime for the treatment of ESBL- and carbapenemase-producing ENT and PSA infections.

Disclosures
D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. S. Vernacchio, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee, Salary.
664. Factors Associated with the Need for ICU Care Among Patients with Human Ehrlichiosis
Authors: Kuriakose Kevin , Pettit April , Schmitz Jonathan , Moncayo Abelardo , Bloch Karen 
Published: November 2018

Abstract

Background
Despite the availability of effective therapy, the case fatality rate of human monocytic ehrlichiosis (HME) is 3%, and has been reported to be higher among the immunocompromised. Little is known about predictors of severe disease.

Methods
We performed an observational cohort study at a tertiary care medical center in Nashville, TN. Patients with a positive whole blood or cerebrospinal fluid Ehrlichia polymerase chain reaction between 2007 and 2017 were included. Clinical and demographic data were obtained by chart abstraction. Modified Poisson Regression was used to estimate the adjusted relative risk (aRR) of requiring intensive care unit (ICU) care, adjusting for age, sex, race, Charlson Comorbidity Index, immunosuppression, patient-reported tick exposure, and number of days from first contact with healthcare system to treatment initiation.

Results
We included 155 patients; median age was 48 years, 64% were male, 94% were Caucasian, 74% reported a tick exposure, and 21% were immunocompromised. 28% of patients required ICU care. Immunosuppression and reported tick exposure were associated with a decreased risk of requiring ICU care. An increasing number of days from first contact with the healthcare system to treatment initiation were associated with an increased risk of requiring ICU care.

Conclusion
Twenty-eight percent of patients required ICU care. We found that a delay in initiation of therapy was associated with an increased risk of requiring ICU care. In contrast to other studies, we found immunosuppression to be associated with milder clinical illness, perhaps reflecting a lower threshold to seek care and thus earlier presentation. Patients with recent tick exposure were also less likely to require ICU care, potentially reflecting a higher index of suspicion for HME among providers. Future studies evaluating the impact of provider education on early recognition and treatment may lead to a decreased need for ICU care in patients with HME.

Disclosures
All authors: No reported disclosures.
665. Key Clinical and Laboratory Features in Early Diagnosis of Ehrlichiosis in an Endemic Area of Long Island, New York
Authors: Kaplun Olga , Smith Kalie , Khoo Teresa , Spitzer Eric , Weinbaum Fredric , Marcos Luis A 
Published: November 2018

Abstract

Background
Human monocytic ehrlichiosis (HME) is a tick-borne disease caused by Ehrlichia chafeensis in the northeast United States. Suffolk County, New York has the highest amount of HME cases in NY (176 from 2010 to 2014). Our aim is to identify risk factors for HME and compare clinical presentation and laboratory findings of young vs. older adults.

Methods
A retrospective chart review from January 1, 2014 to December 31, 2017 was performed on all patients ≥18 years who presented to the ER at Stony Brook University Hospital (SBUH) or Stony Brook Southampton Hospital (SBSH) with (i) ICD-9 code 082.4 or ICD-10 code A77.40 and (ii) a positive E. Chafeensis PCR. Data were collected on demographics, clinical presentation, and laboratory results.

Results
Twenty-seven cases of HME were found and separated into Group 1 (G1, n = 10) or Group 2 (G2, n = 17) based on age (Table 1). G1 had a significantly higher chance of being Hispanic than G2. Twenty-four of the 27 patients (89%) were hospitalized with an average length of stay of 3.4 days (range 1–14 days).The only significant difference in clinical presentation was that G1 was more likely to have myalgia (P = 0.02). 40% or more of patients in both groups presented with an acute kidney injury and the average length of hospital stay in days was 4.0 ± 2.9 and 3.2 ± 3.1 for G1 and G2, respectively. The number of cases overall have increased 6.0% per year between 2014 and 2017. Thrombocytopenia presented in all cases.
Conclusion. HME is prevalent in Suffolk County. Clinical presentation and laboratory findings were largely similar between the two groups, except the younger population more often presented with myalgia. A risk factor in this study was to be young and Hispanic, likely due to occupational exposure.

Disclosures
All authors: No reported disclosures.
674. Epidemiology of Diphtheria and Antimicrobial Resistance Among Diphtheria Cases, Bijapur District, Karnataka, India, 2012–2015
Authors: Mohankumar Sree Kalpana , Paschapur Suresh , Mailare Shankareppa 
Published: November 2018

Abstract

Background
India contributes to 80% of diphtheria cases. Many diphtheria outbreaks were reported from Bijapur district of Karnataka state, India. Analysis of burden and drug sensitivity pattern might help to identify risk groups and to provide guidelines for treatment of diphtheria cases. Our objectives were to describe epidemiology and drug susceptibility of diphtheria cases in Bijapur district.

Methods
We did cross-sectional study between 2012 and 2015. We defined a probable case as inflammation of upper respiratory tract with adherent membranes. We defined a confirmed case as a probable case that was laboratory confirmed by throat culture. We collected line list of probable and confirmed diphtheria cases, population details in Bijapur district and antibiotic sensitivity of culture reports. We calculated attack rates and case fatality rate by taluks of Bijapur district. We calculated proportion of antibiotic resistance among lab confirmed cases.

Results
There were 229 probable cases and 26 confirmed cases of diphtheria. Attack rate was 110/million and case fatality rate was 2% (5/255). Median age of males was 5 years (range: 3 months to 18 years) and females was 6 years (range: 1 year to 18 years). Highest attack rate (290/million) was in Bagewadi taluk, followed by Sindagi taluk (130/ million). Attack rate in Bijapur, Indi and Muddebihal were 80, 80and 70 per million respectively. Incidence of diphtheria cases was 3/million in 2012, 15/million in 2013, 80/million in 2014 and 14/million in 2015. Penicillin resistance was found among 92% (24/26) of cases, cotrimaxozole resistance among 27% cases (7/26) and ampicillin resistance among 15% cases (4/26)}. Multidrug resistance for penicillin and cotrimoxazole was found among 23% (6/26) of cases. Multidrug resistance to penicillin and ampicillin was found among 15% (4/26) of cases). All cases were sensitive to azithromycin, erythromycin, doxycycline, clindamycin, ciprofloxacin, cefotaxime, gentamycin and tetracycline.

Conclusion
Diphtheria incidence increased between 2012 and 2014. Incidence reduced in 2015. Penicillin resistance was common. We recommend sensitising health workers about penicillin resistance and educating them not to use penicillin. We recommend estimating vaccine coverage and vaccine effectiveness among children.

Disclosures
All authors: No reported disclosures.
678. Outbreak of Shiga Toxin-Producing Escherichia coli Infections at Marine Corps Recruit Depot (MCRD), San Diego and Camp Pendleton, California: October–November, 2017
Authors: Keaton Amelia , Hassan Rashida , Luna Sarah , Lee Isabell , Magalhaes Richelle , Bidlack Matthew , Graf Paul , Maves Ryan , Smith Linda , Freer Douglas , Flinn Kimberly , Monk Gregory , Trinh Kelly , Crandall John , Noveroske Douglas , Fortenberry Gamola , Peak Corey , McDonald Eric , Waltz Thomas , Patel Kane , Wagner Darlene , Espiritu Jennifer , Christensen Lori , Gieraltowski Laura 
Published: November 2018

Abstract

Background
Shiga toxin-producing Escherichia coli (STEC) infections are a major cause of foodborne illness and the principal cause of hemolytic-uremic syndrome (HUS). In November 2017, CDC and the US Navy responded to an outbreak of STEC illnesses in military recruits at the Marine Corps Recruit Depot in San Diego (MCRD). We investigated to determine the source of this outbreak and identify prevention and mitigation measures.

Methods
In October 2017, medical staff identified a high number of gastrointestinal (GI) illnesses at MCRD. Recruits with diarrhea submitted stool specimens for culture and/or culture-independent diagnostic testing (CIDT) for GI pathogens. We performed pulsed-field gel electrophoresis (PFGE) on culture isolates. Case-patients were defined as confirmed (PFGE-confirmed STEC infection matching outbreak strains), probable (diagnosis of HUS and/or CIDT evidence of STEC), or suspected (bloody diarrhea). We conducted environmental evaluations of dining facilities, training areas, and barracks. A case–control study was performed using PFGE-confirmed case-patients and platoon-matched controls. We performed product traceback for foods identified as exposure risks by interview or case–control study.

Results
We identified 64 confirmed, 105 probable, and 91 suspected case-patients. Thirty case-patients required hospitalization and 15 had HUS. Ages ranged from 17 to 28 years (median: 18 years). Poor hygiene practices among recruits and inconsistent cooking temperatures within dining facilities were noted. Forty-three case-patients and 135 controls were interviewed about food, hygiene, and environmental exposures. Consumption of undercooked beef was significantly associated with illness (mOR 2.40, CI 1.04–5.72, P = 0.04). We identified a single ground beef supplier for MCRD, but dining facility records did not document the dates on which specific lots of ground beef were used.

Conclusion
Case–control analysis and environmental observations suggested undercooked ground beef as a potential source for this outbreak. We recommended the Navy and Marine Corps retain lot information, address food handling concerns, and improve hygiene among recruits.

Disclosures
All authors: No reported disclosures.
689. Narcolepsy During the 2009–2010 H1N1 Pandemic
Authors: Huang Wan-Ting , Yang TienYu Owen 
Published: November 2018

Abstract

Background
In Taiwan, H1N1 vaccination began on November 1, 2009 and coincided with peak H1N1 pandemic activity. Nationwide ecological and case–control studies have identified no substantial association between the use of H1N1 vaccines and narcolepsy; however, wild-type H1N1 virus infection might have triggered narcolepsy onset, or potentially confounded the findings.

Methods
Data collected in the nationwide case–control study was reanalyzed. Confirmed narcolepsy cases (Brighton levels 1–2 for ages 0–15 years and 1–4a for ages at least 16 years) with onset during November 1, 2009–September 30, 2010 were included and ascertained receipt of H1N1 vaccines. We compared incidence of narcolepsy between the H1N1 vaccinated and unvaccinated population and assessed daily cumulative risk throughout the study period, with adjustment for age. We applied population estimates (census data, 2009) and daily doses of H1N1 vaccines administered (Influenza Vaccine Information System) to calculate the number of persons and person-time for each group.

Results
There were 22 narcolepsy cases; five (23%) occurred after H1N1 vaccination. The vaccinated population had higher incidence (1.2 vs. 1.0 per million person-years, P = 0.711) (incidence rate ratio 1.24, 95% confidence interval [CI] 0.40–3.83), and higher cumulative risk (1.1 vs. 0.9 per million persons, P = 0.772) (risk ratio 1.16, 95% CI 0.43–3.14) of narcolepsy (figure). These differences, however, were not significant.

Conclusion
We found comparable average and cumulative risk of narcolepsy between the H1N1 vaccinated and unvaccinated Taiwanese population during the 2009–2010 pandemic.

Disclosures
All authors: No reported disclosures.
693. Congenital Zika Syndrome: Assessing the Fatality Rate Since the 2015 Zika Outbreak
Authors: Neto Nilson N Mendes , Maia Jessika , Queiroz Igor Thiago , Zacarkim Marcelo Rodrigues , Lins Maria Goretti , Labeaud A Desiree , Aronoff David 
Published: November 2018

Abstract

Background
Many studies have demonstrated a causal link between Zika virus (ZIKV) infection, microcephaly (MCP) and other congenital abnormalities (CA). This study aimed to determine the perinatal case fatality rate in cases of Congenital Zika Syndrome (CZS) in the Rio Grande do Norte State (RN), a Brazilian Northeast State highly impacted by the Zika virus outbreak.

Methods
A cross-sectional study was conducted using data obtained through the State Health Department (SHD) for cases of MCP and CA in Rio Grande do Norte from April 2015 to December 31, 2017. Definition of perinatal period: commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth. Perinatal case fatality rate is defined as the number of deaths as a fraction of the number of sick persons with a specific disease (×100).

Results
During the study period, there were 519 cases of MCP and others CA notified in RN, of which 150 were confirmed and 126 remain under investigation. The remaining 243 cases have been ruled out by presenting normal exams or due to presenting microcephaly by non-infectious causes. Of the total confirmed cases, 30.0% (45/150) died after birth or during pregnancy. 64.4% (29/45) of confirmed deaths had ZIKV infection during pregnancy and 4.4% (02/45) had a positive TORCH blood test. The deaths related to Zika were confirmed using either clinical/epidemiological/radiological (the presence of typical and indicative alterations of congenital ZIKV infection) or clinical/epidemiological/serological (RT-PCR and/or IgM/IgG antibodies against ZIKV). Eleven cases remain under investigation and five were ruled out.

Conclusion
This study highlights a high rate of perinatal lethality (64.4%) in cases of CZS. Despite the growing number of CZS cases, the real incidence and prevalence might be higher due to the underreporting and lack of resources for confirmatory diagnostic tests (laboratory and imaging). Due to the high rate of lethality, our findings predict an increase in the infant mortality rate in areas endemic for arboviruses. Because the severe neurological complications caused by CZS, it is likely to pose a substantial burden on public spending on healthcare. This study may be used to better describe the congenital Zika syndrome, its prognosis and natural history.

Disclosures
All authors: No reported disclosures.
699. Relationship Between Klebsiella pneumoniae Antimicrobial Resistance and Biofilm Formation
Authors: Cusumano Jaclyn , Daffinee Kathryn , Luther Megan , Lopes Vrishali , Caffrey Aisling , LaPlante Kerry 
Published: November 2018

Abstract

Background
Klebsiella pneumoniae is a frequently multidrug-resistant organism with a high propensity to form biofilm. K. pneumoniae is the most common carbapenem-resistant Enterobacteriaceae (CRE), and labeled an urgent threat by the CDC. The relationship between K. pneumoniae biofilm formation and specific antimicrobial resistance patterns has not been well defined.

Methods
K. pneumoniae isolates (n = 139) were evaluated for antimicrobial resistance and biofilm formation (CDC, Providence VA Med. Ctr., Rhode Island Hosp., BEI, and ATCC). Susceptibility was based predominantly on 2017 CLSI (Clinical and Laboratory Standards Institute) breakpoints. Isolates were categorized as multidrug-resistant (MDR: resistant to ≥ 1 antimicrobial in ≥ 3 out of 16 antimicrobial categories) or extensively drug-resistant (XDR: resistant to ≥ 1 antimicrobial in all but ≤ 2 out of 16 antimicrobial categories) based on expert consensus criteria for Enterobacteriaceae (European CDC (ECDC)/CDC, 2012). We collapsed antimicrobial categories described by the ECDC/CDC consensus group into nine categories: penicillins, cephalosporins, monobactam, carbapenems, protein synthesis inhibitors, fluoroquinolones, folate pathway inhibitors, fosfomycin, and colistin. Biofilm formation was assessed using a modified crystal violet method (OD570) and defined by tertile cut-points. Antimicrobial resistance was compared for weak (n = 47) vs. strong (n = 46) biofilm formation by chi-square or Fisher’s exact test. Predictors of strong biofilm formation were identified using logistic regression.

Results
MDR isolates were more common among weak (n = 46/47, 97.9%) vs. strong biofilm formers (n = 35/46, 76.1%; P = 0.002), whereas XDR was similar between groups (n = 12/47, 25.5% vs. n = 13/46, 28.3% P = 0.77). Resistance to penicillins, cephalosporins, monobactams, carbapenems, protein synthesis, or fluoroquinolones was more common among weak biofilm formers (P &lt; 0.05). Carbapenem resistance was inversely associated with strong biofilm formation (odds ratio 0.09; 95% confidence interval 0.02–0.33).

Conclusion
Carbapenem-resistant K. pneumoniae was 91% less likely to form strong biofilm. Potential trade-off mechanisms between antimicrobial resistance and biofilm formation require further exploration.

Disclosures
A. Caffrey, Merck: Grant Investigator, Research grant. The Medicine’s Company: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. K. LaPlante, Merck: Grant Investigator, Research grant. Pfizer Pharmaceuticals: Grant Investigator, Research grant. Allergan: Scientific Advisor, Honorarium. Ocean Spray Cranberries, Inc.: Grant Investigator and Scientific Advisor, Honorarium and Research grant. Achaogen, Inc.: Scientific Advisor, Honorarium. Zavante Therapeutics, Inc.: Scientific Advisor, Honorarium.
729. Improved Detection of Adenovirus with the FilmArray Respiratory Panel 2 Panel in a Pediatric Population
Authors: Everhart Kathy , Wang Huanyu , Xu Li , Leber Amy 
Published: November 2018

Abstract

Background
Human adenovirus (ADV) respiratory infections are associated with up to 8% of all identified viral causes of acute respiratory illnesses, especially among young children. They are therefore included as part of multiplex syndromic respiratory testing. Earlier versions of the FilmArray Respiratory Panel were targeted to genogroups B, C, and E. However, all adenovirus genogroups are associated with disease particularly in immunocompromised patients. Recently, a new version of the FilmArray Respiratory Panel 2 (RP2) has been FDA cleared with significant modifications to the adenovirus assay. The goal of this study was to compare the RP2 adenovirus assay to that of the previous version (RP1.7) and our laboratory-developed (LD) adenovirus PCR.

Methods
Analytical comparison: Ten stocks of know adenovirus serotypes representing genogroups A-F were diluted in M4 media and tested on RP2, RP1.7 and LD PCR to determine the relative limits of detection (LOD). Clinical comparison: A total of 423 pediatric nasopharyngeal samples were tested using RP2, RP1.7, adenovirus LD PCR. In addition we performed genotyping PCRs on most adenovirus positive samples based on the availability.

Results
Analytical evaluation revealed that for the 10 serotypes (18, 32, 7, 14, 5, 6, 20, 29, 4 and 40), RP2 showed at least 100-fold increase in sensitivity for six serotypes representing genogroups A, D and F. For B, C and E, the relative LODs were comparable.
In the 423 clinical samples, there was an overall agreement of 94% between RP2 and RP1.7. Among those RP2+/RP1.7− samples (n = 20), 17 samples were confirmed ADV positive by LD PCR. They all had low viral burden (Ct values &gt;30), among them nine samples had sole detections of adenovirus types A, D and F. Five samples were RP2-/RP1.7+, two samples were confirmed by LD PCR and both were type C. Overall, there was a 22% increase in Adenovirus with RP2 compared with RP1.7.

Conclusion
The RP2 adenovirus assay has enhanced inclusivity and lower LOD for all adenovirus genogroups in comparison to RP1.7. Coupled with its faster run time and additional targets, RP2 represents a significant improvement for the syndromic detection of respiratory infections.

Disclosures
A. Leber, Nationwide Children’s Hospital: Research Contractor, Research support.