bluuebunny/crossref_metadata_2025_split huggingface dataset:
1385. Efficacy of Ceftazidime–Avibactam in Combination with Aztreonam (COMBINE): Solutions for Metallo-β-Lactamase Producing-Enterobacteriaceae (MBL)
Authors: Lodise Thomas P , Smith Nicholas M , Holden Patricia , O’Donnell J Nicholas , Bedard Tyler , Bonomo Robert A , Tsuji Brian T 
Published: November 2018

Abstract

Background
Novel antibiotics will not be available to combat the threat of MBLs until 2021. One strategy to overcome MBLs is to combine CAZ-AVI + ATM. ATM is not hydrolysed by MBLs and AVI offers protection for ATM and CAZ vs. ESBLs and AmpCs. The combination also offers a theoretical advantage to inactivating multiple PBPs by using dual β-lactam therapy. Our objective was to define optimal dosing profiles for clinical use of ATM to add to CAZ-AVI in the hollow fiber infection model (HFIM).

Methods
E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied at a 7.5 log10 CFU/mL in the HFIM. Human dosing regimens of CAZ-AVI 2 g/0.5 g q8h (2 hours infusion) and ATM 2 g q8h (2 hours infusion) were simulated in alone and in combination. Continuous infusion (CI) regimens of CAZ-AVI 6 g/1.5 g per day CI + ATM 6 g/day CI and q8h regimens were given simultaneously and sequentially (ATM given 2 hours after CAZ-AVI). Resistant subpopulations were profiled on single (ATM), double (CAZ/AVI) and triple (ATM/CAZ/AVI) drug plates containing 2/2/4, 8/8/4, or 32/32/4 mg/L over 7 days.

Results
Against E. coli ARLG-1013, ATM alone mirrored growth control (+3.14 at 168 hours) (All units Log10 CFU/mL change vs. baseline). CAZ-AVI alone showed some intrinsic activity (+1.19 at 168 hours). CAZ-AVI 2g/0.5g q8h (2 hours infusion) + ATM 2g q8h (2 hours infusion) given sequentially resulted regrowth and stasis (+0.34 at 168 hours) vs. the simultaneous combination resulted initial bactericidal activity (-3.53 killing within 28 hours) which regrew at (−0.90 at 168 hours). All CI regimens were effective. CAZ-AVI 6g/1.5g per day CI + ATM 6 g/day CI resulted in dramatic killing (up to -5.78 killing within 50 hours) which was sustained (up to -3.90 killing at 168 hours). Comparing the infusion time of CAZ/AVI + ATM on bacterial killing: CI + CI &gt; 2 hours + 2 hours &gt; 30 minutes + 30 minutes. CI + CI resulted in complete suppression of resistance over 7 days. Against K. pneumoniae ARLG-1002, CAZ/AVI (CI) + ATM (CI) resulted in early synergy (&gt;5.0 log killing within 24 hours) and suppression of resistance for more than 168 hours.

Conclusion
The combination of CAZ-AVI + ATM was highly synergistic and suppressed resistance against MBL Enterobacteriaceae in HFIM. ATM efficacy in combination was driven by %T &gt; MIC. A Phase I study will assess safety to provide patients a critically important solution against “untreatable” Gram negatives.

Disclosures
T. P. Lodise, paratek: Consultant and Scientific Advisor, Consulting fee. B. T. Tsuji, Nabriva: Consultant, Consulting fee. Achaogen: Grant Investigator, Educational grant. ARLG, DCRI: Grant Investigator, Grant recipient. NIH/NIAID: Grant Investigator, Grant recipient.
1393. A Phase 1, Randomized, Open-Label, Crossover Study in Healthy Subjects Under Fasting Conditions of Orally Administered Sulopenem Etzadroxil Alone or with Probenecid to Determine the Pharmacokinetics of Sulopenem
Authors: Dunne Michael , Aronin Steven , Dunzo Elise , Puttagunta Sailaja 
Published: November 2018

Abstract

Background
Antimicrobial resistance to available oral antibiotics is becoming progressively more common, precipitating the need for additional treatment options as step-down from initial intravenous (IV) therapy as well as for treatment of infections in the community. Sulopenem (CP-70,429) is a thiopenem antibiotic active against quinolone non-susceptible and ESBL-producing Enterobacteriaceae. As the key pharmacokinetic-pharmacodynamic variable correlating with efficacy for penem antibiotics is time above minimum inhibitory concentration (T &gt; MIC), we examined the utility of probenecid, an OAT-1 inhibitor of β-lactam excretion, on the pharmacokinetic (PK) parameters for the oral prodrug of sulopenem, sulopenem etzadroxil

Methods
Twelve healthy males and females received a single oral dose of 500 mg sulopenem etzadroxil as powder in bottle either alone or co-administered with a single oral dose of probenecid 500 mg in a crossover design with a washout period of 6 days. All doses were administered under fasting conditions. Blood samples for plasma PK analysis were collected and PK parameters for sulopenem, the parent compound of sulopenem etzadroxil, were determined.

Results
Treatment

Conclusion
Probenecid increases the AUC of sulopenem by 28% in the fasted state and extends the mean time over MIC.

Disclosures
M. Dunne, Iterum Therapeutics: Employee and Shareholder, Salary. S. Aronin, Iterum Therapeutics: Employee and Shareholder, Salary. E. Dunzo, Parexel: Consultant, Consulting fee. S. Puttagunta, Iterum Therapeutics: Employee and Shareholder, Salary.
670. Estimating Bordetella pertussis Seroprevalence in Persons Aged 10–25 Years in Mexico Using the 2012 National Health and Nutrition Survey (ENSANUT): Challenges and Lessons Learned
Authors: Lopez-Gatell Hugo , Echaniz-Aviles Gabriela , Garcia-Cisneros Santa , Sánchez-Alemán Miguel Angel , Romero-Martínez Martin , Olamendi-Portugal Maria L , Alpuche-Aranda Celia M 
Published: November 2018

Abstract

Background
Low vaccination rates and under-detection of cases in adolescents and young adults have been implicated in the transmission of Pertussis to children. In this study, the proportion of adolescents and young adults with anti Bordetella pertussis IgG antibodies was estimated in a population-based survey in Mexico.

Methods
Frozen sera and data from 1,581 subjects—1,102 adolescents and 479 young adults (10–19 and 20–25 years old, respectively)—56% female were randomly selected from the Mexico’s National Health and Nutrition Survey (ENSANUT) 2012. CDC/FDA validated PT ELISA test was used to detect anti-pertussis toxin (PT) antibodies. A subset of 300 samples was also tested with Bp-IgG PT ELISA kit (Euroimmun AG, Lubeck, Germany®), both tests used international standards. Threshold values were established to identify vaccination or infection within the previous year, according to a US survey (Baughman et al.). Population-weighted estimates of seroprevalence were calculated.

Results
Overall Bp seroprevalence was 3.9% (95% CI: 2.3, 6.3); 3.1% (1.9, 5.0) in adolescents, and 4.9% (2.2, 11) in young adults. Seroprevalence did not significantly vary by gender, socioeconomic status, region or rural/urban location. Compared with the CDC/FDA PT ELISA, the Euroimmun® test showed 76% sensitivity, 88% specificity.

Conclusion
Booster vaccination to Bp after toddlerhood is not in the Mexican national policy; therefore, anti-PT IgG seropositivity may reasonably be attributed to recent Bp infection. Our weighted estimates of recent Bp infection, which are based on a national population-based serosurvey and a standardized serological test, represent a considerable burden of infections in adolescents and young adults that sharply contrast with the official surveillance reports. Also, the Bp-IgG PT ELISA commercial kit lower sensitivity than the CDC/FDA PT ELISA may lead underestimation of recent infections. In conclusion, assessing pertussis seroprevalence requires careful consideration of the right tests and epidemiological model for interpretation.

Disclosures
All authors: No reported disclosures.
680. “There’s More to This Than Meets the Eye”: Opportunities for Infection Prevention in Optometry Clinics
Authors: Fernandes Priyanka , Oyong Kelsey , Terashita Dawn 
Published: November 2018

Abstract

Background
Los Angeles County Department of Public Health (LAC-DPH) investigated an outbreak of epidemic keratoconjunctivitis secondary to adenovirus between June and July 2017, and all cases were linked to a single optometry clinic. The LAC-DPH aimed to determine whether sub-optimal infection prevention practices used in the implicated clinic were commonplace within other local optometry clinics. The objective of this study was to understand infection prevention practices in optometry clinics within Los Angeles County.

Methods
LAC-DPH conducted a survey consisting of 17 questions related to infection prevention practices among a sample of optometry providers in the county. The survey was administered online (SurveyMonkey) via emails sent to a local optometric society’s listserv and in-person at a local continuing education event for optometrists. The results were analyzed and are represented as percentages.

Results
There were 42 responses, 20 via the online survey (response rate 15%) and 22 via the in-person survey (response rate 22%). The majority worked in an optometry clinic: 77.5% (n = 31). More than half had no written hand-hygiene policy (58.5%, n = 24), 46.2% (n = 18) did not wear gloves while examining patients with eye drainage and about half (48.7%, n = 18) did not use droplet precautions for patients with respiratory symptoms. The vast majority used multi-dose eye-drop vials (92.5%, n = 37) but more than 40% (n = 21) did not discard the vial if the tip came into contact with conjunctiva. The majority (68.4%, n = 26) used alcohol wipes with 70% isopropyl alcohol to disinfect tonometers, while 47.4% (n = 18) used noncontact tonometers and 23.6% (n = 9) used disposable tips (options for this question were not mutually exclusive).

Conclusion
Infection prevention practices in optometry clinics are sub-optimal and must be improved. All optometry clinics must have a hand-hygiene policy and discard multi-dose vials which come into contact with conjunctivae. While the evidence on the best disinfectant for tonometers is limited, commonly used disinfectants like 70% alcohol wipes or 3% hydrogen peroxide have been associated with adenovirus outbreaks. Current evidence suggests that infectious spread via tonometers can be prevented by using disposable covers or by disinfection with 1:10 diluted bleach.

Disclosures
All authors: No reported disclosures.
686. Use of an Influenza-Like Illness School Absenteeism Monitoring System to Identify Seasonal Influenza Outbreaks in the Community: ORCHARDS (Wisconsin, September 2014–June 2017)
Authors: Temte Jonathan , Zheteyeva Yenlik , Barlow Shari , Goss Maureen , Temte Emily , Schemmel Amber , Maerz Brad , Bell Cristalyne , Reisdorf Erik , Shult Peter , Wedig Mary , Haupt Thomas , Conway James , Gangnon Ronald , Fowlkes Ashley , Uzicanin Amra 
Published: November 2018

Abstract

Background
Schools are purported to be primary venues of influenza transmission and amplification with secondary spread to communities. We assessed K—12 student absenteeism monitoring as a means for early detection of influenza activity in the community. Methods. We conducted a 3-year, prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness-associated (a-ILI) absenteeism within the Oregon School District, Oregon, WI (OSD: enrollment = 3,900 students). Absenteeism reporting was facilitated by automated processes within OSD’s electronic student information system. Students were screened for ILI, and, if eligible, visited at home, where pharyngeal specimens were collected for influenza RT-PCR (IVD CDC Human Influenza Virus RT-PCR Diagnostic Panel) and multipathogen testing (Luminex NxTAG RPP). The study definition of a-ILI was validated for 700 children with acute respiratory infections using binomial logistic regression. Surveillance of medically attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining OSD as part of the Wisconsin Influenza Incidence Surveillance Project using the same laboratory testing. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis. Results. Influenza A and B were detected in 54 and 51 of the 700 visited students, respectively. Influenza was significantly associated with a-ILI status (OR = 4.74; 95% CI: 2.78—8.18; P &lt; 0.001). Of MAI patients, 371 had influenza A and 143 had influenza B. a-I was significantly correlated with MAI in the community (r = 0.472; P &lt; 0.001) with a 15-day lead time. a-ILI was significantly correlated with MAI in the community (r = 0.480; P &lt; 0.001) with a 1-day lead time. a-TOT performed poorly (r = 0.278; P &lt; 0.001), following MAI by 9 days (Figure 1). Conclusion. Surveillance using cause-specific absenteeism was feasible to implement in OSD and performed well over a 3-year period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can detect influenza outbreaks in the community, providing early warning in time for community mitigation efforts for seasonal and pandemic influenza.

Disclosures
All authors: No reported disclosures.
692. Effects of Regional Climatic Variability on West Nile Virus Outbreaks in the United States
Authors: Kangath Raghesh Varot , Maduraperuma Buddhika , Borges Juliana Souza , Ramachandrapai Rajasreepai 
Published: November 2018

Abstract

Background
Transmission of WNV to humans in the United States typically occurs between June and September since warm temperatures accelerate mosquito life cycle. Precipitation can cause increase in aquatic breeding but outbreaks often depends upon human water management. We examine epidemiology, patterns of WNV disease transmission, and identification of high-risk areas in the United States from 2003 to 2014.

Methods
Trends and relationships of WNV cases and climatic factors were analyzed among the regions of the United States from 2003 to 2014. Human WNV tabulate data and climatic data were obtained from Centers for Disease Control, and NOAA and Climate Data Guide, respectively. Canonical correspondence analysis (CCA) was performed using variables: (i) neuroinvasive disease cases, non-neuroinvasive disease cases, deaths, presumptiveviremic blood donors, (ii) precipitation, temperature, Palmer Drought Severity Index (PDSI) and population density. The CCA ordination was explained the variability between WNV disease cases andclimatic variables. Biplots were used to visualize the associations between WNV cases and climatic anomalies.

Results
We compared the state wise WNV disease cases in relation to climatic and population density in the United States from 2003 to 2014. A total of 4,064 cases in 2006, 956 cases in 2010 and, 2,141 cases in 2014 were reported in the 32 states of the United States. Colorado state reported the highest WNV cases in 2003 (2,947 cases; 33%), followed by Texas in 2012 (1,868 cases; 35%) and California in 2014 (801 case; 37%). CCA ordination showed distinguishable clustering patterns between south central (Texas, Louisiana, Mississippi, Arkansas, and Oklahoma) and northern Great Plains (North Dakota, South Dakota, and Nebraska) regions (Figure 1). High temperature and prolong drought were the most important variable predictor for high WNV outbreak.

Conclusion
Vector control methods focusing on prevention must be implemented to avoid epidemics of WNV if high temperature is leading to an unusual drought especially at the risk areas, such as Texas and California. However, high temperature with moist spell anomalies in the south central region showed a negative influence on WNV outbreak.

Disclosures
All authors: No reported disclosures.
700. Identification and Whole-Genome Sequencing (WGS) of Meropenem-Vaborbactam (MV) Resistant Klebsiella pneumoniae (MVRKP) Among Patients Without Prior Exposure to MV: Collateral Damage
Authors: Yasmin Mohamad , Chen Liang , Marshall Steven H , Kreiswirth Barry N , Perez Federico , Bonomo Robert A 
Published: November 2018

Abstract

Background
MV is a newly approved β-lactam/β-lactamase inhibitor combination (BLIC) for the treatment of complicated urinary tract infections (cUTI). Vaborbactam is a cyclic boronic acid BLI that was mainly developed as a potent inhibitor of KPC carbapenemases and other Ambler class A&C enzymes. Vaborbactam is inactive against metallo-β-lactamases (MBL) and certain Class D enzymes (e.g. OXA-2 and OXA-48). We encountered a case of MV-resistant Klebsiella pneumoniae (MVRKP)and sought to explore the various mechanisms of MV resistance within KP.

Methods
A 65-year-old nursing home resident with multiple prior hospitalizations and recent exposure to antibiotics (Timeline) developed sepsis secondary to carbapenem-resistant Klebsiella pneumoniae (CRKP) cUTI. WGS of the patient’s isolate was performed. This was followed by random screening for MV resistance and WGS of other isolates from a historical database.

Results
Results of WGS are seen in the table below. Sequencing of our patient’s isolate revealed strain ST258 with a premature stop in aa89 of OmpK35 as well as insertions at Gly134 and Asp135 (i.e., the GD repeat) of OmpK36. Furthermore, the KPC plasmid’s copy number was approximately five times higher than the chromosome. No mutations encoding efflux system AcrAB-TolC were found.

Conclusion
Resistance to MV in KP was found in isolates that predate the drug’s availability. Notably, resistance occurred in the absence of MBLs and OXAs. The mechanism seems to involve outer membrane porin mutations in OmpK35 and/or OmpK36. WGS is a useful tool in identifying the mechanism of resistance especially for newer agents.

Disclosures
All authors: No reported disclosures.
703. Mechanisms of High-Level Ceftolozane/Tazobactam (CT) Resistance Against Pseudomonas aeruginosa and Synergy Between CT and Tobramycin (TOB)
Authors: So Wonhee , Shurko James , Galega Ralph , Quilitz Rod E , Greene John , Lee Grace C 
Published: November 2018

Abstract

Background
Ceftolozane/tazobactam (CT) is a cephalosporin/β-lactamase inhibitor with excellent activity against multi-drug-resistant (MDR) P. aeruginosa (PSA). Several cases of CT-resistance (CT-R) development after exposure have been reported. We recovered a PSA isolate with high-level CT-R from a bacteremic patient with severe, prolonged neutropenia and 5 weeks of CT exposure. Then, multiple mutational pathways and the role of combination therapy were evaluated.

Methods
Minimum inhibitory concentrations (MIC) to CT were determined by Etest. Synergy tests between CT and tobramycin (TOB) were conducted and interpreted based on the fractional inhibitory concentration index (FICI). Furthermore, whole genome sequencing was performed. Paired-end reads were mapped and compared with reference strain PAO1. Variant analyses were conducted using CLC Genomics Workbench.

Results
The MICs for CT and TOB were &gt;256 and 4 mg/L, respectively. The combination revealed synergistic effects (FICI &lt; 0.5) with reduced CT and TOB MICs to 16 and 1 mg/L, respectively. Clinically, combination therapy of CT 3g q8h given over 4 hours and TOB 7 mg/kg q24h successfully cleared the bacteremia within 2 days. Genomic analysis revealed the CT-R isolate contained multiple variants in the ampC gene, including G183D associated with low level CT-R. Two additional variants in aminoacid position 79 (R79Q) and position 105 (T105A) were located inside or near helix-H2 which interacts with the Ω-loop through hydrogen-binding rendering the serine active site more pliable to accommodate larger molecules. Moreover, the CT-R isolate showed a truncated ampD and multiple mutations in mexD, mexT, mexI, and mexR, a primary regulator of mexAB-oprM. The isolate also contained the oprD mutation (Q142X) and an oprD-inactivating mutation (W417X). In addition to these chromosomal mutations, the isolate harbored OXA-50, blaPAO1, and aph(3′)-IIb.

Conclusion
High-level CT-R was likely driven by multiple mutations in the ampC region causing structural changes. While resistance to CT is worrisome, our case of a severe neutropenic patient who rapidly cleared bacteremia on CT 3g qh8 given over 4 hours plus TOB emphasizes the importance of strategic combination and dosing in combating MDR PSA.

Disclosures
All authors: No reported disclosures.
704. Klebsiella pneumoniae Carbapenemase and Verona Integron-Encoded Metallo-β-Lactamase Among Carbapenem-Resistant Enterobacteriaceae in Kentucky
Authors: Spicer Kevin , Roser Lynn , Flinchum Andrea 
Published: November 2018

Abstract

Background
Klebsiella pneumoniae carbapenemase (KPC) and Verona integron-encoded metallo-β-lactamase (VIM) have been the most commonly identified carbapenemases among carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) in Kentucky since 2013. Understanding the frequency and epidemiology of these CP-CRE can help inform prevention strategies.

Methods
We reviewed reports of KPC- and VIM-producing CRE from January 2013 through December 2017. CRE became reportable in Kentucky in February 2015 and statewide request to laboratories and healthcare facilities for isolate submission for mechanism testing was made in September 2017. Prior to that time, mechanism testing for CRE was conducted at a limited number of laboratories or during outbreak investigations. Demographic data included age, sex, and inpatient or outpatient status. Descriptive analyses were performed.

Results
As of December 31, 2017, a total of 156 CP-CRE isolates had been identified (124 KPC, 31 VIM, 1 NDM), with an increase from 2013 (n = 13) to 2017 (n = 48). KPC was identified in isolates from 124 patients; VIM was identified in isolates from 26 patients, with 4 patients (15%) having multiple organisms with the mechanism. KPC was identified most commonly from Klebsiella pneumoniae (57/124, 46%); VIM was identified most commonly from Enterobacter cloacae (14/31, 45%). KPC was found in 6 different Enterobacteriaceae genera; VIM in 4. KPC-producing CRE were identified in 22 acute-care and long-term acute-care facilities in 14 counties, with nine reporting &gt;2 isolates. Fifteen percent (19/124) of KPC-producing CRE were isolated from outpatients. VIM-producing CRE were identified in two acute-care facilities located in two urban areas; one was from an outpatient. Patients with VIM were younger than those with KPC (43 vs. 60 years, P &lt; 0.001).

Conclusion
KPC is the predominant carbapenemase in Kentucky and is more widely disseminated than VIM, which has been limited to two facilities. CRE reporting and mechanism testing have yielded a greater understanding of regional CRE epidemiology and has the potential to facilitate response efforts to slow further spread.

Disclosures
All authors: No reported disclosures.