bluuebunny/crossref_metadata_2025_split huggingface dataset:
599. LiaF is an Activator of the LiaR-Mediated Response Against Daptomycin and Antimicrobial Peptides in Multidrug-Resistant Enterococcus faecalis (Efs)
Authors: Ortiz-Velez Laura C , Rincon Sandra L , Degani Jesse , Shamoo Yousif , Tran Truc T , Arias Cesar A , Panesso Diana 
Published: October 2019

Abstract

Background
Daptomycin (DAP) is a key first-line agent for the treatment of vancomycin-resistant enterococcal infections. Resistance to DAP in enterococci is regulated by the liaFSR three-component regulatory system that consists of a histidine kinase sensor (LiaS), a response regulator (LiaR) and a transmembrane protein of unknown function (LiaF). Previous studies indicate that deletion of isoleucine in position 177 of LiaF results in DAP tolerance and is sufficient to change membrane architecture. Here, we dissect the role of LiaF in DAP resistance

Methods
We generated three liaF mutants in OG1RF, a DAP-susceptible laboratory strain of Efs (DAP MIC = 2 µg/mL): (i) a non-polar, C-terminal truncation of liaF (OG1RFliaF∆152), (ii) a null liaF mutant with a premature stop-codon (OG1RFliaF*11), and (iii) an isoleucine deletion at position 177 (OG1RFliaF177). We determined DAP MIC by Etest and characterized the localization of anionic phospholipids microdomains using 10-nonyl-acridine-orange (NAO). The expression of the liaXYZ (the main target of LiaR) and liaFSR clusters were evaluated by qRT-PCR and relative expression ratios (Log2 fold change) were calculated by normalizing to gyrB expression. We assessed activation of LiaFSR by evaluating surface exposure of LiaX by ELISA. We used the bacterial adenylate cyclase two-hybrid system (BACTH) to evaluate the protein-protein interaction between LiaF and LiaS.

Results
Full deletion of liaF or the C-terminal truncation of LiaF did not have any effect on DAP MICs, membrane architecture or a significant increase in LiaX surface exposure compared with parental strain OG1RF. In contrast, deletion of the codon encoding isoleucine in position 177 of LiaF caused a major increase (8-fold) in LiaX exposure and redistribution of anionic phospholipid microdomains away from the septum without changes in the actual DAP MIC. Transcriptional analyses indicated upregulation (>2 log2-fold) in the liaXYZ gene cluster indicating activation of the stress response. We also observed a positive interaction between LiaF and LiaS.

Conclusion
LiaF is likely a key activator of the LiaFSR stress response and the critical regulatory domain appears to be located in a stretch of four isoleucines toward the C-terminal of the protein.

Disclosures
All authors: No reported disclosures.
628. Integrated Surveillance for Antimicrobial-Resistance in Salmonella From Clinical and Retail Meat Sources—Pennsylvania, 2015–2017
Authors: M’ikanatha Nkuchia M , Kline Kelly E , Boktor Sameh W , Yin Xin , Dettinger Lisa , Tewari Deepanker , Tate Heather 
Published: October 2019

Abstract

Background
Antimicrobial resistance (AMR) in foodborne pathogens of animal origin, including nontyphoidal Salmonella (NTS), is a public health concern. Pennsylvania conducts integrated surveillance for AMR in NTS from human and animal sources in collaboration with the FDA and CDC National Antimicrobial Resistant Monitoring System (NARMS).

Methods
We reviewed pulsed-field gel electrophoresis (PFGE), antimicrobial susceptibility (SST) and whole-genome sequencing (WGS) data for isolates from animal and food sources, including 96 NTS from 2,520 meat samples (poultry, ground beef and pork chops) purchased during 2015–2017 from randomly selected retail outlets in Pennsylvania. SST to 15 antimicrobial agents was done on 109 NTS clinical isolates that had similar PFGE patterns to meat isolates. SST and WGS were used to characterize all isolates from meat and two clinical isolates from 2017.

Results
28 (29.2%) and 17 (17.7%) NTS isolated from meat sources were resistant to ≥3 and ≥5 antibiotics classes, respectively. Resistance to ceftriaxone rose from 12% (3/25) in 2015 to 27% (10/37) in 2016 and resistance to amoxicillin/clavulanate also increased. Plasmid-mediated bla CMY-2 β-lactam resistance genes that hydrolyze extended-spectrum cephalosporins (ESC) increased from 12% in 2015 (3/25) to 18.9% (7/37) in 2016. Four blaCTX-M-65 genes that confer resistance to extended-spectrum β-lactamases (ESBLs) were identified in 2016 (n = 3) and 2017. Of the 109 clinical isolates, 25.7% demonstrated resistance to ≥3 and 11% to ≥5 antibiotics classes, respectively. No clinical isolates were resistant to ceftriaxone in 2015, 12.5% (6/48) and 24.3% (9/37) were resistant in 2016 and 2017, respectively. Resistance to amoxicillin/clavulanate was demonstrated in 8.3% (4/48) of isolates in 2016 (figure). Two clinical isolates carried blaCTX-M-65 ESB Ls genes and were resistant to eight antimicrobial agents (ACSSuTCxNalCot. Phenotype).

Conclusion
NTS (≥25%) from animal and human sources were multidrug-resistant and harbored CMY-2 and CTX-M-65 genes. Dissemination of genes that confer resistance to ESBLs and ESCs in NTS undermines recommended treatment for severe infections and underscores the need for One-Health surveillance and antimicrobial stewardship efforts.

Disclosures
All authors: No reported disclosures.
659. Evaluation of a Rapid Diagnostic Assay for Early Detection of Bacteriuria
Authors: Christian Robbie Lee Anne , Donskey Curtis , Navas Maria 
Published: October 2019

Abstract

Background
Patients with suspected urinary tract infection (UTI) are often prescribed an empiric antibiotic treatment due to delays in obtaining results of urine cultures. The BacterioScan System measures the turbidity of incubating urine specimens to provide a qualitative determination of bacteriuria at a density of >5 × 104 colony-forming units (CFU)/mL within approximately 3 hours. We examined the utility of the BacterioScan assay in predicting bacteriuria and assessed the potential impact of this test to reduce the number of urine cultures processed.

Methods
Urine samples received for culture in the microbiology laboratory of the Cleveland VA Medical Center were collected daily between September 2018 and December 2018. For each specimen, we performed a bacterioscan diagnostic test and compared it with the result of the traditional culture and urinalysis if available. Urinary cultures were categorized into 4 groups as defined in Figure 1. We compared the sensitivity and specificity of the bacterioscan vs. urinalysis (leukocyte esterase and/or pyuria) results.

Results
120 urine samples were tested. As shown in Table 1, the BacterioScan had better sensitivity and specificity than the urinalysis for detection of positive urine cultures. The use of the BacterioScan to rule out UTI could have accurately spared 69 of 120 (57.5%) samples from traditional culture and prevented 26 of 120 (21.6%) from possible misinterpretation as infection due to reporting of growth. BacterioScan resulted in 4 of 31 (12.9%) false negatives, but all occurred when positive cultures were due to viridans streptococci or uropathogens in numbers below 100,000 CFU.ml.

Conclusion
The BacterioScan system is a rapid diagnostic test that provides early information on urine culture results that could help to avoid overuse of empirical antimicrobials in patients with suspected UTI and decrease the workload of the Microbiology Laboratory.

Disclosures
All authors: No reported disclosures.
676. Health-Related Quality of Life (HRQoL) as Measured by the 12-Item Medical Outcomes Study Short-Form (SF-12) Among Adults With Community-Acquired Bacterial Pneumonia (CABP) Who Received Either Lefamulin (LEF) or Moxifloxacin (MOX) in Two Phase 3 Randomized, Double-Blind, Double-Dummy Clinical Trials (LEAP 1 and 2)
Authors: Lodise Thomas , Colman Sam , Alexander Elizabeth , Stein Daniel , Fitts David , Goldberg Lisa , Schranz Jennifer 
Published: October 2019

Abstract

Background
Interest in patient health experience as part of a benefit–risk assessment for new drug approvals is increasing. Patient-centeredness, a key metric in the 2010 Affordable Care Act, is also a growing area of focus in healthcare. LEF, a new antibiotic in development for treating adults with CABP, was noninferior to MOX based on clinical response endpoints in LEAP 1 and 2. HRQoL was prospectively incorporated and evaluated in both studies via SF-12, a well-known survey that measures general health status in 8 domains (physical function, role limitations due to physical problems, bodily pain, general health, vitality, social function, role limitations due to emotional problems, and mental health).

Methods
An exploratory analysis evaluated HRQoL in patients who received LEF or MOX in LEAP 1 (IV-PO treatment) and LEAP 2 (PO-only treatment). SF-12 was measured at baseline (BL) and test-of-cure (TOC; 5–10 days after last study drug dose). SF-12 outcomes assessed included the 8 domains, physical component summary (PCS), and mental component summary (MCS) scores. SF-12 scores were normalized to the 2009 US population reference mean (SD) of 50 (10). A 3-point change on any scale represents a clinically meaningful difference.

Results
Analysis included 1,215 patients (LEF n = 607; MOX n = 608). At BL, all mean SF-12 scores in both treatment groups were well below the US reference mean, indicating a low HRQoL level, consistent with the acute illness of the study population (figure). Clinically meaningful and significant improvements from BL to TOC were observed in all domain, PCS, and MCS scores in both groups. Mean scores were close to the reference mean, indicating an average HRQoL level. No significant differences in mean score improvements from BL to TOC were seen for LEF vs. MOX. SF-12 score improvements at TOC across predefined subgroups (age, sex, number of comorbidities, study, and PORT risk class) were comparable between treatment groups.

Conclusion
Our data indicate that adults with CABP experienced HRQoL improvements with LEF that were comparable with MOX, and treatment with either agent resulted in return to normal HRQoL. When combined with overall study results, these data suggest LEF as a potential alternative to MOX for treatment of adults with CABP.

Disclosures
All authors: No reported disclosures.
679. In vitro Activity of Cefiderocol (CFDC), a Novel Siderophore Cephalosporin, Against Difficult-to-Treat-Resistant (DTR) Gram-Negative Bacterial Pathogens From the Multi-National Sentinel Surveillance Study, SIDERO-WT (2014–2017)
Authors: Longshaw Christopher , Tsuji Masakatsu , Hackel Meredith M , Sahm Daniel F , Yamano Yoshinori 
Published: October 2019

Abstract

Background
DTR organisms are defined as nonsusceptible to all high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems, and quinolones), leaving physicians with limited first-line treatment options. Analyses of electronic health records have shown that patients with DTR Gram-negative bacterial infections are more likely to receive inappropriate antibiotic therapy, have longer hospital stay and increased risk of mortality. CFDC is a novel parenteral siderophore cephalosporin with potent activity against aerobic Gram-negative pathogens, including carbapenem-resistant strains. We evaluated the in vitro activity of CFDC and comparators against DTR pathogens collected by the SIDERO-WT surveillance study.

Methods
A total of 30,459 clinical isolates of Gram-negative bacilli were systematically collected from United States, Canada, and 11 EU countries during 2014–2017. MICs were determined by broth microdilution for a panel of 7 antibiotics, including CFDC, ceftazidime–avibactam (CZA), ceftolozane–tazobactam (C/T), colistin (CST), cefepime (FEP), meropenem (MEM), and ciprofloxacin (CIP) according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller–Hinton broth (CAMHB) except CFDC, for which iron-depleted CAMHB was used. Susceptibility was determined according to CLSI interpretive breakpoints except CST, where EUCAST breakpoints were used. DTR pathogens were defined as being nonsusceptible to FEP, MEM, and CIP according to CLSI breakpoints.

Results
Among 30,459 Gram-negative isolates collected between 2014 and 2017, 9.3% were nonsusceptible to FEP, MEM, and CIP and could be defined as DTR. DTR was most frequently observed in Acinetobacter spp. (55.5%), followed by Burkholderia spp. (19%), Pseudomonas aeruginosa (9.5%), and Enterobacterales (2.7%). Of the 1,173 Stenotrophomonas maltophilia tested, 97% had MEM MIC of ≥8 mg/L; however, only 2.9% could be defined as DTR. Cefiderocol was the most active antibiotic tested against DTR isolates with 94.5% DTR-Acinetobacter spp., 98.3% DTR-P. aeruginosa, and 99.8% DTR-Enterobacterales susceptible (Table 1).

Conclusion
CFDC demonstrated potent activity against DTR Gram-negative pathogens with limited first-line treatment options.

Disclosures
All authors: No reported disclosures.
704. Incidence and Patient Outcomes of S. aureus Isolates from Acute Bacterial Skin and Skin Structure Infections (ABSSSI) with High Iclaprim MIC values in Phase 3 REVIVE Trials
Authors: Huang David B , Charrier Cedric , Le Bras Chloe , Hawser Stephen , Noviello Stephanie S 
Published: October 2019

Abstract

Background
The incidence and outcomes of patients with S. aureus isolates with an iclaprim MIC >8 µg/mL, a concentration that is not systemically achievable, were determined among patients from two Phase 3 studies for the treatment of ABSSSI, REVIVE-1 and -2.

Methods
REVIVE-1 and REVIVE-2 studies were 600-patient, double-blinded, randomized (1:1), active-controlled trials among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg (adjusted for renal function), both administered intravenously over 2 hours every 12 hours for 5–14 days. Patients had a bacterial skin infection suspected or confirmed to be due to a Gram-positive pathogen with a lesion size ≥75 cm2. An early clinical response (ECR) was defined as a ≥20% reduction in lesion size compared with baseline at the early time point (ETP) 48–72 hours after the start of administration of the study drug in the intent-to-treat (ITT) population. A clinical cure, defined as complete resolution of all signs and symptoms of ABSSSI was measured at the end of therapy (EOT) and test of cure (TOC) visit, 7–14 days after the last dose of study drug. At baseline, EOT and TOC visits, ABSSSIs were sampled for microbiological culture and broth microdilution susceptibility testing conducted in accordance with CLSI M7.

Results
The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC >8 µg/mL was 2.0% (16/790). Six were MSSA and 10 were MRSA. The clinical outcomes of these infections included ECR of 63% (10/16), EOT response of 81.3% (13/16) and the TOC response of 75% (12/16). For microbiological outcomes of these infections, the end of therapy response was 92.9% (13/14) and the test of cure response was 92.3% (12/13). In comparison, there was less variation in vancomycin MICs among the S. aureus isolates. For patients who were randomized to vancomycin and had a pathogen identified from their ABSSSI, the pooled ECR was 82.6% (242 of 293) at a vancomycin MIC of 0.5–1 µg/mL and one isolate from a patient with ECR had a MIC of 2 µg/mL.

Conclusion
Patients receiving iclaprim had good clinical and microbiological responses against S. aureus isolates with an iclaprim MIC >8 µg/mL, which are uncommon (2.0%).

Disclosures
All authors: No reported disclosures.
758. High-Throughput Mining of Electronic Medical Records Using Generalizable Autonomous Scripts
Authors: Rochat Ryan H , Demmler-Harrison Gail J 
Published: October 2019

Abstract

Background
The electronic medical record (EMR) has become a modern compendium of health information, from broad clinical assessments down to an individual’s heart rate. The wealth of information in these EMRs hold promise for clinical discovery and hypothesis generation. Unfortunately, as these systems have become more robust, mining them for relevant clinical information is hindered by the overall data architecture, and often requires the expertise of a clinical informatician to extract relevant data. However, as the information presented to the clinician through the digital workspace is derived from the core EMR database, the format is well structured and can be mined using text recognition and parsing scripts.

Methods
Here we present a program which can parse output from Epic Hyperspace®, generating a relational database of clinical information. To facilitate ease of use, our protocol capitalizes on the familiarity of Microsoft Excel® as an intermediary for storing the raw output from the EMR, with data parsing and processing scripts written in SAS V9.4 (Cary, North Carolina).

Results
As a proof of concept, we extracted the diagnosis codes and standard laboratories for 190 patients seen in our Congenital Cytomegalovirus Clinic at Texas Children’s Hospital in Houston, Texas. Manual extraction of these data into Microsoft Excel® took 1 hour, and the scripts to parse the data took less than 5 seconds to run. Data from these patients included: 3800 ICD-10 codes (along with their metadata) and 33,000 individual laboratory values. In total, more than 850,000 characters were extracted from the EMR using this technique. Manual review of 10 randomly selected charts, found the data in perfect concordant with the EMR, a direct reflection of the fidelity of the parsing scripts. On average, an experienced user was able to enter three ICD-10 codes each minute, and six individual laboratory values per minute. At best, this same process would have taken at least 110 hours using a conventional chart review technique.

Conclusion
High-throughput data mining tools have the potential to improve the feasibility of studies dependent upon information stored in the EMR. When coupled with specific content knowledge, this approach can consolidate months of data collection into a day’s task.

Disclosures
All authors: No reported disclosures
1005. The Antibiotic Optimization DOOR: Refining Assessment of Antibiotic Therapy with Desirability of Outcome Ranking
Authors: Smoke Steven , Patel Vishal , Leonida Nicole , DeVivo Maria 
Published: October 2019

Abstract

Background
Desirability of outcome ranking (DOOR) is a novel methodology for incorporating multiple outcomes into a single value to more comprehensively compare therapeutic strategies. Its primary application has been limited to antibiotic clinical trials, incorporating treatment success and antibiotic toxicity into a single measure. We describe the application of DOOR methodology to a retrospective study evaluating antibiotic optimization.

Methods
This was a single-center, retrospective quasi-experimental study conducted at an academic medical center evaluating the impact of prospective pharmacist review of rapid molecular diagnostic testing (RDT) of blood cultures on antibiotic optimization. Two 8-week time periods were evaluated, corresponding to RDT implementation prior to prospective pharmacist review (RDT-only) and RDT with prospective pharmacist review (RDT-PPR). Patients with a positive blood culture who were not on optimal therapy at the time of gram stain were included in the study. Outcomes included the percentage of patients who received optimal therapy, time to optimal antibiotic therapy, and percentage of patients who had therapy de-escalated. An antibiotic optimization DOOR was created with 3 ordinal ranks. The most desirable outcome, rank one, was patients receiving optimal therapy with no missed de-escalation opportunities. Rank two was patients receiving optimal therapy with a missed de-escalation opportunity. The least desirable outcome, rank three, consisted of patients not receiving optimal antibiotic therapy. Time to optimal therapy was used as a tiebreaker for patients in ranks one and two.

Results
A total of 19 and 29 patients were included in the pre and post-intervention periods, respectively. The percentage of patients reaching optimal therapy was 84% (16/19) and 97% ([28/29], P = 0.16). Median time to optimal therapy was 30:28:26 and 22:40:17 (P = 0.32), respectively. DOOR analysis indicated that the probability of a better outcome for the RDT-PPR group than the RDT-only group was 58% (95% CI 54–62).

Conclusion
In this small retrospective study, the use of a novel composite methodology identified the benefit of an intervention that was not detected by standard comparison of individual outcomes.

Disclosures
All authors: No reported disclosures.
1033. Effectiveness of a Physician-Driven Automated Antibiotic Time Out in the Setting of Gram-negative Bacteremia
Authors: Mohayya Sana , Narayanan Navaneeth , Cimilluca Daniel , Vaidya Parth , Malanowski Alexander , Bhowmick Tanaya 
Published: October 2019

Abstract

Background
In an effort to minimize complications associated with over-utilization of antibiotics, many antimicrobial stewardship programs have incorporated an antibiotic time out (ATO). Despite the increasing adoption of the ATO, limited data are available to support its effectiveness. This study was designed to assess the impact of an automated ATO integrated into the electronic medical record (EMR) on the rate of antibiotic modification in patients receiving broad-spectrum antibiotic(s) for Gram-negative bacteremia (GNB).

Methods
This was a single-center retrospective cohort study of inpatients from January 2017 to June 2018 conducted at a large academic medical center. ATO was implemented on October 31, 2017. Adult patients with GNB who received at least 72 hours of a systemic antibiotic were included. Patients with neutropenia or polymicrobial infections were excluded. The primary outcome was the proportion of patients who received a modification of therapy within 24 hours of final culture results. Secondary outcomes included modification at any point in therapy, time to modification of therapy, time to de-escalation, and days of therapy of broad-spectrum antibiotics.

Results
There was a total of 88 patients who met inclusion criteria, 37 patients pre-ATO and 51 patients post-ATO. The primary outcome of modification of therapy within 24 hours of final culture results was not significantly different for patients in the pre-ATO and post-ATO groups (19% vs. 20%, P = 0.94, respectively). The secondary outcome of modification of therapy at any point in therapy was not significantly different between the two groups (62% vs. 66%, P = 0.67). Of the 47 patients who received a modification of therapy, the mean time to modification was significantly shorter in the post-ATO group (52.8 hours vs. 45.26 hours, P < 0.05,). All other secondary outcomes were not significantly different between study groups.

Conclusion
The ATO alert was not associated with a higher rate of antibiotic modification within 24 hours of culture results in patients with GNB, although there was a significant reduction in the time to antibiotic modification. Further efforts are needed to improve the time to modification and optimize antibiotic prescribing practices.

Disclosures
All authors: No reported disclosures.