bluuebunny/crossref_metadata_2025_split huggingface dataset:
1330. Diagnosis and Management of NTM Lung Disease: Effect of Online Educational Interventions on Infectious Disease Specialist Knowledge
Authors: Jackson Edward , Chatterjee Piyali , Smith Susan , Badal Karen , Griffith David E 
Published: November 2018

Abstract

Background
Diagnosis and management of nontuberculous mycobacterial (NTM) lung disease is challenging for clinicians due to its rarity and the need for complicated, multidrug antibiotic regimens. The objective of this study was to determine whether online educational interventions can effectively address knowledge gaps among ID specialists regarding diagnosis and treatment of patients with NTM lung disease.

Methods
Two educational interventions, consisting of a text-based activity with interactive questions, and a video-based discussion between two experts, were developed and made available online. Educational impact of each intervention was assessed using a 3-question repeated pairs pre-/post-assessment study design. Data from a sampling of learners were collected from September 11, 2017 through January 17, 2018. Statistical analyses included a paired (within-physician) two-tailed t-test and McNemar’s χ2 statistic, with Cramer’s V to determine the overall effect of each intervention.

Results
Overall, a total of 1,273 ID specialist learners participated in the two activities from launch through April 30, 2018. Analysis demonstrated a significant improvement (P &lt; 0.05) in overall knowledge with considerable educational impact (V = 0.195 and 0.259). Improvements in specific areas included (figure). Despite gains in knowledge, additional gaps were also identified: (1) Regarding treatment of M. abscessus lung disease, 18% were unable to discern between guideline recommended therapies for M. abscessus and MAC complex NTM, and an additional 14% would treat with a less aggressive, noncurative regimen (n = 211), and (2) regarding treatment of fibrocavitary MAC complex NTM; nearly one-third (31%) would treat a using a thrice-weekly regimen, despite an indication for a daily regimen (n = 114).

Conclusion
Participation in interactive text-based as well as video-based activities improved the ability of ID specialists to make evidence-based decisions in the care of NTM lung disease. The findings also uncovered educational needs that warrant further education in selecting appropriate therapeutic regimens particularly in cases where aggressive therapy is indicated.

Disclosures
E. Jackson, Medscape: Employee, Salary. P. Chatterjee, Medscape: Employee, Salary. S. Smith, BioFire Diagnostics: Independent Medical Education, Educational grant. K. Badal, Medscape: Employee, Salary. D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Bayer Healthcare Pharmaceuticals: Advisor/consultant, Consulting fee. Grifols: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Insmed Incorporated: Advisor/consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.
1333. Developing an Educational Tool to Improve Housestaff Knowledge, Attitudes, and Behavior in Managing Common Infectious Diseases
Authors: Jacob Paul , Person Anna , Bloch Karen , Fiske Christina T , Kuriakose Kevin , Bourgi Kassem , Dougherty David , Dobrzynski David , Staub Milner Owens , Byrge Kelly , Grome Heather , Cohen Caroline , England James , Nair Devika , Kelly Sean 
Published: November 2018

Abstract

Background
Improving internal medicine (IM) trainees skills in managing common infectious diseases is essential to their development as competent physicians. We currently lack quantitative data of the knowledge and attitudes of IM housestaff regarding their management of common infectious diseases. We applied the knowledge, attitude, and behavior model to a pre-intervention survey aimed to uncover housestaff knowledge gaps and discomfort in managing several of the most commonly encountered infectious diseases at our institution. Using this information, we plan to develop a targeted post-survey intervention to increase self-efficacy and improve antimicrobial prescription practices among trainees.

Methods
Survey questions were based on Infectious Disease Society of America (IDSA) guidelines and developed using an iterative process involving interviews of infectious disease physicians and IM housestaff. We chose to focus on cystitis, pneumonia, and skin and soft-tissue infections. The anonymous survey tool was developed using a secure, online platform, and distributed in January 2018. Participation was voluntary and no remuneration for participation was offered.

Results
Out of 165 survey recipients, 50 trainees (30%) responded. Fifty-eight percent of trainees stated that they possessed only an average level of knowledge regarding the management of cystitis, pneumonia, and cellulitis. While 98% of housestaff confirmed that they utilized additional resources for information, only 24% felt routinely comfortable making decisions without an infectious disease consultation. Ninety-six percent of trainees felt that an institution-specific guide describing the management of common infectious diseases would be highly beneficial.

Conclusion
Trainees still lack the knowledge and confidence to make decisions regarding the empiric management of cystitis, pneumonia, and skin and soft-tissue infections at our academic medical center. There is a strong desire for an institution-specific educational resource to provide guidance for these decisions. Increasing trainee self-efficacy and improving their antimicrobial prescription practice patterns should be an educational priority.

Disclosures
All authors: No reported disclosures.
1337. SYN-004 (Ribaxamase) Protects the Gut Microbiome of Patients Treated With Ceftriaxone From Disruption and Reduces the Emergence of Antimicrobial Resistance
Authors: Kokai-Kun John , Le Charles , Trout Kenneth , Cope Julia , Sliman Joseph 
Published: November 2018

Abstract

Background
When β-lactam antibiotics are administered intravenously, a significant portion of each dose can be excreted through the bile into the intestine. This excess antibiotic disrupts the balance of the gut microbiome making the recipient more susceptible to certain infections and can lead to the emergence of antimicrobial resistance. SYN-004 (ribaxamase) is an orally administered β-lactamase designed to be given with IV β-lactam antibiotics (penicillins and cephalosporins) to degrade excess antibiotics excreted into the upper GI tract before they can disrupt the gut microbiome and resistome.

Methods
During a Phase 2b, clinical study with ribaxamase which demonstrated a significant reduction in Clostridium difficile infection in patients receiving ceftriaxone + ribaxamase, longitudinal fecal samples were collected from the patients. DNA extracted from these samples was 16S rRNA and whole genome sequenced, and the sequences were analyzed for changes in the gut microbiome and resistome. Statistical analyses were performed to determine correlations between changes in the gut microbiome and resistome and clinical study data.

Results
Sequence analyses revealed that ribaxamase protected the integrity of the gut microbiome, including preventing enterococcal mono-domination (defined as &gt;30% of the microbiome being from one genus), and identified over 1,300 AMR genes in the gut resistome. LefSe analysis of the gut resistome identified a family of β-lactamases (CfxA) and vancomycin resistance genes which demonstrated a significant increase in placebo-treated vs. ribaxamase-treated patients from pre-to post-antibiotics. Analysis by qPCR supported both new acquisition of these genes and expansion of existing AMR pools. Further statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including β-lactamase gene frequency and study drug assignment, and efflux pump gene frequency and vancomycin resistance.

Conclusion
Taken together, these findings demonstrated that coadministration of ribaxamase with IV β-lactam antibiotics can protect the integrity of the gut microbiome and may help limit the emergence of AMR induced by these antibiotics.

Disclosures
J. Kokai-Kun, Synthetic Biologics, Inc.: Employee, Salary. C. Le, Synthetic Biologics, Inc.: Employee, Salary. K. Trout, Synthetic Biologics, Inc.: Employee, Salary. J. Sliman, Synthetic Biologics, Inc.: Employee, Salary.
1338. A Pooled Analysis of Patients With Wound Infections in the Phase 3 REVIVE Trials: Randomized, Double-blind Studies to EValuate the Safety and Efficacy of Iclaprim Vs. Vancomycin for trEatment of Acute Bacterial Skin and Skin Structure Infections
Authors: Huang David , Corey G Ralph , Holland Thomas L , Lodise Thomas P , O’Rirodan William , Wilcox Mark , File Thomas M , Dryden Matthew , Torres Antoni , Balser Barbara , Desplats Eve 
Published: November 2018

Abstract

Background
The objective of this evaluation was to provide an analysis of pooled efficacy data from two parallel Phase 3 trials of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, compared with vancomycin for the treatment of patients with wound infections including surgical site infections (SSI).

Methods
A pooled analysis of patients with wound infections was conducted from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2), which included a total of 602 patients with wound infections. The data were analyzed separately and then pooled to determine the efficacy of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg. Both drugs were administered intravenously every 12 hours for 5 to 14 days according to the investigator assessment of clinical response. The primary endpoint of these studies was to determine whether iclaprim was noninferior (NI; 10% margin) to vancomycin in achieving a ≥20% reduction in lesion size (early clinical response [ECR] at 48 to 72 hours after initiation of the study drug (early time point [ETP]), compared with baseline in the intent-to-treat (ITT) population.

Results
Iclaprim had similar ECR rates at ETP compared with vancomycin among the subset of patients with wound infections (see table). The median treatment duration for both iclaprim and vancomycin was 7 days (range 5–14 days).

Conclusion
In this post-hoc analysis of the REVIVE studies, iclaprim achieved NI to vancomycin in both studies, based on ECR at ETP, in the subgroup of patients with wound infections. These results suggest that iclaprim may be a valuable treatment option for patients with wound infections, including SSI, suspected or confirmed to be due to Gram-positive pathogens.

Disclosures
D. Huang, Motif BioSciences: Employee, Salary. G. R. Corey, Motif BioSciences: Board Member, Consulting fee. T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. T. P. Lodise Jr., Motif BioSciences: Board Member, Consulting fee. W. O’Rirodan, Motif BioSciences: Board Member, Consulting fee. M. Wilcox, Motif BioSciences: Board Member, Consulting fee. T. M. File Jr., Motif BioSciences: Board Member, Consulting fee. M. Dryden, Motif BioSciences: Board Member, Consulting fee. B. Balser, Motif BioSciences: Consultant, Consulting fee. E. Desplats, Motif BioSciences: Consultant, Consulting fee.
1340. Population Pharmacokinetic (PK) Analysis of APX001 Using Phase 1 Data
Authors: Trang Michael , Bader Justin C , Ople Eric A , Kramer William G , Hodges Michael R , Bhavnani Sujata M , Rubino Christopher M 
Published: November 2018

Abstract

Background
APX001 is a novel antifungal agent which is rapidly converted to the active metabolite APX001A. APX001A exhibits in vitro activity against many clinically important yeast and fungi, including echinocandin- and azole-resistant Candida species. Given this activity, intravenous (IV) and oral (PO) formulations of APX001 are being developed for the treatment of patients with candidemia or invasive candidiasis. Phase 1 data were used to develop a population PK (PPK) model to describe the time-course of APX001A in plasma.

Methods
The PPK model was developed using 3,736 plasma PK samples collected from 128 healthy subjects who received APX001 single and multiple IV and PO doses ranging from 10 to 1,000 mg. Instantaneous conversion was assumed by scaling input doses by the molecular weight ratio of APX001A to APX001. After development of the structural PK model, stepwise forward and backward selection procedures were used to identify significant covariate relationships. Model qualification included standard goodness-of-fit metrics and prediction-corrected visual predictive check (PC-VPC) plots.

Results
A two-compartment model with zero-order IV input, or first-order PO absorption with lag time to account for the apparent delay in oral absorption, best described APX001A plasma PK. Exponential error models were used to estimate interindividual variability (IIV) for all parameters. Interoccasion variability was estimated for the absorption rate constant, bioavailability, and lag time. Body weight was identified as a statistically significant predictor of the IIV on the volume of the central and peripheral compartments. The PPK model provided an accurate and unbiased fit to the plasma data based on individual- and population-predicted concentrations (r2 = 0.977 and 0.873, respectively). The PC-VPC plots for the final PPK model (Figure 1) demonstrated good alignment between observed concentrations and the model predicted 5th, 50th, and 95th percentiles.

Conclusion
A PPK model describing APX001A plasma PK following IV or PO doses was successfully developed. This model will be useful for generating simulated APX001A exposures for use in pharmacokinetic–pharmacodynamic target attainment analyses to support APX001 dose selection.

Disclosures
M. Trang, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. J. C. Bader, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. E. A. Ople, Amplyx Pharmaceuticals, Inc.: Employee, Salary. W. G. Kramer, Amplyx Pharmaceuticals, Inc.: Scientific Advisor, Consulting fee. M. R. Hodges, Amplyx Pharmaceuticals, Inc.: Employee, Salary. S. M. Bhavnani, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. C. M. Rubino, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support.
1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor
Authors: Garvey Edward P , Sharp Andrew , Warn Peter , Yates Christopher M , Schotzinger Robert J 
Published: November 2018

Abstract

Background
VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model.

Methods
MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v.

Results
The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (&gt;99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013).

Conclusion
VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies.

Disclosures
E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.
1349. Global Surveillance of Cefiderocol Against Gram-Negative Clinical Strains Collected in North America: SIDERO-WT-2015
Authors: Tsuji Masakatsu , Hackel Meredith , Echols Roger , Yamano Yoshinori , Sahm Dan 
Published: November 2018

Abstract

Background
Cefiderocol (CFDC) is a novel parenteral siderophore cephalosporin with potent activity against a wide range of Gram-negative pathogens, including carbapenem-resistant strains. Additionally, a recently conducted in vivo murine-based study has demonstrated an incremental exposure-response profile over a dose range without the appearance of adaptive resistance. In this study, we evaluated the in vitro activity of CFDC and comparator agents against clinical isolates collected in 2015–2016 from North America from SIDERO-WT-2015 surveillance study.

Methods
A total of 3,602 isolates (2,470 Enterobacteriaceae, 223 A. baumannii, 85 Acinetobacter spp., 619 P. aeruginosa, 165 S. maltophilia and 17 Burkholderia cepacia, and 23 Burkholderia spp.) collected from the United States and Canada in 2015–2016 were tested. MICs were determined for CFDC, cefepime (FEP), ceftazidime–avibactam (CZA), ceftolozane–tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI guidelines. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller–Hinton broth (ID-CAMHB). Carbapenem nonsusceptible (Carb-NS) strains were defined as MEM MIC ≥2 µg/mL for Enterobacteriaceae, and ≥4 µg/mL for nonfermenters.

Results
CFDC exhibited potent in vitro activity against 3,602 strains of Gram-negative bacteria with an overall MIC90 of 0.5 mg/mL. As shown in the following table, MIC90 of CFDC against P. aeruginosa, A. baumannii, S. maltophilia, and Enterobacteriaceae including the subset of Carb-NS isolates were 0.5, 2, 0.5 and 0.5 mg/mL, respectively. At 4 mg/mL, CFDC inhibited the growth of 99.6% of the isolates while 18.1%, 12.6%, and 13.8% showed resistance to CZA, C/T, and CST, respectively.

Conclusion
CFDC demonstrated potent in vitro activity against the teat isolates collected from North America with greater than 99.6% of isolates having MIC values ≤4 mg/mL, including Carb-NS isolates of A. baumannii, P. aeruginosa, and Enterobacteriaceae. These findings indicate that this agent has high potential for treating infections caused by these problematic organisms.

Disclosures
M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. M. Hackel, IHMA, Inc.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary. D. Sahm, IHMA, Inc.: Employee, Salary.
1352. A Computational Approach for Exploring the Binding Mechanism of Chebulinic Acid on Herpes Simplex Virus-2 and Its Implication on Chikungunya and Dengue
Authors: Thomas Naiju , Kumar Sandeep , Kumar Vikas , Tapryal Suman 
Published: November 2018

Abstract

Background
Chebulinic acid (CA), a natural compound isolated from the tree Terminalia chebula, was recently reported to have shown antiviral activity against Herpes simplex virus-2 (HSV-2). The study showed inhibition activity of CA, preventing the attachment of HSV-2 on the host cells. This activity was speculated to be due to an interaction between CA and viral surface glycoproteins, triggering alterations in its function or making virus particles inert and preventing their attachment to host cells. However, the mechanism of this inhibition was not established. The current study was designed not only to help gain insights of the mechanism of action of CA on HSV-2, but also to computationally check its binding affinity on other enveloped arboviruses, i.e., Chikungunya (ChikV) and Dengue (DenV).

Methods
The viral surface glycoproteins of HSV-2, ChikV, and DenV were subjected to molecular docking with CA using the software, AutoDock Vina. Protein–protein docking was performed with ClusPro online server to elucidate the specific site and residues involved in binding between viral protein and human host receptors. Due to unavailability of crystal structure of Prohibitin, a human receptor for ChikV, structural modeling was performed with i-Tasser server.

Results
The conformations obtained after docking showed good hydrogen bond interactions with a docking energy of −9.3, −8.1, and −8.8 kcal/mol against HSV-2, ChikV, and DenV, respectively. In all three viruses, CA was found to bind specifically at the site directly involved in host attachment, suggesting a possible mechanism of action by which CA inhibits the viral attachment that is consistent with the result obtained from the in vitro experiment on HSV-2. Hence the natural bio-molecule Chebulinic acid has the potential to inhibit the host attachment step of HSV-2, ChikV, and DenV by directly binding to their viral glycoproteins.

Conclusion
Chebulinic acid shows a good propensity as an antiviral agent, capable of acting against multiple enveloped viruses. Additionally, a more potent and specific drug can be designed on the template of CA by process of molecular modification.

Disclosures
N. Thomas, Department of Science and Technology: Government of India funding agency, Salary. S. Kumar, University Grants Commission: Government of India funding agency, Educational grant. V. Kumar, University Grants Commission: Government of India funding agency, Educational grant. S. Tapryal, Department of Science and Technology: Government of India funding agency, Research grant.