bluuebunny/crossref_metadata_2025_split huggingface dataset:
1332. West Coast Transplant ID Conferences, A Model for Building Community in ID Disciplines?
Authors: Allyn Paul , Schaenman Joanna , Schwartz Brian , Vijayan Tara 
Published: November 2018

Abstract

Background
Transplant infectious diseases (TID) is a young and rapidly changing field. Providers need to make patient care decisions with limited clinical data. Challenges faced by TID providers may be different than others in their local ID community. We describe a model where TID faculty from six major transplant centers on the West Coast held periodic web-based conferences to discuss challenging cases and controversial topics in TID.

Methods
In 2011, faculty from six major transplant centers in the states of Washington, Oregon, and California began participating in web-based conferences. To assess impact, we distributed a 30-item survey generated in Qualtrics via email in Spring 2018. Participants were invited if they had ever attended one of the conferences. The survey collected quantitative and qualitative data on how the conferences changed clinical practice and helped build community. Data on conference topics was also collected.

Results
West Coast Transplant ID Conferences were held 12 times between 2011 and 2018 with TID topics covered including management of RSV, antifungal prophylaxis, CMV, and LTBI among others. Sixteen participants responded to the survey representing all six institutions. eight (50%) of respondents spent at least half of their time in the practice of TID. Six (37%) of respondents worked for &lt;5 years and five (31%) reported working more than 10 years in TID. 56% of participants attended ≥4 conferences in the last 3 years. 93% of participants included trainees on the conference call. All respondents agreed or strongly agreed that the topics covered were relevant to their practice. 87.5% felt that the calls generate consensus about difficult or controversial topics. 62.5% reported that they had changed their practice because of the conferences. Only 1 respondent reported that they collaborated on research because of the conference. 100% agreed or strongly agreed that the conferences built a sense of community within TID.

Conclusion
Given improvements in web-based technologies, a community of practice can be easily created despite geographic distance allowing for TID providers to discuss relevant topics that impact practice and enhance sense of community. This model could be reproduced in other areas of infectious diseases.

Disclosures
All authors: No reported disclosures.
1363. Sulopenem Activity Against Enterobacteriaceae Isolates From Patients With Urinary Tract Infection or Intra-Abdominal Infection
Authors: Puttagunta Sailaja , Aronin Steven , Huband Michael , Flamm Robert K , Dunne Michael 
Published: November 2018

Abstract

Background
Sulopenem is a thiopenem antibacterial with oral and parenteral formulations being developed for the treatment of urinary tract infection (UTI) or complicated intra-abdominal infection (cIAI). The activity of sulopenem aligns with the most urgent drug-resistant antimicrobial threats defined by the Centers for Disease Control (CDC), including ESBL-producing strains of Escherichia coli and Klebsiella species. We evaluated the in vitro antibacterial activity of sulopenem against clinical Enterobacteriaceae isolates from patients in North America with UTI or cIAI collected during 2016–2017.

Methods
Sulopenem and other antimicrobial agents were tested for in vitro activity against 1,008 recent (2016–2017) consecutive Enterobacteriaceae isolates collected through the SENTRY Antimicrobial Surveillance Program from patients in North America with UTI (906 isolates) or cIAI (102 isolates). Reference broth microdilution susceptibility testing was conducted using frozen-form panels produced by JMI Laboratories according to CLSI (M07, 2018) guidelines using cation-adjusted Mueller–Hinton broth. Quality control (QC) and interpretation of results were performed in accordance with CLSI M100 (2018) guidelines.

Results
Table 1. Activity of sulopenem and comparator antimicrobial agents against 1,008 Enterobacteriaceae North American isolates
The sulopenem MIC50/90 values for Enterobacteriaceae were 0.03/0.25 µg/mL. For Escherichia coli, Klebsiella species and Proteus mirabilis, the MIC50/90 results were 0.03/0.03 µg/mL, 0.03/0.06 µg/mL, and 0.12/0.25 µg/mL, respectively.

Conclusion
Sulopenem demonstrated potent in vitro activity against organisms commonly implicated in UTI and cIAI. These data support the further clinical development of sulopenem for Gram-negative infections.

Disclosures
S. Puttagunta, Iterum Therapeutics: Employee and Shareholder, Salary. S. Aronin, Iterum Therapeutics: Employee and Shareholder, Salary. M. Huband, JMI Labs: Research Contractor, Grant recipient. R. K. Flamm, Allergan: Research Contractor, Research support. M. Dunne, Iterum Therapeutics: Employee and Shareholder, Salary.
1373. Activity of Ceftriaxone–Sulbactam–EDTA Against Multi-Drug-resistant A. baumannii, P. aeruginosa and Enterobacteriaceae Isolates (WHO Critical Priority Pathogens) Collected from Various Hospitals in India
Authors: Girotra Ruchi , Pyasi Anurag , Chaudhary Manu , Patil N S , Mir Mohd Amin , Chaudhary Saransh , Mandale Pankaj ,   Other Investigators
Published: November 2018

Abstract

Background
Ceftriaxone–Sulbactam–EDTA (CSE) is the first cephalosporin–β-lactamase inhibitor combination with an antibiotic resistance breaker–disodium edetate, recently evaluated in a Phase 3 clinical trial for treatment of adults with complicated urinary tract infections (NCT03477422). The addition of Sulbactam and EDTA expands the spectrum of activity of Ceftriaxone to include extended-spectrum-β-lactamase (ESBL) and metallo-β-lactamase (MBL) producing bacteria. This study evaluated the in vitro activity of CSE against 3,150 isolates (716 (22.73%) E. coli; 435 (13.81%) K. pneumoniae; 1,075 (34.13%) A. baumannii; 924 (29.33%) P. aeruginosa) collected from 22 hospitals in India during 2013–2016.

Methods
A total of 3,150 nonduplicate Gram-negative clinical isolates were collected, and susceptibility testing was conducted using reference broth microdilution method for CSE and comparators. CLSI defined phenotypic methods were used for ESBL and MBL detection, and thereafter, all isolates were further characterized genotypically using single PCRs and a panel of primers for detection of most β-lactamase enzymes, including blaTEM, blaSHV, blaCTX-M, blaAmpC, blaOXA, blaKPC, blaVIM, blaNDM, and blaIMP.

Results
Of the 3,150 isolates, 2,717 (86.25%) were β-lactamase producers, of which, 851 (31.32%) tested positive for ESBL, 1,591 (58.56%) tested positive for MBL, while 275 (10.12%) tested positive for both ESBL and MBL production during phenotypic evaluation. Once the genotype data were available, isolates were re-characterized as per the functional classification of β-lactamases into four distinct categories, including ESBL, AmpC, Carbapenemase and MBL. An astonishing 1,866 (59.23%) isolates harbored at least one MBL gene, of which, the prevalence was the highest in A. baumannii (78.6%), followed by K. pneumoniae (63%), P. aeruginosa (46.6%) and E. coli (44.1%). A summary of the results of susceptibility testing is shown in Figures 1, 2, and 3.

Conclusion
CSE showed a high overall susceptibility in ESBL- and MBL-producing bacteria and could provide a useful alternative to carbapenems and colistin in clinical settings.

Disclosures
R. Girotra, Venus Medicine Research Centre: Employee, Salary. A. Pyasi, Venus Medicine Research Centre: Employee, Salary. M. Chaudhary, Venus Medicine Research Centre: Board Member and Shareholder, Salary. M. A. Mir, Venus Medicine Research Centre: Employee, Salary. S. Chaudhary, Venus Medicine Research Centre: Employee and Shareholder, Salary. P. Mandale, Venus Medicine Research Centre: Employee, Salary.
1376. Antifungal Activity of Cerium Nitrate Against Fungal Isolates Associated with Combat-Related Injuries Including Burns
Authors: Pomerantz Heather , Beckius Miriam , Blyth Dana , Akers Kevin S , Tribble David R , Mende Katrin 
Published: November 2018

Abstract

Background
Fungal infections are a critical cause of morbidity and mortality in burn patients. In addition to debridement and systemic antifungal therapy, various topical adjuncts have been used, and topical burn care is a key component of infection prevention and treatment. Cerium nitrate (CN) has been used in combination with silver sulfadiazine (SS) in burn care. Previous studies showed that CN had bacteriostatic activity, and suggested anti-biofilm activity against Candida biofilms. In this study, we evaluated the in vitro activity of CN against fungal isolates associated with combat-related injuries.

Methods
The efficacy of CN was evaluated against 14 mold (three Aspergillus spp., two Fusarium spp., five different mucormycetes, two Bipolaris spp., one Alternaria spp., one Exophiala spp.) and 21 Candida spp. isolates collected as part of the Trauma Infectious Disease Outcomes Study. Fungicidal activity of various concentrations of CN (2.2%, 1%, 0.5% and 0.2%) was determined using an established time-kill assay. Standard conidia/cell suspensions were prepared according to Clinical and Laboratory Standards Institute guidelines and then exposed to the CN solutions for 24 hours. At different times (0, 5, 15, 30 minutes, 1, 1.5, 3, 6, 12, and 24 hours) aliquots were plated and incubated at 35ºC. Colony forming unit (CFU) counts were determined after 24 hours incubation or after an appropriate time for slow growing molds.

Results
All mold isolates had persistent growth at 24 hours with most having no significant change in colony counts over the 24-hour period. The only exception was Mucor circinelloides, which appeared to have a time-dependent reduction in CFUs at 24 hours for all CN concentrations. Exophiala did not grow as well in CN solutions compared with the control (mean 65 vs. 28.2 CFUs with a difference of mean 37.4 CFUs, P = 0.0001), but this was not time or concentration dependent. All yeast species showed a time-dependent killing after 6–12 hours.

Conclusion
CN demonstrated time-dependent killing of the yeasts. However, very little activity was observed against the tested molds. Since CN is often used in combination with SS there might be a synergistic effect against molds. Further research will evaluate higher concentrations of CN and its toxicity for cells and tissue.

Disclosures
All authors: No reported disclosures.
1378. Evaluation of the In vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae, Including Isolates Resistant to Ceftazidime–Avibactam
Authors: Wilson William R , Kline Ellen , Jones Chelsea , Morder Kristin , Clancy Cornelius J , Nguyen M Hong , Shields Ryan K 
Published: November 2018

Abstract

Background
Meropenem-vaborbactam (M-V) is a novel antibiotic for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections. Our objective was to determine the in vitro activity of meropenem-vaborbactam against genetically-diverse CRE isolates, including those that have developed resistance to Ceftazidime–Avibactam (C-A).

Methods
Minimum inhibitory concentrations (MICs) were determined for meropenem (MER), M-V, and C-A by reference broth microdilution (BMD) methods in triplicate. Vaborbactam and avibactam were tested at fixed concentrations of 8 and 4 µg/mL, respectively. Quality control strains were used and within expected ranges. Polymerase chain reaction (PCR) with DNA sequencing was used to detect resistance determinants, including Klebsiella pneumoniae carbapenemase (KPC) subtypes and porin mutations.

Results
A total of 117 CRE isolates were tested, including K. pneumoniae (Kp; n = 83), E. cloacae (n = 17), E. coli (n = 10), and E. aerogenes (n = 7). Seventy-nine percent harbored blaKPC. KPC subtypes included KPC-2 (n = 32), KPC-3 (n = 41), KPC-3 variants (n = 16), and KPC [not typed] (n = 4, all E. coli). Among 74 K. pneumoniae, 95% had a premature stop codon in ompk35 and ompK36 genotypes included wild type (n = 48), IS5 insertion (n = 13), 135–136 DG duplication (n = 9), and other mutations (n = 4). The median (range) MICs for MER, C-A, and M-V were 8 (0.06 to ≥128), 1 (0.25 to ≥512), and 0.03 (0.015––16), respectively. Corresponding rates of susceptibility were 23, 84, and 98%, respectively. Fifty-three percent and 95% of C-A-resistant isolates were susceptible to MER and M-V, respectively. Among Kp, C-A MICs did not vary by KPC subtype or porin genotype. On the other hand, median M-V MICs were higher among KPC-2 than KPC-3 Kp (0.12 vs. 0.03; P = 0.002), and among Kp with ompK36 porin mutations compared with wild type (0.25 vs. 0.03; P &lt; 0.001). Among Kp with KPC-3 variants (n = 16), the median M-V MIC was 0.03 (0.015––2); 100% were M-V susceptible. Median M-V MICs did not vary by CRE species. Only two isolates were M-V resistant, both were E. cloacae that did not harbor blaKPC.

Conclusion
M-V demonstrates high rates of in vitro susceptibility against diverse CRE isolates, including those that are resistant to C-A. As this agent is introduced into the clinic, it will be important to identify K. pneumoniae isolates harboring KPC-2 with ompK36 porin mutations that demonstrate higher MICs.

Disclosures
M. H. Nguyen, Merck: Grant Investigator, Research grant. Astellas: Grant Investigator, Research grant.
1386. Efficacy of Repeat Dosing of Oral Fosfomycin in a Dynamic Bladder Infection In Vitro Model
Authors: Abbott Iain , Wijma Rixt , Broos Nick , Peleg Anton , Mouton Johan 
Published: November 2018

Abstract

Background
Oral fosfomycin is indicated for uncomplicated urinary tract infections with activity against MDR-uropathogens. Despite off-label use of giving three doses every 2–3 days, limited supporting data are available. We performed pharmacodynamic profiling using a dynamic bladder infection in vitro model to assess adequacy of repeat doses of fosfomycin.

Methods
A bladder infection in vitro model simulating urinary fosfomycin concentrations after 3 g (equiv.) oral doses was used with Mueller–Hinton broth (MHB) with 25 mg/L glucose-6-phosphate. Fosfomycin exposures were validated by LC–MS/MS measurements. Pharmacodynamic response of 16 clinical Enterobacteriaceae isolates were examined (eight E. coli, four E. cloacae, four K. pneumoniae; agar dilution MIC 0.25–64 mg/L) following three doses of fosfomycin given every 72, 48 or 24 hours, compared with single dose therapy. Pathogen kill and resistance was assessed by quantitative cultures on drug-free and fosfomycin-containing Mueller–Hinton agar (MHA +64 mg/L, +512 mg/L).

Results
Fosfomycin exposure following single and multiple doses were accurately reproduced (mean deviation from target 5.0 ± 3.4%, max 11.8%) with minimal variability (mean relative SD 2.7 ± 1.7%, max 8.8%). Fosfomycin high-level heteroresistance was detected prior to drug exposure in 8/16 isolates (proportion 0.00002–0.001% of total population). All isolates with high-level heteroresistance regrew following single dose fosfomycin. Following three doses given every 72 hours, one additional K. pneumoniae isolate was killed. All other isolates regrew with amplification of HLR subpopulation (median proportion: 71.4%, IQR 57.5–100%). Despite dosing 48 and 24 hourly, the same isolates regrew, although HLR subpopulation amplification was reduced (48 hours dosing: 32.0%, IQR 0.005–83.3%; 24 hours dosing: 0.3%, IQR 0.0004–81.3%).

Conclusion
Dynamic in vitro modeling of multiple doses of oral fosfomycin fails to additionally suppress regrowth in the majority of isolates compared with single dose therapy. Baseline high-level heteroresistance is an important predictor for regrowth. These results suggest that giving multiple doses of fosfomycin is not necessarily better than standard single dose therapy. Earlier timing of repeat doses may help suppress the emergence of resistance.

Disclosures
All authors: No reported disclosures.
1389. Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model Against S. aureus (SA) and S. pneumoniae (SPN)
Authors: Lepak Alexander J , Zhao Miao , Liu Qingmei , Wang Ping , Wang Yanli , Bader Justin C , Ambrose Paul G , Andes David R 
Published: November 2018

Abstract

Background
KBP-7072 is a novel aminomethylcycline antibiotic with broad-spectrum activity that includes organisms with drug-resistance to β-lactams and tetracyclines. We examined the PK/PD relationship between KBP-7072 drug exposures and treatment effect using a neutropenic murine pneumonia model against a diverse group of SA and SPN.

Methods
Five SAs (three MRSAs) and six SPNs (three PCNs NS, two TetR) strains were used. MICs were determined by CLSI Methods. Plasma and ELF PK was determined after SC dosing (range 1–256 mg/kg). Lung burden was assessed by CFU counts at the beginning and end of therapy (24 hours). Infected mice were treated with KBP-7072 by SC route: SA dose range 0.25–64 mg/kg/6 hours, SPN dose range 0.06–16 mg/kg/6 hours. The Emax Hill equation was used to model the dose–response data to the PK/PD index AUC/MIC. The magnitude of the PK/PD index (plasma free and ELF total concentrations) associated with net stasis, 1- and 2-log kill were determined in the pneumonia model for all strains.

Results
SA MICs were 0.25 mg/L for all isolates and SPN MICs were 0.008–0.016 mg/L. Plasma PK of KBP-7072 included: Cmax 0.12–25.2 mg/L, AUC0-∞ 1.1–234 mg hour/L, T1/2 3.2–4.6 h. ELF PK by urea correction methods included: Cmax 0.06–13.3 mg/L, AUC0-∞ 0.4–95 mg hour/L, T1/2 3.1–4 hours. ELF penetration based on free plasma drug concentrations (77.5% bound) ranged from 82 to 238%. AUC was linear over the dose range (R2 = 0.99). Potent dose-dependent cidal activity (3–5 log kill) was observed against all strains. AUC/MIC was a robust predictor of efficacy (SA R2 = 0.89, SPN R2 0.80). Median static, 1- and 2-log kill AUC/MIC values are shown in the table.

Conclusion
KBP-7072 demonstrated potent in vivo efficacy against SA and SPN, including strains with elevated minocycline MIC and β-lactam resistance, in the neutropenic murine pneumonia model. A 3–5 log kill was observed and AUC/MIC was strongly associated with efficacy. The AUC/MIC target for net stasis was comparable between SA and SPN at a plasma fAUC/MIC target of ~1 and ELF AUC/MIC target ~2. Cidal targets were similarly very low. All targets were numerically lower than comparative tetracyclines. These results should prove useful for clinical dosing regimen optimization.

Disclosures
A. J. Lepak, KBP Biosciences: Research Contractor, Research support. Q. Liu, KBP Biosciences: Employee, Salary. P. Wang, KBP Biosciences: Employee, Salary. Y. Wang, KBP Biosciences: Employee, Salary. J. C. Bader, KBP Biosciences: Research Contractor, Research support. P. G. Ambrose, KBP Biosciences: Research Contractor, Research support. D. R. Andes, KBP Biosciences: Research Contractor, Research support.
1391. Vancomycin Area Under the Curve (AUC) to Predict Nephrotoxicity: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Aljefri Doaa , Avedissian Sean , Rhodes Nathaniel J , Postelnick Michael , Scheetz Marc H 
Published: November 2018

Abstract

Background
Recent studies have proposed monitoring vancomycin area under the curve (AUC) as a more precise method of attaining goal exposures compared with trough monitoring. Different dosing methods and different exposure-toxicity thresholds have been proposed. Therefore, we aimed to analyze the relationship between vancomycin AUC and nephrotoxicity reported across recent studies.

Methods
A systematic review of Pubmed, Medline, Scopus and compiled references was conducted. We included randomized, cohorts and case–control studies that reported vancomycin AUCs and risk of nephrotoxicity from (January 1, 1990 to January 31, 2018). The primary outcome was nephrotoxicity, defined as an increase in serum creatinine of ≥0.5 mg/L or a 50% increase from baseline on two or more consecutive measurements. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Subset analyses were conducted when possible on the impact of AUC0-24 hours and AUC24-48 hoursr exposures and AUC vs. trough guided dosing on the outcome of nephrotoxicity. AUC nephrotoxicity thresholds ranged between 550 and 700 mg hour/L. We grouped values according to lower (i.e., &lt;650) or higher average AUC, with a threshold value of ≥650 mg hour/L defining higher AUC based on a recent prospective trial.

Results
We identified eight eligible observational studies with a total of 2,491 patients. Of those, five studies reported AUC0-24 associated with nephrotoxicity, two studies reported AUC24-48, and two studies reported nephrotoxicity associated with AUC vs. trough-guided dosing. No RCTs were identified. Lower AUC0-24 values were associated with significantly reduced risk of nephrotoxicity (OR 0.36, 95% CI 0.23–0.56). In a sub-analysis of two studies, AUC24-48&lt;650 mg hour/L was associated with significantly lower risk of nephrotoxicity (OR 0.45, 95% CI 0.27–0.75). Nephrotoxicity associated with AUC-guided dosing was significantly lower than trough-guided dosing (OR 0.68, 95% CI 0.46–0.99).

Conclusion
This meta-analysis suggests that AUC0-24 lower than 650 mg hour/L may result in a decreased risk of nephrotoxicity. AUC-guided vancomycin dosing may result in less vancomycin-associated nephrotoxicity. Additional investigations into the benefit of AUC-guided dosing are warranted.

Disclosures
All authors: No reported disclosures.