bluuebunny/crossref_metadata_2025_split huggingface dataset:
1255. In Vitro Activity of Vancapticin against Methicillin-Resistant Staphylococcus aureus from Periprosthetic Joint Infection
Authors: Cho Hye-Kyung , Karau Melissa J , Greenwood-Quaintance Kerryl E , Hansford Karl A , Cooper Matthew A , Blaskovich Mark A , Patel Robin , Patel Robin 
Published: January 2021

Abstract

Background
The vancapticins are modified vancomycin derivatives developed by adding membrane targeting motifs to the C-terminus of vancomycin. We determined the in vitro activity of a lead vancapticin candidate against periprosthetic joint infection-associated methicillin-resistant Staphylococcus aureus (MRSA) in the planktonic and biofilm states, and the effect of adding 0.002% polysorbate 80 (P-80; Sigma-Aldrich) on vancapticin susceptibility testing.

Methods
Thirty-seven clinical isolates of MRSA collected at Mayo Clinic (Rochester, Minnesota) were studied. Vancapticin minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institutes guidelines. Minimum biofilm bactericidal concentrations (MBBCs) were determined using a pegged lid microtiter plate assay. Vancapticin MIC and MBBC values were assessed with and without P-80. Vancapticin, vancomycin, and dalbavancin biofilm time-kill assays were performed using biofilms formed by 10 MRSA isolates on Teflon coupons.

Results
Vancapticin MICs with and without P-80 ranged from 0.015 to 0.12 μg/mL and 0.25 to 1 μg/mL, respectively. Vancapticin MBBCs with and without P-80 ranged from 0.25 to 4 μg/mL and 1 to 8 μg/mL, respectively. Reductions of biofilm bacterial densities on Teflon coupons after 8 and 24 hours of incubation with vancapticin, vancapticin with P-80, vancomycin, or dalbavancin with P-80 were less than 3-log10 cfu/cm2 for all isolates tested.

Conclusion
Vancapticin has promising in vitro activity against planktonic MRSA and MRSA in a pegged lid biofilm assay, but was not bactericidal against biofilms on Teflon coupons. P-80 decreased vancapticin MICs and MBBCs.

Disclosures
Mark A. Blaskovich, PhD, MAB Consulting (Consultant)The University of Queensland (Employee, Grant/Research Support, Other Financial or Material Support, Inventor on patent) Robin Patel, MD, Accelerate Diagnostics (Grant/Research Support)CD Diagnostics (Grant/Research Support)Contrafect (Grant/Research Support)Curetis (Consultant)GenMark Diagnostics (Consultant)Heraeus Medical (Consultant)Hutchison Biofilm Medical Solutions (Grant/Research Support)Merck (Grant/Research Support)Next Gen Diagnostics (Consultant)PathoQuest (Consultant)Qvella (Consultant)Samsung (Other Financial or Material Support, Dr. Patel has a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued.)Selux Dx (Consultant)Shionogi (Grant/Research Support)Specific Technologies (Consultant)
1264. Assessment of In Vivo Efficacy of CF-296 in addition to Vancomycin (VAN) and Daptomycin (DAP) against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model
Authors: Asempa Tomefa E , DeRosa Nicole A , Cassino Cara , Lehoux Dario , Schuch Raymond , Nicolau David P 
Published: January 2021

Abstract

Background
CF-296 is a novel lysin in pre-clinical development for the treatment of methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections, used in addition to standard of care antibiotics including VAN and DAP. We evaluated the in vivo efficacy of CF-296 alone and in addition to VAN and DAP against S. aureus.

Methods
Eight isolates (1 MSSA and 7 MRSA) were studied. Murine ICR MIC (100% serum) and human MIC (100% serum) for CF-296 ranged from 32-256 mg/L to 0.5-1 mg/L respectively. Broth microdilution MICs for DAP ranged from 0.5-1 mg/L while all isolates exhibited a VAN MIC of 1 mg/L. Neutropenic ICR mice were thigh inoculated with bacterial suspensions (107 CFU/mL). Mice were administered three monotherapy regimens subcutaneously (SC) or intravenously (IV): i) sub-therapeutic VAN, SC (i.e., a dose that yielded bacteria stasis or growth in order to evaluate further bacterial killing), ii) sub-therapeutic DAP, SC, or iii) CF-296 50 mg/kg, IV. Combination of sub-therapeutic VAN or DAP in addition to 5 escalating CF-296 doses ranging from 0.5 to 50 mg/kg were also examined. Control mice were vehicle-dosed. Efficacy was measured as the change in mean thigh bacterial density at 24h relative to 0h controls.

Results
Relative to starting inoculum (5.71 ± 0.27 at 0h), bacterial density in controls increased by +2.49 ± 0.98 log10 CFU/thigh across all 8 strains. On average, VAN, DAP, and CF-296 monotherapy resulted in +0.90 ± 1.21, +1.47 ± 0.80, and +0.87 ± 1.39 log10 CFU/thigh bacteria growth, respectively. In addition to VAN, escalating CF-296 exposures (0.5 – 50 mg/kg) resulted in an augmented dose-response, ranging from bacterial reduction of -0.26 ± 1.10 (with addition of CF-296 0.5 mg/kg) to -1.01 ± 0.41 log10 CFU/thigh (with addition of CF-296 50 mg/kg). Similarly, escalating CF-296 exposures in addition to DAP resulted in an augmented dose-response, ranging from bacterial density of +0.80 ± 1.19 to -0.72 ± 0.59 log10 CFU/thigh.

Conclusion
Compared with 24h control, VAN, DAP, and CF-296 alone displayed modest CFU reduction while CF-296 synergized with VAN and DAP to cause further bacterial killing highlighting a potential role for CF-296 adjunctive therapy against MSSA and MRSA isolates.

Disclosures
Cara Cassino, MD, ContraFect Corporation (Employee)ContraFect Corporation (Employee) Dario Lehoux, PhD, ContraFect Corporation (Consultant) Raymond Schuch, PhD, ContraFect Corporation (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
1268. Dalbavancin for the Treatment of Infections due to Staphylococcus aureus
Authors: Streifel Amber C , Sukerman Ellie , Sikka Monica , Makadia Jina , Lewis James , Luke Strnad 
Published: January 2021

Abstract

Background
Dalbavancin is a lipoglycopeptide antibiotic active against gram-positive organisms. Its extended half-life allows for weekly dosing that can last 4 to 6 weeks with 2 doses. Although approved for treating skin and soft tissue infections, use for more complicated infections is appealing, particularly when daily intravenous antibiotics are impractical. S aureus is the most common cause of complex infections for which dalbavancin is considered at our institution, so we sought to better understand its use.

Methods
We conducted a retrospective study to describe dalbavancin use at our institution for infections caused by Staphylococcus aureus. We identified all patients ≥18 years who received ≥1 dose of dalbavancin. Infectious disease faculty reviewed charts for clinical characteristics and outcomes of the infections.

Results
Fifty-two patients with S. aureus infections (60% MRSA) were treated with at least a partial course of dalbavancin. Twenty-seven (52%) had a history of IV drug use (IDU) and the most common infections were bone and joint infection in 51% and bacteremia in 40% (Table 1). The most common dosing regimen was 1500 mg x 1 in 55% or 1500 mg weekly x 2 in 25% (Table 2). The most common reasons for use of dalbavancin were history of IDU in 48% and lack of a safe home environment in 21%. Suppressive oral antibiotics for the primary infection were prescribed to 3 patients after completing dalbavancin (2 received for other indications). Clinical outcomes include 15% of patients lost to follow-up, readmission due to infection recurrence or dalbavancin adverse effects in 12%, and overall infection recurrence or relapse by day 90 in 31% (Table 3). There were no severe dalbavancin-related adverse drug events.
Table 1. Patient and Disease Characteristics

Table 2. Dalbavancin Use Characteristics

Table 3. Clinical Endpoints

Conclusion
While our results suggest dalbavancin is well tolerated, questions about relapse rates in the treatment of complicated S. aureus infections remain. Further research is needed to evaluate clinical outcomes for dalbavancin compared to standard of care antibiotics and to better elucidate whether relapses were related to true antibiotic failure versus other complexities of the S. aureus infections.

Disclosures
All Authors: No reported disclosures
1270. Early Real-world Evidence in the Use of Eravacycline for the Management of Draconian Infections
Authors: Carr Amy , El Ghali Amer , Kaur Parminder , Minor Sarah B , Casapao Anthony M 
Published: January 2021

Abstract

Background
Eravacycline (ERV) is a next-generation tetracycline approved for complicated intra-abdominal infections (cIAI) with in-vitro activity to multidrug-resistant organisms such as carbapenem resistant Enterobacteriaceae, extended spectrum beta-lactamase, and carbapenem-resistant Acinetobacter baumannii (CRAB). The purpose of this study was to identify the utility of ERV in clinical practice.

Methods
Retrospective case series was conducted on patients at AdventHealth that received at least two doses of ERV. Primary endpoint for the study was clinical success while on ERV, meeting none of the following criteria: changing therapy, mortality, or lack of improvement from sign/symptoms.

Results
Of 23 patients, 74% were males with a mean age of 55 ±18 years and mean body weight of 79 ±27 kg. Mean APACHE II and Charleson scores were 20 (±11) and 6 (±4), respectively. 91% received ERV for an off-label indication or organism. Infection types were respiratory (44%), cIAI (35%), skin (9%), and other (13%). All patients had positive cultures, while 61% were treated as a polymicrobial infection and 17% had bacteremia. Microorganisms included A. xylosoxidans, S. maltophilia, CRAB, and K pneumoniae. 48% had ERV susceptibilities from .06-4 mcg/mL, including two MIC ≥32mcg/mL for S. maltophilia. 70% were given another antibiotic prior to ERV with a median duration of 5 (1-35) days. Median duration of ERV was 8 (3-30) days. 83% percent received ERV in combination with another antibiotic. During treatment, 26% had a Child-Pugh Class C at baseline and 30% had elevated liver function tests. No adverse drug reactions were reported. Upon discharge, 35% continued ERV. Clinical success was observed in 57% (12/21) of patients. Clinical outcome by infection type is summarized in Figure 1. Of 9 cases of clinical failure, 14% were changed to alternative, 19% died while on ERV, and 10% failed to resolve signs/symptoms. Two cases of M. abscessus infections had insufficient follow-up to assess clinical outcome.
Figure 1. Eravacycline Clinical Outcome by Infection Type

Conclusion
Initial real-world experience with ERV differs significantly from the trials regarding severity of illness, types of infection, and clinical outcomes. Further evaluation is necessary for using ERV as combination therapy and in off-label indications.

Disclosures
All Authors: No reported disclosures
1273. Efficacy of Cefiderocol against carbapenem-resistant A. baumannii and P. aeruginosa in ventilator-associated pneumonia mouse model
Authors: Ota Kenji , Kaku Norihito , Uno Naoki , Sakamoto Kei , Kosai Kosuke , Hasegawa Hiroo , Miyazaki Taiga , Izumikawa Koichi , Mukae Hiroshi , Yanagihara Katsunori 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a novel cephalosporin with siderophore structure, characterized by transportation through siderophore receptor on outer membrane of Gram-negative bacteria and structural stability against beta-lactamase. The antimicrobial activity against multidrug resistant bacteria is demonstrated in vitro and in vivo. In this study, we aimed to elucidate the in vivo efficacy of CFDC using ventilator-associated pneumonia (VAP) mouse model.

Methods
The minimum inhibitory concentration (MIC) of CFDC and meropenem (MEPM) against the test Acinetobacter baumannii (Ab) and Pseudomonas aeruginosa (Pa) isolates were measured by broth microdilution assay. Iron depleted medium was used for CFDC. For VAP mouse models, neutropenia was induced by cyclophosphamide intraperitoneal administration, followed by intubation of sterile tube in the trachea and inoculation of bacterial suspension. PK analysis were performed in infected mice, in order to determine treatment regimens to achieve targeted time above MIC (TAM) of free concentrations in plasma. Treatment was initiated 3 hours post infection and continued up to 120 h for survival analysis. To investigate the bactericidal effect, the mice were sacrificed to count bacterial load in the lung at 48 h and 24 h for VAP-Ab and Pa, respectively.

Results
MICs(mg/L) of CFDC and MEPM against Ab were 0.5 and 128, and Pa were 0.008 and 16, respectively. The treatment regimens to achieve target MIC were shown in Table 1. In order to assess dose dependency of CFDC, required doses to achieve TAM of 70%, 90%, and 100% were calculated. These doses used in the studies were achievable in human for CFDC, but not for MEPM due to high MICs of the test strains. In treatment study for VAP-Ab, bactericidal effect was achieved at TAM &gt; 70% in CFDC groups, as well as TAM 30% in MEPM group. In VAP-Pa, bactericidal effect was observed at TAM &gt; 90% in CFDC groups, as well as TAM 30% in MEPM group.
Table 1.Treatment regimen and free TAM against VAP-Ab and Pa

Figure 1. Bacterial load in the lungs of VAP-Ab and Pa

Conclusion
The efficacy of CFDC against VAP-Ab and Pa were demonstrated in this study. Although 90% free TAM was required for bactericidal effect, CFDC was shown to be effective against carbapenem-resistant Gram-negative pathogens at the recommended clinical dosing regimen.

Disclosures
Katsunori Yanagihara, MD, PhD, Shionogi & Co.,Ltd. (Grant/Research Support)
1274. Evaluating the Activity of SPR719, a Novel Aminobenzimidazole, against Nontuberculous Mycobacteria
Authors: Murray Beverly , Hall Danielle , Cotroneo Nicole S , Critchley Ian , Pucci Michael , Stokes Suzanne , Pillar Chris 
Published: January 2021

Abstract

Background
Pulmonary infections caused by Nontuberculous Mycobacteria (NTM) are increasing in prevalence and are associated with high mortality and morbidity. Members of the Mycobacterium avium complex (MAC; primarily M. avium and M. intracellulare) and M. abscessus are most commonly associated with NTM pulmonary disease. Treatment options are limited and new agents with potent activity are needed. In this study, the activity of SPR719, a novel aminobenzimidazole, against NTM is reported.
MIC range and MIC50/90 summary table

Methods
The susceptibility of 58 non-consecutive, non-duplicate clinical NTM isolates was determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) standard M24. Isolates included 20 rapidly-growing mycobacteria (10 M. abscessus/chelonae Group, 6 M. fortuitum Group, and 4 M. mucogenicum Group) and 38 slow-growing mycobacteria (28 MAC and 10 M. kansasii). SPR719 and comparators clarithromycin (CLA), amikacin (AMK), moxifloxacin (MXF), rifabutin (RFB), minocycline (MIN), and imipenem (IPM) were evaluated. Minimum bactericidal concentrations (MBC) for SPR719, CLA, and AMK were determined in accordance with CLSI M26.

Results
The activity of SPR719 and comparators by MIC range and MIC50/90 (µg/mL) is summarized in the accompanying table. SPR719 activity was not affected by resistance to CLA, AMK, or MXF. MBC:MIC ratios for SPR719 and CLA were typically &gt;8 which indicates a bacteriostatic mode of action; AMK MBC:MIC ratios were typically ≤ 4 indicative of bactericidal activity.

Conclusion
SPR719 had potent activity by both MIC50/90 and MIC range across the evaluated NTM species. The SPR719 activity against clinically relevant MAC and M. abcessus/chelonae Group isolates was comparable or superior to the evaluated comparators, and SPR719 was active against isolates resistant to currently utilized agents. These results highlight the potential of SPR719 in the treatment of NTM pulmonary disease.

Disclosures
Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Michael Pucci, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder)
1275. Evaluation of in vitro activity of manogepix against multidrug-resistant and pan-resistant Candida auris from the New York Outbreak
Authors: Zhu Yan Chun , Kilburn Shannon N , Kapoor Mili , Chaturvedi Sudha , Shaw Karen J , Chaturvedi Vishnu 
Published: January 2021

Abstract

Background
An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. NY C. auris isolates demonstrate resistance to fluconazole and variable resistance to other antifungals. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is in clinical development for the treatment of invasive fungal infections.

Methods
We evaluated the susceptibility of 200 NY C. auris isolates (2017-2020) to MGX and 10 comparators. Testing was performed using TREK frozen broth microdilution panels for FLC, VRC, ITC, ISA, POS, AFG, CAS, and MFG. MGX MICs were evaluated (CLSI M27-A3 guidelines) using a 50% reduction in fungal growth endpoint at 24 h. MICs were determined by ETEST® at 24 h for AMB and FLC. We defined pan-resistant C. auris as isolates with in vitro resistance to two or more azoles, all echinocandins, and AMB. The epidemiological cutoff values (ECVs, ECOFFs) for MGX were estimated using the Microsoft Excel spreadsheet calculator ECOFFinder.

Results
MGX demonstrated lower MICs than comparators (MIC50 and MIC90 0.03 mg/L; range 0.004-0.06 mg/L). MGX was 8-32-fold more active that the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than AMB. No differences were found in the MGX or comparators’ MIC50, MIC90, or GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. The MGX epidemiological cutoff value (ECV, 99% cutoff) was 0.06 mg/L.

Conclusion
MGX MICs were low against C. auris isolates including those with variable patterns of resistance to AMB, azoles, and echinocandins. In addition, MGX retained potent activity against six pan-resistant isolates. These data support the continued clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

Disclosures
Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Vishnu Chaturvedi, PhD, Amplyx (Grant/Research Support)
101. Diagnostic Utility of a Multiplex PCR Meningitis/Encephalitis Panel and Impact on Antibiotic Use
Authors: Vanood Aimen , Hospodar Alexandra , Carpenter Christopher F 
Published: January 2021

Abstract

Background
The detection and identification of meningitis and encephalitis pathogens from CSF via traditional microbiologic methods may take several hours to days. The BioFire FilmArray Meningitis/Encephalitis Panel (BioFire), approved by the FDA in 2015, can detect 14 different pathogens within one hour, providing a faster time to diagnosis of a broad range of pathogens. The purpose of this study was to examine the impact of BioFire on length of hospital stay and duration of antibiotic use.

Methods
We conducted a retrospective chart review of patients diagnosed meningitis/encephalitis between 2015 and 2019 at 3 Beaumont Health (BH) hospitals. BioFire was adopted by BH midyear in 2017, allowing for analysis of cohorts over comparable periods before and after the introduction of the panel. Data collected and analyzed included biodemographics, comorbidities, presenting signs and symptoms, CSF analysis results, pathogens, days of antibiotic therapy, length of stay, and mortality.

Results
A total of 161 patients diagnosed with meningitis and/or encephalitis were reviewed, including 59 who underwent testing via BioFire. Of the 161 patients, 68 had a pathogen identified, 50 via traditional methods (6 bacterial and 44 viral) and 18 via BioFire (3 bacterial and 15 viral). West Nile Virus accounted for 17 of the viral infections diagnosed via traditional methods. The mean duration of antibiotic use after the assays resulted was not significantly different between patients with bacterial infections diagnosed by traditional methods or BioFire (11.2 vs 13.0 days, p=0.82) or for those with viral infections (0.1 vs 0 days, p=0.3). The median length of stay was also not significantly different between the two cohorts for patients with bacterial infections (21.7 vs 15.0 days, p = 0.36) or viral infections (6.2 vs. 10.0 days, p = 0.10).

Conclusion
While utilization of the BioFire panel yielded a faster diagnostic result, we have no evidence to demonstrate that it contributes to a significant reduction in duration of antibiotic use or length of stay.

Disclosures
All Authors: No reported disclosures
1280. In-Vitro Activity of Cefiderocol, Imipenem/Relebactam, & Ceftazidime/Avibactam in Ceftolozane/Tazobactam Resistant Strains of Multidrug Resistant Pseudomonas aeruginosa
Authors: Navas Daniel , Charles Angela , Carr Amy , Alexander Jose 
Published: January 2021

Abstract

Background
The activity of imipenem/relebactam (I/R), ceftazidime/avibactam (CZA) and cefiderocol (FDC) were evaluated against clinical isolates of multidrug resistant (MDR) strains of P. aeruginosa which was resistant to ceftolozane/tazobactam (C/T). The recent increase of MDR P. aeruginosa strains isolated from clinical samples has prompted research and development of new antimicrobials that can withstand its multiple resistance mechanisms. C/T is an effective option for treatment of MDR P. aeruginosa in our facility with only 10% of resistance in MDR strains, but the emergence of resistance may occur due to the presence of a carbapenemase gene or an ampC mutation.

Methods
Antimicrobial susceptibility testing for C/T Etest® (bioMérieux, Inc.) were performed on all MDR strains initially screened by the VITEK2® (bioMérieux, Inc.). 10% (n=20) of all MDR isolates were resistant to C/T by the CLSI 2019 breakpoints. These resistant isolates were tested for presence of a carbapenemase gene using the GeneXpert CARBA-R (Cepheid®) PCR and against CZA Etest® (bioMérieux, Inc.) I/R gradient strips (Liofilchem®) and FDC broth microdilution (Thermo Scientific™ Sensititre™).

Results
A total of 20 clinical isolates of MDR P. aeruginosa resistant to C/T were tested following standardized CLSI protocols and techniques. All 20 isolates were screened for the presence of a carbapenemase gene (blaVIM, blaNDM, blaKPC, blaOXA-48, blaIMP). A blaVIM gene was detected in 6 (30%) out of 20 isolates. FDC demonstrated the greatest activity with 85% (n=17) of susceptible isolates (CLSI MIC &lt;4µg/dL). CZA (CLSI MIC &lt;8µg/dL) and I/R (FDA MIC &lt;2µg/dL) showed 15% (n=3) and 10% (n=2) of susceptible isolates respectively. FDC was active against all 6 blaVIM isolates, where all 6 strains were resistant to CZA and I/R as expected. 3 isolates tested non-susceptible against FDC; additional characterization was not performed at this time.

Conclusion
Based on these results, FDC demonstrated the greatest in-vitro activity against C/T resistant strains of MDR P. aeruginosa. FDC also demonstrated activity against all 6 MDR P. aeruginosa carrying blaVIM gene. FDC is a strong option to consider on MDR P. aeruginosa strains based on a resistance testing algorithm and a cost/effective protocol.

Disclosures
All Authors: No reported disclosures