bluuebunny/crossref_metadata_2025_split huggingface dataset:
1257. A phase II Prospective Randomized Study to Assess Ceftolozane-Tazobactam in the Management of Febrile Neutropenia in Patients with Hematological Malignancies
Authors: Chaftari Anne-Marie , Hachem Ray Y , Malek Alexandre , Mulonovich Victor , Szvalb Ariel D , Jiang Ying , Ali Shahnoor , Deeba Rita , Chaftari Patrick , Raad Issam I , Raad Issam I 
Published: January 2021

Abstract

Background
Despite the implementation of successful antibiotic stewardship programs, antibiotic resistance continue to emerge particularly against gram-negative bacteria. With the increase use of antibiotics in high risk patients with hematological malignancies, the empiric therapy with standard antibiotic could be inappropriate. New antibiotics may be useful to cover potential resistant pathogens. We evaluated the role of a new cephalosporin /β-lactamase inhibitor ceftolozane-tazobactam (C/T) in comparison to standard of care (SOC) antibiotics in the empiric treatment of febrile neutropenic cancer patients with hematological malignancies.

Methods
We conducted a prospective randomized open label comparative study to evaluate the safety and efficacy of C/T vs SOC antibiotics consisting of cefepime, piperacillin-tazobactam or meropenem when used in combination with gram positive antibacterial agents. Between May 2018 and March 2020, we enrolled 88 febrile neutropenic patients with hematological malignancies who presented to our emergency center. Patients received at least 72 hours of intravenous study drugs and were followed through end of IV therapy and for up to 42 days.

Results
A total of 88 patients were analyzed of whom 42 received C/T and 46 SOC
antimicrobial agents. The rate of documented bloodstream infections was similar in both groups (CE-TZ 21% vs SOC 26%, p=0.61). Favorable clinical response at end of IV therapy was significantly better in the C/T arm compared to SOC therapy (88% vs 72%, p=0.039), at test of cure (21 days), and last follow-up (42 days). In patients with documented infections, the rate of microbiological eradication was similar in both groups. Drug-related adverse events that led to drug discontinuation was similar in both groups (7%). Similarly overall mortality was similar in both groups.

Conclusion
The empiric use of C/T to cover gram negative organisms in high risk febrile neutropenic patients with hematological malignancies is safe and associated with better clinical outcome than SOC antimicrobial agents. The emergence of resistant pathogens should be further evaluated.

Disclosures
Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)
1259. Activity of eravacycline against staphylococci isolated from periprosthetic joint infections
Authors: Zhuchenko Georg , Schmidt-Malan Suzannah , Patel Robin , Patel Robin 
Published: January 2021

Abstract

Background
Perirosthetic joint infections (PJIs) are costly and difficult to treat. The most common causes of PJIs are Staphylococcus aureus and Staphylococcus epidermidis. Eravacycline is a newer tetracycline with promising activity against Gram-positive and negative bacteria which is approved for treatment of complicated intraabdominal infections. Here, the in vitro activity of eravacycline was assessed against bacteria associated with PJI.

Methods
185 staphylococcal isolates, including 38 methicillin-resistant S. aureus (MRSA), 64 methicillin-susceptible S. aureus (MSSA), 62 methicillin-resistant S. epidermidis (MRSE) and 21 methicillin-susceptible S. epidermidis (MSSE) strains were studied. Minimum inhibitory concentrations (MICs) were determined according to Clinical and Laboratory Standards Institute guidelines (range of 0.06-64 µg/ml tested). Results were analyzed using susceptible breakpoints from EUCAST (≤0.25 µg/ml) and the FDA (≤0.06 µg/ml). Minimum biofilm bactericidal concentrations (MBBCs) were determined using a modification of the Calgary biofilm method. Briefly, biofilms were formed on pegged lids in trypticase soy broth, after which the pegged lids were rinsed in phosphate buffered saline (PBS), transferred to a plate containing dilutions of eravacycline in cation-adjusted Mueller Hinton broth (CAMHB) and incubated for 20-24h. Finally, the pegged lids were again rinsed in PBS and transferred to a plate containing CAMHB and incubated for 24h. The MBBC was the lowest concentration with no visible growth.

Results
MIC50/90 (range) in µg/ml for MRSA, MSSA, MRSE, and MSSE were 0.125/0.125 (≤0.06-0.25), ≤0.06/0.125 (≤0.06-0.25). 0.125/1 (≤0.06-2), and 0.25/1 (≤0.06-1), respectively. Using the EUCAST susceptible breakpoint, 100% of isolates would be considered susceptible, whereas only 54% would be considered susceptible using the FDA breakpoint. MBBC50/90 (range) in µg/ml for MRSA and MSSA were both 8/16 (4-16); for MRSE and MSSE, the values were 4/16 (2-32) and 8/16 (2-32), respectively.

Conclusion
Our data suggest that the FDA susceptible breakpoint may need re-evaluation. Eravacycline has low anti-staphylococcal biofilm activity.

Disclosures
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)
1265. AT-527, an Oral Purine Nucleotide Prodrug Exhibiting Potent In Vitro Antiviral Activity Against Human Coronaviruses, Including SARS-CoV-2
Authors: Good Steven S , Moussa Adel , Zhou Xiao-Jian , Pietropaolo Keith , Sommadossi Jean-Pierre 
Published: January 2021

Abstract

Background
Coronaviruses (CoVs) are the causative pathogens of several human diseases, including seasonal respiratory infections (HCoV-229E and HCoV-OC43), Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV-1) and the novel CoV recently identified as the virus responsible for the current COVID-19 pandemic, SARS-CoV-2. AT-527 is currently in Phase 2 clinical trials and has demonstrated potent activity and a well-tolerated safety profile in HCV-infected subjects. Here we report the in vitro activity of AT-511, the free base form of AT-527, against SARS-CoV-2 and other CoVs.

Methods
BHK-21, Huh-7, RD and differentiated normal human bronchial epithelial (dNHBE) cell cultures were exposed to virus and serial dilutions of test compounds. Independent assessments of antiviral activity were obtained by determining effective concentrations of test compounds required to 1) prevent half-maximal (EC50) virus-induced cytopathic effect (CPE) using MTT or neutral red staining and 2) produce virus yield reductions (VYR) by 90% (EC90) using standard endpoint dilution CCID50 assays in Vero 76 cells. Half maximal cytotoxicity of test compounds was determined by dye (MTT or neutral red) staining in the absence of added virus or by microscopic inspection (dNHBE cells only).

Results
Table 1 presents the in vitro activities of AT-511 against several coronaviruses. Also included in these assays are the antiviral activities of potential COVID-19 oral treatments, including chloroquine, hydroxychloroquine and N4-hydroxycytidine.
Table 1. In Vitro Activity of AT-511 Against Various Human Coronaviruses

Conclusion
The data demonstrate the potent in vitro activity of AT-511 against several CoVs, with individual EC90 values ranging from 0.34 to 1.2 µM against HCoV-229E, HCoV-OC43, SARS-CoV-1 and SARS-CoV-2 and less activity against MERS-CoV (average EC90 = 36 µM). The potent in vitro antiviral activity of AT-511 against SARS-CoV-2 (EC90 = 0.55 µM), associated with the AT-527 safety profile in treated HCV patients, support the ongoing clinical evaluation of the safety and efficacy of AT-527 in COVID-19 patients.

Disclosures
Steven S. Good, MS, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Keith Pietropaolo, B.A., Atea Pharmaceuticals, Inc. (Employee) Jean-Pierre Sommadossi, PhD, Atea Pharmaceuticals, Inc. (Board Member)
100. Development and Implementation of a 2-Tier Testing Algorithm for Clostridioides difficile: An Evaluation of Outcomes on Patients with Indeterminate Results at 90 Days
Authors: Brown Johanna P , Puckett Stephanie 
Published: January 2021

Abstract

Background
There is no definitive gold standard for accurate diagnosis of Clostridioides difficile (C difficile) infection. There is ample evidence that relying on a molecular test such as Polymerase Chain Reaction (PCR) for diagnosis, can lead to over diagnosis and unnecessary treatment. Combined, multi-step algorithms have been proposed to improve specificity of testing. The challenge remains in interpreting discordant or indeterminate results. Additionally, the risk of hospitalization due to lack of treatment for indeterminate results remains unclear.

Methods
To improve C difficile testing, a new 2-tier algorithm was implemented in 2019 starting with PCR testing. An indeterminate result was defined as a sample with a positive PCR and a positive Glutamate Dehydrogenase (GDH)/negative toxin result or a positive PCR and a negative GDH/positive toxin result.
Indeterminate results were classified by episode severity and number. Patient records were reviewed by the Antimicrobial Stewardship (AS) physician and pharmacist to determine true infection versus colonization. Treatment was given as per recent IDSA Guidelines.
All patients with indeterminate results were followed for 90 days for development of infection or hospitalization due to C difficile.
Adults with stool samples submitted for testing between 6/1/2019 and 12/31/2019 were included. A total of 169 specimens were reviewed: 75 were positive, 72 were indeterminate (4 excluded from final analysis) and 22 were negative.

Results
Using a 2-tier testing algorithm, 68 (41%) of all results were indeterminate. Our AS classified 47 (69%) of those as infection and 21 (31%) as colonization.
Patients with indeterminate results who were treated had a low incidence (8.5%) of reinfection requiring hospitalization in the following 90 days. There were no hospitalizations in the untreated group.
Of patients with an indeterminate result who were treated, 42 (89%) were categorized as an initial episode of C difficile infection.

Conclusion
Clinical correlation of indeterminate results is critical to algorithm interpretation.
A combined approach with provider education, an electronic testing advisor, a 2-tier testing algorithm, daily monitoring and prescribing by the AS team resulted in favorable outcomes for patients with indeterminate results

Disclosures
All Authors: No reported disclosures
1266. Characterization of Shifts in Minimum Inhibitory Concentrations During Treatment with Cefiderocol or Comparators in the Phase 3 CREDIBLE-CR and APEKS-NP Studies
Authors: Takemura Miki , Yamano Yoshinori , Matsunaga Yuko , Ariyasu Mari , Echols Roger , Den Nagata Tsutae 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a novel siderophore cephalosporin developed to treat serious carbapenem-resistant (CR) Gram-negative (GN) infections.

Methods
In CREDIBLE-CR (NCT02714595), adults with serious infections caused by CR GN pathogens received CFDC 2 g, q8h, 3-h infusion, or best available therapy (BAT). In APEKS-NP (NCT03032380), adults with nosocomial pneumonia received CFDC or high-dose, extended-infusion meropenem (each 2 g, q8h, 3-h infusion). All treatments were given for 7‒14 days (extendable to 21 days). Biospecimens were collected before the first dose of study drug and at subsequent visits for assessments, and minimum inhibitory concentrations (MIC) to various antibiotics, including CFDC and carbapenems, were determined. Isolates with an increased MIC were evaluated by RT-PCR or whole genome sequencing (WGS) for CFDC resistance-related genes or mutations. Results for genetically related isolates with an elevated MIC during therapy are shown.

Results
On-therapy ≥4-fold CFDC MIC increase was found in 12 out of 106 (CREDIBLE-CR; Table 1) and 7 out of 159 (APEKS-NP; Table 2) isolates, respectively. For most isolates, CFDC MIC increased by 4–8-fold but remained ≤4 µg/mL. Specific mutations which could explain CFDC MIC increases were found in only 3 isolates. Mutations in iron-transport related genes were not identified. Mutation in CFDC target gene PBP-3 was identified in 1 A. baumannii isolate. Class-C enzyme mutation was observed in 2 isolates (CREDIBLE-CR: PDC-30 in P. aeruginosa; APEKS-NP: ACT-17 in E. cloacae), although the contribution to CFDC MIC increase has not been confirmed. In the BAT arm in CREDIBLE-CR, 6 out of 46 isolates had ≥4-fold MIC increase; all post-treatment isolates were resistant to BAT agents (Table 1), although WGS was not conducted for these isolates. In the meropenem arm in APEKS-NP, 5 out of 164 isolates had ≥4-fold MIC increase (Table 2).
Table 1. MIC changes in CREDIBLE-CR

Table 2. MIC changes in APEKS-NP

Conclusion
Among isolates with ≥4-fold MIC increase during CFDC treatment, actual CFDC MIC values remained relatively low for most isolates. Frequency of MIC increase in BAT or meropenem arms was similar to that of CFDC, but the magnitude was greater. Acquisition of contributory mechanism has not been identified except for the mutation in PBP 3 and some β-lactamases.

Disclosures
Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)
1267. Comparative activity of omadacycline against extended-spectrum beta-lactamase positive and negative Escherichia coli and Klebsiella pneumoniae strains recovered from urine specimens
Authors: Stone Tyler J , Kilic Abdullah , Williamson John , Palavecino Elizabeth , Palavecino Elizabeth 
Published: January 2021

Abstract

Background
Omadacycline (OMC) is a novel tetracycline (TET) derivative antibiotic with activity against TET-resistant Enterobacterales. OMC is available in both oral and intravenous formulations and is has been studied as a treatment of uncomplicated urinary tract infection (UTI) and acute pyelonephritis. The purpose of this study was to evaluate OMC activity against extended-spectrum beta-lactamase (ESBL) positive and negative Enterobacterales strains recovered from urine specimens.

Methods
Urine samples from patients with suspected UTI were quantitatively plated onto blood agar and MacConkey agar plates in the microbiology lab of Wake Forest Baptist Medical Center. After overnight incubation, colonies were identified to the species level by MALDI-TOF system. Susceptibility testing was performed for isolates of E. coli and K. pneumoniae. OMC and TET susceptibility testing was performed by disk diffusion and gradient strip methodologies. Results were interpreted in accordance with the Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration breakpoints. Isolates were tested in triplicate. ESBL screening and susceptibility testing to oral antibiotics commonly prescribed for UTI were performed by the MicroScan WalkAway System. Susceptibility rates and MIC50/90 were calculated and subsets of isolates were analyzed using descriptive statistics.

Results
A total of 204 isolates, including 102 E. coli and 102 K. pneumoniae, were tested. All but 1 isolate (99.5%) exhibited categorical agreement in results generated by the strip (Table 1) and disk (data not shown) methods and this was considered a minor error involving an intermediate result. OMC MIC90 for E. coli and K. pneumoniae were 6 µg/mL and &gt;32 µg/mL, respectively. OMC displayed increased susceptibility rates compared to TET regardless of isolate species or ESBL positivity (Table 2).
Table 1. Omadacycline Minimum Inhibitory Concentrations (MICs, µg/mL)

Table 2. Susceptibilities of Oral Antibiotics Used to Treat UTI (% S)

Conclusion
OMC exhibits promising antimicrobial activity against TET-resistant and ESBL-positive E. coli and K. pneumoniae. OMC displays superior activity to ESBL positive E. coli when compared to ESBL positive K. pneumoniae. These data support the development of OMC as a much needed option in the treatment of UTI caused by resistant Enterobacterales.

Disclosures
Tyler J. Stone, PharmD, Paratek (Research Grant or Support) Abdullah Kilic, MD, Paratek (Grant/Research Support) John Williamson, PharmD, Paratek (Research Grant or Support) Elizabeth Palavecino, MD, Paratek (Grant/Research Support)Paratek (Grant/Research Support)
1269. Differences in Interpretative Breakpoints Between CLSI, FDA and EUCAST Impact Reporting of Susceptibility and Resistance to Cefiderocol
Authors: Yamano Yoshinori , Takemura Miki , Longshaw Christopher , Echols Roger 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a siderophore cephalosporin with broad coverage of aerobic Gram-negative (GN) bacteria. Provisional breakpoints (BP) were approved by CLSI in 2018, with FDA and EUCAST providing clinical BP in 2019 and 2020, respectively; however, BPs differ markedly between organizations, reflecting differences in labelling, PK/PD standards and availability of clinical study data during regulatory review. Here we compare susceptibility rates based on these different BPs.

Methods
Susceptibility rates for each bacterial species were determined using CFDC BP from each organization and the MICs of 28,629 GN clinical isolates from 3 consecutive years of SIDERO-WT surveillance studies (2014–17). The analysis used all isolates and sub-grouped isolates based on meropenem (MEM) susceptibility (CLSI BP) or carbapenemase production.

Results
Within the overall Enterobacterales group, ≥98.5% isolates were interpreted as susceptible to CFDC regardless of BP used. However, the proportion of susceptible differed significantly (82.5–98.6%) when applied to MEM-non-susceptible (NS) isolates. Similarly, against most carbapenemase producers, susceptibility ranged from 80 to 100%, however for NDM producers, only 51% of isolates were defined as susceptible by FDA or EUCAST BP vs 84% using the CLSI BP. Against Pseudomonas aeruginosa including MEM-NS isolates, susceptibility was ≥94% despite different BPs recommended by FDA (1 mg/L), EUCAST (2 mg/L) and CLSI (4 mg/L). This changed the proportion of IMP-producing isolates classified as susceptible from 100% (CLSI) and 81% (EUCAST) to only 19% (FDA). Against other non-fermenters, susceptibility was ≥91% irrespective of BP used.
Table 1. Susceptibility rates against Enterobacterales based on breakpoints from each organization

Table 2. Susceptibility rates against non-fermenters based on breakpoints from each organization

Conclusion
Differences in BPs between FDA, CLSI and EUCAST could impact on the reporting of susceptibility or resistance to CFDC, particularly for MEM-NS isolates. PK/PD model simulations support 100% fT &gt;MIC up to an MIC of 4 mg/L, and in Phase 3 trials the mean trough concentration of unbound cefiderocol was &gt;4 mg/L. The potential impact of these differences on clinical decision making are important as the greatest clinical utility for CDFC is expected to be in patients with carbapenem-resistant GN infections due to limited treatment options.

Disclosures
Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)
1279. In Vitro Activity of Nacubactam (OP0595) Alone and in Combination with β-Lactams against β-Lactamase-Producing Enterobacterales Isolated in Japan
Authors: Nagira Yu , Yamada Keiko , Okade Hayato , Senju Nami , Tsutsumi Yuko , Tabata Yuji , Kato Kazuhiko 
Published: January 2021

Abstract

Background
Nacubactam (NAC) is a novel serine β-lactamase inhibitor in clinical development, and inhibits Ambler class A, class C, and some class D β-lactamases. In addition, it has penicillin-binding protein (PBP) 2-dependent antibacterial activity and an ‘enhancer’ effect when combined with β-lactams bound to PBP3. This study assessed the in vitro activity of NAC alone and in combination with β-lactams against IMP-type metallo-β-lactamase-producing and ESBL-producing Enterobacterales isolated in Japan.

Methods
The MICs for the clinical isolates in Japan were determined and time kill studies were performed. IMP and ESBL genes were detected by PCR. The MICs were determined by broth microdilution method following CLSI methodology. β-lactams and NAC were tested as a ratio of 1:1. Time kill profiles were also studied according to CLSI methodology.

Results
The MIC50/MIC90s of NAC alone against 112 IMP-producing Enterobacterales and 154 ESBL-producing Enterobacterales were 2/ &gt;32 and 2/8 mg/L, respectively. Regarding the MICs of cefepime (FEP)/NAC and aztreonam (ATM)/NAC against IMP-producing isolates, the MIC90s were 2 and 1 mg/L and the MIC ranges were 0.06 - 32 and 0.06 - 4 mg/L, respectively. The MIC90s of FEP/NAC and ATM/NAC against ESBL-producing isolates were 0.5 and 1 mg/L. These MIC90s of β-lactam/NAC against IMP-producing and ESBL-producing isolates were significantly lower than those of β-lactam alone (&gt;128 mg/L). The highest MIC of ATM/NAC against IMP-producing isolates was lower than that of FEP/NAC. In addition, bactericidal activities of β-lactam/NAC were observed at the lower concentration of β-lactam compared to that of β-lactam alone.

Conclusion
NAC in combination with β-lactams showed excellent in vitro activities against not only ESBL-producing Enterobacterales but also IMP-producing Enterobacterales isolated in Japan. ATM/NAC tended to show higher antimicrobial effect against IMP-producing isolates by the enzyme stability of ATM. These results support the complex activities of NAC which works as a β-lactamase inhibitor, an antibacterial agent and also an enhancer when combined with β-lactams. Furthermore, these will be useful for selecting a partner β-lactam for NAC.

Disclosures
Yu Nagira, MS, Meiji Seika Pharma Co., Ltd. (Employee) Keiko Yamada, BS, Meiji Seika Pharma Co., Ltd. (Employee) Hayato Okade, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee) Nami Senju, BS, Meiji Seika Pharma Co., Ltd. (Employee) Yuko Tsutsumi, MS, Meiji Seika Pharma Co., Ltd. (Employee) Yuji Tabata, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee)