bluuebunny/crossref_metadata_2025_split huggingface dataset:
1046. Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered as a Booster to Adults ≥ 59 Years of Age
Authors: Robertson Corwin A , Jacqmein Jeffry , Selmani Alexandre , Galarza Katherine , Oster Philipp 
Published: December 2021

Abstract

Background
MenACYW-TT (MenQuadfi®, Sanofi) is a quadrivalent (serogroups A, C, W, and Y) meningococcal tetanus toxoid conjugate vaccine. It was recently approved for use in persons aged ≥ 2 years in the US and persons aged ≥ 1 year in Europe and certain other countries; trials in infants as young as 6 weeks are ongoing. This study evaluated seroresponse after a MenACYW-TT booster given to adults who received either quadrivalent meningococcal polysaccharide vaccine (MSPV4) or MenACYW-TT three years earlier at age ≥ 56 years. Immune persistence up to 7 years after primary vaccination was also evaluated.

Methods
This was a Phase 3 randomized, open-label study (NCT04142242) of adults aged ≥ 59 years who participated in previous studies of MenACYW-TT vs MPSV4 (NCT01732627 and NCT02842866). The study was conducted in the US and Puerto Rico. Immune response and persistence were assessed with a serum bactericidal assay using human complement (hSBA). Sufficiency of the vaccine seroresponse was considered demonstrated if the lower limit of the 1-sided 97.5% CI for the percentage of subjects with an hSBA vaccine seroresponse against serogroups A, C, W and Y was &gt; 40%. Safety data were collected up to 30 days after booster vaccination.

Results
A total of 471 persons were enrolled. Sufficiency of a MenACYW-TT booster was demonstrated for MPSV4- and for MenACYW-TT-primed subjects. hSBA seroresponse rates were higher among MenACYW-TT- vs MPSV4-primed subjects (79.3%–93.1% vs 49.2%–60.8%, respectively). Three to 7 years after primary vaccination, hSBA geometric mean titers (GMTs) and seroprotection rates (SPRs) declined in both MenACYW-TT- and MPSV4-primed subjects, with hSBA GMTs and SPRs for serogroups C, W, and Y generally remaining higher for MenACYW-TT- vs MPSV4-primed subjects; those for serogroup A were similar regardless of priming vaccine. Rates of adverse events following a MenACYW-TT booster were similar between MenACYW-TT- and MPSV4-primed subjects. No safety concerns were identified.

Conclusion
A MenACYW-TT booster was well tolerated and immunogenic when administered to either MPSV4- or MenACYW-primed adults aged ≥ 59 years. Up to 7 years after primary vaccination, immune persistence for serogroups C, W, and Y tended to be greater for MenACYW-TT vs MPSV4.

Disclosures
Corwin A. Robertson, MD, MPH, FACP, Sanofi Pasteur (Employee, Other Financial or Material Support, Stockholder) Alexandre Selmani, PhD, Sanofi Pasteur (Employee) Katherine Galarza, MD, Sanofi Pasteur (Employee) Philipp Oster, MD, Sanofi Pasteur (Employee, Stockholder)
1052. Characterisation of the DNA binding properties of ridinilazole, a selective antibiotic currently in phase III trials for the treatment of Clostridioides difficile
Authors: Mason Clive , Avis Tim , Coward Chris , Powell David , Duperchy Esther , Hu Chenlin , Jahangir Alam M , Begum Khurshida , Garey Kevin W , Reich Stefanie , Moss Stephen 
Published: December 2021

Abstract

Background
Clostridioides difficile infection (CDI) is recognised by the CDC as an “urgent threat” in the USA, responsible for nearly 13,000 deaths, and carries an economic burden ranging from &5.4 to &6.3 billion per year. In a phase II study, ridinilazole was shown to be effective at treating CDI and decreasing subsequent recurrence compared to vancomycin. However, the precise mechanism of action of ridinilazole has yet to be fully elucidated. We now present data that reveals ridinilazole clearly co-localises with DNA in C. difficile and binds with high affinity to the minor groove of DNA. These interactions are predicted to have consequences on cellular functions within C. difficile.

Methods
High resolution confocal microscopy was used to track the intracellular localisation of ridinilazole in C. difficile. Fluorescence intensity was used to characterise the DNA binding properties of ridinilazole; sequence specificity was demonstrated with AT- or GC-rich DNA polymers, and tight binding was shown using short double-stranded oligonucleotides. Hanging drop vapour diffusion enabled co-crystallisation and subsequent structural determination of DNA-bound ridinilazole.

Results
Confocal microscopy revealed clear co-localisation of ridinilazole to the DNA within C. difficile. Ridinilazole demonstrated a dose-dependent increase in fluorescence in response to increasing concentration of target DNA. Fluorescence binding studies revealed that ridinilazole shows a preference towards AT-rich DNA sequences. Tight binding characteristics were demonstrated by ridinilazole in complex with short double-stranded oligonucleotides, returning dissociation constants (Kd) of 20 – 50 nM. Crystallisation enabled co-structures of ridinilazole bound to the minor groove of double-stranded DNA oligonucleotides to be solved.

Conclusion
Ridinilazole demonstrates tight binding with sequence specificity within the minor groove of DNA and co-localises with DNA in C. difficle. Further analysis is ongoing to fully understand this novel mechanism of action, the downstream consequences of these interactions and how they contribute to the bactericidal activity of ridinilazole.

Disclosures
Clive Mason, PhD, Summit Therapeutics (Employee, Shareholder) Tim Avis, n/a, Summit therapeutics (Shareholder) Chris Coward, PhD, Summit Therapeutics (Employee, Scientific Research Study Investigator, Shareholder) David Powell, PhD, Summit Therapeutics (Employee) Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support)
1058. In Vitro and In Vivo Antibacterial Activity of Cefiderocol against Burkholderia spp
Authors: Oota Merime , Hama Hitomi , Yoshitomi Toriko , Nakamura Rio , Takemura Miki , Yamano Yoshinori , Hackel Meredith , Sahm Daniel F 
Published: December 2021

Abstract

Background
Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp.

Methods
MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416 (CFDC MIC: ≤ 0.031 μg/mL, MEM MIC: 4 μg/mL) was used. Male CD (SD, immunocompetent, n=4-5) rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted.

Results
Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC50/MIC90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of fT &gt;MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the fT &gt;MIC achieved in this model exceeds the target fT &gt;MIC (75% for CFDC and 26% for MEM against Acinetobacter baumannii, respectively) required to cause 1 log10 reduction in murine thigh infection models1,2).
1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AAC
In vitro activity of CFDC and comparator agents against Burkholderia spp.

Conclusion
CFDC has potential for treating respiratory tract infections caused by Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of fT &gt;MIC of ≤ 4 ug/mL3).3) N. Kawaguchi. 2021. AAC

Disclosures
Merime Oota, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1069. In Vitro Activity of Tebipenem Against Clinically Significant Gram-Negative Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat , Rosenblatt Joel , Hachem Ray Y , Raad Issam I , Chaftari Anne-Marie 
Published: December 2021

Abstract

Background
Gram negative (GN) bacterial infections are on the rise in patients with cancer and frequently require extended hospital stays that may lead to a major increase in healthcare cost. This study aimed to evaluate the in vitro activity of a novel oral carbapenem, tebipenem against recent gram-negative clinical isolates from our cancer patients.

Methods
All 173 clinical isolates from our cancer patients including 36 Extended Spectrum Beta-Lactamase (ESBL) isolates from blood cultures were tested against tebipenem and other comparators. Clinical and Laboratory Standards Institute (CLSI) approved broth microdilution method was used. Appropriate ATCC controls were included. MIC50, MIC90, MIC ranges and percent of susceptibility calculations ware made using FDA breakpoints when available. The tebipenem provisional susceptibility breakpoint for most GN organism is ≤ 0.125 mg/L.

Results
Tebipenem and comparators antibiotics susceptibility percent (S: %), and MIC90 are shown in the table below. Tebipenem demonstrated highly potent activity against Escherichia coli, Klebsiella pneumoniae (including ESBL producing strains), Enterobacter cloacae and inhibited 90% of the Enterobacter aerogenes strains screened. MIC90s ranged from 0.06-0.25 mg/L for all tested Enterobacteriaceae. At a provisional breakpoints of 0.125 mg/L, the susceptibilities, MICs and ranges were comparable to meropenem, and ertapenem.
Comparative study between Tebipenem and comparators for MIC90 (mg/L.) and Susceptibility (%) results against Gram-Negative Bacteria Isolated from Patients with Cancer

Conclusion
Our data demonstrate that oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from cancer patients, and it has similar activity to that of other tested carbapenem. Further clinical evaluation for oral carbapenem treatment of bacterial infections is warranted.

Disclosures
All Authors: No reported disclosures
1070. In vitro Activity of PLG0206 Against Isolates Commonly Found in Periprosthetic Joint Infections (PJI)
Authors: Huang David , Steckbeck Jonathan , Pillar Chris , Murray Bev , Huganfel David , Shinabanger Dean 
Published: December 2021

Abstract

Background
PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections. In this study, the activity of PLG0206 was evaluated by broth microdilution against 104 isolates of Staphylococcus epidermidis, 53 other coagulase-negative staphylococci (CoNS), 3 S. aureus, and 66 Gram-negative isolates consisting of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Methods
Imipenem, levofloxacin, tigecycline, linezolid, vancomycin, oxacillin, ceftazidime, colistin, and amikacin were tested as comparators. Testing was conducted in accordance with guidelines from the Clinical and Laboratory Standards Institute (CLSI; M7 and M100). Test organisms consisted of reference strains from the American Type Culture Collection, the Centers for Disease Control Antibiotic Reference Bank and clinical isolates from the Micromyx repository. The media employed for testing in the broth microdilution MIC assay for all organisms were cation-adjusted Mueller Hinton Broth and for PLG0206 only included RPMI-1640 medium supplemented with 0.002% P-80.

Results
Activity of PLG0206 in RPMI against CoNS, S. aureus, and resistant Gram-negative* pathogens are shown in Table.
Activity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogens

Activity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogens

Conclusion
PLG0206 was found to have potent antimicrobial activity when evaluated in RPMI against
S. epidermidis, CoNS non-epidermidis, S. aureus, Enterobacterales, P. aeruginosa, and A. baumannii, including isolates with multi-drug resistance.

Disclosures
David Huang, MD, PhD, Peptilogics (Employee) Jonathan Steckbeck, PhD, Peptilogics (Employee) Chris Pillar, PhD, Micromyx (Employee) Bev Murray, BS, Micromyx (Employee) David Huganfel, BS, Micromyx (Employee) Dean Shinabanger, PhD, Micromyx (Employee)
1072. In Vitro Antibacterial Susceptibility Testing of Sulopenem Against Category A and B Bio-threat Bacterial Pathogens
Authors: Dunne Michael , Aronin Steven I , Halasohoris Stephanie A , Pysz Lisa M , Lembirik Sanae , Meinig James M 
Published: December 2021

Abstract

Background
Sulopenem is a thiopenem β-lactam antibiotic being developed for the treatment of infections caused by multi-drug resistant bacteria. Sulopenem possesses potent activity against species of the Enterobacterales that encode ESBLs or AmpC-type β-lactamases that confer resistance to third generation cephalosporins. It has also demonstrated good in vitro microbiological activity against a range of bacterial pathogens including penicillin resistant S. pneumoniae, β-lactamase-producing H. influenzae and M. catarrhalis. Sulopenem is available as intravenous and oral pro-drug formulations, and its activity aligns with the most urgent drug-resistant antimicrobial threats defined by the CDC.

Methods
Bacterial inoculums were prepared by suspending colonies into cation adjusted Mueller Hinton broth (CAMHB) from 18-24 h (B. anthracis, B. pseudomallei and B. mallei plates incubated at 35ºC); or 36-48 h (F. tularensis and Y. pestis plates incubated at 35ºC and 28ºC, respectively). Sheep blood agar plates were used for B. anthracis and Y. pestis. Chocolate agar plates were used for F. tularensis, B. pseudomallei and B. mallei. Suspended cultures were diluted with CAMHB to achieve a turbidity equivalent to a 0.5 McFarland standard. MICs were determined by the microdilution method in 96-well microplates according to CLSI guidelines (Clinical and Laboratory Standards Institute, 2020). Antibiotic ranges used for sulopenem were 0.03 - 64 μg/mL and 0.004 - 8 μg/mL for the diversity strains of B. anthracis, F. tularensis, Y. pesis, B. mallei, and B. pseudomallei, based on a final well volume of 100 μl after inoculation.

Results
A summary of sulopenem MIC90 results versus bio-threat bacterial pathogens in presented in the table. Criteria for down selection into mice was met for all pathogens except F. tularensis.
Sulopenem MIC90 Summary for Down Selection Criteria

Conclusion
Sulopenem is active in vitro against a number of bio-threat pathogens at concentrations likely to be achieved after oral dosing in humans and meets criteria to be tested in the murine model of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei.

Disclosures
Michael Dunne, MD, Iterum Therapeutics (Board Member, Consultant, Shareholder) Steven I. Aronin, MD, Iterum Therapeutics (Employee, Shareholder)
1073. Sulbactam-Durlobactam Has Potent Activity Against Multidrug-Resistant Acinetobacter baumannii Clinical Isolates From Thai Patients With Chronic Infections
Authors: Wannigama Dhammika Leshan , Higgins Paul G , Hurst Cameron , Abe Shuichi , Hongsing Parichart , Luk-In Sirirat , Kueakulpattana Naris , Laowansiri Matchima , Tanasatitchai Chanikan , Srisakul Sukrit , Kicic Anthony , Chatsuwan Tanittha , Moussa Samir , Miller Alita 
Published: December 2021

Abstract

Background
Due to the increase in multi-drug resistance (MDR) of Acinetobacter baumannii chronic infections with accompanying considerable morbidity and mortality, it is imperative to find effective novel treatments. Durlobactam (DUR) is a potent broad-spectrum inhibitor of Ambler classes A, C and D serine β-lactamases that effectively restores sulbactam (SUL) activity against MDR A.baumannii isolates. SUL-DUR is currently in late-stage development for the treatment of infections caused by Acinetobacter spp., including drug resistant isolates. In this study, we sought to evaluate potency of SUL-DUR against MDR A. baumannii isolates collected from Thai patients with chronic infections.

Methods
Non-duplicative clinical strains were isolated during 2016–2019 from 200 chronically infected patients in different medical wards with a variety of different infections at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Susceptibility testing of SUL-DUR and comparator agents was performed according to CLSI guidelines. SUL-DUR was also tested on a background of imipenem (IPM) therapy (SUL-IPM titrated at a 1:1 ratio plus DUR fixed at 4 mg/L). Data analysis was performed using CLSI and EUCAST breakpoint criteria where available.

Results
This collection of isolates was 92% sulbactam-resistant (using a breakpoint of 4 mg/L), 91% carbapenem-resistant, 74% amikacin resistant and 8% colistin resistant. In contrast, the SUL-DUR MIC90 was 4 mg/L compared with 64 mg/L for sulbactam alone. SUL-DUR was equally potent across antibiotic-resistant subsets. Only 6 isolates (3%) had SUL-DUR MIC values &gt;4 mg/L. Interestingly, addition of imipenem to SUL-DUR showed similar potency as SUL-DUR alone, with an MIC90 of 2 mg/L.

Conclusion
SUL-DUR showed potent in vitro activity against contemporary clinical isolates from a hospital in Bangkok, Thailand. If successfully developed, SUL-DUR may be an important new therapeutic option for the treatment of MDR Acinetobacter infections.

Disclosures
Alita Miller, PhD, Entasis Therapeutics (Employee)
1074. The Relationship Between the Patient’s Body Mass Index and Dalbavancin’s Efficacy in the Treatment of Invasive Gram-Positive Infections
Authors: Avery Lisa , Sessa Julia , Conn Kelly M , Slish Judianne , Adamchick Lauren , Louie Ted 
Published: December 2021

Abstract

Background
Dalbavancin is a long-acting lipoglyopeptide antibiotic used in the treatment of invasive gram-positive infections. There is a lack of published research on the effect of obesity on dalbavancin’s pharmacokinetics. The primary objective was to determine if obesity correlates to clinical failure at 90 days for patients with gram-positive infections treated with dalbavancin.

Methods
This retrospective observational study reviewed the use of dalbavancin from 1/1/2015- 3/31/2021 at 2 community hospitals. Patients were included if ≥ 18 years and received at least one dose of dalbavancin as an inpatient or at an outpatient infusion center. Patients were excluded if not seen by a provider within 90 days post last infusion. The primary outcome was clinical failure (CF). CF at 90 days was a composite of one or more of the following: need for additional antibiotics, dalbavancin intolerance, hospital readmission for same indication, need for additional surgery/debridement, or death. Clinical cure (CC) was defined as not meeting the criteria for CF. Patient demographics, BMI, indication, achievement of source control, Charlson Comorbidity Index (CCM) were collected. Descriptive statistics were used. To determine if a BMI cut-point exists between CC and CF, a classification & regression tree (CART) analysis was performed.

Results
A total of 81 patients received dalbavancin with 19 patients excluded for lack of follow up. Patient demographics: mean age (SD) 45.3 (15.8) years, 50% male; CCM 2.6 (3.1). Indications included osteomyelitis n=22, endovascular n=12, diabetic foot/skin soft tissue n=9, septic joint n=8, other n=11. A total of 29 (47%) of patients were bacteremic; 34 (55%) having source control. CF occurred in 15 of 62 (24%) patients. CF was compared with weight, BMI, CCM, albumin and source control. A difference existed in the median (IQR) BMI between CF 32.5 kg/m2 (25.1 – 42.8) and CC 25.5 kg/m2 (22.1 – 28.2); p=.029. A BMI cutpoint was not identified in CART analysis.

Conclusion
There is a relationship between increased BMI and 90-day CF in patients treated with dalbavancin. A higher BMI was found among those with with CF. Future studies are necessary to determine if a BMI based weight adjustment is necessary.

Disclosures
Lisa Avery, PharmD, BCPS, BCIDP, Merck (Other Financial or Material Support, Spouse Employer)
1077. In Vitro Activity of Delafloxacin Agent Against Bacterial Isolates Recovered from Patients with Cancer
Authors: Gerges Bahgat , Raad Issam I , Rosenblatt Joel , Shelbume Samuel , Prince Randal , Rolston Kenneth 
Published: December 2021

Abstract

Background
Fluoroquinolones have been used for infection prevention in patients with cancer (PWC). They are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms (GPO). Quinolone resistance is increasing and many institutions are using combination regimens for antimicrobial prophylaxis. We evaluated the in vitro activity of delafloxacin (DLX), a novel fluoroquinolone, and selected comparators against 560 bacterial isolates from PWC.

Methods
Isolates were from recent blood cultures. Susceptibility testing and time kill studies (TKS) were performed using CLSI approved methodology. Appropriate ATCC control strains were used. We calculated MIC50, MIC90, MIC ranges and percent susceptibility using FDA breakpoints when available. TKS were performed on 4 streptococcus mitis isolates at concentrations of MIC, 4x MIC, and 8x MIC.

Results
DLX was more active than ciprofloxacin (CIP) and levofloxacin (LEV) against methicillin-susceptible (MSSA), and resistant (MRSA) S. aureus, coagulase-negative staphylococci (CoNS), and viridans group streptococci (VGS), and had similar activity against beta-hemolytic streptococci. It also had low MICs for Bacillus species (SPP.), Listeria monocytogenes, Micrococcus spp., and Rothia spp. Overall GPO susceptibility was 73% to DLX, 42% to CIP, and 52% to LEV. The activity of DLX against Enterobacterales was similar to CIP and LEV. All 3 agents had moderate activity against Citrobacter spp., and non-MDR P. aeruginosa. Notably, all 3 quinolones had poor activity against E. coli, P. mirabilis, and MDR P. aeruginosa, all common pathogens in PWC. All 3 had low MICs for Acinetobacter spp. DLX and LEV achieved peak bactericidal activity at 6-8 h against all 4 VGS isolates (maximum activity at 8x MIC) but this was not always sustained at 24 h.
Table 1. Percent Susceptibility of selected Gram-positive isolates to Delafloxacin, Ciprofloxacin and Levofloxacin

Table 2. Percent Susceptibility of selected Gram-negative isolates to Delafloxacin, Ciprofloxacin and Levofloxacin

Figure 1. Bactericidal Activity of DLX at 1x , 4x, and 8x MIC against VGS - Time Kill Study

Conclusion
DLX is more active than CIP and LEV against many GPO from PWC (including S. aureus and VGS), but like these agents there are significant gaps in its coverage against GNB. It is probably not suitable as a single agent for antimicrobial prophylaxis in high-risk PWC. The current practice of combining a quinolone with a beta-lactam probably still represents the best option in PWC who need prophylaxis.

Disclosures
Kenneth Rolston, MD, Tetraphase Pharmaceuticals (Grant/Research Support)