bluuebunny/crossref_metadata_2025_split huggingface dataset:
2109. In vitro and in vivo Killing Kinetics of Zosurabalpin (RG6006) Against Acinetobacter baumannii
Authors: Erbetti Isabelle , Ferrari Livia , Ortombina Alessia , Savoia Paola , Felici Antonio , Bissantz Caterina , Zampaloni Claudia 
Published: November 2023

Abstract

Background
Zosurabalpin (RG6006) is a novel antibiotic active against Acinetobacter spp., including carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex organisms. Here we describe and compare the kinetics of killing in static in vitro and in vivo neutropenic murine thigh and lung infection models.

Methods
The killing activity of Zosurabalpin was evaluated against 8 carbapenem resistant A. baumannii (CRAB) isolates (MIC range of 0.12 to 8 mg/L).
In vitro Time-Kill studies were performed over 24 hours at sub-MIC and multiples of the MIC (from 0.25x to 128x MIC) with regular time point samplings (from 0, 2, 4, 8, 12, 16, 20 and 24 hours), plating, and CFU counting.
The in vivo killing efficacy of RG6006 at 2 or 3 dose levels was assessed in 5 thigh and 5 lung infection models induced by 6 A. baumannii (MIC range 0.125 - 8 mg/L). Bacterial burden in matrices of interest was determined at different timepoints up to 48 hours.

Results
In vitro, the bactericidal activity (defined as a 99.9% [or ≥ 3 log10] reduction in CFUs) of Zosurabalpin was reached in all tested isolates (lowest bactericidal concentration: 4x-32x MIC) and with a relatively slow killing kinetic (≥ 12 hours). No regrowth was observed at or above 8x/16x MIC depending on the isolate.
In vivo, generally, no regrowth was observed. In all 5 lung and 3 thigh infection studies, all dosing regimen achieving a net bacterial reduction after 24 hours, showed continued suppression of growth over the 48 hours period. In 2 thigh infection studies induced by isolates with MIC 4 and 8 mg/L full bactericidal efficacy was observed without any signs of regrowth at the highest dose tested.

Conclusion
Zosurabalpin overall exhibited a bacterial killing effect, both in vitro and in vivo, against CRAB. The comparison of in vitro and in vivo time-kill data demonstrates that in vitro observed regrowth generally does not translate into, and potentially overestimates, in vivo regrowth.
This project has been funded by BARDA (HHSO100201600038C)

Disclosures
Isabelle Erbetti, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Livia Ferrari, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Alessia Ortombina, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Paola Savoia, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Antonio Felici, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Caterina Bissantz, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche Claudia Zampaloni, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche
2122. In Vitro Activity of Cefepime-Taniborbactam Against Clinically Significant Gram-Negative Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat Z , Truong Y Lan , Rosenblatt Joel , Hachem Ray Y , Chaftari Anne-Marie , Shelburne Samuel A , Raad Issam I 
Published: November 2023

Abstract

Background
Gram negative (GN) bacterial infections are on the rise in patients with cancer (PWC). There is an urgent need for new therapies to address the rise of infections caused by multidrug resistant (MDR) GN pathogens. Taniborbactam is a β-lactamase inhibitor in combination with cefepime may offer a potential treatment option for patients with serious GN bacterial infections. This study aimed to evaluate the in vitro activity of a novel combination of cefepime-taniborbactam and comparators against recent Gram-negative clinical isolates from PWC.

Methods
Recent GN clinical isolates from PWC were tested against cefepime-taniborbactam and comparators. Clinical and laboratory Standards Institute (CLSI) approved broth microdilution method was used. Appropriate ATCC controls were included. MIC90, and percent of susceptibility calculations were made using FDA breakpoints when available. We tested 100 GN isolates and further testing is ongoing.

Results
Cefepime-taniborbactam and comparators antibiotics susceptibility percentage (S: %), and MIC90 are shown in the table below. Cefepime-taniborbactam demonstrated highly potent activity against all of tested Enterobacterales including extended spectrum Beta-lactamase (ESBL), and carbapenem-resistant Enterobacterales (CRE) as well as against P. aeruginosa and Stenotrophomonas maltophilia. At a provisional breakpoint of 16/4 mg/L, cefepime-taniborbactam showed highest activity against all tested isolates when compared to cefepime and other comparators, including activity against ESBL, CRE, MDR P. aeruginosa and S. maltophilia.
Comparative study between cefepime-taniborbactam and comparators for MIC90 (mg/L.) and Susceptibility (%) results against Gram-negative bacteria isolated from patients with cancer

Conclusion
Our data demonstrate that cefepime-taniborbactam has promising activity against clinically significant multidrug-resistant (MDR) GN bacterial pathogens isolated from PWC and it showed high activity compared to other commonly used broad spectrum antimicrobial agents.

Disclosures
Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2123. Novel Antimicrobial Polycarbonate Coating for Intravenous Connectors
Authors: Truong Y Lan , Gerges Bahgat Z , Rosenblatt Joel , Raad Issam I 
Published: November 2023

Abstract

Background
IV connectors are ubiquitous access junctions in vascular access circuits. Unlike vascular catheters and IV lines made from soft polymers, connectors are made from rigid polycarbonate (PC) to prevent deformation during manipulation. In accessing PC connectors (PCCs) for infusion, PCCs are vulnerable to becoming microbially contaminated. Here we report development of a novel antimicrobial polycarbonate coating for preventing microbial colonization of IV connectors.

Methods
The FDA recently approved a new antimicrobial polyurethane catheter coating that comprised Minocycline (M), Rifampin (R), and Chlorhexidine (C). We spray-coated MRC onto PCCs as sequential laminate layers of M, R and C in PC or blend PC and polycarbonate-urethane copolymers. MRC coated PCCs were immersed in tubes filled with 50% serum + 50% saline to simulate elution of the coatings. After 7 days (typical interval of use prior to replacement of IV connectors), eluted connectors were exposed to challenge inocula of key CLABSI pathogen clinical isolates for 24 hours and the number of colonizing microbes were enumerated by sonication, serial dilution, plating and colony counting. Non-coated PCCs were positive controls.

Results
Table 1 presents number of viable colonies recovered after 7 days elution and following 24 hour microbial challenges with Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PA) and Candida albicans (CA).

Conclusion
The absence of microbial colonization of the MRC IV connectors demonstrates the efficacy and durability of the novel MRC polycarbonate laminate coating. MRC coated connectors merit further testing in vitro and in vivo for their potential to prevent CLABSI.

Disclosures
Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2124. Novel Polygalacturonic and Caprylic Acid (PG+CAP) Antimicrobial Wound Ointment Effectiveness in Eradicating C. auris Biofilms In Vitro
Authors: Truong Y Lan , Gerges Bahgat Z , Rosenblatt Joel , Raad Issam I 
Published: November 2023

Abstract

Background
Candida auris (CA) is a multidrug-resistant fungal pathogen of increasing concern and has caused infection outbreaks in hospitals as a result of nosocomial transmission. CA has caused both invasive bloodstream and wound infections with significant morbidity and mortality. Recently, a novel polygalacturonic and caprylic acid (PG+CAP) antimicrobial wound ointment was highly effective in healing microbially contaminated chronic wounds in a pilot prospective randomized clinical trial when compared to MediHoney. In order to better combat CA wound infections, here we assessed the effectiveness of PG+CAP and MediHoney wound ointments in eradicating mature CA biofilms in vitro.

Methods
A well-established biofilm eradication model was used to quantify antimicrobial efficacy. Forty-eight-hour biofilm of two different strains of CA (AR0381 and AR0382) were formed separately on silicone discs and then exposed to PG+CAP or MediHoney wound ointment for two hours. The silicone discs were sonicated in neutralizer, then serially diluted, plated and counted to enumerate viable colonies remaining following exposure to the ointments. Positive controls were discs that had no wound ointment treatment.

Results
Figure 1 presents the median number of viable colonies recovered from 6 replicates following two-hour exposures of the mature CA biofilms to the wound ointments and positive control.

Conclusion
Both ointments fully eradicated biofilm for CA strain AR0381. PG+CAP fully eradicated AR0382 biofilm (greater than 5-log reduction) but MediHoney achieved less than a 3-log reduction against AR0382. The difference between PG+CAP and MediHoney for AR0382 was significant (p = 0.02). These results suggest PG+CAP might be a promising ointment for use in treating CA wound infections and merits further study.

Disclosures
Joel Rosenblatt, PhD, Novel Anti-Infective Technologies, LLC: Licensed Technology Issam I. Raad, Distinguished Professor, Novel Anti-Infective Technologies, LLC: Technology License
2125. Activity of Novel β-Lactam/β-Lactamase Inhibitor Combinations against Serine-Carbapenemase producing Carbapenem-Resistant Pseudomonas aeruginosa
Authors: Lee Su Young , Gill Christian M , Nicolau David P 
Published: November 2023

Abstract

Background
Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLI), avibactam, relebactam, and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL) /BLI combinations against serine-carbapenemase producing P. aeruginosa is unknown. The present study sought to compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam, and meropenem against serine-β-lactamase producing P. aeruginosa.

Methods
Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. Minimum inhibitory concentrations (MICs) were determined by broth microdilution to each novel-BL/BLI and BL alone. In vitro potency was assessed by MIC50/90 and percent of isolates susceptible per CLSI guidance.

Results
GES was the most common carbapenemase identified (n=59) followed by KPC (n=8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/ &gt;16 mg/L and 13% of all isolates were defined as susceptibility. Against the KPC-producing isolates, 38% were susceptible to imipenem/relebactam compared with 0% for imipenem. The meropenem/vaborbactam MIC50/MIC90 were &gt;16/ &gt;16 mg/L, and 6% of isolates were susceptible which was similar to meropenem alone (MIC50/90, &gt;8/ &gt;8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms.

Conclusion
Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine-carbapenemase harboring P. aeruginosa. While imipenem/relebactam displayed some activity particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity with MICs similar to meropenem alone. These data can be integrated with rapid molecular diagnostics to guide empiric therapy.

Disclosures
Christian M. Gill, PharmD, Cepheid: Grant/Research Support|Entasis therapeutics: Grant/Research Support|Everest Medicines: Grant/Research Support|Shionogi: Grant/Research Support David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support
2151. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against Pseudomonas aeruginosa Collected from Patients with Presumed Hospital- and Community-Acquired Respiratory Tract Infections: ATLAS Global Surveillance Program, 2017-2021
Authors: Wise Mark G , Stone Gregory , Sahm Daniel F 
Published: November 2023

Abstract

Background
The β-lactamase inhibitor, avibactam, has potent inhibitory activity against Class A, Class C, and certain Class D serine β-lactamases. This study evaluated the in vitro activity of ceftazidime-avibactam (CZA) and comparators against respiratory tract infection (RTI)-associated Pseudomonas aeruginosa isolated from presumed community-acquired (CA; cultured &lt; 48 hours after hospital admission) and hospital-acquired (HA; cultured ≥48 hours post-admission) infections collected from 2017-2021.

Methods
11,780 non-duplicate P. aeruginosa were collected from 246 sites in 54 countries as part of ATLAS 2017-2021 (excluding mainland China and North America) from respiratory tract infections for which the length of hospitalization was specified. Susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2023 breakpoints. Meropenem-nonsusceptible (MEM-NS) isolates were screened for the presence of β-lactamase genes. All MEM-NS isolates were screened in 2017-2020, whereas ∼25% of those collected in 2020 and 2021 were screened.

Results
CZA was the most active agent examined against the CA-infection isolates, inhibiting 92.3% of the population (Table). Against the HA isolates, 89.0% were susceptible to CZA, a percentage slightly lower than amikacin (89.4%). Removing MBL-producers increased the percentages susceptible to CZA for both groups by 2-3 percentage points. Approximately 68-70% of the meropenem-nonsusceptible isolates from both groups were susceptible to CZA, values similar to those demonstrated by amikacin and ceftolozane/tazobactam.

Conclusion
The percentage of CA and HA isolates from respiratory tract infections inhibited by CZA was approximately 15 and 20 percentage points higher, respectively, than the percentages inhibited by meropenem, and slightly higher (1-2 percentage points) than ceftolozane-tazobactam. The potent in vitro activity of CZA against HA isolates was exceeded only by amikacin, an agent discouraged as monotherapy for P. aeruginosa infections outside of the urinary tract by the CLSI. CZA remains an excellent therapeutic choice for use against P. aeruginosa, regardless of whether they’re CA or HA.

Disclosures
Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2157. Phase 1 Study in Healthy Chinese Subjects of Novel Prodrug, MRX-4
Authors: Yang Haijing , Li Size , Wang Hailin , Cao Guoying , Zhang Jing 
Published: November 2023

Abstract

Background
MRX-4 is a prodrug of contezolid (MRX-1), a new oxazilidone approved in China. We evaluated the safety and pharmacokinetic (PK) profile of IV and oral MRX-4 and its metabolites.

Methods
This randomized, double-blind, placebo-controlled study was conducted at Huashan Hospital, (Shanghai, China) with four-arm design: a) IV, single-dose escalation group (500 mg, 1000 mg, 1500 mg, or 2000 mg); b) IV, repeated-dose group (2000 mg loading dose followed by 1000 mg maintenance dose, q12 h for 11 consecutive days using 1-1.5 hr infusion time); c) oral, single-dose escalation group (500 mg or 1500 mg); d) oral, repeated-dose group (1500 mg, q12 h for 11 consecutive days). Safety evaluation was conducted in each dose group.
The blood and urine concentrations of MRX-4, MXR-1, and the inactive metabolites (MRX-1352) were measured, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

Results
A total of 70 subjects completed the trial. MRX-4 concentration was not possible to measure due to rapid hydrolisis into MRX-1352. In the MRX-4 group, 67 treatment-emergent adverse events (TEAEs) were observed in 27 of 55 subjects (49%); 24 TEAEs occurred in 14 subjects in the IV group (n = 36) and 43 TEAEs in 13 subjects in the oral group (n = 19). Six adverse drug reactions (ADRs) were observed in 4 subjects in the IV group, which were predominantly a mild transient decrease in white blood cells that self-resolved. In the oral group, 23 ADRs were observed in 9 of 19 subjects (47%), primarily nausea and vomiting that self-resolved in the 1500 mg repeated-dose group. No decrease in platelet count was observed in any dose group. PK parameters of the inactive intermediate metabolite (MRX-1352), and the active metabolite (MRX-I, contezolid) are shown:

Conclusion
MRX-4 was safe and well tolerated among Chinese healthy subjects, with treatment adverse events being mild and transitory. MRX-4, administered via IV or oral, demonstrated rapid and complete conversion to contezolid. PK parameters support the potential for use of MRX-4 as the IV companion to oral contezolid.

Disclosures
All Authors: No reported disclosures
2159. Analysis of Resistance to Oral Standard-of-Care Antibiotics for Urinary Tract Infections Caused By Escherichia coli and Staphylococcus saprophyticus Collected in the United States in 2022
Authors: Arends S J Ryan , Kapoor Renuka , Torumkuney Didem , Scangarella-Oman Nicole E , Mendes Rodrigo E 
Published: November 2023

Abstract

Background
Gepotidacin is a novel, bactericidal, first-in-class triazaacenapthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and binding site and provides well-balanced inhibition of 2 different Type II topoisomerase enzymes. This study reports on the in vitro activity of gepotidacin and other oral antibiotics when tested against contemporary Escherichia coli and Staphylococcus saprophyticus clinical isolates collected from patients with UTIs for a gepotidacin uUTI global surveillance study.

Methods
A total of 1,001 E. coli and 92 S. saprophyticus isolates were collected during 2022 from 45 medical centers located within the United States. Most isolates (77%) tested were cultured from urine specimens collected from patients seen in ambulatory, emergency, family practice, and outpatient medical services. Bacterial identifications were confirmed by MALDI-TOF MS. Isolates were tested for susceptibility by CLSI methods at a central laboratory (JMI Laboratories). MIC results for oral antibiotics licensed for the treatment of uUTI and drug-resistant subsets were interpreted per CLSI guidelines.

Results
Gepotidacin (MIC50/90, 2/4 µg/mL) displayed good activity against 1,001 E. coli isolates as 98.8% of all observed gepotidacin MICs were ≤4 µg/mL (Table). Other oral agents tested against these isolates demonstrated the following rates of susceptibility (S): amoxicillin-clavulanate (85.2% S), ampicillin (55.6% S), ciprofloxacin (78.8%S), fosfomycin (99.3% S), mecillinam (93.5%S), nitrofurantoin (97.5% S), and trimethoprim-sulfamethoxazole (73.3% S). Gepotidacin maintained similar MIC50 values (ranging from 1 – 2 µg/mL) and MIC90 values (ranging from 2 – 4 µg/mL) against these drug-resistant subsets. Against S. saprophyticus isolates, gepotidacin (MIC50/90, 0.06/0.12 µg/mL) inhibited all isolates at ≤0.12 µg/mL. Most oral agents showed &gt;90% S against S. saprophyticus isolates, except for penicillin (7.6% S).

Conclusion
Gepotidacin demonstrated in vitro activity against contemporary E. coli and S. saprophyticus from US urine isolates. This activity remained unaffected by resistance to other oral standard-of-care antibiotics.

Disclosures
S J Ryan Arends, PhD, Cipla: Grant/Research Support|GSK: Grant/Research Support Renuka Kapoor, PhD, GSK: Grant/Research Support Didem Torumkuney, PhD, GSK: Grant/Research Support Nicole E. Scangarella-Oman, MS, GSK: Employee and shareholder Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support
2166. Real-world susceptibilities to newer antibiotics in Enterobacterales and Pseudomonas aeruginosa including carbapenem non-susceptible and multi-drug resistant isolates : A multicenter analysis
Authors: Riccobene Todd , Ai ChinEn , Yu Kalvin , Gregory Sara , Kim Brooke , Debabov Dmitri , Gupta Vikas 
Published: November 2023

Abstract

Background
Infections caused by multi-drug resistant (MDR) Gram-negative pathogens are increasingly problematic in healthcare settings and are associated with worse clinical outcomes in critically ill patients. We conducted a multicenter evaluation of real-world susceptibilities to newer antibiotics.

Methods
Adult patients (≥ 18 years old) with facility reported antibiotic susceptibility from 2018-2022 across 100 facilities in the BD Insights Research Database (Franklin Lakes, NJ) were evaluated for overall and carbapenem non-susceptible (Carb-NS) Enterobacterales (ENT) and Pseudomonas aeruginosa (PSA) across respiratory, blood, urine, intra-abdominal, skin/wound, and other sources.

Results
A total of 27676 susceptibility results for Gram-negative pathogens were available for one or more of the antibiotics in Table 1 across 100 facilities, of which 79.9% (22101) and 19.6% (5420) were for ENT and PSA, respectively (Table 2). Ninety percent of susceptibility results for newer antibiotics were for E coli (42.9%), P aeruginosa (19.6%), K pneumoniae (14.6%), P mirabilis (8.1%), and E cloacae (4.8%). The top 3 antibiotics tested for ENT were CZA (11,667), TOL-TAZ (10,127), and MEV (211) and for PSA were TOL-TAZ (3172), CZA (1900), and FDC (317). For antibiotics reporting &gt; 30 isolates, susceptibilities were highest for CZA in overall (98.7%), MDR (92.9%) and Carb-NS (85.0%) ENT and for FDC in overall (95.6%) and Carb-NS PSA (93.3%) (Table 3). Susceptibility of Carb-NS ENT to CZA was lower in 2022 (76.7%) than in 2018 (93.5%) but was consistent from 2019-2021 (85.7-87.7%). In Carb-NS ENT, TOZ-TAZ S was lower than CZA each year, ranging from 13.4 to 43.3% (Figure 1). CZA S was higher in 2022 than in 2018-2021 for Carb-NS PSA and was 82.0% compared to 86.4% for TOL-TAZ (Figure 1).

Conclusion
Real-world susceptibilities of all ENT were &gt; 90% to CZA, TOL-TAZ, and MEV. Susceptibilities of Carb-NS ENT to CZA and MEV were &gt;80%. Real-world susceptibilities of all PSA were &gt; 85% for CZA, TOL-TAZ, and FDC. Susceptibilities of Carb-NS PSA were &gt; 70% to CZA, TOL-TAZ, and FDC. Newer antibiotics remain an important option for management of resistant ENT and PSA.

Disclosures
Todd Riccobene, PhD, AbbVie: Employee salary|AbbVie: Stocks/Bonds ChinEn Ai, MPH, Becton, Dickinson and Company: Employee Kalvin Yu, MD, FIDSA, BD: Stocks/Bonds Sara Gregory, PhD, Becton, Dickinson and Company: Employee Brooke Kim, RN, BSN, MSM, AbbVie: Employee|AbbVie: Stocks/Bonds Dmitri Debabov, PhD. Molecular biology, Abbvie Inc.: Employee of Abbvie that participated in design, study conduct, financial support, interpretation of data, review, and approval of the publication Vikas Gupta, PharmD, Becton, Dickinson and Company (BD): Employee of BD|Becton, Dickinson and Company (BD): Stocks/Bonds