bluuebunny/crossref_metadata_2025_split huggingface dataset:
P-1077. Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam (C/T) Real-world Analysis (SPECTRA): Clinical Outcomes and Treatment Patterns from Mexico
Authors: Saldivar Ines , Ayala Pedro Martínez , Ortiz Adrian Camacho , Castañeda-Méndez Paulo , Morfin-Otero Rayo , Zhou Yanbing , Polis Thales , Yucel Emre 
Published: January 2025

Abstract

Background
Reported are results of SPECTRA data from Mexico

Methods
SPECTRA (n=617) is a 7-country multicentre retrospective observational study, including hospitalized adult patients (≥18 years) treated with C/T for ≥48 hours. Medical records were reviewed for 30 days after the last dose of C/T or until death. Reported are clinical outcomes and treatment patterns in Mexico.Table 2.All-cause in-hospital mortality (ACHM) in the Mexico cohort

Results
Mean age of patients (n=59) is 55.2 years, and 47.5% were female. Common comorbidities were diabetes mellitus (DM) uncomplicated (18.6%) and DM with end organ damage (3.4%), transplantation (16.9%), heart disease (16.9%), chronic kidney disease (11.9%), chronic pulmonary disease (10.2%), acute kidney injury (10.2%), and end-stage renal disease (3.4%). From positive cultures (n=32) were found 21 multi-drug resistant (MDR) Pseudomonas aeruginosa (PsA) (65.6%) and 4 MDR Enterbacterecea (12.5%). C/T was used to treat pneumonia (30/59, 50.8%), complicated intra-abdominal infection (9/59,15.3%), complicated urinary tract infection (8/59, 13.6%), bone and joint infection (8/59, 13.6%), and sepsis (8/59, 13.6%). Mean time from the index hospitalization admission to C/T initiation is 16.0 days. Mean time from the first microbiology (MB) sample for the index infection to C/T initiation is 1.9 days. C/T treatment duration was median 8.0 days (Q1:Q3; 5, 11). Doses included 54.2% 1.5g/Q8h; 39.0% 3g/Q8h; 5.1% 750mg/Q8h; 1.7% 1g/Q8h. C/T rank of initiations: first-line (49.2%), second-line (42.4%), third-line (6.8%), fourth-line (0), fifth-line (1.7%), sixth+line (0). Of all the cases, empiric therapy accounted for (37/59) 62.7%, definitive therapy in (17/59) 28.8%, and undetermined (5/59) (8.5%).
Clinical success rate for treating the index infection with C/T is 79.7% of patients (Table 1). All-Cause-Hospital-Mortality (ACHM) is 16.9%. Median time from index date to death is 12.0 days (Table 2). ICU admission is reported in 42.4% of cases, with a median ICU length of stay at 20.0 days (Table 3).Table 3.ICU admission and LOS during the index hospitalisation from the Mexico† ICU LOS if ICU admission was related to index infection.CI, confidence interval; ICU, intensive care unit; LOS, length of stay; SD, standard deviation.

Conclusion
Results show real-world effectiveness of C/T in Mexico, more research is warranted.

Disclosures
Yanbing Zhou, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company) Thales Polis, MD, MSD: Stocks/Bonds (Public Company) Emre Yucel, PhD, Merck: I am a full time Merck Employee and own stocks in the retirement plan provided by Merck.|Merck: Stocks/Bonds (Public Company)
P-1086. COT-832, a Novel Polyene Macrolide Antifungal (I): In Vitro Antifungal Activity against Candida, Aspergillus, and Mucor, etc., Hemolytic Activity, and Cytotoxicity
Authors: Maki Hideki , Nishiyama Yuri , Ohara Takafumi , Sugimoto Hideki 
Published: January 2025

Abstract

Background
A novel polyene macrolide antifungal, COT-832 was created by SHIONOGI through structurally modifying Amphotericin B(AmB). Invasive fungal infections are commonly treated with antifungal drugs such as azoles, polyenes, and echinocandins; however, their efficacy is limited and mortality rates remain high. Therefore, the development of more effective and safer antifungal drugs is needed. AmB is available in formulations such as Fungizone (FGZ), which utilizes a deoxycholic acid formulation, and AmBisome (L-AMB), which employs a liposome formulation. While these polyene antifungals exhibit activity against a wide range of fungal species, their usage is often discontinued due to the nephrotoxicity associated with AmB itself. This study aimed to evaluate the antifungal activity, hemolytic activity, and cytotoxicity of COT-832 in vitro.

Methods
Antifungal activity was assessed using the CLSI method on clinical isolates from Japan (2012-2016). Hemolysis activity was measured after applying compounds to 4% sheep red blood cells for 24 hours. Cytotoxicity was evaluated by applying compounds to HepG2 cells for 2 hours and measuring lactate dehydrogenase (LDH) levels in the supernatant with Cytotox96 assay for calculating cell survival rate.

Results
Antifungal activity: COT-832 exhibited MIC90 of 0.5-2 µg/mL against Aspergillus and Candida, matching AmB's MIC. It also showed efficacy against azole-resistant A. fumigatus and echinocandin-resistant C. glabrata. COT-832's MIC90 for Cryptococcus was 0.5 µg/mL, surpassing AmB. Similar MICs were observed for rare molds.
Hemolytic activity: AmB caused hemolysis from 0.625 µg/mL, reaching 80% at 2.5 µg/mL. COT-832 displayed an 8% hemolysis rate at 2.5 µg/mL.
Cytotoxicity: AmB reduced cell count from 2 µg/mL, while no noticeable decrease occurred with COT-832 up to 72 µg/mL.

Conclusion
COT-832 exhibits comparable antifungal activity to AmB while demonstrating reduced toxicity against various cells, up to a tenfold decrease compared to AmB. These findings suggest that COT-832 has potential for development as a safer polyene macrolide antifungal drug, offering potent antifungal activity across a wide range of fungal species.

Disclosures
Hideki Maki, PhD, Shionogi & Co., Ltd.: employee|Shionogi & Co., Ltd.: employee Yuri Nishiyama, MS, Shionogi & Co., Ltd.: employee Takafumi Ohara, n/a, Shionogi & Co., Ltd.: employee Hideki Sugimoto, n/a, Shionogi & Co., Ltd.: employee
P-1089. Pharmacokinetics of Rifaquizinone in Rats and Dogs Following Intra-Articular Administration
Authors: Wang Huan , Cheng Qin , Xiong Haiwei , Ma Zhenkun 
Published: January 2025

Abstract

Background
Rifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of prosthetic joint infections (PJIs). RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. The current studies investigate the pharmacokinetics (PK) of RFQ following intra-articular (IA) administration to rats and dogs.

Methods
In the first study, 18 male rats were assigned into Group 1-3 and received a single dose of 10 mg/kg RFQ formulated in 5% (w/v) glucose, saline, or 4% (w/v) Solutol HS15 in 5% (w/v) glucose, respectively. In the second study, six (3/sex) beagle dogs received a single dose of 3 mg/kg RFQ in 5% (w/v) glucose on the left leg and an equal volume of vehicle on the right leg. Blood and synovial fluid samples were collected and concentrations of RFQ were determined by liquid chromatography tandem mass spectrometry.

Results
Following a single dose of IA administration of 10 mg/kg RFQ in rats, the maximum plasma concentrations (Cmax) were 289, 130 and 139 ng/mL in Group 1, Group 2 and Group 3, respectively. The mean synovial fluid concentrations of RFQ reached 76,844, 371,887 and 367,912 ng/mL at 24 hour after dosing for Group 1, Group 2, and Group 3, respectively. Following a single dose of IA administration of 3 mg/kg of RFQ in dogs, the Cmax in plasma was 736 ng/mL, while the mean synovial fluids concentrations at 12 and 36 hours post dosing were 77,300 and 2,240 ng/mL, respectively. The synovial fluid concentration were 38.7 and 1.12 fold higher than the minimum biofilm bactericidal concentration inhibit 90% bacterial growth (MBBC90) for S. aureus (MBBC90 = 2,000 ng/mL) and 309 and 8.96 fold higher than the MBBC90 for S. epidermidis (MBBC90 = 250 ng/mL).

Conclusion
The 5% (w/v) glucose appeared to be the best vehicle for IA administration of RFQ based on the tolerability and elimination profile. RFQ reached a high local synovial fluid concentration significantly higher than the MBBC90 for S. aureus and S. epidermidis for a prolonged period of time, while maintaining a low systemic exposure. The current studies supporting further evaluation of RFQ for the treatment of PJI via IA administration.

Disclosures
Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Qin Cheng, Master, TenNor Therapeutics (Suzhou) Ltd: Employee Haiwei Xiong, Master, TenNor Therapeutics (Suzhou) Ltd: Investigator Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee
P-1097. Efficacy of Rifaquizinone in a Murine Model of Prosthetic Joint Infection (PJI) with Fluoroquinolone-Sensitive and -Resistant Staphylococcus aureus
Authors: Pulse Mark E , Nguyen Phung , Valtierra David , Peterson Kelly , Ma Zhenkun , Wang Huan , Weiss William J 
Published: January 2025

Abstract

Background
Rifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of serious or life-threatening bacterial infections including those caused by gram-positive pathogens that have developed or acquired resistance to commonly used antibiotics and those associated with medical devices. RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. Current studies sought to evaluate the therapeutic efficacy of RFQ following intraperitoneal (IP) administration for 7- to14-day treatment in a murine model of S. aureus prosthetic joint infection (PJI).

Methods
K-wire was implanted in right hindlimb femurs of C57/BL6 mice followed by infection with 6.5-6.9 log10 CFU of a fluoroquinolone-sensitive (UNT005-4) or -resistant (UNT002-3) S. aureus strain. Doses of RFQ, ciprofloxacin, vancomycin, and vehicle were IP administered BID for 7 or 14 consecutive days starting 7 or 21 days after infection. Infected wires and femurs were collected and processed for CFU counts from untreated groups at the start of treatment and treated/vehicle groups within 18 hours of the final administered dose.

Results
In the 7 day UNT005-4 infection study, mean wire and femur counts for the infection group were 4.77 log10 CFU and 7.89 log10 CFU on Day 7 and for vehicle treatment were 5.02 log10 CFU and 6.83 log10 CFU on Day 14. Comparatively, RFQ at doses of 10, 25, and 62.5 mg/kg for 7 days treatment significantly reduced mean wire and femur counts by &gt; 2.40 and &gt; 1.60 log10 CFU. In the 21 day UNT005-4 infection study, compared to the infection and vehicle treatment, the same doses of RFQ administered for 14 days significantly reduced mean counts by &gt;1.02 log10 CFU for wires and &gt; 0.88 log10 CFU for femurs. In the 21 day UNT002-3 infection study, RFQ administered for 14 days significantly reduced mean counts by &gt; 1.50 log10 CFU for wire and &gt; 0.9 log10 CFU for femur. As expected, reduction in mean counts following 7 or 14 days of ciprofloxacin and vancomycin treatments were less than RFQ.

Conclusion
RFQ IP administered doses significantly reduced wire- and femur-associated counts for both S. aureus strains, and despite UNT002-3 resistant to ciprofloxacin treatment, the RFQ remained efficacious in the murine PJI model.

Disclosures
Mark E Pulse, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator Phung Nguyen, BS, TenNor Therapeutics (Suzhou) Ltd: Investigator David Valtierra, Master, TenNor Therapeutics (Suzhou) Ltd: Investigator Kelly Peterson, PhD, TenNor Therapeutics (Suzhou) Ltd: Investigator Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee William J Weiss, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator
P-1109. A phase 2, randomized, double-blind study of ibezapolstat compared with vancomycin for the treatment of Clostridioides difficile infection: clinical and microbiome evaluation
Authors: Eubank Taryn A , Jahangir Alam M , Begum Khurshida , McPherson Jacob , Jo Jinhee , Silverman Michael , Garey Kevin W 
Published: January 2025

Abstract

Background
Ibezapolstat (IBZ) is Gram-positive selective spectrum antibiotic that inhibits the bacterial DNA polymerase IIIC currently in clinical trial development for the treatment of C. difficile infection (CDI) in adults. In the open-label, non-comparative, phase 2a study, 10 of 10 IBZ-treated CDI patients experienced clinical cure. The purpose of the phase 2b CDI study was to assess the safety, efficacy, and microbiome change of IBZ versus vancomycin (VAN).

Methods
Phase 2b (ClinicalTrials.gov, number NCT04247542) was a randomized, double-blind, active-comparator study. Participants with signs and symptoms of CDI and a positive enzyme immunoassay toxin test result were recruited from 12 centers in the USA and randomly assigned (1:1) to receive oral IBZ 450 mg every 12 h or oral VAN 125 mg every 6 h for 10 days. Stool was collected daily for microbiome evaluations. The primary endpoints were clinical cure at the end of therapy visit and safety. Secondary endpoints included microbiologic and microbiome evaluations.

Results
Thirty patients were recruited and were assessed in the per protocol analysis. (IBZ: n=16; VAN n=14). Fifteen of 16 (93.8%) patients given IBZ had a clinical cure versus 14 of 14 (100%) patients given VAN. IBZ and VAN were well tolerated with no serious drug-related events. C. difficile was eradicated from all stool samples after day 3 of treatment for IBZ-treated patients while three VAN-treated patients had C. difficile growth after day 3. IBZ demonstrated consistent preservation of key Bacillota species while significant decreases were observed in VAN-treated patients. CDI recurrence occurred in two patients given VAN and no patients given IBZ.

Conclusion
In the phase 2b study, IBZ had a clinically comparable cure rate and safety profile to oral vancomycin. Favorable microbiologic and microbiome findings were observed with IBZ-treated patients along with a lower rate of CDI recurrence. These results warrant further development in phase 3 trials.

Disclosures
Michael Silverman, MD, Acurx: Advisor/Consultant Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support
P-1121. Unconventional Selection Pressures for Resistance in Immunocompromised Gut Resistomes: A Multicenter Observational Study of Pediatric Hematopoietic Stem Cell Transplant Recipients
Authors: Duggar Marygrace , Jia Qidong , Sun Yilun , Tang Li , Margolis Ellie 
Published: January 2025

Abstract

Background
Increased antibiotic exposure contributes to antibiotic resistance in immunocompromised hosts. Studying how antibiotic courses alter resistance development in their gut community, a common source of bloodstream infections, helps identify treatments posing risk for colonization with Multidrug Resistant Organisms (MDROs).

Methods
Stool samples were collected from 163 children pre, day +30, and post-neutrophil engraftment during HSCT, approved by IRBs at St. Jude Children’s Research Hospital and University of Bologna. DNA extracted from these samples underwent Illumina metagenome sequencing, yielding 25 million reads/sample. Antibiotic resistance genes (ARGs) were identified using MEGARes (v 3.0). The children, with median age 8.4, mainly underwent HSCT for Acute Myeloid Leukemia (60%), with majority receiving reduced intensity conditioning (66%). They received multiple antibiotic doses (median 42 daily doses) for fever and neutropenia, infection treatment, and prophylaxis (trimethoprim-sulfamethoxazole at all institutions; fluoroquinolones exclusively at St Jude). ARG abundance was adjusted for sequencing depth and gene length, and changes over time were compared based on antibiotic exposure using linear mixed models.

Results
In pediatric HSCT recipients, the resistome, collection of antibiotic resistance genes in the stool microbial community, differed from healthy children and those with leukemia (fig 1). Surprisingly, levels of antibiotic resistance genes for commonly used antibiotics like Glycopeptides, Pseudomonal Cephalosporins, Aminoglycosides and Fluoroquinolones didn’t increase in children treated with those specific antibiotics. Increases in MDRO related genes (e.g. multidrug efflux pumps, ESBL, vanA) were linked to exposure to antibiotics with anaerobic activity.

Conclusion
Commonly used antibiotics may minimally affect pediatric HSCT patient’s resistomes due to limited gut penetration or prior exposures saturating selection. Other factors like turnover, radiation, inflammation, or conditioning may drive ARG selection. Antibiotics with anaerobic activity link to MDRO related genes suggest colonization resistance may hinder MDRO colonization, warranting increased stewardship.

Disclosures
Ellie Margolis, MD PhD, ICLR: Stocks/Bonds (Private Company)
P-1125. Impact of a Persuasive Antimicrobial Stewardship Program on Antibiotic Consumption and Mortality in a Neonatal Unit: A Before-and-After Study
Authors: Londono-Ruiz Juan Pablo , Betancourt Santiago Loaiza , Rodriguez-Acosta Diana Lucia , Rodriguez Viviana 
Published: January 2025

Abstract

Background
Antimicrobial Stewardship Programs (ASPs) have established themselves as the most effective strategy for reducing the consumption of unnecessary antibiotics, and thereby minimizing the emergence of antimicrobial resistance and adverse effects. However, implementing ASPs in neonatal units presents unique challenges due to their high use of antibiotics and the limited clinical tools available to diagnose infections. The aim of this study is to present the results of a before-and-after study that evaluated the impact of implementing an ASP with persuasive strategies on antibiotic consumption in a neonatal unit.

Methods
The study was conducted in a neonatal unit of a general hospital that attends approximately 200-400 deliveries per month and has a high-risk obstetric program. The ASP was initiated with a weekly round of antibiotic control and an analysis and feedback strategy. Weekly education and training sessions were conducted for all staff, and the pediatric infectious diseases service was made available for permanent consultation. Local guidelines were developed and shared with all unit personnel, and the Days of Therapy (DOT) of the main antibiotics used was measured. Data analysis was performed using the R program.

DOT and Mortality in Pre-ASP and Post-ASP periods

Results
DOT measurements of ampicillin, gentamicin, amikacin, piperacillin-tazobactam, cefepime, and vancomycin were collected since 2021. In November 2022, a spot study was conducted to identify the microbiology of the neonatal unit, and the ASP was implemented. An analysis and feedback strategy were used, with additional support from a weekly round that included neonatologists, pediatricians, therapists, and nursing staff. The monthly DOT are shown in Figure 1. The average DDDs were compared between the period before the ASP and the period after, revealing a significant decrease in all antibiotics except for vancomycin (Table 1). A mortality rate of 2.08 per 100 live births was documented in the Pre-ASP period, which decreased to 1.2 per 100 live births in the post-ASP period.

Conclusion
Antibiotic stewardship programs that implement persuasive measures can be effective in reducing the consumption of most antibiotics in a neonatal unit. Mortality did not increase despite the reduced use of antibiotics.

Disclosures
All Authors: No reported disclosures
P-1130. Association Between Procalcitonin, CRP Values and Antibiotic Use in Children with Community-Acquired Pneumonia
Authors: Montenegro Liliana Arriola , Mulekar Madhuri S , Hassouneh Linda 
Published: January 2025

Abstract

Background
Procalcitonin (PCT) and C-reactive protein (CRP) are biomarkers used to help identify bacterial etiologies of community-acquired pneumonia (CAP) as it is often challenging to differentiate between viral and bacterial causes. This study evaluated the association between PCT, CRP values, and antibiotic initiation in children with CAP.

Methods
This single-center, retrospective study evaluated patients aged 6 weeks to 19 years who presented with acute signs or symptoms of lower respiratory tract illness from December 1 2022 to December 31, 2023. Enrolled were patients with PCT and CRP values obtained within the first 24 hours of their hospital visit. The primary outcome was the initiation of antibiotics within the first 36 hours of the encounter. Patients with tracheostomy, prior antibiotic use, aspiration, or hospital-acquired pneumonia were excluded. PCT and CRP were categorized into 4 groups correlating to values suggesting very unlikely, unlikely, likely, and very likely bacterial infection. Bivariate and logistic regression analyses were conducted.
Patients outcomes (admission to PICU, pleural effusion and need for intubation) by Procalcitonin levels

No association was seen between patient outcomes and procalcitonin levels.

Results
The study included 193 patients, 83% of whom received antibiotics. Among these, 11% had a PCT &lt; 0.1 ng/ml and 8% had a CRP &lt; 0.3 mg/dl. Third-generation cephalosporins (3GC) were the most commonly used antibiotic (n=139, 72%). PCT and CRP values were strongly associated with initiation of antibiotics (p&lt; 0.0001). CRP &gt;10 mg/dl had a 14.8% increase in odds of receiving antibiotics (95% confidence interval [CI]: 2.8, 78.2), and PCT &gt;0.5 ng/mL had a 6.9% increase in odds (95%CI: 2.3, 21.2) compared to the reference category (PCT &lt; 0.3 ng/mL and CRP &lt; 0.3 mg/dL respectively). A CRP of ≥10mg/dL and PCT of &gt;0.5 ng/mL were associated with using 3GC and methicillin-resistant Staphylococcus aureus (MRSA) coverage. Days of hospitalization, pleural effusion, intubation, and PICU admission were not associated with PCT and CRP values.

Conclusion
Most subjects received antibiotics including those with normal PCT and CRP levels, suggesting a possible overuse of antibiotics. Higher levels of PCT and CRP were associated with antibiotic initiation and usage of broad-spectrum antibiotics, identifying opportunities for antibiotic stewardship.

Disclosures
All Authors: No reported disclosures