bluuebunny/crossref_metadata_2025_split huggingface dataset:
2525. Identification of lead compounds, belonging to 26-membered thiopeptide antibiotics for new anti-tuberculosis therapeutic agents
Authors: Son Young-Jin , Hwang Hee-Jong , Shyaka Clovis , Kim Dahyun , Lee Jusuk , Eum Seokyong , Lee Sun-Kyung 
Published: November 2023

Abstract

Background
Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). The incidence of TB patients is increasing globally and the wide spread of multi- and extensively drug-resistant TB poses a significant burden to patients. This situation calls for an urgent medical need to develop new anti-TB drugs. Through our proprietary medicinal chemistry platform on D-series 26-membered thiopeptide, we have identified a few lead compounds, such as AJ-099 and AJ-206 that exert potent activity against multi-drug resistant TB strains.

Methods
In vitro minimal inhibitory concentration (MIC) was measured and a Mtb-infected human macrophage model was used to evaluate anti-mycobacterial activity of our compounds in drug-sensitive or multidrug-resistant TB isolates. Cellular toxicity and some in vitro ADME tests were also performed and examined.

Results
We found that our lead compounds exert potent anti-TB activity on H37Rv(MIC: 0.125-0.5 μg/mL) and showed similar MIC levels in multidrug-resistant clinical isolates. In the macrophage infection model, AJ-099 and AJ-206 showed comparable antimycobacterial effects to isoniazid. These compounds showed no cytotoxicity, relatively safe ADME properties, and no hERG inhibition.
In vitro antibacterial activity in multi-drug resistant M. tuberculosis strains
Antibacterial activity in macrophage infection model
In vitro ADMET properties of lead compounds

Conclusion
AJ-099 and AJ-206 may be potential anti-TB therapeutic agents that possess novel modes of action, low cardiac and cellular toxicities.

Disclosures
Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Clovis Shyaka, n/a, A&J Science: Employee of A&J Science Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science
2527. Impact of Hypoalbuminemia on Clinical Outcomes Among Patients with Obesity Treated with Ceftriaxone
Authors: Rivera (O'Connor) Christina G , Abu Saleh Omar M , McHugh Jack W , Draper Evan , Mara Kristin , Hannan Kellie Arensman 
Published: November 2023

Abstract

Background
Due to extensive protein binding, use of ceftriaxone in the setting of hypoalbuminemia may result in suboptimal drug exposure via higher concentrations of unbound drug resulting in increased volume of distribution and increased drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone for a bacterial infection.

Methods
This retrospective review included adult inpatients with weight &gt; 100 kg or body mass index (BMI) &gt; 40 who received ceftriaxone 2 grams intravenously every 12 hours for at least 72 hours for one of the following indications: bloodstream infection, pneumonia, urinary tract infection, non-enterococcal endocarditis, skin and soft tissue infection, or bone and joint infection. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Clinical cure was defined as resolution of signs and symptoms compatible with active infection without need to change or extend antibiotic therapy due to inadequate effect of ceftriaxone. Microbiologic cure was defined as negative repeat sterile site cultures, if applicable. Secondary outcomes included length of stay, mortality, and 30-day readmission. Outcomes were analyzed with Mann-Whitney U tests, Pearson’s chi-squared tests, and Fisher’s exact tests (α level = 0.05).

Results
137 patients were included, 34 of whom had a serum albumin ≤ 2.5 g/dL. Patients were predominantly white (94.2%) and male (69.3%) with a median BMI of 48.6 (Table 1). Clinical success, a composite of clinical and microbiologic cure, was achieved in 76.5% and 92.2% (p = 0.013) of those with and without hypoalbuminemia, respectively. Clinical cure was significantly more common among those without hypoalbuminemia (93.2%) as compared to those with hypoalbuminemia (76.5%) (p = 0.007). Death during hospitalization was more common (14.7% vs. 0%, p &lt; 0.001) and median length of stay was longer (14 vs. 9 days, p = 0.009) in the hypoalbuminemia group. No difference was seen in 30-day readmission (23.5% vs. 11.7%, p = 0.089).

Conclusion
Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 grams every 12 hours.

Disclosures
Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria
2535. Physiological-based pharmacokinetic analysis of drug–drug interactions between isavuconazole and vincristine in pediatric subjects
Authors: Choules Mary P , Otsuka Yukio , Kovanda Laura , Bonate Peter , Sinnar Shamim , Desai Amit 
Published: November 2023

Abstract

Background
Invasive fungal diseases (IFD), including invasive aspergillosis (IA) and invasive mucormycosis (IM), occur primarily in immunocompromised and/or hospitalized pediatric patients and are associated with morbidity and mortality. Pediatric patients being treated for leukemia with vincristine frequently experience secondary fungal infections, requiring treatment. Isavuconazole (ISAV) is approved for the treatment of IA/IM in adults; but there is limited data for its use in pediatric patients. Isavuconazonium sulfate is the prodrug of the active triazole ISAV, an antifungal agent that inhibits sterol 14α-demethylase. Isavuconazonium is rapidly converted by plasma esterases to ISAV, which is subsequently metabolized by the liver through CYP3A. ISAV was found in clinical drug–drug interaction (DDI) studies to be a moderate inhibitor of CYP3A, an inducer of CYP2B6, and to have inhibitory potential for P-gp and OCT-2 transporters. Because vincristine is eliminated hepatically via CYP3A and biliary excretion through P-gp, there is a potential for interaction with triazoles. Therefore, a physiological-based pharmacokinetic (PBPK) analysis was conducted to assess the potential for interaction between ISAV and vincristine.

Methods
PBPK models were built for ISAV and vincristine in a pediatric cancer population using Simcyp® simulator software with in vitro and in vivo data. The final verified models were used to predict change in vincristine exposure following coadministration with ISAV.

Results
The predicted geometric mean (GM) area under the curve (AUC) ratio of vincristine co-administered with ISAV ranged from 1.54-fold to 1.69-fold depending on the dosing scheme used for the prediction as detailed in Table 1. Coadministration of vincristine when ISAV was at steady state (14 days) did not result in a significant difference in the magnitude of DDI from other dosing schemes. No effect was predicted on the GM Cmax ratio of vincristine regardless of the ISAV dosing scheme.

Conclusion
ISAV is predicted to be a weak inhibitor of vincristine elimination in pediatric cancer participants, and DDI modelling predicts a slight increase in vincristine exposure when vincristine is co-administered with ISAV.

Disclosures
Mary P. Choules, PharmD, PhD, Astellas Pharma Global Development, Inc.: Astellas Employee Yukio Otsuka, MSc, Astellas Pharma Global Development Inc.: Astellas Employee|Astellas Pharma Global Development Inc.: Stocks/Bonds Laura Kovanda, PhD, Astellas Pharma Global Development Inc.: Astellas Employee Peter Bonate, PhD, Astellas Pharma Global Development, Inc.: Astellas Employee Shamim Sinnar, MD, PhD, Astellas Pharma Global Development, Inc.: Astellas Employee Amit Desai, PhD, Astellas Pharma Global Development, Inc.: Astellas Employee
143. Correlation Between Identification of Gram-positive Resistance Genes and Antimicrobial Susceptibility Profiles in Gram Positive Bacteria
Authors: Ilyas Sahrish , Chasan Rachel , Nowak Michael D , Patel Gopi , Sordillo Emilia Mia , Rana Meenakshi M , Gitman Melissa R 
Published: November 2023

Abstract

Background
GenMark ePlex BCID panels detect common gram-positive resistance genes, allowing for earlier optimization of empiric therapy. Data regarding genotypic and phenotypic concordance of isolates remains limited. Our primary objective was to study the prevalence of mecA and mecC among Staphylococcus aureus isolates and of vanA and vanB among Enterococcus spp. and determine the concordance with phenotypic susceptibility profiles.

Methods
The study was conducted at the clinical microbiology laboratory of Mount Sinai Health System (NY, NY). Samples were collected between March 2019 and April 2021. Presumptive identification and molecular data were obtained from ePlex BCID Panels and compared to phenotypic susceptibility testing performed on Vitek or Microscan systems.

Results
Data were obtained from 1493 isolates tested on the GenMark ePlex BCID gram positive panels. The total prevalence of mecA in Staphylococcus aureus isolates was 460/989 = 46.5%. There was no mecC detected. Of the 460 mecA positive S. aureus isolates, 99% were oxacillin resistant and 1.0% were oxacillin susceptible. Of the 529 mecA negative S. aureus isolates, 98.5% were oxacillin susceptible and 1.5% were oxacillin resistant.
The total prevalence of vanA in enterococcus isolates was 38% (193/504), 81% were detected in E. fecium sp, 17% in E. fecalis sp, 0.5% in E. gallinarium sp and 1.5% in E. raffinosus sp. The total prevalence of vanB was 1.1% (6/504). E. faecium accounted for 83% and E. faecalis for 16% of the isolates. Of the vanA positive isolates, 7/193 (3.6%) were vancomycin susceptible, 2 were e. fecalis and 5 were e. fecium species. None of the isolates in which vanB detected were vancomycin susceptible.
No van gene was detected in 305 of enterococcus isolates. Of these, 250/305 (81%) were E. faecalis sp and 36/305 (11%) were E. faecium sp. 290/305 total isolates were vancomycin susceptible and 15 were vancomycin resistant, of which 12/15 were E. gallinarum and E. avium (which are intrinsically resistant), 1 was E. faecium and 2 were E. faecalis.

Conclusion
Our data shows overall that the susceptibility profile and resistance gene detection by ePlex correlated well with overall minimal discordance. Further studies are needed to determine the optimal management when phenotypic genotypic discordance occurs.

Disclosures
Meenakshi M. Rana, MD, Eli Lilly: advisory board
2546. Administration of Crushed Posaconazole Delayed Release Tablets Failed to Achieve Therapeutic Levels
Authors: Kane Nicholas , Rikard Rachel , McCrory Katie , Marx Ashley H 
Published: November 2023

Abstract

Background
Posaconazole (POS) delayed release tablets (DRTs) are utilized for prophylaxis or treatment of invasive fungal infections. Other POS formulations are limited by impaired absorption, lack of indication for adult patients, and need for intravenous (IV) access. Small retrospective case series have demonstrated success with administration of crushed POS DRTs via enteral feeding tubes (EFTs). In October 2022, UNC Health permitted administration of POS DRTs via EFTs. This study aims to evaluate POS levels in patients that received crushed POS DRTs via EFTs.

Methods
This single-center, retrospective cohort study included patients that received crushed POS DRTs via EFTs with concurrent POS therapeutic drug monitoring (TDM). The primary outcome was achievement of serum POS level per indication of prophylaxis ( &gt; 700 ng/mL) or treatment ( &gt; 1000 ng/mL). The secondary outcome was the proportion of patients whose therapy was altered in response to POS level.

Results
A total of 10 patients were included (Table 1), with both prophylaxis (40%) and treatment (60%) indications. Most were initiated on oral or IV POS (80%). Crushed POS DRTs were administered via nasogastric (70%), post-pyloric (20%), and nasoduodenal (10%) routes. Therapeutic levels with crushed POS DRTs occurred in three patients (30%) and only two patients (20%) maintained therapeutic levels (Figure 1). Of the patients that transitioned from IV or oral POS to crushed POS DRT that maintained the same POS dose, 75% experienced a decrease in their serum POS level. Based on the initial crushed POS DRT level, three patients transitioned to IV or oral POS and 3 had their crushed POS DRT dose modified.

Conclusion
Crushed POS DRTs administered via EFTs failed to achieve therapeutic POS levels in 70% of patients. Caution should be used when implementing crushed POS DRTs and internal data should be reviewed if already implemented. Study limitations include small sample size, single-center design, and limited attempts to titrate crushed POS DRT regimens. Future studies should assess the clinical utility of crushed POS DRTs and explore the impact of standardized nursing administration, drug-drug interactions, and enteral feeding interactions/routes on crushed POS DRT pharmacokinetics.

Disclosures
All Authors: No reported disclosures
2557. Development of Rabbit Models of Ventilator-Associated Carbapenem-Resistant Acinetobacter baumannii Pneumonia
Authors: Petraitis Vidmantas , Petraitiene Ruta , Naing Ethan 
Published: November 2023

Abstract

Background
Carbapenem-resistant (CR) Gram-negative bacteria are emerging worldwide as global public health threats. Mortality rates from these pathogens are especially high in immunocompromised patients. Ventilator-associated bacterial pneumonia (VABP) is among the most intractable of CR Gram-negative bacterial infections. We therefore aimed to develop rabbit animal models of VABP caused by CR strains of Acinetobacter baumannii.

Methods
Persistently neutropenic NZW rabbits were used throughout the study. A novel endotracheal tracheostomy system was developed for intubation. The early-phase intubated model (0-24h) received mechanical ventilation, while the late-phase intubated model (72-96h) was ambulatory. Ventilators were set to FiO2=40% and PEEP=8mmHg. The following outcome variables were assessed: survival, residual tissue bacterial burden (log CFU/g), residual BAL bacterial burden (log CFU/mL), lung weights, pulmonary lesion score, histology, pulse O2 saturation, radiographic imaging, pro-inflammatory cytokines, quantitative tissue and BAL PCR, and histology.

Results
Within the first 12h post-inoculation, mean bacterial burdens in lung tissue and BAL fluid, respectively, which were established at approximately 106 CFU/g and 105 CFU/mL, persisted through 24h in the early-phase model and were increased in the late-phase model (72-96h) to approximately 107 CFU/g, and 106 CFU/mL. Mean Max SpO2 was ≥99 mmHg and mean nadir SpO2 was ≥74 mmHg. Serial thoracic radiographs over the course of 12-96h demonstrated progressive multilobar pneumonic infiltrates, while lung histology revealed progressive development of focal bronchopneumonia, intra-alveolar hemorrhage, alveolar epithelial cell necrosis, macrophage activation, monocytic infiltration, alveolar septal disruption, and microcolonies of bacteria.

Conclusion
The new rabbit model of VABP produced by CR A. baumannii recapitulates the pathophysiological, microbiological, diagnostic imaging, and histological patterns of human disease by which to assess critically needed new antimicrobial agents against this lethal infection.

Disclosures
All Authors: No reported disclosures
2567. Clinical Outcomes of Vancomycin Area-Under-the-Curve Monitoring: A Quasi-Experimental Study
Authors: Viteri Alina , Tucker Natalie , Flynn Ryan , Foreman Jena K 
Published: November 2023

Abstract

Background
Previous studies that demonstrated decreased nephrotoxicity with area-under-the-curve (AUC) vancomycin dosing compared to trough monitoring used two levels and a spreadsheet model for calculating AUC. The purpose of this study was to evaluate if the same reduction in acute kidney injury (AKI) was achieved while using a single level Bayesian monitoring program.

Methods
This retrospective quasi-experiment was performed at two sites within the same health system. The primary objective was to assess the rate of AKI between vancomycin dosed by trough monitoring as compared to AUC monitoring using a Bayesian software program. Secondary objectives included mean daily dose of vancomycin, number of vancomycin levels, and severity of AKI. Patients were included in the study if they were 18 years or older with at least one vancomycin concentration drawn. Patients were excluded if they had a baseline serum creatine greater than 2 mg/dL, received renal replacement therapy of any type, or received &gt; 1 dose of vancomycin prior to admission.
Patients were matched 1:1 based on acute physiology and chronic health evaluation II score, body mass index, and vancomycin indication. Multivariable logistic and Cox proportional hazards regression were used to examine the independent association between the monitoring strategy (trough vs AUC) and nephrotoxicity.

Results
Few differences in baseline characteristics were identified between groups. More patients were treated for pneumonia, bacteremia, or urinary tract infection in the trough group, whereas more were treated for skin and soft tissue infection in the AUC group. The AUC group (255 patients) had a 16% incidence of AKI in comparison to the trough group (265 patients) with a 19% incidence of AKI (p = 0.517). Of the secondary outcomes, those in the AUC group received lower daily doses than patients in the trough group (p = 0.015). Multivariable regression analysis identified similar results for each of the study outcomes including the primary outcome (OR 1; 95% CI 0.62 – 1.63).

Conclusion
The use of a single level Bayesian monitoring for vancomycin dosing did not result in a decreased incidence of acute kidney injury when compared to trough monitoring.

Disclosures
All Authors: No reported disclosures
2589. Legionella pneumonia in cancer patients: 12-year experience at MD Anderson Cancer Center 2009-2021
Authors: Matsuo Takahiro , Wurster Sebastian , Jiang Ying , Tarrand Jeffrey , Kontoyiannis Dimitrios P 
Published: November 2023

Abstract

Background
Legionella pneumonia (LP) is an uncommon, yet severe pneumonia in cancer patients, but its clinical features are scarcely studied in contemporary cohorts. Therefore, this study aimed to characterize the clinical manifestations, therapy, and outcomes of LP in contemporary cancer patients.

Methods
We identified cancer patients with LP at MD Anderson Cancer Center in 2009-2021. LP was diagnosed using Legionella urine antigen and/or culture from sputum, tracheal aspirate, or bronchoalveolar lavage. Species identification was achieved by Matrix-assisted laser desorption ionization–time-of-flight mass spectrometry or 16S rRNA. Independent predictors of 30-day mortality after LP diagnosis were determined using multivariable logistic regression analysis.

Results

Table 1.

Conclusion
We identified 64 LP patients; of which 47 (73%) were caused by Legionella pneumophila and 17 (27%) by Legionella non-pneumophila (Figure 1). Most patients (66%) had hematological malignancy, and 31% had a history of hematopoietic stem cell transplantation (HSCT). Lymphopenia (&lt; 1000 cells/µl) was common (75%). Twenty patients (31%) had lung coinfections, especially those with a history of HSCT (9/20, 45%). A total of 30 co-pathogens were isolated, with Gram-negative bacteria, cytomegalovirus, and respiratory viruses (7/30, 23% each) being the most common co-pathogens (Figure 2). Twenty-five patients (39%) had hyponatremia and 17 (27%) had acute kidney injury. Most patients (64%) had bilateral lung involvement. All but one patient received appropriate antibiotics at the onset of LP. Thirty-day mortality of LP was 23% (Table 1). Independent predictors of 30-day mortality were hyponatremia (adjusted odds ratio [aOR], 3.03 [95% CI, 1.21-10.43], P = 0.013), bilateral lung involvement (aOR, 3.78 [95% CI, 1.16-28.98], P = 0.019), and Sequential Organ Failure Assessment (SOFA) score ≥5 (aOR, 2.76 [95% CI, 1.08-9.44], P = 0.029).

Disclosures
Dimitrios P. Kontoyiannis, MD, MS, ScD, PhD, AbbVie: Board Member|Astellas: Grant/Research Support|Cidara: Board Member|Gilead: Grant/Research Support|Merck: Advisor/Consultant|Scynexis/MSGERC: Board Member
148. Antibiotic duration for lower respiratory tract infections with and without procalcitonin monitoring: a propensity score matched cohort across an integrated healthcare network
Authors: Livorsi Daniel J , Heren Jamie , Alexander Bruce , Lund Brian 
Published: November 2023

Abstract

Background
Clinical trials have shown that procalcitonin (PCT) testing is efficacious in reducing antibiotic duration, but it is not known whether the test is also effective in routine clinical practice. The goal of this study was to evaluate whether PCT use in patients with lower respiratory tract infections (LRTI) was associated with shorter antibiotic duration.

Methods
We performed a retrospective cohort study across Veterans Affairs acute care hospitals that were ordering PCT with some degree of frequency between January 2018 and December 2021 and included patients with LRTI (acute exacerbations of COPD and pneumonia) that lacked complicating factors (Figure 1). The primary outcome was length of antibiotic therapy. We used 1:1 nearest neighbor propensity score matching to estimate the difference in the primary outcome between PCT-tested and non-tested patients. Patients were fixed matched on hospital site and admission date, and propensity scores were calculated using a logistic regression model that included demographics, ward location, infection type, comorbidities, severity of illness, and antibiotic class.
Figure 1. Flow diagram of patient selection based on inclusion and exclusion criteria

Results
Eighty-one (65%) VA hospitals had on-site PCT testing; all 81 sites had a pharmacist devoting at least some time to antibiotic stewardship activities. Of the 35,610 admissions that met inclusion criteria, 6,015 (17%) had ≥ 1 PCT test at least 48 hours into their antibiotic course (Table 1); in these patients, the median number of PCT tests checked was 2 (interquartile range, 1-3). Using propensity scores, 3,903 patients in the PCT group were matched to 3,903 patients in the no PCT group: the length of therapy was higher in the PCT group compared to the no PCT group with median of 8 days (IQR 6-11) compared to 7 days (IQR 5-10) and mean difference of 0.4 days (p&lt; 0.01, Table 2).

Conclusion
In this retrospective propensity-matched cohort of patients with LRTI across 81 hospitals, we failed to demonstrate shorter antibiotic duration for patients who underwent PCT testing compared to those who did not. While our findings suggest that PCT use may not be effective for reducing antibiotic duration for LRTI under real-life circumstances, it is unclear if the PCT test was optimally implemented at these sites and whether other stewardship activities may have minimized the test's overall impact.

Disclosures
Daniel J. Livorsi, MD, Merck: Grant/Research Support