bluuebunny/crossref_metadata_2025_split huggingface dataset:
2508. Evaluation of Infectious Diseases Complications in US Veterans with Opioid Use Disorder, a Single Site Experience
Authors: Srivastava Pronoma , Modi Viraj , Lier Audun J 
Published: November 2023

Abstract

Background
Opioid use disorder (OUD) affects 2.7 million people in the United States and rates of OUD diagnosis are rising in US Veterans (USV). Injection drug use (IDU), including opioids, can lead to acquisition of bloodborne infections and severe injection related infections (SIRI). This study aims to describe infectious diseases epidemiology, substance use characteristics, and health care utilization in persons who inject drugs (PWID) and non-PWID with OUD who presented to the Northport Veterans Affairs Medical Center (NVAMC).Table 1.Demographic characteristics of USV with OUD, stratified by history of injection substance use. OUD, opioid use disorder. MOUD, medication for opioid use disorder. USV, US Veterans. PTSD, post-traumatic stress disorder.

Methods
Data was collected from a retrospective chart review of Veterans aged &gt;18 years who had an ICD9 or ICD10 diagnosis of OUD and presented to the NVAMC between 2010-2020. Demographics, concomitant substance use and prior overdose histories, receipt of medications for opioid use disorder (MOUD), prior infection histories, hospitalizations, and emergency department (ED) visits were compared between PWID and non-PWID. Two-sample T-tests and Chi-square analyses were utilized.

Results
We identified 502 USV with a diagnosis of OUD. Mean age was 52.6 years, 469 (93.4%) were male, 396 (78.9%) were white, 172 (34.3%) were employed and 216 (43%) had health insurance. Post-traumatic stress disorder (n=275, 54.8%) was the most frequent psychiatric diagnosis and 216 (43%) USV had a history of IDU. PWID were more likely to have unstable housing (71.3% PWID vs 21.7% non-PWID, p&lt; 0.001), be unemployed (60.2% PWID vs 43.7% non-PWID, p&lt; 0.001), use cocaine (77.8% PWID vs 59.1% non PWID, p&lt; 0.001), have a history of incarceration (49.1% PWID vs 38.5% non PWID, p=0.002), and have a prior overdose (53.7% PWID vs 27.3% non PWID, p&lt; 0.001). Among PWID, 134 (62%) had hepatitis C virus and 30 (13.9%) had at least 1 SIRI, most frequently a skin and soft tissue infection (n=29, 13.4%). PWID were more likely to be hospitalized with an infection (26.4% PWID vs. 12.2% non PWID, p&lt; 0.001) and had more inpatient admissions (5.5 PWID vs. 3.51 non PWID, p=0.003). ED visit frequency did not differ between groups.Table 2.Characteristics of SIRI and non SIRI among Veterans with OUD presenting to the Northport VAMC. SIRI, severe injection-related infection. OUD, opioid use disorder. SSTI, skin and skin structure infection. HBV, hepatitis B virus. HCV, hepatitis C virus. LOS, length of stay.

Conclusion
Veterans with OUD frequently present to the NVAMC with infections that require hospitalization. USV with OUD, especially PWID, would benefit from increased social support, as well as screening and treatment for OUD related infections.

Disclosures
All Authors: No reported disclosures
2518. Lead optimization on 26-membered thiopeptide antibiotics and identification of pre-clinical candidates against Clostridioides difficile and Staphylococcus aureus for impetigo
Authors: Hwang Hee-Jong , Son Young-Jin , Kim Dahyun , Lee Jusuk , Shyaka Clovis , Kwak Jin-Hwan , Pai Hyunjoo , Rho Mina , Park Jong-Hwan , Kim Young-Rok , Jung Sungji 
Published: November 2023

Abstract

Background
Thiopeptides are structurally complex natural products that exert potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. However, there has not been any attempt to conduct extensive medicinal chemistry campaign on these natural products, due to their chemical complexity. The advent of efficient syntheses of thiopeptides led us to identify promising pre-clinical candidates: AJ-024 against Clostridioides difficile and AJ-147 against Staphylococcus aureus for the indication of impetigo.

Methods
AJ-024 was screened against extensively classified C. difficile clinical isolates. Its time-kill kinetics and in vivo mouse efficacy were investigated against hypervirulent C. difficile ribotype 027. Metagenomic sequencing (16S rRNA) was performed to examine AJ-024's impact on gut microbiome.
Similarly, AJ-147 was screened against methicillin-resistant S. aureus clinical isolates. Its time-kill kinetics, as well as its in vivo SSTI model were investigated. Pro-inflammatory cytokines were measured.
Pharmacokinetic studies of these two agents, as well as their ADME properties and toxicity have also been investigated.

Results
AJ-024 has potent antibacterial activity, along with rapid bactericidal action against C. difficile ribotype 027 resulting in 99.99% reduction in 4X MIC in 3 hours. No recurrence was observed in the mouse in vivo model and this was corroborated by our 16S rRNA sequencing data. AJ-024 exerts minimal impact on beneficial gut-microbiome.
AJ-147 exhibited a potent antibacterial activity against mupirocin resistant S. aureus. In vivo efficacy in a SSTI model revealed that AJ-147 is x1,000 more active than mupirocin. AJ-147 downregulates pro-inflammatory cytokines, such as IL-1ß and IL-6, that might elicit beneficial host immune response.
Impact of AJ-024 on gut microbiome
Investigation of AJ-024's impact on gut microbiome through 16s rRNA sequencing
In vivo efficacy of AJ-147 in SSTI model
AJ-147 compares favorably to mupirocin and downregulates pro-inflammatory cytokines

Conclusion
Our medicinal chemistry campaign on thiopeptide antibiotics have led us to identify two preclinical candidates, AJ-024 and AJ-147. These two agents possess distinctive advantages compared to the first-line of treatments for each indication. Efforts are being directed to the completion of IND-enabling studies.

Disclosures
Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science Clovis Shyaka, n/a, A&J Science: Employee of A&J Science
2520. A Phase 1b Study of the Safety, Pharmacokinetics, and Ex Vivo Tick Killing of the Lyme Prophylaxis Candidate TP-05
Authors: Lim Jeremy J , Crean Christopher S , Partin Hilary A , Trevejo Jose M , Neervannan Seshadri 
Published: November 2023

Abstract

Background
In the U.S., Lyme disease is the most common vector-borne disease caused by infection with B. burgdorferi bacteria following a bite by a tick vector. TP-05 (lotilaner oral capsule), an isoxazoline, is a selective inhibitor of insect and acarine GABA mediated chloride channels, which paralyzes the nervous system and eventually leads to death of ticks and other ectoparasites. This Phase 1b study was conducted to evaluate the safety, tolerability, food-effect, and pharmacokinetics of TP-05 after single and multiple dose administration in healthy subjects. In addition, serum samples from TP-05 dosed subjects were tested in an ex vivo tick kill model.

Methods
40 healthy adult subjects were randomized across five single-ascending dose (SAD) cohorts to receive TP-05 or placebo (25, 100, 400, 600 mg under fed conditions, and 600 mg under fasted conditions). Subjects were followed up to Day 151. 24 healthy adult subjects were randomized across three multiple-ascending dose (MAD) cohorts to receive TP-05 or placebo under fed conditions (250 mg Day 1 and 75 mg Day 29; 250 mg Day 1 and 250 mg Day 29; 300 mg Day 1 and 75 mg weekly for 4 weeks). Subjects were followed through Day 151. Whole blood samples from the MAD cohorts were collected to evaluate the ex vivo lotilaner concentration dependent killing of ticks.

Results
61 subjects (95.3%) completed the study. The most common study drug related treatment-emergent adverse event (TEAE) was headache (6 subjects [9.4%] overall; 5/6 receiving TP-05 and 1/6 receiving placebo) and it was not dose dependent. One placebo subject experienced a nonfatal serious adverse event (gunshot wound) and one subject discontinued the study due to COVID-19; both events were considered unrelated to study drug. TP-05 demonstrated a dose proportional increase in AUCs and Cmax under fed conditions. Tmax under fed conditions ranged from 5-8 hours post-dose. The half-life was approximately 8 weeks. Ex vivo tick feeding model showed killing of adult and nymph ticks as early as 2 hours post-dose. At Day 151, there was decreased survival indicating a sustained effect of TP-05.

Conclusion
TP-05 was generally safe and well tolerated among healthy adult subjects. Data from this study supports TP-05’s mechanism of action and potential as a prophylactic therapy for Lyme disease.

Disclosures
Jeremy J. Lim, PharmD, Roche Pharmaceuticals: Stocks/Bonds Seshadri Neervannan, PhD, Abbvie: Stocks/Bonds
2524. Safety and Pharmacokinetics of PA-001, a New Potential COVID-19 Drug That Targets the S2 Subunit of SARS-CoV-2 Spike Protein, in Healthy Subjects
Authors: Kurasaki Haruaki , Ohuchi Masaki , Matsui Katsuma , Matsumoto Masatoshi , Nagatomo Kazutaka , Kawamura Naoki , Ito Shoko , Yonemura Takuma , Chiyoda Takeshi , Yamamoto Asuka , Shimoi Akihito , Masuya Keiichi , Kitamura Hidetomo , Murakami Masato 
Published: November 2023

Abstract

Background
Frequent emergence of new variants of the SARS-CoV-2 virus continues to be a concern in treatment of COVID-19 infection, despite the approval of several drugs in recent years. To address this problem, we identified a new macrocyclic peptide, PA-001, which targets the highly conserved S2 subunit of the SARS-CoV-2 spike protein, and confirmed in vivo efficacy in mouse models. Here, we report the clinical safety and pharmacokinetics of PA-001 in healthy subjects (jRCTs031210601).

Methods
Thirty healthy Japanese male volunteers were divided into 5 cohorts (Steps 1 - 5). In each cohort, PA-001 was administered via 1-hour intravenous infusion to 6 subjects at 0.3, 1, 2, 4 or 8 mg, and pharmacokinetics and safety were monitored.

Results
In all cohorts, the plasma concentrations of PA-001 reached Cmax at 1 hour after administration and decreased with T1/2 of 2.30 to 3.39 hours (Figure 1, Table 1). Elimination rate constant (Kel), CL, Vss and mean residence time (MRT) of PA-001 were 0.216 to 0.309/h, 2,340 to 2,850 mL/h, 9,090 to 11,700 mL and 3.19 to 4.27 h, respectively, and there was no significant difference among each cohort. The 95% confidence interval for the slope using the power model was 0.984 (0.932 to 1.04) for Cmax and 1.00 (0.941 to 1.07) for AUCinf, respectively, confirming the linearity of pharmacokinetic parameters of PA-001 in human plasma.
No serious adverse events were observed in this clinical research. Adverse events occurred in 1 subject from Step 3 (n=6) and in 2 subjects from Step 5 (n=6), while no adverse events were observed in other cohorts. Observed adverse events include: extremity pain (1 subject from Step 3), increase in C-reactive protein levels (1 subject from Step 5) and increase in neutrophile count (1 subject from Step 5). All adverse events were mild and subjects recovered without any additional treatment All adverse events were not causally related to PA-001.

Conclusion
The results showed the safety of PA-001 up to 8 mg when administered as a single intravenous dose over one hour to healthy adult males. Furthermore, PA-001 in plasma was quickly eliminated after administration was completed and there was linearity in the dosage range of 0.3 mg–8 mg. Upon this encouraging data, IND submission for PA-001 is under preparation.

Disclosures
All Authors: No reported disclosures
142. When You Can't Call It Colonization, Consider Cutting It Out: Mitigating Panels of Unusual Size to Improve C. difficile Diagnostic Specificity
Authors: Ilges Dan , Grant Leah , Huang Angela , Siebeneck Eric , Castro John , Seville Maria T , Grys Thomas , Speiser Lisa , Graf Erin 
Published: November 2023

Abstract

Background
The BioFire® FilmArray® Gastrointestinal Pathogen Panel (GIPP) tests for 22 potential pathogens in stool, including Clostridioides difficile. C. difficile nucleic acid is detected via nested polymerase chain reaction (PCR) targeting toxin A (TcdA) and/or toxin B (TcdB) genes. While PCR-based diagnostic methods are highly sensitive, they lack specificity to differentiate colonization from C. difficile infection (CDI). Mayo Clinic Arizona (MCA) uses enzyme immunoassay (EIA) testing for toxin A/B and glutamate dehydrogenase antigens with reflex to PCR for discordance as the primary algorithm for diagnosing CDI; however, GIPP PCR testing circumvents this algorithm. When used in patients with low pretest probability for CDI, clinical false positives can lead to inappropriate diagnosis and treatment of colonization.
GIPA Results in the Electronic Medical Record Pre-Intervention
MCA Standalone C. difficile Testing Algorithm
Abbreviations – EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic acid amplification test

Methods
We convened a multidisciplinary quality improvement team to reduce the detection and treatment of C. difficile colonization secondary to GIPP test results. Surveys were sent to providers and nurses as part of a formal gap analysis and included questions around ordering patterns, knowledge of appropriate tests, and associated costs. Baseline data was compiled from GIPP orders in MCA from 1/1/2022-9/30/2022.

Results
There were 1978 GIPP orders for 1694 patients during the study period (∼7 GIPPs/day). Most orders (65%) originated from ambulatory settings. The most common positive target was C. difficile (355/723, 49%), which resulted in treatment for suspected CDI in 94.9% (337/355) of cases. Of the 49 providers who responded to the survey, 86% ordered the GIPP at least monthly. Testing for C. difficile was the 2nd most common reason for ordering the GIPP. Most providers underestimated the cost of the panel and were unfamiliar with the differences between the GIPP and EIA testing algorithm. Nurses sought clarification on stool samples suitable for GIPP testing. Following education and modifications to ordering in the electronic health record, the decision was made to remove the C. difficile target from the GIPP.
Provider Understanding of C. difficile Testing Methods
GIPA Results in the Electronic Medical Record Post-Intervention

Conclusion
Multiplex PCR panels are comprehensive but require careful implementation to facilitate diagnostic stewardship. Facilities with robust standalone C. difficile testing algorithms may consider removing the C. difficile target from the GIPP.

Disclosures
All Authors: No reported disclosures
2539. Towards Biomarker-Guided Model Informed Precision Dosing – A Case Study With Continuously Infused Vancomycin in Sepsis
Authors: Ermtraud Julian , Uster David , De Cock Pieter , Wicha Sebastian 
Published: November 2023

Abstract

Background
Model-informed precision dosing can streamline the dosing individualization of vancomycin in patients with severe bacterial infections. Yet, currently utilized models are limited to predicting the pharmacokinetics (PK). In this study, a pharmacometric model was developed that described the longitudinal relationship between PK and CRP after continuous infusion of vancomycin. Subsequently, its forecasting performance was evaluated.

Methods
In a clinical dataset in 67 patients with sepsis, the PK was linked to the CRP time courses using a turnover model with an effect compartment. For the forecasting analysis, scenarios with different numbers of TDM samples were tested to investigate how many are needed for valid predictions of future (unobserved) PK and CRP samples.

Results
Overall, the developed pharmacometric model described the PK and CRP data well, except sudden CRP increases potentially occurring due to other effects than the treated infection. The half maximal effective concentration of vancomycin was estimated to be 20.3 mg/L (95 % CI= 18.9 - 21.5 mg/L). The usage of just one CRP concentration from routine clinical data led to imprecise predictions. The inclusion of a single vancomycin concentration improved the predictive performance, but a second plasma sample of vancomycin and CRP was required to increase accuracy and precision significantly.Figure 3.Comparison of the predictive performance of the model for the pharmacokinetics (PK) and pharmacodynamics (PD) of future (unobserved) data using the relative bias and the relative root mean squared error when different amounts of information (observed data from 0-3 or all occasions) were provided to the model.

Conclusion
The present study corroborates the currently used therapeutic range for continuously infused vancomycin of 20-25 mg/L. The future tendency of the time course of up to 14 (range: 1-14) CRP measurements and vancomycin concentrations with a given vancomycin therapy regime was adequately predicted when at least two measurements of CRP and vancomycin were provided to the model, in particular if the tendency of CRP was increasing or decreasing was predicted well. These predictions are only trustworthy if there are no other events with an influence on the CRP concentration. Further biomarkers with a higher specificity for bacterial infections should be investigated or the model needs to be refined to handle such events.

Disclosures
All Authors: No reported disclosures
2540. Can aminoglycoside dosing be improved through use of pharmacokinetic models from other aminoglycosides?
Authors: Faldasz Jonathan , Hughes Jasmine 
Published: November 2023

Abstract

Background
Model-informed precision dosing (MIPD) has been shown to improve target exposure attainment. However, the clinical effectiveness of MIPD rests on the predictive accuracy of the model used. Despite increased aminoglycoside (AG) use, PK models remain sparse, leading to an ongoing search for viable models. This study aimed to determine whether the use of MIPD incorporating a PK model designed for a single AG drug could improve predictive accuracy in treatment across other AG drugs.

Methods
Patient data entered into the InsightRX Nova MIPD platform during routine clinical care was de-identified and analyzed retrospectively. Patients were included for analysis if they received at least one dose of amikacin (AK), gentamicin (GM) or tobramycin (TO) and at least one therapeutic drug monitoring sample was collected within 48 hours of an administered dose. For each patient and for each model, samples were grouped by dosing interval and iteratively used to predict future levels (Figure 1) using Bayesian forecasting, mimicking clinical implementation of MIPD. Prediction error was assessed using root mean square error (RMSE) and percent of samples within 20% of predicted values.

Results
RMSE and percent of samples within range are shown in Figure 2 and Figure 3, respectively. For adults treated with AK (N = 145), the adult models for GM and TO and the pediatric model for GM on average performed better than the drug- and age-matched models. For adults treated with GM (N = 811), the adult AK models performed equally well as the drug- and age-matched models. For children treated with GM (N = 67), the drug- and age-matched model performed the best. For adults treated with TO (N = 239), the AK pediatric model and the adult GM model out-performed the age- and drug-matched model. For children treated with TO (N = 100), all models out-performed the age- and drug-matched model.

Conclusion
Pharmacokinetic similarity between AGs translates to models that apply well to other drugs within this class, particularly when matching the development population age. However, there is considerable variability between models for a particular drug and age, so individual models should be validated in the intended MIPD population. Further study is needed to test the generalizability of these findings, and explore subpopulations.

Disclosures
Jonathan Faldasz, PharmD, InsightRX: Salaried employee Jasmine Hughes, PhD, InsightRX: Employee
2541. Steady-state PK of Fixed Dose Dolutegravir+Rilpivirine in Hemodialysis
Authors: Gupta Samir K , Friedman Allon , Zeruesenay Desta 
Published: November 2023

Abstract

Background
Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state PK of FDC DTG+RPV in those requiring hemodialysis (HD) has not been previously studied.

Methods
We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG (50mg)+RPV(25mg) in HIV-negative adults either requiring HD (n=4; 2 men, 2 women) or with normal renal function, defined as CrCl ≥ 75mL/min (n=2; 1 man, 1 woman). All participants received DTG+RPV daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated LC/MS/MS assay method (QTRAP 6500+LC-MS/MS system) with turboelectrospray source operating in both positive (confirmation) and negative (quantification) modes. We did not evaluate dialysis extraction of DTG+RPV. Descriptive PK parameters were calculated.

Results
No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The 4 HD and 2 normal renal function participants were of similar ages (range, 50-60 vs 53-58 years) and BMI (range, 18.5-28.2 vs 20.3-24.0 kg/m2). The Table shows the PK parameters assessed in the study population for circulating plasma DTG, DTG-glucuronide (DTG’s primary metabolite), and RPV.

Conclusion
In this study, HD did not lead to clinically appreciable differential exposures to DTG and RPV; the markedly increased exposure to DTG-glucoranide (which is considered inert) in HD suggests increased UGT1A1 activation. All participants maintained exposures throughout the dosing interval greater than the reported IC90 efficacy values for DTG (64ng/mL) and RPV (12ng/mL). These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD.

Disclosures
Samir K. Gupta, MD, Gilead Sciences: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Allon Friedman, MD, Eli Lilly: Advisor/Consultant|Eli Lilly: Stocks/Bonds|GI Dynamics: Advisor/Consultant|Gila Therapeutics: Advisor/Consultant