bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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

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

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
2542. Attenuation of Polymyxin and Aminoglycoside-Associated Nephrotoxicity
Authors: Hudson Cole , Smith James E , Eales Brianna , Liu Xinli , Kajiji Shama , Truong Luan , Tam Vincent
Published: November 2023

Background

The clinical use of aminoglycosides and polymyxins to treat multidrug-resistant Gram-negative bacterial infections is hindered by dose-limiting nephrotoxicity. Recently, there has been increased interest in reducing the nephrotoxic potential of these antibiotics to combat the antimicrobial resistance crisis. We identified zileuton, an FDA-approved anti-inflammatory drug, via a virtual screen indicating that it has desirable properties as a potential nephroprotectant. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury.

Methods

Sprague-Dawley rats (n=10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Doses were chosen based on prior pharmacokinetic studies to achieve a systemic exposure comparable to that in humans after a standard dose. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 minutes before antibiotic administration each day. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥ 2x elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was conducted to characterize the extent of renal injury.

Results

Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100% within 10 days, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton 4 mg/kg and 10 mg/kg, respectively. Additionally, histopathology confirmed reduced renal injury in animals receiving concomitant zileuton.

Conclusion

This pilot study suggests that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat multidrug-resistant Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and characterize pharmacokinetics to correlate with clinical dosing in humans.

Disclosures

All Authors: No reported disclosures
2544. Population pharmacokinetic meta-analysis of BV100 in healthy subjects and renally impaired subjects
Authors: Moss Jon , Watts Michael , Marc Gitzinger , Kemmer Christian , Husband Lisa , Dale Glenn
Published: November 2023

Background

We recently identified rifabutin as having potent antibacterial activity towards Acinetobacter baumannii under nutrient limiting conditions.

BV100 is the abbreviation for a novel intravenous formulation of rifabutin under development for the treatment of serious infections due to A. baumannii. The overall objective of this analysis was to use all available data to build a population pharmacokinetic model capable of describing the kinetics of BV100 after single and multiple IV infusions in healthy subjects and renally impaired subjects and to provide, through simulation of popPK models, estimates of efficacious doses of BV100.

Methods

The analysis was conducted via nonlinear mixed-effects modelling using NONMEM (ICON Development Solutions, version 7.4). Data extraction, exploratory analysis, and all graphical displays and statistical tests were performed in R version 4.1.2. Simulations for visual predictive checks (VPCs) were executed using NONMEM. Exposure simulations were accomplished in R using the “RxODE” library. Simulations of the final popPK model were conducted to directly compare model-predicted Cmax and AUC(0-24) between healthy subjects and subjects with renal impairment.

Simulations of the final popPK model were done to identify the dose at which subjects of varying degrees of renal impairment were expected to achieve target exposures above specified threshold values for 1-log reduction in bacteria at MIC values of 0.5, 1 and 2 mg/L.

Results

A total of 1740 PK samples from 95 subjects were used in the final popPK model inference. A three compartment popPK model with inter-individual variability (IIV) on clearance, volumes of the central compartment (V1), peripheral compartment (V2) and the inter-compartmental clearance (Q3) produced predictions in agreement with measured BV100 plasma concentrations. Model simulations predict that at steady state, q12h dosing of 150, 250 and 525 mg is sufficient for 90% of subjects with any level of renal impairment to achieve rifabutin exposures expected to achieve 1-log reduction in bacterial load at MIC values of 0.5, 1 and 2 mg/L, respectively.

Conclusion

The PK of intravenous BV100 is adequately described by a three-compartment linear popPK model.

Disclosures

Gitzinger Marc, PhD, BioVersys AG: Ownership Interest Christian Kemmer, PhD, BioVersys AG: Ownership Interest Lisa Husband, MBBS BSc MRCPCH, BioVersys AG: Ownership Interest Glenn Dale, PhD, BioVersys AG: Ownership Interest
2551. Assessing Meropenem Concentrations in Children with Septic Shock: Population-Based Pharmacokinetic (PK) Modeling of Meropenem Demonstrates Variability from Acute Kidney (AKI) to Augmented Renal Clearance (ARC)
Authors: Le Jennifer , Huynh Julie , Bradley John S , Vo Brandon , Momper Jeremiah , Capparelli Edmund
Published: November 2023

Background

The primary objective of this study was to characterize meropenem (MERO) pharmacokinetics (PK) in critically ill infants and children with septic shock to develop dosing recommendations to achieve therapeutic drug exposure in this complex population with a spectrum of renal function from augmented renal clearance (ARC) to acute kidney injury (AKI).

Methods

Children ≥4 weeks old hospitalized with septic shock requiring fluid resuscitation and pressors, receiving MERO 20 mg/kg IV every 8 hr as standard-of-care, were enrolled and studied prospectively from 2019 to 2023. Population PK modeling was used to derive Bayesian post-hoc PK parameters (NONMEM 7.3). Renal biomarkers (serum creatinine [SCr], cystatin C [CYS], serum neutrophil gelatinase-associated lipocalin [NGAL]) were evaluated as covariates. Estimated glomerular filtration rate (e-GFR) was calculated by the modified Schwartz equation.

Results

A total of 304 MERO serum concentrations were included from 26 participants. Median age was 12.6 yr (range 1.2-19.6); weight 38.4 kg (10-98); SCr 0.36 mg/dL (0.09-2.57); CYS 448.9 mg/d (178.3-1824.1), and NGAL 176.05 ng/mL (29.3-1000). Median MERO serum concentration was 11 mcg/mL (range 0.033-217, interquartile range [IQR] 1.873-37.85). A two-compartment model with allometrically scaled weight on clearance (0.75) best described the data. Significant covariates (final model) were e-GFR, CYS, NGAL, age, diagnosis of appendicitis and albumin. Using the final model, the median CL was 0.15 (range 0.05-0.51, interquartile range [IQR] 0.06-0.25) L/hr/kg and V1 0.20 (0.07-0.57, IQR 0.12-0.31) L/kg, with GFR 139 (23-364, IQR 93-204) mL/min/1.73 m2 (Figure). The distribution of MERO concentrations, CL and GFR across quartiles documents wide variations in renal function observed in septic shock, from AKI to ARC (Figure).

Meropenem Serum Concentration, Meropenem Renal Clearance, and Glomerular Filtration Rate, by Quartiles

Conclusion

Wide variation in MERO plasma exposure was documented in children with septic shock across the spectrum of renal function. GFR-based dosing recommendations may optimize MERO dosing and improve outcomes in this population.

This work was supported by NICHD grant 1 R01 HD095547-01

Disclosures

Edmund Capparelli, PharmD, Melinta: Advisor/Consultant
2555. Metronidazole Dosing in Patients with and without Obesity Undergoing Colorectal Surgery: Should body size or composition be a factor?
Authors: Pai Manjunath P , Matvekas Aleksas , Rajanayake Krishani , Carrier Theresa , Nguyen Allison , Ross Brian , Sullivan June , Alikhani Radin , Abdelnabi Mohamed , Regenbogen Scott , Byrn John , Su Grace , Wang Stewart
Published: November 2023

Background

Metronidazole (MET) is administered on a fixed-dose basis irrespective of body size in adults but studies suggest that dose adjustment may be needed (PMID: 33969405). This study evaluated plasma and fat tissue pharmacokinetics (PK) of MET in patients undergoing elective colorectal surgery.Table 1.Patient demographics, body size, morphomic and pharmacokinetic values by obese group. Data reported as median (5th, 95th percentile) valuesFigure 1.Visual predictive check illustrating observed and model predicted metronidazole concentrations in plasma and fat tissue samples stratified by patients with and with out obesity

Methods

Adult patients (age ≥ 18 years) undergoing elective colorectal procedures with a preoperative CT scan available were prospectively enrolled. MET was administered as standard of care (500 mg) intravenously 15-60 prior to incision with blood sampling performed at the end of infusion, before incision, and at surgical closure. Fat tissue samples were collected at incision and closure. Samples were assayed by an LC-MS/MS method. Population PK analyses were performed by co-modeling plasma and fat MET concentrations and comparing weight, body surface area (BSA), morphomics, and conventional patient demographics as covariates. Morphomics are body dimensions and composition (e.g. muscle and fat areas) parameters generated using CT scan data.

Results

Data were acquired from 67 patients (n=36 male) with comparisons between groups reported in Table 1. A 1-compartment model adequately characterized plasma MET profiles with a mean (CV) volume of distribution (V) and clearance (CL) of 24.4 (62.5%) L and 4.04 (34.2%) L/h. A two-compartment structure with transfer rate constants, with vertebral height (compared to weight or BSA) as a covariate of V and age as a covariate of CL provided the best co-model fit for plasma and fat tissue (Figure 1). The median [5th, 95th percentile] sampling period was 3.3 [1.6, 6.4] hours with an AUCτ of 44.0 [22.0, 83.4] h*mg/L and 6.79 [3.11, 13.6] h*mg/L in plasma and fat tissue. No significant difference was observed in plasma or fat exposures or their ratio as a surrogate for tissue penetration between obese and non-obese patients. Simulations suggest a lower probability (≤62.6%) of achieving an AUC∞/MIC of 70 in adults under the age of 50 years.

Conclusion

Plasma and fat tissue exposures of MET are similar in obese and non-obese patients undergoing elective colorectal surgeries. Age may be a more relevant factor than body size or composition for metronidazole dose adjustment.

Disclosures

Stewart Wang, MD, PhD, Applied Morphomics, Inc.: patent for analytic morphomics|Applied Morphomics, Inc.: Ownership Interest|mBioHealth: Ownership Interest|Surgical Risk Management: Ownership Interest
2564. Population Pharmacokinetics and Pharmacodynamics of Cefepime in Hospitalized Obese and Non-Obese Patients
Authors: Shin Beomjin , Chung Eun Kyuong , Cheatham S Christian , Fleming Megan R , Healy Daniel P , Kays Michael B
Published: November 2023

Background

The objectives of this study were to describe population pharmacokinetics (PK) of cefepime and to evaluate pharmacodynamics (PD) of cefepime based on population PK model with various dosing regimens through Monte Carlo simulation to optimize dosing regimens for obese patients.

Methods

Hospitalized adult patients who required antimicrobial therapy with cefepime for a suspected or documented bacterial infection were included in this study. Patients were stratified into either obese (body mass index [BMI] ≥ 30 kg/m2) or non-obese (BMI < 30 kg/m2) group. Based on serial concentration-time data in serum at steady state, population PK analysis was performed using NONMEM. Monte Carlo simulations were conducted in 6000 virtual patients using PK parameters of the final model for the following dosing regimens: 1 g q6h, 1 g q8h, 1 g q12h, 2 g q8h, and 2 g q12h. Probability of target attainment (PTA) for ≥ 60% free drug concentrations exceed the minimum inhibitory concentration (fT >MIC) was calculated at MICs ranging from 0.125 to 32 mg/L. Dosing regimens with PTAs ≥ 90% were considered optimal.

Results

A total of 176 serum cefepime concentrations obtained from 24 patients (15 obese and 9 non-obese patients) were included in the population PK analysis. A one-compartment model best described the serum concentration-time data of cefepime. Fixed-exponent allometric scaling for volume of distribution with TBW significantly improved the model fit. Creatinine clearance was the only covariate significantly associated with cefepime PK, specifically systemic clearance (CL). Model-estimated V and half-life were significantly different between obese and non-obese patient groups (P < 0.01). At MICs ≤ 8 mg/L, all simulated intermittent infusions achieved PTA ≥ 90% in obese patients except 1 g q12h; only 2 g q8h regimen achieved PTA ≥ 90% in non-obese patients. For prolonged infusions, all tested dosing regimens achieved PTA > 90% except 1 g q12h in obese patients and q12h regimens in non-obese patients.

Conclusion

Obesity significantly alters the PK of cefepime. However, it does not warrant alternative dosing in obesity. Prolonged infusions or larger doses may be considered at higher MICs or fT >MIC targets. Dosage adjustments based solely on obesity may be unnecessary.

Disclosures

All Authors: No reported disclosures
2570. The intraoperative pharmacokinetics of ampicillin and sulbactam and the effect of massive bleeding in recipients of living donor liver transplantation
Authors: Wakimoto Yuji , Okamoto Koh , Yamamoto Takehito , Akamatsu Nobuhisa , Kariya Taro , Hoshino Yoko , Harada Sohei , Hashimoto Hideki , Jubishi Daisuke , Yamaguchi Ryo , Tanaka Takehiro , Kaneko Junichi , Okugawa Shu , Uchida Kanji , Takada Tappei , Hasegawa Kiyoshi , Tsutsumi Takeya
Published: November 2023

Background

The current guidelines recommend redosing of prophylactic intraoperative antimicrobials based on their half-life or in case of bleeding greater than 1,500 mL. However, data to support this practice is scarce. Orthotopic liver transplantation is often accompanied by massive bleeding. Therefore, we aimed to characterize the intraoperative pharmacokinetics of the prophylactic antimicrobial to analyze the pharmacokinetic parameters in recipients of living-donor liver transplantation (LDLT).

Methods

The recipients of LDLT who were 20 years or older without allergy to any beta-lactams were included. All participants received intravenous ampicillin-sulbactam (ABPC-SBT) 2-1 gram one hour before and every three hours during surgery over 30 minutes. The amount of blood loss and relevant parameters were recorded. Blood samples were collected every hour during surgery. The total plasma concentrations of ABPC and SBT were determined using a liquid chromatography-tandem mass spectrometry. Noncompartmental analysis was applied to calculate the clearances of ampicillin and sulbactam. The probability of target attainment (PTA) was determined based on the breakpoints proposed by The Clinical Laboratory Standards Institute assuming that the protein binding rate of ABPC and SBT were 28% and 38%, respectively.

Results

Twenty recipients were included (Table). The median age, weight, and amount of blood loss of the recipients were 52 years, 62.1 kg, and 11,158 mL, respectively. A median of calculated creatinine clearance were 99.6 mL/min. The total concentrations of ABPC and SBT in plasma and the amount of blood loss are shown (Figure 1, 2). Twelve participants (60%) achieved the PTA of 100% in both ABPC and SBT during surgery. The model-independent clearances of ABPC and SBT were 80.3 and 77.2 mL/min, respectively. Although bleeding greater than 20,000mL tended to increases the clearances of ABPC and SBT, the overall time above minimum inhibitory concentration of common pathogens was at acceptable level during surgery.

The pharmacokinetics of ampicillin in the recipients in the living donor liver transplantation.

The pharmacokinetics of sulbactam in the recipients in the living donor liver transplantation.

Conclusion

Intraoperative redosing of ABPC-SBT every three hours achieved the PTA of 100% in 60% of the LDLT recipients despite intraoperative massive bleeding.

Disclosures

All Authors: No reported disclosures
146. Review of Urine Culture Screening Practices Prior to Urologic Procedures
Authors: Jeong Anthony J , Dudek Sessen , Bennett Jessica G , Thomas-Gosain Neena
Published: November 2023

Background

Screening for UTIs prior to urologic procedures is a well-established practice. However, screening for asymptomatic bacteriuria remains more controversial, especially for procedures considered to be low-risk for complications. The aim of this study was to characterize current screening practices at our facility.

Methods

This retrospective study reviewed outpatient urologic procedures performed between 10/01/2022 and 12/31/2022. Procedures were stratified by risk based on current American Urological Association guidance. Charts were reviewed for the following information: urinary symptoms, ucx results, antibiotic prescriptions, post-op complications. The primary outcome was the incidence of urinary (GU) infection or infection related hospitalization (IRH) within 30 days post-procedure. Secondary outcomes include ucx screening rates and risk of infection based on presence of urinary symptoms.

Results: 210 procedures were reviewed. Risk of GU infection ranged from 8.2% to 12.9%, with the highest rates seen in intermediate- and high-risk procedures. Risk of IRH increased by increasing level of risk (Table 1).

Pre-op ucx were ordered in 35% of procedures, however frequency of ordering varied based on level of risk, with intermediate-risk (96%) much more likely to have been screened and no screening was done prior to high-risk procedures (Table 2).

Symptomatic patients were more likely to have a pre-op ucx (60.4% vs 28.2% if asymptomatic). Ucx positivity was 3-fold higher if patient was symptomatic. Rates of GU infection and IRH varied based on presence of symptoms and whether preop ucx was ordered. (Table 3)Table 1:Risk of GU infection or IRH by ucx ordering, stratified by risk*no data since no ucx were ordered in high-risk groupTable 2:Preoperative ucx ordering by risk stratificationTable 3:Ucx screening by symptom status

Conclusion

In this study sample, risk of infectious complications (especially IRH) increased with increasing level of procedural risk. However, screening trends were inconsistent limiting conclusions about the impact of ucx on the incidence of infectious complications prior to intermediate and high-risk procedures.

The rate of ucx screening was higher when urinary symptoms were present, but clear trends did not appear. This study highlights the need for consistent screening practices, primarily based on risk of procedure. Larger numbers may help answer the question of whether or not screening should be based on presence of symptoms.

Disclosures

All Authors: No reported disclosures
2581. Desirability of Outcome Ranking and Response Adjusted for Antibiotic Risk (DOOR/RADAR) Post-Hoc Analysis Supports Equipoise for Antibiotic Initiation Strategies in ICU-Acquired Pneumonia
Authors: Guidry Christopher A , Chollet-Hinton Lynn , Baker Jordan , O’Dell Jacob C , Beyene Robel T , Watson Christopher M , Sawyer Robert G , Simpson Steven Q , Atchison Leanne , Derickson Michael , Cooper Lindsey C , Pennington G Patton , VandenBerg Sheri , Halimeh Bachar N
Published: November 2023

Background

Pneumonia is the most common ICU-acquired infection and source of potential sepsis in ICU populations but can be difficult to diagnose in real-time. Despite limited data, rapid initiation of antibiotics is endorsed by society guidelines. We hypothesized that a post-hoc analysis of a recent randomized pilot study would show no difference between two antibiotic initiation strategies.

Methods

The recent Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP) was a pragmatic cluster-randomized pilot of antibiotic initiation strategies for intubated patients with suspected but not yet proven ICU-acquired pneumonia. Participating ICUs were cluster-randomized to either an immediate initiation protocol or a specimen-initiated protocol where a gram stain was required for initiation of antibiotics. Patients in the study were divided into one of seven mutually exclusive outcome rankings (DOOR): 1) Survival, No Pneumonia, No adverse events; 2) Survival, Pneumonia, No adverse events; 3) Survival, No Pneumonia, ventilator-free-alive days ≤14; 4) Survival, Pneumonia, ventilator-free-alive days ≤14; 5) Survival, No Pneumonia, Subsequent episode of suspected pneumonia; 6) Survival, Pneumonia, Subsequent episode of suspected pneumonia; and 7) Death. These rankings were further refined using the duration of antibiotics prescribed for pneumonia (RADAR). Analysis was performed using R and adjusted for clustering.

Results

There were 186 patients enrolled in the study: 93 in each group. After applying the DOOR analysis, a randomly selected patient in the specimen-initiated group was just as likely to have a better outcome as a patient in the immediate initiation group (DOOR probability: 50.8%; 95% CI: 42.7-58.9%). After applying the RADAR analysis, the likelihood of a randomly selected patient in the specimen-initiated arm having a better outcome than a patient in the immediate arm was 52.5% (95% CI: 44.2-60.6%; p=0.31).

Conclusion

We found that patients in whom antibiotics were withheld until there was objective evidence (specimen-initiated group) had similar outcome rankings to patients where antibiotics were started immediately. This confirms the findings of the TARPP pilot trial and further gives evidence for equipoise between these two treatment strategies

Disclosures

Robert G. Sawyer, MD, AbbVie: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant
2585. Identification of Risk Factors for Pseudomonas aeruginosa in Patients with Community-Acquired Pneumonia
Authors: Karajeh Jenna , Sapozhnikov Julia , Adams Jenna , Albarillo Fritzie S , Santarossa Maressa , Hoff Brian M
Published: November 2023

Background

Community-acquired pneumonia (CAP) is a leading infectious cause of hospitalization, morbidity, and mortality worldwide. As the etiology of CAP continues to evolve, antibiotic-resistant bacteria are becoming more prevalent in the community setting. Among these pathogens is Pseudomonas aeruginosa. Although incidence of CAP due to P. aeruginosa is low, it has been linked to severe illness and poor clinical outcomes, highlighting the challenge in treating this infection. Identifying local risk factors for pneumonia due to drug-resistant pathogens, specifically P. aeruginosa, can potentially reduce the overuse of unnecessary empiric broad-spectrum antipseudomonal agents and increase appropriateness of empiric antibiotic treatment regimens.

Methods

A single-center, retrospective cohort study was conducted in patients who were treated for CAP at a large academic medical center from August 1, 2019 through July 31, 2022. Specimen data were reviewed and separated into two groups. The P. aeruginosa group was composed of P. aeruginosa-positive respiratory specimens whereas the non-P. aeruginosa group comprised all other pathogens and specimen-negative results. The primary endpoint was to identify risk factors for P. aeruginosa in patients with CAP at our institution.

Results

A total of 206 patients were screened and 79 of them were included in the analysis (39 P. aeruginosa encounters and 40 non-P. aeruginosa encounters). Baseline characteristics were well-distributed between groups. A univariate analysis determined 13 variables were significant at P < 0.2. This P-value was used for entry into the logistic regression model. Of the 13 variables, four were determined to be correlated most closely with CAP due to P. aeruginosa: chronic pulmonary disease (OR, 12.4 [95% CI, 2.5 to 61]), prior intravenous antibiotics within the last 12 months (OR, 15.7 [95% CI, 3.2 to 77.2]), sputum production (OR, 8.1 [95% CI, 1.6 to 41.3]), and tube feeds at time of admission (OR, 21.2 [95% CI, 1.2 to 360.5]).

Conclusion

Although the study sample size was small, chronic pulmonary disease, prior intravenous antibiotics within the last 12 months, sputum production, and tube feeds at time of admission correlated most closely with CAP due to P. aeruginosa at our institution.

Disclosures

All Authors: No reported disclosures
2588. Burden of Mortality and Antimicrobial Resistance of Bacterial Pathogens Associated with Lower Respiratory Tract and Other Thorax Infection in United States in 2019: A Systematic Analysis
Authors: Mallyala Sahithi Rao , Chirumamilla Avinash , Raj Deepti , Gajjar Jay , Patel Sneh , Dekhne Anushka , Desai Hardik Dineshbhai
Published: November 2023

Background

Detailed information about the impact of bacterial antimicrobial resistance (AMR) on Lower Respiratory Tract and other thorax Infections (LRTIs) is currently unavailable. It is important to have precise data on bacterial AMR to develop effective programs and policies for controlling AMR and to use antibiotics prudently for optimal treatment of LRTI patients. The primary objective of this research is to present extensive estimates of the mortality due to "bacterial pathogens" and its "AMR" of LRTIs in the United States in 2019.

Methods

Mortality data associated with bacterial antimicrobial resistance and lower respiratory tract infection (LRTI) pathogens were acquired from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) in 2019.

Results

In United States, there were 88089 deaths (95% uncertainty interval [UI]: 66909-117145) due to bacterial pathogens in LRIT in 2019. Highest number of deaths observed due to Staphylococcus aureus (34.04%), followed by Streptococcus pneumoniae (18.30%), Pseudomonas aeruginosa (12.48%) in LRTI in 2019. There were 10984 deaths attributed to and 46482 deaths associated with bacterial AMR in LRTI in 2019.

Conclusion

Bacterial pathogens causing LRTIs are a significant cause of mortality in the United States. Moreover, antimicrobial resistance (AMR) among these pathogens has become a growing concern, exacerbating the burden of LRTI-related deaths. The implementation of such measures, along with the promotion of antimicrobial stewardship, can help to mitigate the impact of LRTI-associated deaths and preserve the effectiveness of available antimicrobial agents for the future.

Disclosures

All Authors: No reported disclosures
2599. Impact of Alveolar Neutrophilia on Outcomes in Patients with Suspected Ventilated Hospital-Acquired Bacterial Pneumonia
Authors: Saravolatz Louis , Albin Owen
Published: November 2023

Background

Ventilated hospital-acquired bacterial pneumonia (vHABP) is a major source of morbidity & mortality in hospitalized patients. Clinical risk scores and systemic biomarkers have limited clinical & prognostic utility in vHABP. Alveolar biomarkers—specifically alveolar neutrophilia (AN), the percentage of polymorphonuclear cells (PMN%) present in bronchoalveolar lavage (BAL) fluid—gauge the host inflammatory response directly at the site of infection, offering an attractive but untested predictive risk biomarker in vHABP. We aimed to generate preliminary data exploring AN as a vHABP biomarker.

Methods

We performed a retrospective cohort study of intensive care unit (ICU) patients with vHABP from 2010-2023. vHABP was defined as development of acute hypoxic respiratory failure requiring invasive mechanical ventilation, clinical suspicion of pneumonia by treating teams prompting performance of BAL respiratory culture, and BAL PMN% > 50%. Patient demographic characteristics, comorbidities and acute severity of illness metrics were abstracted via chart review. PMN% values were dichotomized using median split rounded to the nearest PMN% decile ( > or < 80% PMN% in BAL fluid). Study outcomes included ventilator-free days, ICU length of stay and vHABP-directed antibiotic treatment duration within 30 days of vHABP.

Results

44 patients met study inclusion criteria. 30 (68%) had a BAL neutrophil of > 80%. Patients with BAL PMN > 80% had a numerically higher use of tracheostomy and trend towards lower P/F ratio at the time of vHABP diagnosis [Table 1]. BAL PMN > 80% was associated with a 15% decrease in ventilator-free days (p < 0.01) and a 25% longer ICU length of stay (p < 0.01) than those with BAL PMN < 80% [Figure 1]. There was no significant difference in post-BAL vHABP-directed antibiotic duration in patients with and without BAL PMN > 80%.

Conclusion

Though limited by low sample size, this exploratory study suggests AN may be a potentially useful predictive risk biomarker in vHABP. Larger-scale, prospective studies of alveolar biomarkers—including AN—in vHABP are warranted.

Disclosures

Owen Albin, MD, Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant