bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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 &lt; 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 &gt;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 &lt; 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 &gt; 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 &gt;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

Abstract

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

Abstract

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

Abstract

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