bluuebunny/crossref_metadata_2025_split huggingface dataset:
1301. Breakthrough Invasive Fungal Infections based on CYP2C19 Levels in Patients Who were on Voriconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) undergoing Induction Chemotherapy
Authors: Singam Hareesh v , Pasikhova Yanina , Quilitz Rod , Greene John N , Baluch Aliyah 
Published: January 2021

Abstract

Background
Voriconazole (Vori) is often used for prophylactic anti-fungal therapy in induction chemotherapy for Acute Myeloid Leukemia (AML) patients due to predictable absorption and an extended spectrum antifungal activity. Vori is metabolized predominately by CYP2C19 to metabolites with less antifungal activity. There has been a great interest in understanding CYP2C19 as it significantly affects drug metabolism and pharmacokinetics of numerous drugs including voriconazole.
Approximately 39% of patients are genetically predicted to be CYP2C19 ultra-rapid or rapid metabolizers and thus are at an increased risk of breakthrough fungal infection. This study assesses the incidence of breakthrough invasive fungal infections (bIFI) at Moffitt Cancer Center based on CYP2C19 activity. bIFI is defined as new fungal infection while on vori, leading to treatment with liposomal amphotericin B, echinocandin, and/or different triazole.

Methods
This is a single-center retrospective analysis of patients who underwent induction chemotherapy for newly diagnosed AML and received voriconazole as the primary antifungal prophylaxis between July 2017 and June 2019. The patients enrolled were over 18 years old and did not have a history of stem cell transplant or solid organ transplant, Human Immunodeficiency Virus, relapsed AML or received systematic antifungal therapy 30 days prior. CYP2C19 were checked for each of the patients between July 2017 to June 2019 who were undergoing induction chemotherapy for newly diagnosed AML. It was checked within one week of admission. The patients were categorized as rapid metabolizers, intermediate metabolizers, normal metabolizers, and unknown CYP2C19.

Results
There was an incidence of 20.2% (18/89) bIFI in patients who were on Vori in this study. Of these patients with bIFI infections, 15.7% (3/19) of patients were rapid metabolizers, 14.7% (5/34) were normal metabolizers, 28.5% (4/14) were intermediate metabolizers and 0% (0/3) were poor metabolizers. There were 31% (6/19) breakthrough infections in patients with unknown CYP2C19 characteristics.

Conclusion
There is no significant statistical difference (p=0.6) among CYP2C19 categories with respect to breakthrough of invasive fungal infections at Moffitt Cancer Center between July 2017 - June 2019.

Disclosures
Rod Quilitz, Pharm D., Astellas (Advisor or Review Panel member)
1302. Cefiderocol Population Pharmacokinetics and Probability of Target Attainment in Plasma and Epithelial Lining Fluid in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infections
Authors: Katsube Takayuki , Kawaguchi Nao , Echols Roger , Wajima Toshihiro , Nicolau David P 
Published: January 2021

Abstract

Background
Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach.

Methods
PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance.

Results
The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was &gt;90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was &gt;90% against MICs ≤2 μg/mL and &gt;85% against MICs ≤4 μg/mL, regardless of renal function.
Table. Probability of Target Attainment for 75% fT&gt;MIC or 75% fT&gt;MIC,ELF

Conclusion
The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function.

Disclosures
Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
1310. Implementation of AUC:MIC Pharmacy to Dose in an Academic Medical Center: A Pilot Study
Authors: Idusuyi Ann-Marie , Campion Maureen , Belusko Kathleen 
Published: January 2021

Abstract

Background
The new ASHP/IDSA consensus guidelines recommend area under the curve (AUC) monitoring to optimize vancomycin therapy. Little is known about the ability to implement this recommendation in a real-world setting. At UMass Memorial Medical Center (UMMMC), an AUC pharmacy to dose protocol was created to manage infectious diseases (ID) consult patients on vancomycin. The service was piloted by the pharmacy residents and 2 clinical pharmacists. The purpose of this study was to determine if a pharmacy to dose AUC protocol can safely and effectively be implemented.

Methods
A first-order kinetics calculator was built into the electronic medical record and live education was provided to pharmacists. Pharmacists ordered levels, wrote progress notes, and communicated to teams regarding dose adjustments. Patients were included based upon ID consult and need for vancomycin. After a 3-month implementation period, a retrospective chart review was completed. Patients in the pre-implementation group were admitted 3 months prior to AUC pharmacy to dose, had an ID consult and were monitored by trough (TR) levels. The AUC group was monitored with a steady state peak and trough level to calculate AUC. The primary outcome evaluated time to goal AUC vs. time to goal TR. Secondary outcomes included number of dose adjustments made, total daily dose of vancomycin, and incidence of nephrotoxicity.

Results
A total of 64 patients met inclusion criteria, with 37 patients monitored by TR and 27 patients monitored by AUC. Baseline characteristics were similar except for weight in kilograms (TR 80.0 ±25.4 vs AUC 92.0 ±26.7; p=0.049). The average time to goal AUC was 4.13 (±2.08) days, and the average time to goal TR was 4.19 (±2.30) days (p=0.982). More dose adjustments occurred in the TR group compared to the AUC (1 vs 2; p=0.037). There was no difference between the two groups in dosing (TR 15.8 mg/kg vs AUC 16.4 mg/kg; p=0.788). Acute kidney injury occurred in 5 patients in the AUC group and 11 patients in the TR group (p=0.765).

Conclusion
Fewer dose adjustments and less nephrotoxicity was seen utilizing an AUC based protocol. Our small pilot has shown that AUC pharmacy to dose can be safely implemented. Larger studies are needed to evaluate reduction in time to therapeutic goals.

Disclosures
All Authors: No reported disclosures
1314. Neonatal Serum Gentamicin Concentrations following Maternal Once-daily Gentamicin Dosing
Authors: Wilson Genene A , Nelson Allison , Bhagat Palak , Bondi Deborah , Shah Pooja , Kumar Madan 
Published: January 2021

Abstract

Background
Gentamicin is commonly used for peripartum infections. Given literature supporting efficacy of once-daily dosing (ODD) of 5 mg/kg for chorioamnionitis, University of Chicago Medicine made the change from three times daily dosing (TIDD) to ODD. As gentamicin readily cross the placenta, it would be expected that maternal ODD would result in higher gentamicin neonatal serum concentrations following birth.

Methods
This was a single-center, retrospective chart review of all neonates born to mothers receiving peripartum ODD gentamicin within 12 hours of delivery between October 2019 and March 2020. A STAT random gentamicin serum concentration was obtained upon admission in neonates when initiation of antibiotics was desired. Specific dosing recommendations (Table 1) were developed utilizing neonatal population-based pharmacokinetics. The primary outcome was initial neonatal gentamicin serum concentration at birth. Other outcomes were also evaluated. Results were evaluated in two groups based on neonatal serum concentrations of less than 2 mcg/mL (Group 1) versus 2 mcg/mL or greater (Group 2).
Table 1: Neonatal gentamicin dosing algorithm

Results
Thirty-two mother-newborn dyads were included in this study. Baseline demographics are shown in Table 2. Newborns had a median gestational age of 39.4 weeks and median birth weight of 3.39 kilograms. The mean initial gentamicin concentration was supratherapeutic at 3.06 + 1.92 mcg/mL among all newborns (Table 3). The mean maternal dose in Group 1 (n=11) was 3.52 mg/kg (3.34, 4.77) based on actual body weight and 4.78 mg/kg (4.34, 5.18) in Group 2 (n=21) (p=0.025). The median time between maternal gentamicin administration and time of delivery varied between the groups at 0.5 hours versus 2.63 hours, respectively (p=0.005). All newborn gentamicin concentrations were less than 2 mcg/mL for maternal doses given less than 1 hour prior to delivery (n=8) (Figure 1). Overall protocol compliance rate was 81.3%. There were no significant differences in nephrotoxicity or ototoxicity between groups.
Table 2. Baseline Demographics

Table 3. Outcomes

Figure 1. Comparison of maternal gentamicin time from administration to delivery and neonatal serum gentamicin concentrations

Conclusion
This study suggests peripartum ODD of gentamicin may lead to clinically significant serum concentrations in neonates if administered between 1 to 12 hours of birth. Further studies are warranted to evaluate the effects of maternal ODD of gentamicin on newborns.

Disclosures
All Authors: No reported disclosures
1318. Pharmacokinetics and Safety of Cefepime-Taniborbactam (formerly Cefepime/VNRX-5133) in Subjects with Renal Impairment
Authors: Geibel Brooke , Dowell James A , Marbury Thomas C , Smith William , McGovern Paul C , Richards Cynthia , Henkel Tim 
Published: January 2021

Abstract

Background
Taniborbactam is a novel, non-ß-lactam, ß-lactamase inhibitor with activity against serine (Class A, C, D) and metallo (Class B) ß-lactamases including epidemiologically important carbapenemases. Both cefepime and taniborbactam are predominantly renally excreted and are likely to require dose adjustment in patients with renal impairment and end-stage renal disease (ESRD). The current study was designed to evaluate the pharmacokinetics and safety in patients with renal impairment and ESRD.

Methods
This was a Phase 1, open-label study in subjects with normal renal function (eCLCR ≥ 90 mL/min) matched to subjects with mild, moderate, and severe renal impairment (eGFR 60-89, 30-59, and &lt; 30 mL/min/1.73m2, respectively), and patients with ESRD on hemodialysis. Subjects received a single dose of cefepime 2 g and taniborbactam 500 mg; subjects with ESRD received a single dose before HD and after a 9 day washout period, following HD. PK parameters including AUC0-inf and total body clearance (CL) were evaluated. Safety assessments included adverse events (AEs), vital signs, clinical laboratory evaluations, electrocardiograms, and physical examinations.

Results
Thirty-three subjects were enrolled; 67% male, 58% white and 39% black/African Americans. Median age and BMI were 55.0 years and 29.5 kg/m2, respectively. For both cefepime and taniborbactam, exposures increased, and CL decreased with increasing renal impairment (see Table). The hemodialysis extraction ratio was 49.7% and 47.4% for taniborbactam and cefepime respectively. No safety signals were observed and there were no serious adverse events.
Table

Conclusion
Cefepime and taniborbactam CL is similarly reduced with varying degrees of renal impairment. Dialysis removes a high fraction of both drugs. Dose adjustments recommended for cefepime are appropriate for taniborbactam.

Disclosures
Brooke Geibel, BS, Venatorx Pharmaceuticals (Employee, Shareholder) James A. Dowell, PhD, Venatorx Pharmaceuticals (Independent Contractor) Thomas C. Marbury, MD, Venatorx Pharmaceuticals (Independent Contractor) William Smith, MD, Venatorx Pharmaceuticals (Independent Contractor) Paul C. McGovern, MD, Venatorx Pharmaceuticals (Employee) Cynthia Richards, MD, Venatorx Pharmaceuticals (Independent Contractor) Tim Henkel, MD, PhD, Venatorx Pharmaceuticals (Employee, Shareholder)
1321. Population Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Analyses for Dalbavancin in Pediatric Patients
Authors: Carrothers Timothy J , Lagraauw H Maxime , Lindbom Lars , Riccobene Todd 
Published: January 2021

Abstract

Background
Dalbavancin is a lipoglycopeptide approved for treating adults with acute bacterial skin and skin structure infections (ABSSSI). It has a terminal half-life of &gt;14 days, which allows for administration as a single-dose regimen. Pediatric studies for dalbavancin include three phase 1 studies and a phase 3 study in patients from birth to 17 years with ABSSSI or neonatal sepsis.

Methods
A population PK model was developed using 1124 concentrations from 211 pediatric patients. Allometric scaling of clearance, and volume parameters was included with exponents fixed at 0.75 and 1, respectively. Based on exploratory analysis and prior knowledge, serum albumin was included as a covariate on all PK parameters, and creatinine clearance or estimated glomerular filtration rate (eGFR) was included as a covariate on clearance. eGFR for patients &lt; 2 years accounted for renal maturation. Additional covariates were assessed by stepwise covariate modeling (SCM). The final model was qualified by visual predictive checks (VPCs) and bootstrapping and was used to simulate 1000 PK profiles for various pediatric age groups, ranging from preterm neonates to adolescents. PK/PD target attainment (PTA) was calculated for targets associated with stasis, 1-log kill, and 2-log kill of Staphylococcus aureus in the murine thigh infection model.

Results
Dalbavancin PK was well-characterized by a 3-compartment model. SCM did not find any significant covariates besides albumin, weight, and renal function. VPCs demonstrated that the final model has good predictive performance across the full age range. Simulations showed that single-dose regimens of 22.5 mg/kg for patients &lt; 6 years and 18 mg/kg for patients 6 to &lt; 18 years resulted in PTA ≥94% for MICs up to 2 mg/L for the stasis target and up to 0.5 mg/L for the 2-log kill target. PTA for pediatric patients was similar to adults, and exposures (AUCs) were contained within the range for adults administered 1500 mg.

Conclusion
Dalbavancin PK in pediatric patients was well-characterized by a 3-compartment model with allometric scaling of clearance and volume and with albumin and renal function included as covariates. Simulations with the final model demonstrate adequate PTA across the entire age range for the regimens used in the phase 3 pediatric study.

Disclosures
Timothy J. Carrothers, ScD, AbbVie (Employee) H. Maxime Lagraauw, PhD, qPharmetra (Employee) Lars Lindbom, PhD, qPharmetra (Employee) Todd Riccobene, PhD, AbbVie (Employee)
1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
Authors: Smith Nicholas M , Chen Liang , Boissonneault Katie Rose , Lodise Thomas , Holden Patricia N , Bulitta Juergen B , Bonomo Robert A , Kreiswirth Barry N , Tsuji Brian T 
Published: January 2021

Abstract

Background
The scourge of MBLs among Gram negatives, such New Delhi Metallo-beta-lactamase-producing Klebsiella pneumoniae, has resulted in an overwhelming need for new treatmens. Worryingly, additional acquisition of plasmid-mediated polymyxin resistance through the mcr gene can produce strains resistant to all last line agents. The novel combination of aztreonam (ATM, which is not an MBL substrate) with avibactam (AVI, to inhibit extended spectrum beta-lactamases that inactivate ATM) has been proposed to restore ATM activity.

Methods
K. pneumoniae SZ04 harboring blaNDM-5, blaCTX-M-55, and mcr-1 (MICATM = 128 mg/L, MICPolymyxin B = 4 mg/L, MICAmikacin = 1 mg/L, MICceftazidime/avibactam &gt; 16/4 mg/L) was studied at two initial inoculum (106 and 108 cfu/mL) over 24h in static time kills (SCTK). Concentration arrays of 2-, 3-, and 4-drug combinations of low- and package insert-dose polymyxin B (PMB) ± low- and package insert-dose amikacin (AMI) ± package insert dosing of ATM/AVI were simulated in &gt; 200 individual arms of SCTK. Data were summarized using the Log Ratio Area (LRA) which is calculated by integrating the area under the bacterial killing curve, normalizing to the growth control, then log-transforming. A Hill-type function was fit to the data in order to determine the maximum effect (Emax) and drug concentration for 50% effect (EC50).

Results
When simulating the maximum free concentration of amikacin 15 mg/kg (52 mg/L) in combination with package insert concentrations of ATM/AVI, there was a marked reduction of 3.22 in the LRA compared to the growth control for the 108 cfu/mL starting inocula. Combining ATM with low amikacin (0.813 mg/L) and polymyxin B (0.125 mg/L) resulted in a reduction in LRA of 4.32 at 106 cfu/mL. Model fitting results showed a statistically significant difference in EC50 to amikacin between low and high inocula at 1.24 and 18.1 mg/L, respectively. Combination of AMI with low-concentration PMB (0.125 mg/L) resulted in an increase in the Emax of amikacin to -5.68.

Conclusion
The use of ATM/AVI combinations is a promising option against MBL and MCR co-producing K. pneumoniae. Low-dose strategies of polymyxin or amikacin dosing in combination with ATM/AVI is merits further testing for future translation to the clinical setting to improve efficacy and optimize treatment.

Disclosures
Thomas Lodise, PharmD, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
1326. Vancomycin Area Under the Concentration-Time Curve (AUC) Estimation Using a Bayesian Approach Versus First-Order Pharmacokinetic Equations: A Pilot Study
Authors: Pearson Jeffrey , Alsowaida Yazed S , Pharm B S , Kubiak David W , Kovacevic Mary P , Dionne Brandon 
Published: January 2021

Abstract

Background
Current guidelines endorse area under the concentration-time curve (AUC)-based monitoring over trough-only monitoring for systemic vancomycin. Vancomycin AUC can be estimated using either Bayesian modeling software or first-order pharmacokinetic (PK) calculations. The objective of this pilot study was to evaluate and compare the efficiency and feasibility of these two approaches for calculating the estimated vancomycin AUC.

Methods
A single-center crossover study was conducted in four medical/surgical units at Brigham and Women’s Hospital over a 3-month time period. All adult patients who received vancomycin were included. Patients were excluded if they were receiving vancomycin for surgical prophylaxis, were on hemodialysis, if vancomycin was being dosed by level, or if vancomycin levels were never drawn. The primary endpoint was the amount of time study team members spent calculating the estimated AUC and determining regimen adjustments with Bayesian modeling compared to first-order PK calculations. Secondary endpoints included the number of vancomycin levels drawn and the percent of those drawn that were usable for AUC calculations.

Results
One hundred twenty-four patients received vancomycin during the study, of whom 47 met inclusion criteria. The most likely reasons for exclusion were receiving vancomycin for surgical prophylaxis (n=40) or never having vancomycin levels drawn (n=32). The median time taken to assess levels in the Bayesian arm was 9.3 minutes [interquartile range (IQR) 7.8-12.4] versus 6.8 minutes (IQR 4.8-8.0) in the 2-level PK arm (p=0.004). However, if Bayesian software is integrated into the electronic health record (EHR), the median time to assess levels was 3.8 minutes (IQR 2.3-6.8, p=0.019). In the Bayesian arm, 30 of 34 vancomycin levels (88.2%) were usable for AUC calculations, compared to 28 of 58 (48.3%) in the 2-level PK arm.

Conclusion
With EHR integration, the use of Bayesian software to calculate the AUC was more efficient than first-order PK calculations. Additionally, vancomycin levels were more likely to be usable in the Bayesian arm, thereby avoiding delays in estimating the vancomycin AUC.

Disclosures
All Authors: No reported disclosures