bluuebunny/crossref_metadata_2025_split huggingface dataset:
1324. Target Attainment of Exebacase, a First-In-Class Antibacterial Lysin, to Determine Optimal Doses for Adult Patients with Staphylococcus aureus (S. aureus) Bloodstream Infections (Bacteremia) Including Endocarditis
Authors: Ghahramani Parviz , Khariton Tatiana , Chiu Joannellyn , Cassino Cara 
Published: January 2021

Abstract

Background
Exebacase, a novel, antibacterial direct lytic agent for the treatment of S. aureus bacterimia and endocarditis, studied in Phase 1 and 2 trials, demonstrated potential to improve clinical outcomes when used in addition to conventional antibiotics. Objectives were to develop population PK (PPK) model and perform target attainment (TA) simulations to determine optimal clinical doses.

Methods
PPK model was developed with data from 72 patients receiving Exebacase, in addition to the standard of care, as single 2-hr infusion of 0.25 mg/kg (0.12 mg/kg for patients with creatinine clearance (CrCL) &lt; 60 mL/min). PPK model was used for TA simulations of various IV regimens.

Results
3-compartment model best fit the data, parameters were well estimated (CL=4.2 L/hr (RSE=5.5%), Vc=4.5 L (RSE=8.2%)). Total volume of distribution (Vd) was 20.2 L. Values were lower than estimated previously in healthy subjects, CL=7.1 L/hr and Vd=27.7 L. CrCL was the only clinically meaningful covariate. Patients with moderate and severe renal impairment are expected to have 1.3 to 2-fold higher AUC0-24 or Cmax than patients with normal renal function. Age was statistically significant on peripheral clearance but was not clinically meaningful (≤4% effect on exposure).
TA simulations were stratified by renal function across a range of fixed as well as weight-based doses (all simulated as 2-hr infusion). In patients with normal renal function or mild impairment, 18 mg dose result in Cmax and AUC0-24 of 1254 ng/mL and 3026 ng*hr/mL, respectively. In patients with moderate or severe renal impairment, 12 mg dose result in Cmax and AUC0-24 of 1107 ng/mL and 3099 ng*hr/mL, respectively. In ESRD patients including hemodialysis, 8 mg dose result in Cmax and AUC0-24 of 910 ng/mL and 3109 ng*hr/mL, respectively. These exposures place &gt;99% subjects above efficacious thresholds of AUC/MIC &gt;0.2 established in animals.

Conclusion
PPK model described exebacase PK in patients adequately. CL and Vd were estimated to be 40% and 17% lower, respectively, than healthy subjects. CrCL was the only clinically meaningful covariate requiring dose adjustment. TA assessments identified doses that achieve minimum efficacy target (AUC/MIC≥0.2) in &gt;99% of patients with S. aureus. Based on these simulations, fixed dosing schedule was recommended.

Disclosures
Parviz Ghahramani, PhD, PharmD, MSc, MBA, Consultant to ConatFect (Consultant) Tatiana Khariton, PhD, Consultant to ConatFect (Consultant) Joannellyn Chiu, PhD, Consultant to ConatFect (Consultant) Cara Cassino, MD, ContraFect Corporation (Employee)ContraFect Corporation (Employee)
1328. Vancomycin exposure and utilization following implementation of an AUC-guided monitoring guideline in children
Authors: Quraishi Ruquaya , Ashouri Negar , Beuttler Richard , Tran Martin T 
Published: January 2021

Abstract

Background
The 2009 guideline for vancomycin (VAN) monitoring recommended trough (TR) of 15-20 mg/L to correlate with AUC/MIC ≥ 400. Studies have suggested attainment of target AUC/MIC ratio with TR 7-11 mg/L in most children. Prior to 2018, TR 15-20 mg/L was the primary target for VAN therapeutic monitoring at CHOC Children’s. Beginning in 2018, a clinical guideline was implemented which recommend targeting AUC/MIC of 400-600 or TR of 7-15 mg/L. Our objectives are to evaluate differences in VAN utilization, exposure, nephrotoxicity and cost savings between pre (Pre-guideline, pG) and post implementation (Post-guideline, PG) of a VAN monitoring guideline at CHOC Children’s.

Methods
Retrospective chart review of patients prescribed VAN between Jan 2016 – Jun 2017 (pG) and Jan 2018 – Jun 2019 (PG). Primary objectives evaluated differences in pharmacokinetic (PK), AUC and rate of nephrotoxicity in patients 3 months to &lt; 18 years who received VAN ≥ 24 hour with ≥ 1 TR. Secondary objectives assessed differences in overall VAN utilization following guideline implementation.

Results
Seventy patients were included in the PK analysis, 35 in pG and 35 in the PG group. Median age, weight, gender, baseline creatinine, concurrent nephrotoxic agents were similar. There were no differences in duration of therapy or starting doses (mg/kg/day) between the two groups. The highest daily dose (mg/kg) and AUC (mg*h/L) attained was significantly higher in pG compared to PG group (74.9 vs. 59.9, p = 0.002 and 647 vs. 469, p &lt; 0.0001), respectively. Changes in AUC from the initial regimen to the highest adjusted regimen was also higher in pG group (532 vs. 647, p = 0.0008) while there was no difference in PG group (459 vs. 469, p = 0.647). More patients experienced nephrotoxicity in pG compared to PG (11.4% (4/35) vs. 0 (0/35), p = 0.039). Logistic regression analysis identified AUC 800-900 as a significant risk for nephrotoxicity. Compared to pG, PG resulted in a net reduction in VAN utilization of 19.7 DOT per 1000 patient days, savings of $100,150 and 738 fewer levels drawn.

Conclusion
In line with the 2020 consensus guideline recommendation for AUC-based VAN monitoring, our study found AUC-guided VAN monitoring in children resulted in less exposure, utilization, and nephrotoxicity.

Disclosures
All Authors: No reported disclosures
1329. Vancomycin Therapeutic Drug Monitoring: How to hit the Curve
Authors: Vala Michael , Chapin Ryan , Mercuro Nicholas J , McCoy Christopher 
Published: January 2021

Abstract

Background
For the management of serious S. aureus infections, area-under-the curve to minimum inhibitory concentration (AUC/MIC) applied dosing is recommended as the preferred method to goal trough-based monitoring. This pharmacodynamic dosing demonstrates efficacy with optimized exposure and decreased nephrotoxicity. While two levels are ideal for estimating AUC/MIC mathematically, the logistics and costs may outweigh the benefits of this approach. This study will compare AUC/MIC estimates using two single-level pharmacokinetic calculators (C2 and C3) and a Bayesian dosing calculator (C1) versus steady-state troughs.

Methods
A retrospective cohort study using a data repository to identify patients from 2019 included patients on intravenous vancomycin for greater than 48 hours with a steady state trough. Patients on dialysis or with unstable renal function were excluded. Vancomycin AUC/MIC and peak levels were estimated using C1, C2, and C3. The objective was to assess correlation of trough levels of 10-20mcg/ml to an AUC/MIC of 400-600 mg∙h/L. Secondary outcomes included examining the difference in R-squared values of the three calculators, and the percentage of patients with dose adjustments.

Results
55 patients met inclusion criteria. Of 55 troughs, 78% were 10-20mcg/ml and 5% were &gt;20mcg/ml. On average, the three calculators found 85% of all initial troughs and 93% of therapeutic troughs correlated to an AUC &gt;400. However, less than half of therapeutic troughs corresponded to an AUC of 400-600 mg∙h/L. Nearly 70% of patients had one or more dose adjustments often for unclear reasons as the AUC/MIC target of 400-600 mg∙h/L was met in 29-63% of initial adjustments. The three different calculators showed noticeable variability in calculating AUC/MIC.
Figure 1

Figure 2

Figure 3

Conclusion
A weak relationship between AUC/MIC and steady state troughs was found. Excess vancomycin exposure was demonstrated in 39% of therapeutic troughs. Over 25% of dose adjustments were deemed unnecessary. Utilizing AUC/MIC estimates for vancomycin may limit excess exposure while reducing the overall number of drug levels. Selecting a single-level calculator is problematic with the high degree of variation between calculators.
Figure 4

Disclosures
All Authors: No reported disclosures
1331. Reducing Inpatient Antimicrobial Treatment Duration for Febrile Infants through Implementation of Rapid Diagnostic Testing and Clinical Risk Definition
Authors: Erdem Guliz , Watson Joshua , Buckingham Don , Ramilo Octavio , Barson William J 
Published: January 2021

Abstract

Background
The management approach to febrile infants remain challenging. Despite new advances in rapid diagnostic testing, febrile infants with a viral infection could receive prolonged antimicrobial treatment due to concerns for co-existing serious bacterial infection (SBI). We sought to decrease the duration of antibiotic treatment in febrile infants less than 8 weeks of age hospitalized on inpatient infectious disease service following sepsis evaluation, who have enterovirus, parechovirus, or respiratory viruses detected, from average 30 hours to 24 hours and sustain for six months.
Figure 1. Antibiotic Treatment Duration of Infants Underfoing Evaluation for Sepsis

Figure 2. Length of Stay in Infants Underfoing Sepsis Evaluation

Methods
A new management guideline that defined “low-risk” infants, as well as inclusion and exclusion criteria, was created to monitor the accurate duration of parenteral treatment and length of hospitalization. Respiratory viruses were detected by a multiplex PCR assay. We created a QlikSense App for further clinical characterization of patients and follow-up. This management guideline was adapted as a quality improvement division initiative. Control charts were used to assess the impact of the interventions.
Figure 3. Readmissions in Infants Underfoing Sepsis Evaluation

Results
The management guideline was developed and implemented by pediatric infectious disease faculty. Febrile infants &lt; 8 weeks of age were included if they had both documented viral infections and sepsis evaluation. 178 infants were admitted with fevers in 2018 and 148 infants were admitted in 2019. The mean inpatient antibiotic treatment duration decreased from 27.7 hours in 2018 to 24.9 hours in 2019 (P &gt; 0.05) (Figure 1). There was no significant difference in length of hospitalization or 30-day readmission rates (Figure 2 and 3). There was no reported readmission for SBI.

Conclusion
Antibiotic treatment could be discontinued in clinically stable infants with a documented viral infection after 24 hours of negative blood, CSF, and urine bacterial culture incubation so as not to receive unnecessary prolonged inpatient treatment that may increase side effects. In addition to possible decreased treatment side effects our protocol led to decreased patient care costs with no documented changes in readmission rates.

Disclosures
Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member)
1332. Single Dose Oral Amoxicillin Challenge is a Safe and Effective Strategy to Delabel Penicillin Allergies among Low Risk Hospitalized Children
Authors: Searns Justin B , Stein Amy , MacBrayne Christine , Sarin Tara , Lin Taylor , Duffey Hannah , Hicks Allison , Wickstrom Kaylee , Bajaj Lalit , Bauer Maureen , Carel Kirstin 
Published: January 2021

Abstract

Background
Over 90% of children with reported penicillin allergy can tolerate penicillin without incident. Developing effective and safe strategies to remove inappropriate penicillin allergies has the potential to improve care; however, guidance on how to identify, test, and delabel patients is limited.

Methods
In April 2019, Children’s Hospital Colorado (CHCO) implemented a penicillin allergy clinical pathway (CP) alongside a risk assessment tool to stratify patients based on allergic history (Figure 1). Patients at “no increased risk” were educated and delabeled without testing. Low risk patients were offered an oral amoxicillin drug challenge with close observation. A single, non-graded, treatment dose of amoxicillin (45 mg/kg, max dose 1000mg) was used for low risk patients, and no preceding allergic skin testing was performed. Patients with no signs or symptoms of allergic response 60 minutes after amoxicillin administration were delabeled. Children delabeled of penicillin allergies on the CHCO hospital medicine service were compared between the pre-CP (1/1/17-3/31/19) and post-CP (4/1/19-3/31/20) cohorts.
Figure 1. Penicillin Allergy Risk Assessment

Results
Pre-CP, 683/10624 (6.4%) patients reported a penicillin allergy and 18/683 (2.6%) were delabeled by discharge. Post-CP, 345/6559 (5.3%) patients reported a penicillin allergy and 47/345 (13.6%) were delabeled by discharge (P-value &lt; 0.0001, Figure 2). Among the 47 post-CP patients, 11 were delabeled by history alone, 19 underwent oral amoxicillin drug challenge per CP, and 17 received a different treatment dose penicillin per treatment team. Only one penicillin-exposed patients had a reaction. This patient developed a delayed, non-progressive rash and had penicillin allergy restored to their chart. No patient required emergency medical intervention, and none were “relabeled” penicillin allergic in the 6 months following discharge.
Figure 2. Monthly Rate of Penicillin Allergic Patients Delabeled by Discharge

Conclusion
A drug challenge using a single non-graded dose of oral amoxicillin is a safe and effective strategy to delabel low risk children of inappropriate penicillin allergies when implemented alongside a risk assessment tool. Further studies are needed to evaluate the long-term benefits of delabeling inappropriate penicillin allergies and to continue monitoring for adverse events.

Disclosures
All Authors: No reported disclosures
1333. A Cross-Sectional Analysis of Inappropriate Outpatient Antibiotic Use in Children Insured by Kentucky Medicaid
Authors: Wattles Bethany A , Jawad Kahir S , Feygin Yana , Kong Maiying , Vidwan Navjyot , Stevenson Michelle D , Smith Michael J 
Published: January 2021

Abstract

Background
Kentucky (KY) consistently has one of the highest rates of outpatient pediatric antibiotic prescribing in the nation. Previous analyses identified significant variation in volume of antibiotic prescribing by geographic location, patient demographics, and provider type, but less is known about the appropriateness of this prescribing. We describe appropriateness of outpatient antibiotic prescribing in children insured by KY Medicaid.

Methods
We utilized KY Medicaid pharmacy and medical claims from 2017 for children &lt; 20 years. Patient demographic variables were abstracted from Medicaid enrollment data. Antibiotic prescriptions were identified by NDC and matched to medical claims within 3 days prior to fill date to identify corresponding diagnoses via ICD-10 codes. A previously published appropriateness classification scheme (Chua, BMJ 2019) was applied to categorize antibiotic prescriptions as “appropriate”, “potentially appropriate”, “inappropriate” or “not associated with indication”.

Results
Of the 779,751 antibiotic prescriptions included, 19.5% were appropriate, 45.3% were potentially appropriate, 20.8% were inappropriate, and 14.4% were not associated with an indication (Table 1). Inappropriate prescriptions were more common among children 0-2 years (24.4%) and those living in non-metro areas (22.2%). Antibiotics prescribed by general practitioners were also more likely to be inappropriate (22.2%). The most common diagnoses for each category are summarized in Table 2. Amoxicillin was the most commonly prescribed antibiotic in all categories. Azithromycin was more frequently prescribed for inappropriate indications or those not associated with a diagnosis code. Cefdinir was more common for appropriate and potentially appropriate indications.
Table 1: Antibiotic Prescription Characteristics, 2017

Table 2: Top Diagnoses for Antibiotic Prescriptions by Category

Conclusion
Inappropriate antibiotic prescribing is more common among young children living in non-metro areas seen by general practitioners. Outpatient antibiotic stewardship interventions should target these patient demographics and provider types. This classification scheme to describe inappropriate prescribing is feasible for use in pediatric Medicaid patients and could serve as a valuable metric for provider feedback reports on antibiotic use.

Disclosures
Bethany A. Wattles, PharmD, Kentucky Medicaid (Grant/Research Support)Merck (Grant/Research Support) Michael J. Smith, MD, MSC.E, Kentucky Medicaid (Grant/Research Support)Merck (Grant/Research Support)
1336. Alcohol Impregnated Caps and Ambulatory CLABSI: Multicenter Cluster Randomized, Crossover Trial
Authors: Milstone Aaron , Milstone Aaron , Rosenberg Carol E , Yenokyan Gayane , Koontz Danielle W , Miller Marlene R 
Published: January 2021

Abstract

Background
Central line-associated bloodstream infections (CLABSI) cause significant morbidity and mortality and occur more commonly in the ambulatory setting in pediatric oncology patients. Whether alcohol impregnated caps placed on central venous lines can prevent CLABSI in ambulatory pediatric oncology patients is unknown.

Methods
We performed a cluster-randomized, 2 period, crossover trial at 16 pediatric hematology/oncology clinics. Clinics were randomly assigned to usual ambulatory central line care per each institution (control) compared to use of 70% isopropyl alcohol-containing caps at home (intervention). Caps were only used in the ambulatory setting. The primary outcome was ambulatory CLABSI. Secondary outcomes included ambulatory mucosal barrier injury (MBI) CLABSI, secondary blood stream infections, single positive blood cultures, and positive blood cultures.

Results
Of the 16 participating clinics, 15 clinics completed both assignment periods. As assigned, there was no statistically significant reduction in incidence of ambulatory CLABSI in patients using 70% isopropyl
alcohol-impregnated caps at home (1.23 per 1000 days, 95% CI 0.94, 1.60) compared with standard practices (1.38 per 1000 days, 95% CI 1.08, 1.77; adjusted incidence rate ratio [aIRR] 0.83, 95% CI 0.61,
1.12). There was no reduction in incidence of ambulatory MBI-CLABSI (aIRR 0.57, 95% CI 0.23, 1.40), single positive blood culture (aIRR 1.35, 95% CI 0.74, 2.48), or positive blood cultures (aIRR 0.80, 95% CI 0.60, 1.07). In the per protocol analysis, there was a reduction in incidence of positive blood cultures in ambulatory patients using 70% isopropyl alcohol-impregnated caps at home (1.51 per 1000 days, 95% CI
1.14, 2.00) compared with standard practices (1.88 per 1000 days, 1.47, 2.39; aIRR 0.72, 95% CI 0.51, 1.00).

Conclusion
Isopropyl alcohol- impregnated caps did not lead to a statistically significant reduction in CLABSI rates in ambulatory hematology/oncology patients, however, there was a reduction in positive blood cultures in the ambulatory setting in the per protocol analysis. Further research is needed to understand the clinical impact of alcohol-impregnated caps in the ambulatory setting.

Disclosures
All Authors: No reported disclosures
1337. An Outpatient Antimicrobial Stewardship Initiative for Urinary Tract Infections in Primary Care Pediatrics
Authors: Mannix Mary Kathryn , Islam Shamim 
Published: January 2021

Abstract

Background
Studies have showed that 30% of antibiotics prescribed in the outpatient setting are unnecessary. Acute UTI constitutes a significant health burden in outpatient pediatrics affecting ~2.8% of children every year. Antibiotics are often started empirically when diagnosing UTI making pediatric UTIs an ideal target for outpatient stewardship. The primary objective was to reduce the use of broad-spectrum empiric antibiotics with a secondary objective to study antibiotic discontinuation in culture negative cases.

Methods
The electronic medical records of two pediatric practices were screened for patients aged 2 months to 18 years diagnosed with uncomplicated UTI using ICD-10 codes N39, R30 and R35. The definition of a positive urine culture was &gt; 50,000 CFU/ml if catheterized and &gt; 100,000 CFU/ml if clean-catch specimen. A two-year pre-intervention period began in January 2018. An audit and review of urine culture processes were studied at each site with a subsequent educational intervention, a direct, one-hour session focused on the use of cephalexin as first-line empiric therapy based on the local antibiogram. The post-intervention period began at each site after the intervention. A COVID-19 sub-analysis was performed for the post-intervention period.

Results
During the study, 515 encounters and 113 encounters were included during the pre- and post-intervention periods, respectively. 74.4% (383/515) of pre-intervention encounters had empirically prescribed antibiotics; higher-generation cephalosporins (i.e. cefdinir, cefprozil) most frequently. Antibiotics were empirically prescribed in 75.2% (85/113) of post-intervention encounters with a statistically significant increase in cephalexin use (32/85, 37.6%, p &lt; 0.01) and reduction in higher-generation cephalosporin use (p &lt; 0.01), Figure 1. In the COVID-19 analysis, empiric antibiotic prescribing trended towards baseline as providers were relying largely on telemedicine, Figure 2.
Figure 1: Empiric Antibiotic Prescribing Pre- and Post-InterventionF

Figure 2: Empiric Antibiotic Prescribing - %

Table 1: Pre- and Post-Intervention

Conclusion
The educational intervention was effective in changing antibiotic prescribing with an increased use of narrow spectrum antibiotics. This change waned without reinforcement and reliance on telemedicine during COVID-19. Antibiotic discontinuation in culture-negative cases remains an important area for improvement.

Disclosures
All Authors: No reported disclosures