Assessing Nephrotoxicity Associated With Different Vancomycin Dosing Modalities in Obese Patients at a Community Hospital

Background: Vancomycin requires therapeutic drug monitoring (TDM) based on its pharmacokinetic properties, and guidelines have shifted to analyzing area under the curve over 24 hours (AUC24) rather than trough concentrations due to nephrotoxicity concerns and correlation to efficacy. Obesity is an established risk factor for vancomycin-induced nephrotoxicity due to increased drug exposure based on dosing calculations and volume of distribution estimation. The aim of this study is to assess the relationship between AUC-based versus trough-based dosing and nephrotoxicity among obese patients receiving vancomycin. Methods: This research project was conducted as a retrospective, observational, single-centered study which included obese adults who received at least 48 hours of vancomycin. The electronic medical record provided data for patients with vancomycin pharmacokinetic consults either evaluated with trough-only or AUC-based dosing. The primary objective was to compare the development of nephrotoxicity after vancomycin initiation, while secondary objectives included vancomycin loading dose exposure, total daily dose of vancomycin, and whether target TDM was attained. Nominal data were evaluated utilizing the chi-square test and continuous data using the independent samples t-test or Mann-Whitney test. The a priori level of significance was .05. Data analysis was performed using Microsoft Excel and SAS statistical software. Results: Two hundred fifty-four patients were included in the primary analysis. Four patients in the AUC cohort (6.3%) developed nephrotoxicity compared to 32 (17.4%) in the trough cohort ( P = .035). Both cohorts received a median of 4 days of therapy; however, the median loading dose per actual body weight in the AUC cohort was 20 mg/kg as compared to 16 mg/kg in the trough cohort. Of the 130 patients with available TDM in the trough cohort, 97 (74.6%) did not meet target attainment as compared to 15 of the 57 in the AUC cohort (26.3%) ( P < .001). Conclusions: AUC dosing was associated with a statistically significant reduction in AKI occurrence despite overall higher loading dose exposure as compared to the trough cohort. Though maintenance dose exposure was similar between both cohorts, patients in the AUC cohort maintained therapeutic concentrations at a higher percentage than the trough cohort.

Efficacy of intranasal fluticasone propionate and budesonide in management of allergic rhinitis—a prospective comparative study

Background Allergic rhinitis (AR) or Hay fever is a chronic inflammation of the nasal mucosa induced by IgE-mediated hypersensitivity due to exposure of various allergens. AR occurs as a response against these inhaled allergens that cause inflammation of nasal mucosal membranes. In this study, a reliable treatment for allergic rhinitis with maximum effectiveness and minimal side effects was assessed. This study compared the effectiveness of intranasal Fluticasone propionate (FUP) and intranasal Budesonide (BUD) in reducing the eosinophil count and in improving the nasal and ocular symptoms. This prospective study was conducted on 62 cases of allergic rhinitis and patients with mild-to-moderate allergic rhinitis were selected for the study. They were randomly divided into two groups; group I consists of 30 patients who received intranasal Fluticasone propionate aqueous spray, total daily dose of 200 μg (50 μg/spray) as 2 sprays in each nostril administered once daily, whereas the group II consists of 32 patients who received intranasal Budesonide aqueous spray, total daily dose of 400 μg/day (100 μg/spray) as 1 spray in each nostril administered twice daily. Results Analysis on patient-based symptom scores revealed that both the groups showed statistically significant reduction in symptoms. Fluticasone propionate was found to be significantly more effective (P < 0.05) than Budesonide in reducing sneezing, nasal itching and majority of symptoms of individual symptom scores. Budesonide showed somewhat similar effect in reducing nasal blockage at 4 weeks of treatment. Conclusion Clinically, both the drugs showed statistically significant improvement when compared to baseline, but Fluticasone propionate was superior at reducing nasal symptoms, ocular symptom and eosinophil count.

Ergocalciferol in New-onset Type 1 diabetes: A Randomized Controlled Trial

Background The impact of the anti-inflammatory and immunomodulatory actions of Vitamin D on the duration of partial clinical remission (PR) in youth with type 1 diabetes (T1D) is unclear. Objective To determine the effect of adjunctive ergocalciferol on residual β-cell function (RBCF) and PR in youth with newly-diagnosed T1D who were maintained on a standardized insulin treatment protocol. Hypothesis Ergocalciferol supplementation increases RBCF and prolongs PR. Methods A 12-month randomized, double-blind, placebo-controlled trial of 50,000 IU of ergocalciferol per week for 2 months, and then once every 2 weeks for 10 months, versus placebo in 36 subjects of ages 10-21years(y), with T1D of &lt;3 months, and a stimulated C-peptide (SCP) level of ≥0.2nmol/L (≥0.6ng/mL). The ergocalciferol group had 18 randomized subjects (10m/ 8f), mean age 13.3±2.8y; while the control group had 18 subjects (14m/4f), age 14.3±2.9y. Results The ergocalciferol treatment group had significantly higher serum 25-hydroxyvitamin D at 6 months (p=0.01) and 9 months (p=0.02) than the placebo group. At 12 months, the ergocalciferol group had a significantly lower serum TNF-α concentration (p=0.03). There were no significant differences between the groups at each timepoint from baseline to 12 months for SCP concentration (p=0.08), HbA1c (p=0.09), insulin-dose-adjusted A1c (IDAA1c), or total daily dose of insulin. Temporal trends for rising HbA1c (p=0.044) and IDAA1c (p=0.015) were significantly blunted in the ergocalciferol group. Conclusions Ergocalciferol significantly reduced serum TNF-α concentration and the rates of increase in both A1c and IDAA1c suggesting a protection of RBCF and PR in youth with newly-diagnosed T1D.

Enhanced recovery after surgery protocol and postoperative opioid prescribing for cesarean delivery: an interrupted time series analysis

Introduction Enhanced recovery after surgery (ERAS) pathways have emerged as a promising strategy to reduce postoperative opioid use and decrease the risk of developing new persistent opioid use in surgical patients. However, the association between ERAS implementation and discharge opioid prescribing practices is unclear. Study design We conducted a retrospective observational quasi-experimental study of opioid-naïve patients aged 18+ undergoing cesarean delivery between February 2015 and December 2019 at a large academic center. An interrupted time series analysis (ITSA) was used to model the changes in pain medication prescribing associated with the implementation of ERAS to account for pre-existing temporal trends. Results Among the 1473 patients (out of 2249 total) who underwent cesarean delivery after ERAS implementation, 80.72% received a discharge opioid prescription vs. 95.36% at baseline. Pre-ERAS daily oral morphine equivalents (OME) on the discharge prescription decreased by 0.48 OME each month (p<0.01). There was a level shift of 35 more OME prescribed (p<0.01), followed by a monthly decrease of 1.4 OMEs per month after ERAS implementation (p<0.01). Among those who received a prescription, 61.35% received a total daily dose greater than 90 OME compared to 11.35% pre-implementation (p<0.01), while prescriptions with a total daily dose less than 50 OME decreased from 79.86 to 25.85% after ERAS implementation(p<0.01). Conclusion Although ERAS implementation reduced the overall proportion of patients receiving a discharge opioid prescription after cesarean delivery, for the subset of patients receiving an opioid prescription, ERAS implementation may have inadvertently increased the prescribing of daily doses greater than 90 OME. This finding highlights the importance of early and continued evaluation after new policies are implemented.

621. Identifying Quality-Improvement Interventions to Improve Inpatient Intravenous Vancomycin Safety at an Academic Medical Center

Background The reported incidence of intravenous (IV) vancomycin-associated acute kidney injury (AKI) is highly variable. The primary purpose of this study was to determine the baseline rate of IV vancomycin-associated AKI at the University of Utah Hospital (UUH) and Huntsman Cancer Institute (HCI) with the goal of identifying areas of focus for future quality improvement (QI) initiatives. Methods This was a retrospective descriptive study of patients ≥ 18 years old, hospitalized at UUH or HCI, who received at least daily scheduled doses of IV vancomycin for ≥ 72 hours between November 1, 2018 and October 31, 2019. AKI was defined using the serum creatinine (SCr) aspect of the AKIN criteria. Variables assessed for association with AKI included demographic characteristics, hospital and unit where vancomycin was initiated, duration of therapy, administration method, and concomitant nephrotoxic medications. Multivariable logistic regression was used to identify variables independently associated with AKI as potential QI interventions. Results One thousand eighty-six patients were included. Baseline patient characteristics are listed in Table 1. Throughout our system, 19.7% of patients experienced an AKI while receiving vancomycin. Univariate comparisons are listed in Table 1. Variables independently associated with AKI on multivariable analysis included total body weight (HR 1.02, 95% CI [1.01-1.03]), concomitant administration of calcineurin inhibitors or vasopressors (HR 1.97, 95% CI [1.18-3.29] and HR 1.68, 85% CI [1.07-2.64] respectively), duration of vancomycin therapy (HR, 1.04, 95% CI [1.02-1.06]), and administration in specific units (see Table 1). Administration of vancomycin by continuous infusion showed a protective effect (HR 0.13, 95% CI [0.02-1.12]) as did baseline SCr and total daily dose of vancomycin (HR 0.76, 95% CI [0.61-0.94] and HR 0.63, 95% CI [0.51-0.78] respectively); the latter two are likely a reflection of the study design. The median hospital length of stay in days was longer in individuals experiencing an AKI (19 vs 10, p &lt; 0.0001). Table 1. Univariate and Multivariate Associations with Vancomycin-Associated Acute Kidney Injury aFor continuous variables, the HR reported is for each unit increase Table 1. (Continued) Univariate and Multivariate Associations with Vancomycin-Associated Acute Kidney Injury aFor continuous variables, the HR reported is for each unit increase Conclusion Several variables associated with vancomycin-associated AKI within our health system were identified. Future QI interventions to improve vancomycin safety will be pursued. Disclosures Russell J. Benefield, PharmD, Paratek Pharmaceuticals (Grant/Research Support)

1108. Evaluation of Vancomycin Dosing in Adolescents

Background Pediatric vancomycin dosing varies based on age and renal function. Recent literature suggests previously recommended doses of 45-60 mg/kg/day may be insufficient to achieve an AUC:MIC ratio of 400-600 mg-hr/L and higher doses of at least 60 mg/kg/day may be required. However, data to guide dosing in adolescents is limited. Methods A single-center, retrospective chart review of patients aged 12 to 18 years who received vancomycin and had therapeutic drug monitoring (TDM) performed between July 2017 to June 2020 were included. The primary endpoint was the median total daily dose (TDD) of vancomycin required to achieve therapeutic serum concentrations. Secondary endpoints were to characterize how factors such as age, weight, trough versus AUC monitoring, malignancy, and trauma may influence dosing. The safety endpoint was the development of acute kidney injury (AKI). Results 130 vancomycin courses in 86 patients were included. Baseline characteristics are presented in Table 1. Of the 130 vancomycin courses, 50 courses (38%) achieved therapeutic serum concentrations at a median TDD of 49.8 mg/kg/day (IQR 42 – 59.4). This was not statistically different from the sub- or supra-therapeutic groups (p=0.22). Based on age, the median TDD for 12-14 year olds was higher at 60 mg/kg/day (IQR 45-78.8; n=14) than for 15-16 and 17-18 year olds [45.3 mg/kg/day (IQR 41.1-51; n=15), 48 mg/kg/day (IQR 42-52; n=21), respectively]. Obese patients needed a median TDD of 43.5 mg/kg/day vs at least 51 mg/kg/day in healthy and overweight patients. Finally, AUC guided dosing resulted in a slightly lower overall median TDD vs trough guided dosing (45.8 mg/kg/day vs 50.5 mg/kg/day). Additional dose requirements based on age, weight, TDM and other characteristics are presented in Table 2. Of the 15 patients who developed AKI per pRIFILE criteria, 2 were classified as injury and 3 as failure. Table 2. Total Daily Dose Course Analysis Conclusion To achieve therapeutic levels, adolescents 12 to14 years old need higher empiric doses of 60 mg/kg/day compared to 45 mg/kg/day in 15 to 18 year olds. Obese patients, however, may require lower TDD than underweight, healthy, and overweight patients. Patients that receive AUC versus trough monitoring may also require lower TDD to achieve therapeutic concentrations. More data is needed to further evaluate our findings. Disclosures All Authors: No reported disclosures

Can the AHCL System Be Used in T1D Patients with Borderline TDDI? A Case Report

(1) Background: Intensive insulin therapy using continuous subcutaneous insulin infusion (CSII) with continuous real-time glucose monitoring (rt CGM) is the best option for patients with T1D. The recent introduction of a technology called Advanced Hybrid Closed Loop (AHCL) represents a new era in the treatment of type 1 diabetes, the next step towards better care, as well as improving the effectiveness and safety of therapy. The aim is to present the case of a T1D patient with a borderline total daily dose of insulin being treated with the Medtronic AHCL system in automatic mode. (2) Materials and Methods: A 9-year-old boy, from October 2020, with type 1 diabetes in remission was connected to the Minimed™ 780G (AHCL) system in accordance with the manufacturer’s recommendations (daily insulin dose > 8 units, age > 7). Records of the patient’s history were collected from visits to The Department of Children’s Diabetology, as well as from the Medtronic CareLink™ software and the DPV SWEET program from October 2020 to April 2021. (3) Results: The patient’s total daily insulin requirement decreased in the first 6 weeks after the AHCL was connected, which may reflect the remission phase (tight glycemic control with a healthy lifestyle). The lowest daily insulin requirement of 5.7 units was also recorded. In a three-month follow-up of the patient treated with AHCL, it was found that for almost 38% of the days the insulin dose was less than 8 IU. (4) Conclusions: The AHCL system allows safe and effective insulin therapy in automatic mode, as well as in patients with a lower daily insulin requirement. The AHCL system should be considered a good therapeutic option for patients from the onset of T1D, as well in the remission phase.

Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids. This enabled the linking of antibacterial response at a single time point in an animal or in vitro infection model with one of three summary pharmacokinetic (PK) measures of in vivo exposure to the antibiotic. The summary PK exposure measures were normalised to the minimum inhibitory concentration (MIC), an in vitro measure of the pharmacodynamic (PD) potency of the drug. The three PK-PD indices (ratio of maximum concentration to MIC, ratio of area under the concentration-time curve to MIC, time concentration is above MIC) have been used extensively since the 1980s. While these MIC-based summary PK-PD metrics have undoubtedly facilitated the development of new antibiotics and the clinical application of both new and old antibiotics, it is increasingly recognised that they have a number of substantial limitations. In this article we use a historical perspective to review the origins of the three traditional PK-PD indices before exploring in detail their limitations and the implications arising from those limitations. Finally, in the interests of improving antibiotic development and dosing in patients, we consider a model-based approach of linking the full time-course of antibiotic concentrations with that of the antibacterial response. Such an approach enables incorporation of other factors that can influence treatment outcome in patients and has the potential to drive model-informed precision dosing of antibiotics into the future.

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry

Background: Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown. Methods: Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose. Results: Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65–0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10–3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56–2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39–2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89–1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases. Conclusions: In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.

Feasibility & Efficacy of Deprescribing rounds in a Singapore rehabilitative hospital- a randomised controlled trial

Background Deprescribing is effective and safe in reducing polypharmacy among the elderly. However, the impact of deprescribing rounds remain unclear in Asian settings. Hence, we conducted this study. Methods An open label randomised controlled trial was conducted on patients of 65 years and above, under rehabilitation or subacute care and with prespecified medications from a Singapore rehabilitation hospital. They were randomised using a computer generated sequence. The intervention consisted of weekly multidisciplinary team-led deprescribing rounds (using five steps of deprescribing) and usual care. The control had only usual care. The primary outcome is the percentage change in total daily dose (TDD) from baseline upon discharge, while the secondary outcomes are the total number of medicine, total daily cost and TDD up to day 28 postdischarge, overall side-effect rates, rounding time and the challenges. Efficacy outcomes were analysed using intention-to-treat while other outcomes were analysed as per protocol. Results 260 patients were randomised and 253 were analysed after excluding dropouts (female: 57.3%; median age: 76 years). Baseline characteristics were largely similar in both groups. The intervention arm (n = 126) experienced a greater reduction of TDD on discharge [Median (IQR): − 19.62% (− 34.38, 0.00%) versus 0.00% (− 12.00, 6.82%); p < 0.001], more constipation (OR: 3.75, 95% CI:1.75–8.06, p < 0.001) and laxative re-prescriptions (OR: 2.82, 95% CI:1.30–6.12, p = 0.009) though death and hospitalisation rates were similar. The median rounding time was 7.09 min per patient and challenges include the inconvenience in assembling the multidisciplinary team. Conclusion Deprescribing rounds can safely reduce TDD of medicine upon discharge compared to usual care in a Singaporean rehabilitation hospital. Trial registration This study is first registered at Clinicaltrials.gov (protocol number: NCT03713112) on 19/10/2018 and the protocol can be accessed on https://www.clinicaltrials.gov.