Trough Range Research Articles

Mitigating Risk of Acute Kidney Injury Among Children With Methicillin-resistant Staphylococcus aureus Osteomyelitis.

Children with acute hematogenous osteomyelitis (AHO) from methicillin-resistant Staphylococcus aureus (MRSA) are treated with vancomycin despite the risk of acute kidney injury (AKI). This study evaluates the rate of AKI and resource utilization for children with or without AKI when vancomycin is used in this setting. Children with MRSA AHO treated with vancomycin were retrospectively studied. AKI was assessed by clinical diagnosis and Kidney Disease Improving Global Outcomes (KDIGO) criteria. Cohorts of children with or without AKI were compared for differences in treatment, resource utilization, and outcomes. Multivariate logistic regression analysis assessed factors associated with risk for AKI. Cost analysis was performed using the Pediatric Health Information System and Healthcare Cost and Utilization Project databases. Among 85 children studied, 14 (16.5%) had chart-diagnosed AKI and 24 (28.2%) met KDIGO criteria. Children with AKI had more febrile days and higher thrombosis rates. They had longer vancomycin treatment (8 vs 5d), higher troughs (27.8 vs 17.5mg/L), and prolonged hospitalization (19.9 vs 11.1d). Multivariate analysis found a maximum vancomycin trough level (odds ratio: 1.05, P = 0.003) with a cutoff of 21.7mg/L predicted AKI.Only 2 of 20 (10%) children who had MRSA isolates with a minimum inhibitory concentration of 2 achieved therapeutic vancomycin levels. Pediatric Health Information System data of 3133 children with AHO treated with vancomycin identified 75 (2.4%) with AKI who had significantly longer lengths of stay (13 vs 7d) and higher billed charges ($117K vs $51K) than children without AKI. Chart documentation of AKI (16.5%) grossly underestimated KDIGO-defined occurrence (28.2%). This study showed that vancomycin-associated AKI required substantially greater resource utilization and higher health care costs. Lowering the targeted trough range, shortening the duration of vancomycin therapy, and considering alternative antibiotics when minimum inhibitory concentration ≥2 will reduce the risk and cost of AKI among children with MRSA AHO. Level III-retrospective comparative therapeutic study.

Age-Related Changes in Vancomycin Protein Binding: Is It Time to Take It Seriously?

Vancomycin (VAN) protein binding in plasma is influenced by illness and age; hence, doses titrated according to total concentrations are fraught. In this study, model-estimated free VAN concentrations (EFVC) were compared with assumed free VAN concentrations (AFVC) in neonates, children, and adults in the intensive care unit and those on dialysis. Patient cohorts were identified from the hospital database. Demographics, clinical characteristics, total VAN concentrations, and laboratory variables were obtained from electronic health records. EFVC was derived from 6 models identified in the literature. For all models, total VAN concentration was the most important predictor; other predictors included albumin, total protein, and dialysis status. The AFVC was calculated as 50% of the total concentration (ie, assumption of 50% bound). Differences between EFVC and AFVC in adults were insignificant; however, differences in pediatric intensive care unit patients, according to 2 different models, were significant: mean ± SD = 4.1 ± 1.58 mg/L and 4.7 ± 2.46 mg/L ( P < 0.001); the percentages within the free VAN trough range = 30.4% versus 55.1% and 30% versus 55.1%; and the supratherapeutic percentages = 65.2% versus 31.9% and 66.7% versus 31.9%, respectively. In neonates, the difference between EFVC and AFVC was mean ± SD = 6.9 ± 1.95 mg/L ( P < 0.001); the percentages within the free VAN trough range for continuous and intermediate dosing were 0% versus 81.3% and 14.3% versus 71.4%, and the supratherapeutic percentages were 100% versus 6.25% and 71.4% versus 0%, respectively. The fraction of free unbound VAN is higher in sick children and neonates than in adults. Therefore, total VAN concentrations do not correlate with the pharmacologically active free VAN concentrations in the same manner as in adults. Adjusting VAN doses in neonates and children to target the same total VAN concentration as the recommended therapeutic range for adults may result in toxicfree concentrations.

Predictors of Plasma Levels of Direct Oral Anticoagulants Among Patients with Atrial Fibrillation in Need of Elective Cardiac Procedures.

The withdrawal timing of direct oral anticoagulants (DOACs) among patients in need of elective invasive surgery is based on DOAC pharmacokinetics in order to perform the procedure out of the DOAC peak plasma concentration. We aimed to investigate the prevalence and predictors of plasma levels of DOACs out of trough range in patients with atrial fibrillation (AF) in need of elective cardiac procedure. We evaluated all consecutive AF patients on DOAC therapy in need of elective cardiac procedure, admitted to our division from January 2022 to March 2022. All patients underwent DOAC plasma dosing the morning of procedure day. They were categorized as in range, above range, and below range, according to the DOAC reference range at the downstream point. The timing of discontinuation of DOAC therapy was considered as appropriate or not, according to the current recommendations. The clinical predictors of out-of-range DOAC plasma levels have been evaluated. We included 90 consecutive AF patients (56.6% male, mean age 72.95 ± 10.12years); 74 patients (82.22%) showed DOAC concentration out of the expected reference range. In half of them (n, 37), the DOAC plasma concentration was below the trough reference range. Of the study population, 17.7% received inappropriate DOAC dosages (10% overdosing, 7% underdosing), and 35.5% had incorrect timing of DOAC withdrawal (26% prolonged, 9.5% shortened). At multivariable analysis, inappropriate longer DOAC withdrawal period (OR 10.13; P ≤ 0.0001) and increased creatinine clearance (OR 1.01; P = 0.0095) were the independent predictors of plasma DOAC levels below the therapeutic trough range. In contrast, diabetes mellitus (OR 4.57; P = 0.001) was the only independent predictor of DOAC plasma level above the therapeutic trough range. Increased creatinine clearance and inappropriate longer drug withdrawal period are the only independent predictors of DOAC plasma levels below the reference range; in contrast, diabetes is significantly correlated with DOAC plasma levels above the reference.

Determining steady-state trough range in vancomycin drug dosing using machine learning

BackgroundVancomycin is a renally eliminated, nephrotoxic, glycopeptide antibiotic with a narrow therapeutic window, widely used in intensive care units (ICU). We aimed to predict the risk of inappropriate vancomycin trough levels and appropriate dosing for each ICU patient. MethodsObserved vancomycin trough levels were categorized into sub-therapeutic, therapeutic, and supra-therapeutic levels to train and compare different classification models. We included adult ICU patients (≥ 18 years) with at least one vancomycin concentration measurement during hospitalization at Mayo Clinic, Rochester, MN, from January 2007 to December 2017. ResultThe final cohort consisted of 5337 vancomycin courses. The XGBoost models outperformed other machine learning models with the AUC-ROC of 0.85 and 0.83, specificity of 53% and 47%, and sensitivity of 94% and 94% for sub- and supra-therapeutic categories, respectively. Kinetic estimated glomerular filtration rate and other creatinine-based measurements, vancomycin regimen (dose and interval), comorbidities, body mass index, age, sex, and blood pressure were among the most important variables in the models. ConclusionWe developed models to assess the risk of sub- and supra-therapeutic vancomycin trough levels to improve the accuracy of drug dosing in critically ill patients.

Effect of letermovir initiation on tacrolimus concentrations among lung transplant recipients receiving concomitant azole antifungal prophylaxis.

The antiviral letermovir has been increasingly used as off-label cytomegalovirus prophylaxis in solid organ transplant recipients. Observational studies have reported notable increases in tacrolimus (FK) exposure following letermovir; however, whether a significant interaction occurs in the setting of existing moderate-to-strong CYP3A4 inhibition is unknown. Therefore, the purpose of this study was to evaluate FK trough changes before and after letermovir among lung transplant recipients receiving azole antifungal prophylaxis. This retrospective cohort study included lung transplant recipients newly initiated on letermovir between 2019-2022 following valganciclovir intolerance. Tacrolimus doses and concentrations were collected up to 30 days before and after the letermovir start date. No pre-emptive FK dose adjustments occurred prior to letermovir initiation. Patients admitted to the hospital or lacking an appropriately timed trough in the pre- or post-period were excluded. A total of 78 lung transplant recipients receiving FK (1.5mg median total daily dose) and itraconazole (56.4%), isavuconazole (25.6%) or posaconazole (17.9%) prophylaxis were included. Letermovir was started at a median of 8.4 months post-transplant. The pre-/post-letermovir median FK trough was 9.6/9.0ng/mL (p = .151), median dose-corrected trough was 4.2/4.7ng/mL/mg (+11.9%, p = .032), and median weight-based dose-corrected trough was 362/326 [ng/mL]/[mg/kg/day] (-9.9%, p = .036). There was no significant difference in the proportion of patients within their goal trough range before and after letermovir initiation (62%vs. 72%, p = .229). Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate-to-strong CYP3A4 inhibitors.

A real-time feeding behavior monitoring system for individual yak based on facial recognition model.

Feeding behavior is known to affect the welfare and fattening efficiency of yaks in feedlots. With the advancement of machine vision and sensor technologies, the monitoring of animal behavior is progressively shifting from manual observation towards automated and stress-free methodologies. In this study, a real-time detection model for individual yak feeding and picking behavior was developed using YOLO series model and StrongSORT tracking model. In this study, we used videos collected from 11 yaks raised in two pens to train the yak face classification with YOLO series models and tracked their individual behavior using the StrongSORT tracking model. The yak behavior patterns detected in trough range were defined as feeding and picking, and the overall detection performance of these two behavior patterns was described using indicators such as accuracy, precision, recall, and F1-score. The improved YOLOv8 and Strongsort model achieved the best performance, with detection accuracy, precision, recall, and F1-score of 98.76%, 98.77%, 98.68%, and 98.72%, respectively. Yaks which have similar facial features have a chance of being confused with one another. A few yaks were misidentified because their faces were obscured by another yak's head or staff. The results showed that individual yak feeding behaviors can be accurately detected in real-time using the YOLO series and StrongSORT models, and this approach has the potential to be used for longer-term yak feeding monitoring. In the future, a dataset of yaks in various cultivate environments, group sizes, and lighting conditions will be included. Furthermore, the relationship between feeding time and yak weight gain will be investigated in order to predict livestock weight.

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed.Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States).Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 to meet the target trough range of 5–15 ng/mL.Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz®, 2 mg, 3 mg, and 5 mg.

ALPS like: Trekking Sirolimus and its Fallouts

A three-year-old male presented to our multispecialty clinic with recurrent fever without periodicity, neutropenia, diffuse lymphadenopathy, and splenomegaly. Family history was notable for two maternal cousins with hypogammaglobulinemia and neutropenia. Pertinent labs include elevated CD3 positive, double negative cells (7.7%, 156 cells/mcl), elevated IL-10 (85.6 pg/mL); and elevated IL-18 (3145 pg/mL). Rheumatologic studies returned unremarkable (ANA was weakly positive, with extracted nuclear antigen antibody panel within normal limits). Abdominal ultrasound revealed splenomegaly (14 cm). Whole genome sequencing for the patient and parents was negative, including no diagnostic abnormalities in the FAS, FASLG or CASP10 genes.The patient was diagnosed with probable ALPS, per the 2009 revised ALPS criteria (Oliveira et al, Blood, 2010). He was started on colchicine for fevers but was transitioned to sirolimus several weeks later due to lack of clinical improvement. Mirroring a prior study that evaluated sirolimus for children with ALPS, sirolimus was initiated at a dose of 2.3 mg/m2, targeting goal trough levels 5–15 ng/mL (Bride et al. Blood, 2016). Sirolimus trough levels are depicted in Table 1 and Figure 1. [Display omitted] At follow up 3 months later, the patient’s CD3 positive, double negative T cells normalized (0.2%, 3 cells/mcl), splenomegaly improved (10.7 cm), lymphadenopathy was no longer palpable, and cytokine levels normalized. Despite consecutive subtherapeutic sirolimus trough levels preceding the 3-month evaluation, probable ALPS markers improved.Sirolimus has caused toxicity. Baseline lipid panel prior to sirolimus therapy demonstrated elevated triglycerides and low HDL, likely related to ALPS (Sriram et al, Case Reports Immunol, 2016). While HDL improved, total cholesterol and LDL increased and triglycerides remain elevated. He has developed hypertension while on sirolimus.These findings demonstrate that sirolimus trough alone may not predict clinical response. Given the excellent correlation between trough levels and area under the concentration-time curve (AUC) for sirolimus (Stenton et al. Clin Pharmacokinetics 2005), it is unlikely that AUC sirolimus measurements would either be of clinical benefit or better explain the patient’s clinical response. This patient’s excellent clinical response despite multiple subtherapeutic sirolimus trough levels suggests that further research to determine the optimal sirolimus trough range may be indicated.

In Outpatients Receiving Parenteral Vancomycin, Dosing Adjustments Produced by Area Under the Curve-Based and Trough-Based Monitoring Differ Only at the Extremes of the Therapeutic Trough Range.

Area under the curve (AUC)-based vancomycin dosing reduces nephrotoxicity but is burdensome. Reviewing 115 adults receiving ≥2 weeks of outpatient vancomycin, we found AUC-based and trough-based dose adjustments discordant only for troughs <12 or >16 mg/L. Selective versus universal outpatient AUC calculation would likely offer similar benefit with reduced workload.

Blood Pressure and Mortality in the 4D Study

Introduction: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear. Methods: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers. Results: Mean age was 66.3 years, mean blood pressure 146/76 mm Hg, mean time suffering from diabetes 18.1 years, and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP, and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we also did not detect any significant mortality prediction for PP, SBP, DBP, or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70–80 mm Hg. Discussion: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and CVM that may no longer be significantly modulated by blood pressure control.

Therapeutic Drug Monitoring of Vancomycin in Jordanian Patients. Development of Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System (SECS).

Vancomycin is a commonly used antibiotic for multi-drug resistant gram-positive infections treatment, especially methicillin-resistant Staphylococcus aureus (MRSA). Despite that, it has wide individual pharmacokinetic variability and nephrotoxic effect. Vancomycin trough concentrations for 57 Jordanian patients were measured in plasma and saliva through immunoassay and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. Plasma levels were within accepted normal range, with exception of 6 patients who showed trough levels of more than 20 μg/ml and vancomycin was discontinued. Bayesian dose-optimizing software was used for patient-specific pharmacokinetics prediction and AUC/MIC calculation. Physiological-based pharmacokinetic (PBPK) vancomycin model was built and validated through GastroPlus™ 9.8 using in-house plasma data. A weak correlation coefficient of 0.2478 (P=0.1049) was found between plasma and saliva concentrations. The suggested normal saliva trough range of vancomycin is 0.01906 to 0.028589 (μg/ml). Analysis of variance showed significant statistical effects of creatinine clearance and albumin concentration on dose-normalized Cmin plasma and saliva levels respectively, which is in agreement with PBPKmodeling. It can be concluded that saliva is not a suitable matrix for TDM of vancomycin. Trough levels in plasma matrix should always be monitored for the safety of patients.

Influence of Natural Gas Hydrate’s Property Weakening from Dissociation on Subsidence of Seabed Sediments: A Simulation Study

The dissociation of natural gas hydrate in the seabed during hydrate production can lead to substantial weakening in soil mechanic properties, which in turn results in the deformation and even destruction of the seafloor sediments, thereby posing a potential threat to the safety of the undersea engineering infrastructures. A better understanding of the effect of soil mechanical weakening on seabed deformation will benefit the prediction and/or determination of geological conditions for safer hydrate production. In this work, a three‐dimensional model of the submarine geological body was established and engineering properties of hydrate reservoir under different degrees of hydrate dissociation were determined. Such model and engineering parameters were applied for simulation calculation on examining the effect of hydrate dissociation degree on soil subsidence using FLAC3D software. The simulation results show that the subsidence of sediments is centrally distributed within the dissociation area and the subsidence of hydrate‐bearing sediment’s top surface is much more severe than that of the overlying layer. Subsidence on the horizontal section above the hydrate reservoir presents an essentially symmetric dish‐like subsidence trough, with the greatest subsidence in the centre and approximately constant subsidence beyond the trough range. The radius of the subsidence trough increases with the increase of the degree of dissociation, and the increasing extent in the early dissociation stage (lower dissociation degree) is greater than in the middle and the later stage (higher dissociation degree). As the degree of hydrate dissociation increases, subsidence of both the overlying layer and the HBS increases. Especially when the decomposition exceeds a certain threshold, the seafloor subsidence increases rapidly. The simulation results in this work are of guiding significance for deformation monitoring and infrastructure deformation prevention in practical hydrate production projects.

1085. Comparison of the Incidence of AKI in Vancomycin AUC Based Goal Trough Dosing vs. Traditional Trough Dosing in the Outpatient Setting

Abstract Background Recent changes to vancomycin guidelines recommend dosing by targeting an AUC of 400-600 in most patients, due to similar effectiveness and reduced rates of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine of ≥ 0.5 mg/dl, a 50% increase in serum creatinine from baseline on two consecutive readings, or a decrease in creatinine clearance from 50% from baseline on two consecutive readings. The purpose of this study was to assess the incidence of AKI in patients receiving vancomycin dosed by AUC based trough goals and vancomycin dosed by traditional trough goals (15-20 mcg/mL) in the outpatient setting. Methods This study was performed by retrospective chart review using the electronic health record. Patients receiving vancomycin outpatient as continuation of therapy after discharge from December 1, 2018 through March 24, 2021 were reviewed. The primary objective was incidence of AKI in patients receiving vancomycin outpatient with trough goals derived from patient specific AUC calculations compared to patients receiving vancomycin by traditional goal troughs. Secondary objectives included rate of treatment failure, average AUC estimated trough range, and number of regimen changes required. Results There were a total of 65 patients in the traditional trough dosing group and 53 patients in the AUC trough dosing group. The incidence of AKI was higher in the traditional trough dosing group compared to the AUC trough group (23.1% vs 5.7%; p=0.01). There were no differences in incidence of treatment failure. The mean AUC estimated trough range was 11.4-16.9 mcg/mL. There were significantly less average regimen changes required in the AUC dosing group (1.64 vs 1.13; p=0.006). Patients receiving AUC trough dosing were 78% less likely to develop AKI as patients receiving traditional trough dosing (HR 0.221, 95%CI 0.051 – 0.968). Conclusion There was a significantly lower incidence of AKI in patients receiving vancomycin dosed by AUC based troughs compared to traditional trough dosing. Continuing AUC trough based dosing for vancomycin in the outpatient setting is convenient and may lead to reduced rates of AKI. Disclosures Dustin R. Carr, PharmD, BCPS, BCIDP, AAHIVP, Merck (Speaker’s Bureau)

Outpatient vancomycin therapy: Acute kidney injury in individualized AUC-based goal trough ranges versus traditional trough dosing

BackgroundRecent changes to vancomycin guidelines recommend area under the curve concentration (AUC) monitoring in most patients, owing to similar effectiveness and reduced rates of acute kidney injury (AKI). ObjectiveThe purpose of this study was to assess the incidence of AKI in patients receiving vancomycin dosed by AUC-based goal troughs and vancomycin dosed by traditional trough goals (15-20 mcg/mL) in the outpatient setting. MethodsPatients were included if they received vancomycin outpatient for at least 1 week. The primary objective was comparing the incidence of AKI in patients receiving vancomycin as an outpatient with trough goals derived from patient-specific AUC calculations determined as an inpatient with that of patients receiving vancomycin by traditional goal troughs. Secondary objectives included assessing the rate of treatment failure, AUC estimated trough range, and number of regimen changes required. ResultsThere were 65 patients in the traditional trough dosing group and 53 patients in the AUC trough dosing group. The incidence of AKI was lower in the AUC trough group (5.7% vs. 23.1%; P = 0.01). There were no differences in the incidence of treatment failure. The median AUC estimated trough range was 11.4-17.1 mcg/mL. There were statistically significant less average regimen changes required in the AUC dosing group (1.13 vs. 1.64; P = 0.006). ConclusionThere was a statistically significant lower incidence of AKI in patients receiving vancomycin dosed by individualized AUC-based trough ranges compared with that of patients receiving traditional trough dosing. Developing a process for individualized AUC-based trough ranges can facilitate a convenient monitoring method to use the benefits of vancomycin AUC dosing as an outpatient.

Evaluation of dosing strategies and trough concentrations of vancomycin in patients undergoing continuous venovenous hemofiltration.

Recommendations regarding vancomycin dosing in critically ill patients on continuous venovenous hemofiltration (CVVH) are limited. The purpose of this study was to evaluate current dosing practices of pharmacists for patients treated with CVVH, develop guidelines for optimal dosing and monitoring of vancomycin to improve target trough attainment, and reduce pharmacist workload. A retrospective cohort study. was performed of critically ill adult patients from January 2015 to December 2018. Patients were included if they received vancomycin during CVVH for at least 48h. Patients with significant residual kidney function, defined as daily urine output >400ml or significant fluctuations (≥1000ml/h in a 24-h period) in their hemofiltration rates, were excluded. Interruptions in CVVH up to 6h/day were permitted. Dosing strategies with two dosing categories were defined: (1) dosing based on random serum levels (dosing by level, DBL) or (2) scheduled vancomycin dosing (SD). Academic medical center in Detroit, Michigan. Critically ill adult patients. During the study period, 942 patients were evaluated and 200 met inclusion criteria, for a total of 586 serum vancomycin levels. There were 141 patients with 443 random vancomycin serum levels in the DBL group and 59 patients with143 vancomycin trough levels in the SD group. Mean vancomycin trough levels were similar between groups (17.1±6 vs. 16.5±4mcg/ml) for the DBL and SD groups, respectively. For the primary end point of overall target trough achievement of 15-20mcg/ml, significantly more trough levels in the SD group were in the 15-20mcg/ml range compared with the DBL group, 50% vs. 38%; p<0.001, respectively. When target trough range was extended to 10-20mcg/ml, success rates were similar between groups (74% DBL vs. 82% SD, p=0.021). The number of interventions required by the pharmacist, including notes per day and orders per day, were reduced by approximately 50% when the SD strategy was utilized. Scheduled vancomycin dosing regimens of 15-22mg/kg every 12-24h were required to yield trough levels in the 15-20mcg/ml range. Target vancomycin trough achievement of 15-20mcg/ml occurred more frequently when vancomycin was scheduled at a dose of 15-22mg/kg every 12-24h based on ultrafiltration rate and may alleviate the time and cost associated with frequent vancomycin serum monitoring.

MO732HD-PATIENTS WITH ATRIAL FIBRILLATION TREATED ADEQUATELY AND SAFE WITH DOAC BY INDIVIDUAL DOSING USING ROUTINE ANTI-XA DRUG-EFFECT MONITORING: LONG-TERM CLINICAL PRACTICE DATA

Abstract Background and Aims Hemodialysis (HD) patients (Pts) with nonvalvular atrial fibrillation (AF) on anti-vitamin-K oral anticoagulation (VK-OAC) are at high risk for cardio-vascular events, major bleeding and rapid vascular/valvular calcification. Thus, current VK-OAC is debated since prospective studies are missing, but all direct oral anticoagulation drugs (DOACs) are not labeled for ESRD. We studied the clinical feasibility of long-term DOAC treatment in HD-pts using individual dosing by regular anticoagulant drug-effect monitoring. Method We analysed 9 HD-patients with AF (median age 77 yrs; range=R: 59-86; 7 Male) on DOAC therapy for at least 6 months (n=1 rivaroxaban=Riva, n=8 apixaban=Apix) initiated by cardiologist with patients informed consent with lower dose as in CKD-4 under regular (weekly) anti-Xa drug-effect monitoring (prior HD) using available routine laboratory test validated for low-molecular heparin: Target trough range (12-24h after drug) was 0.1-1.0 U/ml (=prophylactic to therapeutic anti-Xa levels; test range &amp;lt;0.1, &amp;gt;1.6 U/ml). Bleeding caused drug stop/reduction until anti-Xa control. Results Median study time was 14 months (R: 6-24). We analysed 310 anti-Xa levels on Apix and 83 levels on Riva. After dose adjustment finally 2 Apix-Pts (22%) received full CKD-4 dose (35 mg/week=wk) and 7 patients (78%) had median dose of 10 mg/wk (10-27 mg; 6x Apix) or 40 mg/wk Riva, i.e. 29% and 38% of usual CKD-4 dose. Two Pts with higher dose had clinical reasons: short-bowl-syndrome (less resorption) or high grade (3-4) left atrial sludge (therapeutic goal). Overall, median anti-Xa level was 0.47 U/ml (R: &amp;lt;0.1-&amp;gt;1.6) and 80% were in center-accepted targets: 0.1-1.2 U/ml. Lower dose Pts had higher in-target-rate (83%) than the 2 high dose Pts (70%) by more exceeding the upper limit. During our study we saw no cerebral/systemic thrombo-embolic event or major bleeding, but 2 pts had epistaxis (need out-patient intervention), 1x persistent macrohematuria (need catheterization) and 3 pts. had multiple subcutaneous hematoma, none needed event-related transfusion. We saw two non-cardiovascular deaths (22%; 2/9): 1x pneumonic sepsis, 1x advanced cancer. Conclusion We provide new clinical feasibility data on long-term DOACs therapy in HD-patients. Since DOACs are not labelled for ESRD we recommend strict indication plus regular anti-Xa drug-effect monitoring for adequate individual dosing. Our data support initial doses as for CKD-4 but applied only on HD-free days (4x/wk; =57% of usual) and adjustment in steady-state (1-2 wks): final individual doses were increased up to 100% in some patients, but mostly were reduced to 30-40% of usual CKD-4 doses. Overall, this individual dosing approach for DOACs provided adequate anti-Xa levels to prevent thrombo-embolic as well as major bleeding events. This initial data need to be confirmed in larger studies to improve evidence-based management of HD-patients with nonvalvular AF.

Vancomycin Prescribing Practices and Therapeutic Drug Monitoring for Critically Ill Neonatal and Pediatric Patients: A Survey of Physicians and Pharmacists in Hong Kong.

Background: Deviations from the optimal vancomycin dosing may occur in the neonatal and pediatric population due to inconsistencies in the recommended dosing algorithms. This study aims to collect the expert opinions of clinicians who practice in the neonatal or pediatric intensive care units (NICU/PICUs) of 12 major medical centers in Hong Kong.Methods: This was a multicenter, cross-sectional study. Eligible physicians and pharmacists completed a structured questionnaire to identify the challenges they encountered when selecting the initial intermittent vancomycin dosing. They also answered questions concerning therapeutic monitoring services (TDM) for vancomycin, including the targeted trough levels for empirical vancomycin regimens administered for complicated and uncomplicated infections.Results: A total of 23 physicians and 43 pharmacists completed the survey. The top clinical parameters reported as most important for determining the initial vancomycin dosing were renal function (90.9%), post-menstrual/postnatal age (81.8%), body weight (66.7%), and suspected/documented pathogen (53.0%). Respondents reported challenges such as difficulties in determining the optimal initial dose for a targeted level (53.0%), inconsistencies between dosing references (43.9%) and a lack of clear hospital guidelines (27.3%). Half of the pharmacists (48.8%) reported that they had helped to interpret the TDM results and recommend vancomycin dose adjustments in >75% of cases. For methicillin-resistant Staphylococcus aureus infection, physicians, and pharmacists reported target trough levels of ~10–15 and 15–20 mg/L, respectively. For suspected moderate/uncomplicated Gram-positive infections physicians tended to prefer a lower trough range of 5–10 mg/L, while pharmacists preferred a range of 10–15 mg/L.Conclusions: Our results demonstrate that clinicians used varying vancomycin dosing guidelines in their practices. The multidisciplinary TDM service in Hong Kong can be improved further by establishing a standardized dosing guideline and implementing a well-structured, evidence-based service protocol. Future work includes conducting drug utilization studies to evaluate real-world antimicrobial usage patterns and the impact on tangible clinical outcomes, and developing pharmacokinetic-guided dose calculator for antimicrobials in critically ill neonates and pediatric patients.

Correlation of the lithostratigraphic facies relationships and depositional environments of the uppermost Silurian through Lower Devonian strata across the central Darling Basin, western New South Wales, SE Australia

This paper is focused on the detailed lithostratigraphic facies characterisation of the paleo-environments of the uppermost Silurian through Lower Devonian Winduck Interval strata from the Bancannia South 1, Pondie Range 1 and Booligal Creek 1 and 2 wells, across the central Darling Basin of western New South Wales. Based on data from both wireline logs and drill cores and cuttings, an interpretation of paleo-environments and evolution of the depositional facies is presented. Our approach involves two key interpretations. The first outcome was the delineation of the Winduck Interval section (maximum observed thickness of approximately 1475 m) and formal subdivision into lower and upper Winduck Intervals, based on well data from the central Bancannia Trough, southern Pondie Range Sub-basin and northwestern flank of the Blantyre Sub-basin. The second outcome is based on the internal lithostratigraphy of the Winduck Interval represented by 11 sedimentary lithofacies organised into three lithofacies associations (LFAs). LFA-X1 is interpreted as distributary-channel sandstone complex deposits, LFA-X2 is interpreted as distributary mouth bar with small-scale braided delta plain complex deposits and LFA-X3 is interpreted as tidal channel sands with proximal delta front complex deposits. Subsurface lithostratigraphic facies analysis relationships and depositional environments of the Winduck Interval section have implications for evaluating the hydrocarbon potential and may assist future exploration efforts in the central Darling Basin, especially the Bancannia Trough and Pondie Range Sub-basin. KEY POINTS A detailed lithostratigraphic facies characterisation of the paleo-environments of the uppermost Silurian–Lower Devonian Winduck Interval strata in the central Darling Basin is presented. Evaluation and interpretation of the Winduck Interval section in study area was subdivided into two informal stratigraphic units, a lower Winduck Interval and an upper Winduck Interval. Eleven distinct sedimentary lithofacies codes (LFs), which have been recognised in the internal lithostratigraphy of the Winduck Interval from the Bancannia South 1, Pondie Range 1 and Booligal Creek 1 and 2 wells, have been grouped into three lithofacies associations (LFAs). Lithostratigraphic facies analysis relationships and depositional environments of the Winduck Interval section has implications for evaluating the hydrocarbon potential and may assist future exploration in the Bancannia Trough and Pondie Range Sub-basin.

Factors predicting vancomycin therapy outcomes in hemodialysis outpatients and the role of the nephrology stewardship pharmacist.

Vancomycin is the default antibiotic to treat methicillin-resistant Staphylococcus aureus (MRSA) in hemodialysis (HD) units. Current guidelines recommend a vancomycin trough range of 15 to 20 mg/L for serious infections. Data regarding the clinical success of these recommendations are scarce in HD patients. The purpose of this studies is to evaluate the treatment outcomes of vancomycin in HD patients. A retrospective chart review of HD outpatients who received parenteral vancomycin for suspected or documented MRSA infections in a community hospital in southwestern Ontario, Canada. Stepwise binary logistic regression analysis was conducted to identify the independent predictors of the treatment outcomes. Of 77 HD patients, 113 vancomycin treatment courses were identified. The unadjusted bivariate comparisons suggested that there was no difference between treatment success and failure groups in terms of: mean loading dose (1663.6 ± 451.9 mg vs. 1614.3 ± 471 mg, P = 0.621), mean pre-HD concentration after loading dose (12.78 ± 4.4 mg/L vs. 13.34 ± 4.5 mg/L, P = 0.601), and mean maintenance dose (1012.1 ± 108 mg vs. 1069.7 ± 227 mg, P = 0.093). The groups were, however, different on their mean pre-HD drug concentration after maintenance dose (15.99 ± 4.6 mg/L vs. 19.9 ± 5.8 mg/L, P = 0.002). The adjusted logistic regression results, however, suggested that the type of infection was the only independent predictor of vancomycin success (OR = 11.07; 95% confidence interval [CI] = 3.2-38.48). Specifically, patients treated for bacteremia were 11 times more likely to experience cure as compared with diabetic foot infection and/or osteomyelitis. Similarly, those with skin and soft tissue infections were 10.7 times more likely to experience cure than those with diabetic foot infection and/or osteomyelitis (OR = 10.7; 95% CI = 3.63-31.58). The suggested vancomycin pre-HD concentration in the guidelines did not predict the treatment outcomes. Patients with bacteremia and/or skin or soft tissue infections were more likely to achieve clinical cure than patients with diabetic foot/osteomyelitis infections.

Targeted Aspergillus Prophylaxis With Voriconazole in Heart Transplant Patients: A Focus on the Interaction With Tacrolimus.

Background: Voriconazole is a commonly used agent for the treatment and prophylaxis of invasive aspergillosis (IA) in heart transplant recipients. Complicating its use with this population is its significant interaction with the calcineurin inhibitors tacrolimus and cyclosporine. Most primary literature pertaining to this interaction focuses on use of voriconazole in allogeneic hematopoietic stem cell recipients. There is little information pertaining to the efficacy of voriconazole for IA prophylaxis or its effects on tacrolimus pharmacokinetics in heart transplant patients. Objective: Evaluate the use of voriconazole for invasive Aspergillus (IA) targeted prophylaxis in heart transplant recipients with a focus on the drug-drug interaction between voriconazole and tacrolimus and its impact on tacrolimus dose after discontinuation of voriconazole. Methods: This single-center, nonrandomized, retrospective, sequential study reviewed the use of targeted prophylaxis protocol in heart transplant recipients at Abbott Northwestern Hospital from January 2015 through May 2017. Results: Patients screened for targeted prophylaxis protocol from 2015 through 2017 had a 0% incidence of IA. This was in comparison to a 7% incidence of IA for a historical group of recipients from 2010 to 2014 prior to the use of the protocol. Additionally, patients on voriconazole needed on average a 67% reduction in tacrolimus dose (mg/kg/day) while on voriconazole compared with similar patients not on voriconazole to stay within the tacrolimus trough level protocol range. On discontinuation of voriconazole, a preemptive 100% tacrolimus dose increase resulted in 55% of tacrolimus trough levels within protocol range on first check. Overall, after 1-month post-voriconazole discontinuation, a 215% average increased tacrolimus dose was needed to maintain a level within the protocol trough range. Conclusion and Relevance: This study corroborates that targeted IA prophylaxis with oral voriconazole for up to 90 days is associated with a reduction in the incidence of IA in new heart transplant recipients. The pharmacokinetic analysis was able to provide more details on the effects of the interaction between voriconazole and tacrolimus in heart transplant recipients. Application of these data will better aid transplant centers to handle the effects of voriconazole discontinuation on patients on tacrolimus.