Initial Trough Research Articles

Creation and Validation of a Pediatric Vancomycin Nomogram for a Goal Trough of 10–15 mg/L at a Quaternary Care Children’s Hospital

Abstract Background Recent data suggest a serum vancomycin (vanc) trough (VT) of 11mg/L correlates with an AUC/MIC24 > 400 which has shown to be the optimal concentration to eradicate MRSA infection and improve mortality. There are currently limited published recommendations on how to achieve such a VT in children. This study validates a vancomycin nomogram used to achieve a VT of 10–15 mg/L in pediatric inpatients (pts) at a quaternary care children’s hospital. Methods This is an 18 month (mo) prospective analysis beginning in September 2015. Included pts were ≥2 mo of age and had ≥2 consecutive VT. Pts receiving renal replacement therapy or those with a serum creatinine (Scr) of ≥0.5 mg/dL from a prior admission or within 48 hours of vanc initiation were excluded. The starting dose (SD) of vanc was determined by age and creatinine clearance (CrCl) (Tables 1 and 2). CrCl was measured by Bedside Schwartz equation for patients ≤18 years old (yo) and Cockcroft-Gault equation for patients >18 yo. The maximum CrCl was set to 120 ml/minute. Patients who were on vanc and experienced a Scr increase of ≥0.5 mg/dL were considered to have acute kidney injury (AKI). The study had a 6 mo evaluation period which led to a revised version (RVN) on March 2016. The primary endpoint (PE) was achievement of 10–15 mg/L by the Second VT for patients with the First trough outside of this range, using our RVN (Table 3). Results Overall, a total of 276 patients received vanc, 17 and 29 patients were dosed according to the initial and RVN, respectively. For young children (Table 1), the SD for patients with a CrCL ≥90 ml/minute was therapeutic, sub-, and supra-therapeutic in 43.75%, 47.5% and 8.75%, respectively. For older children (Table 2), the SD for patients with a CrCl ≥100 ml/minute was therapeutic, sub-, and supra-therapeutic in 41.1%, 35.7% and 23.2%, respectively. The initial VN was successful 12/17 (70.6%) in achieving the PE. Success in achieving the PE after the RVN was 26/29 (89.7%). In the RVN group, the most common initial troughs were 5–7 mg/L (33.3%), followed by >18 mg/L (27.6%). The mean VT using the RVN was 13.7 mg/L. The overall AKI incidence throughout the study was 3.2% (9/276) and 0% using the RVN. Conclusion Our RVN led to a Second VT within a target range of 10–15 mg/L for 89.7% of patients, allowing for more accurate and safer use of vancomycin in our institution. Disclosures All authors: No reported disclosures.

Vancomycin use, dosing and serum trough concentrations in the pediatric population: a retrospective institutional review.

Background:Vancomycin is used primarily for Gram-positive infections. Recommended dosage regimens and targeted therapeutic levels vary between institutions.Objectives:This study aims to describe therapeutic levels according to initial vancomycin doses and patient’s age. A secondary objective was to evaluate appropriateness of vancomycin use in our hospital.Methods:A retrospective chart review was conducted at the Children’s Hospital of Eastern Ontario. Patients included in this study were classified by age (neonates, infants, children and adolescents) and categorized into those who received vancomycin ≤5 and >5 days. Initial vancomycin dosing regimens and corresponding initial trough levels obtained were evaluated. Initial trough levels drawn in relation to the third, fourth, or fifth doses corresponding to the first course of therapy were analyzed. Acceptable trough levels ranged from 5-20 mg/L.Results:One-hundred-and-sixty-four patients who received intravenous vancomycin in 2013 were included. Of the 229 courses of vancomycin, 190 (83%) were used 5 days or less (mean 4.9 days). Sixteen infants (88.9%) and 21 adolescents (100%), who received vancomycin empiric dosing of 60 mg/kg/day, had initial trough levels >5mg/L. However, in the children’s group 20 (37.7%) did not reach levels >5 mg/L. None of vancomycin minimum inhibitory concentration (MIC) values were >1mg/L for the four patients who had infections due to methicillin-resistant Staphylococcus aureus strains.Conclusions:In our institution, initial empiric vancomycin dosing of 60 mg/kg/day resulted in levels ≥5mg/L in most infants and adolescents. It remains unclear why some children aged 1-12 years did not achieve these levels.

The Impact of Pediatric-Specific Vancomycin Dosing Guidelines: A Quality Improvement Initiative.

There are limited data guiding vancomycin dosing practices in the pediatric population to target the goal troughs recommended by national vancomycin guidelines. In this study, we sought to improve adherence to guideline trough targets through a quality improvement intervention. A retrospective analysis was first conducted to assess baseline performance. A multidisciplinary team then developed and implemented a standardized dosing algorithm recommending 15 mg/kg per dose for mild and moderate infections (goal trough: 10-15 µg/mL) and 20 mg/kg per dose for severe infections (goal trough: 15-20 µg/mL), both delivered every 6 hours (maximum single dose: 750 mg). The impact of the intervention was evaluated prospectively using standard statistics and quality improvement methodology. The outcome measures included the percentage of patients with an initial therapeutic trough and the time to therapeutic trough. A total of 116 patients (49 preintervention, 67 postintervention) were included. Postintervention, there was a significant increase in the percentage of patients with an initial therapeutic trough (6.1% to 20.9%, P = .03) and in the percentage of patients with initial troughs between 10 and 20 µg/mL (8.2% to 40.3%, P < .001). The time to therapeutic trough decreased from 2.78 to 1.56 days (P = .001), with the process control chart showing improved control postintervention. Vancomycin-related toxicity was unchanged by the intervention (6.1% versus 4.5%; P = .70). Using quality improvement methodology with standardized higher initial vancomycin doses, we demonstrated improved adherence to national trough guidelines without noted safety detriment.

Voriconazole Dosing in Children Younger Than 3 Years Undergoing Cancer Chemotherapy or Hematopoietic Stem Cell Transplantation.

There are limited pediatric population pharmacokinetic data for voriconazole dosing, particularly in younger children. In a cohort of 34 patients younger than 3 years receiving voriconazole, the majority (n = 23, 68%) had a low initial serum concentration <1 mg/L. Among 23 children <2 years old, 19 (83%) had an initial trough <1 mg/L. There was large intra- and interindividual variability in trough levels. Dosing also varied from 3.3 to 19.6 mg/kg per dose. Only 2 of 34 patients had a documented adverse drug reaction attributable to voriconazole. More data are needed to establish optimal dosing in very young children.

Impact of Pharmacy Practice Model Expansion on Pharmacokinetic Services: Optimization of Vancomycin Dosing and Improved Patient Safety.

Background: The impact of pharmacy interventions on optimizing vancomycin therapy has been described, however interventions vary among studies and the most optimal pharmacy practice model (PPM) for pharmacokinetic (PK) services has not been established. Objective: The purpose of this study is to demonstrate the value of 24 hours a day, 7 days a week (24/7) PK services. Methods: New PK services were implemented in 2 phases with institutional PPM expansion. Phase 1 included universal monitoring by pharmacists with recommendations made to prescribers during business hours. Phase 2 expanded clinical pharmacists' coverage to 24/7 and provided an optional 24/7 pharmacist-managed PK consult service. We compared vancomycin therapeutic trough attainment, dosing, and clinical and safety outcomes between phases 1 and 2 in adult inpatients receiving therapeutic intravenous vancomycin. Results. One hundred and fifty patients were included in each phase. Phase 2 had a greater proportion of vancomycin courses with therapeutic initial trough concentrations (27.5% vs 46.1%; p = 0.002), higher initial trough concentrations (10.9 mcg/mL vs 16.4 mcg/mL; p < 0.001), and optimized initial vancomycin dosing (13.5 mg/kg vs 16.2 mg/kg; p < 0.001). Phase 2 also saw significant reduction in the incidence of vancomycin-associated nephrotoxicity (21.1% vs 11.7%; p = 0.038). Dose optimization and improvement in initial target trough attainment were most notable among intensive care unit (ICU) patients. Conclusions. Our study demonstrated that 24/7 PK services implemented with institutional PPM expansion optimized vancomycin target trough attainment and improved patient safety.

Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia.

Trough cyclosporine (CsA) blood level can influence incidence of graft-versus-host disease (GVHD) and relapse in patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplant (HSCT). We sought to determine factors affecting initial trough CsA level (CsA-1) and its impact on transplant outcome in acute leukemia. Seventy-seven patients underwent HSCT for acute leukemia between January 2008 and March 2013 and were included. GVHD prophylaxis included CsA + methotrexate. (MTX) in 53 patients and CsA + mycophenolate mofetil (MMF) in 24 patients CsA-1 was measured on day 3-5 of starting CsA and subsequent dose was modified to achieve therapeutic level of 150-200. ng/mL. According to CsA-1, patients were divided into three groups - 27 in Group A (dose escalated), 13 in Group B (dose de-escalated), and 37 in Group C (same dose continued). On univariate analysis, cyclophosphamide with total-body irradiation (TBI) based conditioning regimen and lower body mass index (BMI) were associated with lower CsA-1, while use of fludarabine and higher BMI were associated with higher CsA-1. On multivariate analysis, only fludarabine use and BMI affected CsA-1. Incidence of acute and chronic GVHD (aGVHD and cGVHD), transplant-related mortality, relapse incidence, and relapse-free and overall survival (OS) were similar in the three groups. While fludarabine use in conditioning regimen and higher BMI leads to higher CsA-1, transplant outcomes are not affected by CsA-1.

Cystatin C–Guided Vancomycin Dosing in Critically Ill Patients: A Quality Improvement Project

The aim of the study was to determine whether a vancomycin dosing algorithm based on estimated glomerular filtration rate from creatinine and cystatin C levels (eGFRcr-cys) improves target trough concentration achievement compared to an algorithm based on estimated creatinine clearance (eCLcr) in critically ill patients. This prospective quality improvement project evaluated intensive care unit (ICU) patients started on intravenous vancomycin using one of 2 different strategies. Dosing regimens were selected and implemented after an individualized goal trough range was established (10-15 or 15-20mg/L). Steady-state goal trough achievement was compared between treatment arms with and without adjustment for potential confounders. 3 medical and surgical ICUs at a single tertiary medical center. During January 2012 to October 2013, vancomycin was dosed according to eCLcr using the Cockcroft-Gault formula (control arm). During December 2013 to May 2015, a multidisciplinary quality improvement team implemented a novel vancomycin dosing algorithm according to eGFRcr-cys using the CKD-EPI equation (intervention arm). Steady-state initial goal vancomycin trough concentration achievement. More patients in the intervention arm (67 of 135 [50%]) achieved therapeutic trough vancomycin levels than in the control arm (74 of 264 [28%]; OR, 2.53; 95% CI, 1.65-3.90; P<0.001). Improved trough achievement was maintained even after adjustment for age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, fluid balance, baseline CLcr, surgical admission diagnosis, presence of sepsis, and goal trough concentration range (adjusted OR, 2.79; 95% CI, 1.76-4.44; P<0.001). Clinical outcomes were similar between groups. Nonrandomized, incomplete algorithm compliance. A vancomycin dosing nomogram based on eGFRcr-cys significantly improved goal trough achievement compared to eCLcr among ICU patients with stable kidney function. Further studies are warranted to characterize the relationship between use of cystatin C-guided dosing and clinical outcomes.

Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.

A high-dose 12 mg/kg/day (6 mg/kg twice daily) voriconazole regimen was recommended by the CDC to treat patients injected with contaminated methylprednisolone acetate that caused a multi-state fungal outbreak in 2012-13. Therapeutic drug monitoring results of this unique regimen are unknown, as is the most appropriate dosing weight for obese patients. We evaluated voriconazole trough measurements for this dosing scheme, as well as the use of adjusted body weight dosing for obese patients. Voriconazole trough levels were analysed in obese (BMI ≥35 kg/m 2 ) and non-obese (BMI <35 kg/m 2 ) patients who were given initial therapy with 12 mg/kg/day. Of 138 patients, the first steady-state voriconazole troughs were supratherapeutic (>5 mg/L) in 65 (47%) patients, therapeutic (2-5 mg/L) in 57 (41%) patients and subtherapeutic (<2 mg/L) in 16 (12%) patients. Twenty-three patients had pre-steady-state dose decreases due to supratherapeutic levels, with subsequent first steady-state troughs in the therapeutic ( n = 17) and subtherapeutic ( n = 6) categories. Voriconazole doses >11 and >8 mg/kg/day produced mainly first steady-state supratherapeutic troughs in 44 obese and 94 non-obese patients, respectively. An initial 12 mg/kg/day was progressively lowered to a median maintenance dose of 8.5 mg/kg/day in the obese and 8.6 mg/kg/day in the non-obese. A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. Adjusted body weight dosing in obese patients resulted in a similar maintenance dose to total body weight dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes

1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear.2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VICmin was adjusted on daily dose (VICmin/D) for overcoming effect of dose.3. A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VICmin/D in Group 1 (R2 = .255, p < .001). Only age was confirmed as a factor of VICmin/D in Group 2 (R2 = 0.144, p = .021).4. Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3.

Application of Enhanced Hadamard Error Correcting Code in Video-Watermarking and his comparison to Reed-Solomon Code

Error Correcting Codes are playing a very important role in Video Watermarking technology. Because of very high compression rate (about 1:200) normally the watermarks can barely survive such massive attacks, despite very sophisticated embedding strategies. It can only work with a sufficient error correcting code method. In this paper, the authors compare the new developed Enhanced Hadamard Error Correcting Code (EHC) with well known Reed-Solomon Code regarding its ability to preserve watermarks in the embedded video. The main idea of this new developed multidimensional Enhanced Hadamard Error Correcting Code is to map the 2D basis images into a collection of one-dimensional rows and to apply a 1D Hadamard decoding procedure on them. After this, the image is reassembled, and the 2D decoding procedure can be applied more efficiently. With this approach, it is possible to overcome the theoretical limit of error correcting capability of ( d -1)/2 bits, where d is a Hamming distance. Even better results could be achieved by expanding the 2D EHC to 3D. To prove the efficiency and practicability of this new Enhanced Hadamard Code, the method was applied to a video Watermarking Coding Scheme. The Video Watermarking Embedding procedure decomposes the initial video trough multi-Level Interframe Wavelet Transform. The low pass filtered part of the video stream is used for embedding the watermarks, which are protected respectively by Enhanced Hadamard or Reed-Solomon Correcting Code. The experimental results show that EHC performs much better than RS Code and seems to be very robust against strong MPEG compression.

CYP2C19 Genotype-Guided Dosing and Voriconazole Concentrations in Hematopoietic Stem Cell Transplant Patients (HSCT) Receiving Antifungal Prophylaxis

Background: Therapeutic drug monitoring of voriconazole is useful due to its unpredictable pharmacokinetics, narrow therapeutic index, and exposure-response relationship as sub-therapeutic initial troughs may cause a higher risk for invasive fungal infections (IFIs) and related mortality. Voriconazole is metabolized largely via cytochrome P450 2C19 (CYP2C19) and studies suggest that the greatest risk of sub-therapeutic voriconazole concentrations are in CYP2C19 rapid (RMs) and ultrarapid metabolizers (UMs). Herein we present interim results from the first prospective study investigating the impact of CYP2C19 genotype-guided voriconazole dosing on trough concentrations and clinical outcomes in adult allogeneic HSCT patients receiving voriconazole as antifungal prophylaxis.Methods: Buccal swabs were obtained on the day of admission from all patients scheduled for allogeneic HSCT. DNA was extracted using the Magmax DNA multi-sample kit and TaqMan® Drug Metabolism Genotyping Assays were used to detect single nucleotide polymorphisms in the CYP2C19 gene associated with *1, *2, *3 and *17 alleles. Patients harboring the *1/*17 (RM) or *17/*17 (UM) genotypes received oral voriconazole 300 mg twice daily post-transplant, whereas all other patients received the standard 200 mg twice daily dose. All patients started antifungal prophylaxis on day +1 post-transplant with IV micafungin until patients were able to tolerate oral medications, upon which voriconazole was initiated (approximately 7-10 days post-transplant) and continued until day +100 post-transplant. Trough levels were obtained at steady state (5-7 days after starting voriconazole) and subsequent doses were adjusted to target a pre-specified therapeutic range of 1.0-5.5 mg/L. The primary objective was the proportion of patients with sub-therapeutic voriconazole concentrations (<1.0 mg/L) at steady state. Secondary objectives included the proportion of patients within each phenotype category with sub-therapeutic concentrations at day 5-7, the proportion of patients with supratherapeutic concentrations at day 5-7, the incidence of voriconazole-related toxicities, and incidence of IFI.Results: Evaluable genotypes and trough levels were available for 26 patients at the time of analysis (46% female and 54% male; mean age 50 years) (8% UMs, 23% RMs, 46% normal [NMs], 19% intermediate [IMs] and 4% poor metabolizers [PMs] for CYP2C19). Patients had a primary diagnosis of either acute myeloid leukemia (N=9), lymphoma (N=7), myeloproliferative disease (N=4), acute lymphocytic leukemia (N=3), chronic myeloid leukemia (N=2), or plasma cell leukemia (N=1), and received either a busulfan and cyclophosphamide-based myeloablative regimen or fludarabine, cyclophosphamide, and total body irradiation-based reduced intensity regimen. The percentage of patients with sub-therapeutic voriconazole trough levels at day 5-7 was reduced from historically 50% to 30.8% with CYP2C19 genotype-guided dosing. The study was designed at the one-sided alpha = 0.05 significance level, and the observed results were statistically significant (P = 0.038). Of patients with sub-therapeutic initial trough concentrations (N=8), none were RMs or UMs compared to 80% in historical controls (P <0.001). Of these 8 patients, 5 were NMs and 3 were IMs. No supra-therapeutic trough concentrations were observed. There were no grade 3/4 drug-related adverse events and no patients experienced an IFI.Conclusion: CYP2C19 genotype-guided voriconazole dosing significantly reduced the percentage of patients with initial sub-therapeutic trough concentrations at day 5-7. Importantly, no RMs or UMs were sub-therapeutic when receiving a higher starting dose of 300 mg twice daily. Other factors may influence trough levels beyond CYP2C19 status, including body composition, compliance, food and drug interactions, other genetic factors, and timing of the level, as suggested by low troughs even in NM and IM patients. We anticipate enrolling a total of 60 evaluable patients to complete this study. Preliminary results suggest that CYP2C19 genotype-guided dosing improves the ability to achieve therapeutic concentrations sooner, thus minimizing the need for subsequent dose adjustments and additional trough levels (possibly reducing overall costs), and providing early adequate drug exposure in order to decrease the incidence of IFIs. [Display omitted] DisclosuresPatel:Janssen Pharmaceuticals: Consultancy, Research Funding; Myriad Genetics: Research Funding. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees.

Risk Factors for Non-Therapeutic Initial Steady-State Vancomycin Trough Concentrations in Children and Adolescents Receiving High Empiric Doses of Intravenous Vancomycin

Achieving vancomycin troughs of 15-20μg/mL remains challenging in children. Our objective was to identify risk factors associated with non-therapeutic initial vancomycin troughs in children. We conducted a retrospective cohort study of children who received intravenous vancomycin with at least one initial steady-state trough obtained. Patients who achieved therapeutic troughs (15-20μg/mL in the 20-mg/kg/dose sub-cohort and 10-15μg/mL in the 15-mg/kg/dose sub-cohort) were compared with those with subtherapeutic troughs (<15 and <10μg/mL, respectively) and supratherapeutic troughs (>20 and >15μg/mL, respectively) separately to determine risk factors associated with non-therapeutic troughs. A total of 153 vancomycin courses in 140 patients met study eligibility criteria. Of 45 patients who received 20mg/kg/dose of empiric vancomycin, 60, 16, and 24% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73m2 increase in initial creatinine clearance (CrCl) was associated with a 47% increase in the odds of an initial subtherapeutic trough (adjusted odds ratio [aOR] 1.47; 95% CI 0.98-2.22). Of 108 patients who received 15mg/kg/dose of empiric vancomycin, 62, 19, and 19% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73m2 increase in initial CrCl was associated with an 18% increase in the odds of an initial subtherapeutic trough (aOR 1.18; 95% CI 1.02-1.37). Achieving vancomycin troughs of 15-20μg/mL for severe Gram-positive infections continues to be challenging in children, even at higher empiric doses of 20mg/kg/dose IV every 6-8 h. Children with higher initial CrCls are particularly susceptible to subtherapeutic initial steady-state vancomycin troughs.

Association Between Enoxaparin Dosage Adjusted by Anti–Factor Xa Trough Level and Clinically Evident Venous Thromboembolism After Trauma

ImportanceTrauma patients are at high risk for developing venous thromboembolism (VTE). The VTE rate when enoxaparin sodium is dosed by anti–factor Xa (anti-Xa) trough level is not well described.ObjectiveTo determine whether targeting a prophylactic anti-Xa trough level by adjusting the enoxaparin dose would reduce the VTE rate in trauma patients.Design, Setting, and ParticipantsSingle-institution, historic vs prospective cohort comparison study at an urban, academic, level I trauma center. The prospective cohort was enrolled from August 2014 to May 2015 and compared with a historic cohort admitted from August 2013 to May 2014. Trauma patients who received enoxaparin adjusted by anti-Xa trough level (adjustment group) were compared with those who received enoxaparin sodium at a dosage of 30 mg twice daily (control group). Patients were excluded if they were younger than 18 years, had a length of hospital stay less than 2 days, or had preexisting deep vein thrombosis. Patients were excluded from the adjustment group for changes in the choice of thromboprophylaxis (heparin, enoxaparin once-daily dosing, early ambulation), hospital discharge before initial trough levels could be drawn, or incorrect timing of trough levels.ExposuresAnti-Xa trough levels were monitored in patients in the adjustment group receiving 3 or more consecutive doses of enoxaparin sodium, 30 mg twice daily. Patients with a trough level of 0.1 IU/mL or lower received enoxaparin sodium increased by 10-mg increments. After providing 3 adjusted doses of enoxaparin, the trough level was redrawn and the dosage was adjusted as necessary. Patients in the control group received enoxaparin sodium at a dosage of 30 mg twice daily without adjustments.Main Outcomes and MeasuresRates of symptomatic VTE (deep vein thrombosis and pulmonary embolism, confirmed by duplex ultrasonography and chest computed tomographic angiography, respectively) and bleeding risk.ResultsA total of 205 patients (mean [SD] age, 41.3 [18.2] years; 75.1% male) were studied, 87 in the adjustment group and 118 in the control group, with similar baseline characteristics and injury profiles. Subprophylactic anti-Xa troughs were noted in 73 of 87 patients (83.9%) in the adjustment group, and the majority of patients (57 of 87 patients [65.5%]) required dosage adjustment of enoxaparin sodium to 40 mg twice daily. Incidence of VTE was significantly lower in the adjustment group than in the control group (1.1% vs 7.6%, respectively; P = .046). When the adjustment group was compared with the control group, no significant difference was noted in the rate of packed red blood cell transfusion (6.9% vs 12.7%, respectively; P = .18) or mean (SD) hematocrit at discharge (34.5% [6.3%] vs 33.4% [6.8%], respectively [to convert to proportion of 1.0, multiply by 0.01]; P = .19).Conclusions and RelevanceIn this study, subprophylactic anti-Xa trough levels were common in trauma patients. Enoxaparin dosage adjustment may lead to a reduced rate of VTE without an increased risk of bleeding.

Rapid Attainment of Optimal Trough Concentrations in Organ Failure Mitigated by Teicoplanin

The effective treatment of infections with teicoplanin requires an initial loading dose to reach optimal trough concentrations rapidly enough. The optimal dosage of teicoplanin was previously established, and an optimal trough concentration of 15-20 μg/mL was assumed based on weight and estimated creatinine clearance. Teicoplanin treatment was performed with software-based monitoring of teicoplanin concentrations. We compared serum chemistry parameters and sequential organ failure assessment (SOFA) scores in patients with initial teicoplanin trough concentrations 0.05). Teicoplanin initial trough concentrations have been thought to contribute to improvement of organ failure. To maintain therapeutic concentrations of teicoplanin in patients with high disease severity, it was useful to ensure that initial trough values were ≥ 15 μg/mL. The initial dosage schedule of teicoplanin in emergency intensive care should consider disease severity.

Currently used dosage regimens of vancomycin fail to achieve therapeutic levels in approximately 40% of intensive care unit patients.

ObjectiveThis study aimed to assess whether currently used dosages of vancomycin for treatment of serious gram-positive bacterial infections in intensive care unit patients provided initial therapeutic vancomycin trough levels and to examine possible factors associated with the presence of adequate initial vancomycin trough levels in these patients.MethodsA prospective descriptive study with convenience sampling was performed. Nursing note and medical record data were collected from September 2013 to July 2014 for patients who met inclusion criteria. Eighty-three patients were included. Initial vancomycin trough levels were obtained immediately before vancomycin fourth dose. Acute kidney injury was defined as an increase of at least 0.3mg/dL in serum creatinine within 48 hours.ResultsConsidering vancomycin trough levels recommended for serious gram-positive infection treatment (15 - 20µg/mL), patients were categorized as presenting with low, adequate, and high vancomycin trough levels (35 [42.2%], 18 [21.7%], and 30 [36.1%] patients, respectively). Acute kidney injury patients had significantly greater vancomycin trough levels (p = 0.0055, with significance for a trend, p = 0.0023).ConclusionSurprisingly, more than 40% of the patients did not reach an effective initial vancomycin trough level. Studies on pharmacokinetic and dosage regimens of vancomycin in intensive care unit patients are necessary to circumvent this high proportion of failures to obtain adequate initial vancomycin trough levels. Vancomycin use without trough serum level monitoring in critically ill patients should be discouraged.

The Impact of Pharmacist Led Vancomycin Order Set Implementation in a Computerized-Prescriber-Order-Entry (CPOE) System at a Tertiary Care Centre: A Quasi Experimental Study

Introduction: Our hospital has developed a vancomycin protocol in order to improve vancomycin dosing and prevent improper sampling time of vancomycin levels and treatment failure. The study objective is to evaluate the impact of implementing a vancomycin order set integrated into a Computerized-Prescriber-Order-Entry (CPOE) system by pharmacist in adult surgical wards to optimize vancomycin dosing and monitoring. Primary objective: Evaluation of the correct sampling time of vancomycin trough levels by implementing a vancomycin order set guiding nurses and physicians on the appropriate sampling time. Secondary objectives: Evaluation of the impact of vancomycin order set integrated into CPOE system on vancomycin initial doses, appropriate use based on indication and time to reach target therapeutic level. Method: This study was a prospective quasi-experimental study. Patients who are >18 years, admitted to surgical wards, receiving new vancomycin orders, creatinine clearance ≥15 ml/min and weighing 40-120 kg were eligible. We excluded patients receiving vancomycin loading doses, prophylaxis, treatment course <5 days and random or peak vancomycin levels. Educational sessions were provided to the surgical residents on the use the order set by pharmacy resident, subsequently vancomycin orders were then reassessed after the order set implementation. Results: Total of 272 vancomycin trough levels were collected (136 levels in the pre-phase and 136 levels in the post-implementation phase) from 33 patients who met the study eligibility criteria. A 10% reduction in inappropriate vancomycin trough levels in the post-implementation phase was observed compared to the pre-phase (p=0.478) Appropriate vancomycin initial doses for the study patients were 2 out of 11 doses (18%) in the pre-phase and 22 doses in the post-phase (50%) (p=0.078). Conclusion: The implementation of an institutional vancomycin order set did not result in a significant change in appropriate vancomycin initial dosing and trough level sampling time in the adult surgical wards in our hospital.

Pharmacist and Physician Collaborative Practice Model Improves Vancomycin Dosing in an Intensive Care Unit.

Objective:A pharmacist and physician collaborative practice intervention to improve the initial dosing of vancomycin was implemented with the goal of decreasing the number of subtherapeutic first troughs and increasing the number of therapeutic troughs.Methods:Using the best available evidence, a nomogram was created to determine the initial vancomycin dose. The nomogram utilized actual bodyweight and glomerular filtration rate (eGFR) estimated with the MDRD4 equation. The dose was based on the 2009 ASHP/IDSA/SIDP guidelines, which recommended 15–20 mg/kg every 8–12 hours. Providers ordered “vancomycin IV dosed per pharmacy”.Results:The pre- (n = 75) and post-intervention (n = 108) cohorts had similar age, gender distribution, weight, and eGFR. The median total daily vancomycin dose was similar in pre- and post-intervention groups (2000 mg), although the median first trough was higher following the intervention (13.0 vs. 14.8 mcg/ml, p = 0.03). Following the intervention, the proportion of first troughs under 10 mcg/ml decreased (32% to 13%, p = 0.003), while the proportion of troughs in the 10 – 20 mcg/ml therapeutic range increased (50.7% vs. 69.4%, p= 0.01). There was no difference in the proportion of troughs over 20 mcg/ml (17.3% vs. 17.6%, p= 0.96).Conclusions:A multi-disciplinary intervention utilizing a nomogram-based pharmacy collaborative practice model significantly improves the proportion of therapeutic initial vancomycin troughs and decreases the number of subtherapeutic troughs by half.

Extended Simulation of Tropical Cyclone Formation in the Western North Pacific Monsoon Trough

Abstract Previous studies suggest that the low-frequency background makes an important contribution to the predictability of tropical cyclone (TC) activity on the intraseasonal time scale by providing large-scale conditions favorable for TC formation. Extended numerical experiments were conducted to demonstrate additional low-frequency influence on TC activity, which results from the development of a synoptic-scale wave train. The cyclonic circulation of the wave train provides low-level synoptic-scale disturbances for TC formation. The observed TC formation events over the western North Pacific during 14 August–10 September 2004 were first successfully simulated with the initial and lateral conditions derived from the National Centers for Environmental Prediction (NCEP) Final (FNL) Operational Global Analysis. Then the 27-day extended experiment was repeated only with the initial and lateral boundary conditions derived from the FNL low-frequency (longer than 20 days) background. It is found that the development of the synoptic-scale wave train can be well simulated with TCs forming in the cyclonic circulations of the wave train although the wavelength of the simulated wave train is substantially reduced in the absence of higher-frequency influences with periods shorter than 20 days. Sensitivity experiments indicate that the development of wave trains is sensitive to the initial monsoon trough structure. This study suggests that the synoptic-scale wave train can develop in situ and does not need upstream precursors.

An Evaluation of Systemic Vancomycin Dosing in Obese Patients.

We retrospectively identified 67 patients with severe or morbid obesity (body mass index ≥35 kg/m2) who had received intravenous vancomycin at our institution. We observed that an initial dose of 45 to 65 mg/kg vancomycin per day based upon ideal body weight rather than actual body weight was more predictive of initial trough concentrations between 15 and 20 mcg/mL.

Identification of Risk Factors for Initial Elevated Vancomyin Trough Concentrations.

Background: Recent literature suggests that elevated vancomycin trough concentrations (>20 µg/mL) may be associated with an increased risk of nephrotoxicity and lead to an increase in mortality and hospital length of stay. Objective: The purpose of this study was to identify variables that may be predictive of elevated initial vancomycin trough concentrations. Methods: Retrospective case-control study of all adult patients who had an initial vancomycin trough concentration measured between January 1, 2013, and December 31, 2014. Case patients had an initial trough concentration >20 µg/mL, while control patients had an initial trough concentration of ≤20 µg/mL. Patients were excluded from the study if they were in the intensive care unit, had unstable renal function, or if they had cystic fibrosis, solid organ transplant, or bone marrow transplant. Results: Of the 512 vancomycin trough concentrations reviewed, 54 patients met the case definition, while 140 patients were randomly selected as controls. In a multivariate model, baseline serum creatinine, body mass index, heart failure, and malignancy were all independently predictive of an initial vancomycin concentration >20 µg/mL. Conclusions: Reduced baseline renal function coupled with increasing body mass index is associated with an increased risk of an elevated initial vancomycin trough concentration. This risk is further enhanced by the presence of heart failure and/or malignancy. When these risk factors are present, it may be prudent to consider implementation of individualized dosing to achieve initial target concentrations.