Ex vivo assessment of sulbactam-durlobactam clearance during continuous renal replacement therapy to guide dosing recommendations
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Sulbactam-durlobactam is approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. Patients with serious Acinetobacter infections may require support with continuous renal replacement therapy (CRRT), which presents challenges for optimal dosing of antibiotics. Sulbactam-durlobactam dosing regimens were derived for this population using an ex vivo CRRT model and Monte Carlo simulation (MCS). Transmembrane clearance (CLTM) was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets and with effluent rates of 1, 2, and 3 L/h. Pre-filter, post-filter blood, and effluent samples were collected over 60 min to calculate sieving (SC) and saturation (SA) coefficients for CVVH and CVVHD, respectively. An established population pharmacokinetic model was integrated with the CLTM; then, a 1,000 patient MCS was conducted to determine exposures of potential dosing regimens. Adsorption and degradation in the ex vivo CRRT model were negligible. The overall mean ± standard deviation SC/SA was 1.14 ± 0.12 and 0.93 ± 0.08 for sulbactam and durlobactam, respectively. In multivariable regression analyses, effluent rate was the primary driver of CLTM for both drugs. For effluent rates <3 L/h, sulbactam-durlobactam 1 g-1g q8h as 3 h infusion achieved a high probability of pharmacodynamic target attainment while retaining area under the curve exposures consistent with the standard dose in non-CRRT patients. For effluent rates ≥3 to 5 L/h, the optimal regimen was 1 g-1g q6h 3 h infusion. Sulbactam-durlobactam regimens that provide optimum drug exposures for efficacy and safety were identified for CRRT based on the prescribed effluent rate.Keywords:
Ex vivo
Renal replacement therapy
Metabolic clearance rate
Sulbactam
Category: RRT Technique Characteristics Presenter: Dr WAN HASNUL HALIMI WAN HASSAN Keywords: CRRT, AKI, Fixed CRRT dosing, Adjustable CRRT dosing, outcome
Renal replacement therapy
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Introduction: Children are at increased risk of medication-associated adverse events, often due to weight-based dosing errors. We aimed to reduce the proportion of medications that were administered where the dosing weight was ≥ 10% different from the recorded weight. Methods: We adopted in-situ usability testing to iteratively improve design of clinical decision support that would enable accurate dosing weight documentation by prompting clinicians to update weight if recorded weight was > 10% different and it had been at least 7 days since the last dosing weight update. Results: The proportion of medication administrations with difference >10% between their recorded weight and dosing weight decreased from 13.1% (56,256/ 429,006) in the baseline period to 9.5% (35,560 / 372,443) in the intervention period (P < 0.001). Discussion and Conclusion: User-centered design of an interruptive alert improved the accuracy of dosing weights during medication administrations without substantial alert burden. In-situ usability testing is an effective approach to rapidly obtain feedback from frontline users and iterate on the design to effect desired behavior changes
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Abstract A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration‐approved manufacturer’s labels, and published studies in the literature. One hundred twenty‐six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty‐two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information.
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Long term daily dosing for patients and families may be challenging due to food aversions, dosing protocols, and age of the patient. The few long term studies suggest that low quantity daily dosing is associated with passing higher dose challenges over the long term, whereas high dose maintenance may protect for longer avoidance intervals. We review the data for peanut and suggest several strategies for your patients.
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To reduce dosing errors when administering orally ingested over-the-counter liquid medications, the US Food and Drug Administration (FDA) and the Consumer Healthcare Products Association released voluntary recommendations for dosing directions and dosing devices. This study assessed recommendation adherence for national brand name orally ingested over-the-counter liquid pediatric analgesics/antipyretics and cough, cold, and allergy medications available after the FDA guidance was finalized in 2011 to identify and prioritize specific improvements to dosing directions and devices.Recommendations were categorized as top tier or low tier based on potential to directly address ≥3-fold dosing errors. Two independent reviewers assessed dosing directions and accompanying dosing devices for adherence to recommendations.Of 68 products, 91% of dosing directions and 62% of dosing devices adhered to all top tier recommendations; 57% of products adhered to every top tier recommendation, and 93% adhered to all or all but one. A dosing device was included with all products. No dosing directions used atypical volumetric units (eg, drams), and no devices used volumetric units that did not appear in dosing directions. Six products used trailing zeros or failed to use leading zeros with decimal doses; eight did not use small font for fractions. Product adherence to low tier recommendations ranged from 26% to 91%.Products adhered to most recommendations in the final FDA guidance and Consumer Healthcare Products Association guideline, suggesting that these voluntary initiatives promote adherence to recommendations. Improving adherence to recommendations should be prioritized based on potential to reduce harm.
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This chapter explains the rational behind the concept of pharmacokinetics-guided dosing and dashboards, and the expected benefit of dashboards in improving therapy with monoclonal antibodies in inflammatory disease. It outlines a brief description of the various dosing strategies (both the induction and maintenance phases). In four dosing strategies, induction phase doses were administered as a two-hour intravenous infusion fixed at 5 mg kg-1 at Weeks 0, 2, and 6 as per label recommendations. Maintenance phase doses varied depending on the strategy: label dosing, stepwise adaptive dosing, proportional adaptive dosing, and Bayesian adaptive dosing. The goal of adaptive dosing strategies using Bayesian systems is to identify a dose/dosing frequency that maximizes the likelihood of an individual patient achieving a target exposure associated with an improved clinical outcome. The development of Bayes dosing systems in inflammatory bowel diseases currently presents challenges in defining how the development and implementation of such devices are funded, reimbursed, and implemented clinically.
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This study investigated whether dosing frequency affects antipsychotic medication adherence among patients with schizophrenia.Databases from the Department of Veterans Affairs were used to assess adherence among patients with a diagnosis of schizophrenia. Adherence was measured by using antipsychotic medication possession ratios (MPRs). Adherence was compared among patients who experienced an increase or decrease in dosing frequency and among patients on stable regimens of once-daily or more than once-daily dosing.Among patients with a dose increase (N=1,639), those with increases in dosing frequency (N=258) had a mean change in MPRs of -.105, compared with -.002 for those without a dosing frequency change (N=1,381) (p<.001). Patients with decreases in dosing frequency (N=1,370) had a small but significant increase in mean MPRs (MPR change=.045) when compared with 2,740 patients without a dosing frequency change (MPR change=-.018) (p<.001). Among patients on stable regimens (N=32,612), there were no significant differences in MPRs between those receiving once-daily dosing (MPR=.80) and those receiving more than once-daily dosing (MPR=.80).Among patients on less stable dosing regimens, increases in dosing frequency may result in modest decreases in adherence.
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Sensitivity and specificity of dosing alerts for dosing errors among hospitalized pediatric patients
To determine the sensitivity and specificity of a dosing alert system for dosing errors and to compare the sensitivity of a proprietary system with and without institutional customization at a pediatric hospital.A retrospective analysis of medication orders, orders causing dosing alerts, reported adverse drug events, and dosing errors during July, 2011 was conducted. Dosing errors with and without alerts were identified and the sensitivity of the system with and without customization was compared.There were 47,181 inpatient pediatric orders during the studied period; 257 dosing errors were identified (0.54%). The sensitivity of the system for identifying dosing errors was 54.1% (95% CI 47.8% to 60.3%) if customization had not occurred and increased to 60.3% (CI 54.0% to 66.3%) with customization (p=0.02). The sensitivity of the system for underdoses was 49.6% without customization and 60.3% with customization (p=0.01). Specificity of the customized system for dosing errors was 96.2% (CI 96.0% to 96.3%) with a positive predictive value of 8.0% (CI 6.8% to 9.3). All dosing errors had an alert over-ridden by the prescriber and 40.6% of dosing errors with alerts were administered to the patient. The lack of indication-specific dose ranges was the most common reason why an alert did not occur for a dosing error.Advances in dosing alert systems should aim to improve the sensitivity and positive predictive value of the system for dosing errors.The dosing alert system had a low sensitivity and positive predictive value for dosing errors, but might have prevented dosing errors from reaching patients. Customization increased the sensitivity of the system for dosing errors.
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Studies have reported high prevalence of inappropriate dosing in patients with renal impairment, which was significantly reduced with pharmacists' interventions. The objective of this study was to assess the proportions of renal drug dosing errors following the implementation of pharmacists-led renal drug dosing adjustment program. This was a quasi-experimental study conducted at the King Abdul Aziz Medical City, a tertiary teaching hospital, Jeddah, Saudi Arabia. The study comprised of 3 phases. The pre-phase and post-phase evaluated drug orders for dosing appropriateness. During the intervention phase, a renal drug dosing adjustment program was implemented, which included educational sessions on dosing in renal insufficiency and a renal drug dosing guidance. The primary outcome was to assess the change in the proportions of dosing errors following the intervention. In the pre-phase, inappropriate dosing was noted in 20.1% (70/348) of orders that required dosing adjustment. Among the total dosing errors, 44.2% (31/70) were further corrected, and pharmacists have documented intervention in 48.3% (15/31) of the corrected orders. In the post-phase, inappropriate dosing was noted in 21.9% (76/346) of orders that required dosing adjustment. Among the total dosing errors, 39.4% (30/76) were further corrected, and pharmacists have documented intervention in 66.6% (20/30) of the corrected orders. There was no statistically significant difference in inappropriate drug dosing between pre-phase and post-phase with a P = 0.56. The intervention was not associated with significant reduction in renal dosing errors, although pharmacist involvement in the corrected orders orders increased after the implementation of the intervention. This may indicate the need to integrate renal dosing guidance into the hospital prescribing system to optimize drug dosing in renal patients.
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Nivolumab has received regulatory approval to be given by weight-based or flat dosing every two weeks or by flat dosing every four weeks. However, flat dosing would lead to unnecessarily high doses for patients with lower body weight, increasing the drug usage and probability of toxicity. We review the rationale of using a four-weekly hybrid dosing strategy using weight-based and flat-dosing regimens adopted by some jurisdictions.
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