Dose Ratios between High Dose Oral Morphine or Equivalents and Oral Methadone

Background: Methadone is a commonly used opioid in hospice and palliative care for patients with refractory pain. Various methadone dose conversion methods utilize progressively higher morphine equivalent dose (MED) to methadone dose ratios to compensate for increased methadone potency with escalating opioid doses. Objective: The purpose of this study was to determine the dose ratio between equianalgesic doses of high dose oral morphine (daily doses \u3e1200 mg morphine or MED) and oral methadone. Methods: This study was a retrospective chart review of 324 patients who received methadone at Strong Memorial Hospital or the associated outpatient clinic during a nine-month period in 2011. Ten patients met the study inclusion and exclusion criteria. A Wilcoxon signed-rank test was used to compare the pain scale scores. The Spearman correlation coefficient was used to assess level of correlation between morphine dose and methadone dose. Results: Patients rotated to methadone from high opioid doses had a two-point improvement in median pain scale scores after conversion (p=0.039). However, there was no correlation identified for patients taking daily doses \u3e1200 mg oral morphine or MED prior to methadone rotation (p=0.19). There were no reported methadone adverse effects during the study. Conclusions: No correlation was identified between high MED doses and methadone at dose stabilization after opioid rotation. A fixed maximum methadone dose of 30 mg/day produced clinically meaningful improvements in pain scores without adverse drug effects. Caution should be exercised before considering rotation to methadone doses higher than 30 mg/day in a patient receiving \u3e1200 mg oral MED/day

Initial Characterization of Micafungin Pulmonary Delivery via Two Different Nebulizers and Multivariate Data Analysis of Aerosol Mass Distribution Profiles

Pharmaceutical aerosols have been targeted to the lungs for the treatment of asthma and pulmonary infectious diseases successfully. Micafungin (Astellas Pharma US, Deerfield, IL, USA) has been shown to be an effective antifungal agent when administrated intravenously. Pulmonary delivery of micafungin has not previously been reported. In the present pilot study, we characterize the performance of two nebulizers and their potential for delivering micafungin to the lungs as well as the use of multivariate data analysis for mass distribution profile comparison. The concentration of micafungin sodium increased by 21% when delivered by the Acorn II nebulizer and by 20% when delivered by the LC Plus nebulizer, respectively, from the first to the second sampling period. The Acorn II nebulizer delivered a fine particle fraction FPF(5.8) (%<5.8 microm) of 92.5 +/- 0.8 and FPF(3.3) (%<3.3 microm) of 82.3 +/- 2.1 during the first sampling period. For the LC Plus nebulizer, FPF(5.8) was 92.3 +/- 0.1 and FPF(3.3) was 67.0 +/- 0.7 during the first sampling period. The mass median aerodynamic diameter (MMAD) increased from 1.67 +/- 0.05 to 1.77 +/- 0.04 mum (Acorn II nebulizer) and from 2.09 +/- 0.01 to 2.20 +/- 0.01 microm (Pari LC Plus nebulizer) from the first to the second sampling periods. These changes in MMAD were statistically significant by paired t test. Multivariate data analysis showed that this could be explained systematically by greater drug deposition on stages with larger cutoff sizes and reduced drug deposition on stages with smaller cutoff sizes rather than multimodal deposition or other anomalies in size distribution

Significant regional differences in antibiotic use across 576 US hospitals and 11 701 326 adult admissions, 2016-2017

BACKGROUND: Quantifying the amount and diversity of antibiotic use in United States hospitals assists antibiotic stewardship efforts but is hampered by limited national surveillance. Our study aimed to address this knowledge gap by examining adult antibiotic use across 576 hospitals and nearly 12 million encounters in 2016-2017. METHODS: We conducted a retrospective study of patients aged ≥ 18 years discharged from hospitals in the Premier Healthcare Database between 1 January 2016 and 31 December 2017. Using daily antibiotic charge data, we mapped antibiotics to mutually exclusive classes and to spectrum of activity categories. We evaluated relationships between facility and case-mix characteristics and antibiotic use in negative binomial regression models. RESULTS: The study included 11 701 326 admissions, totaling 64 064 632 patient-days, across 576 hospitals. Overall, patients received antibiotics in 65% of hospitalizations, at a crude rate of 870 days of therapy (DOT) per 1000 patient-days. By class, use was highest among β-lactam/β-lactamase inhibitor combinations, third- and fourth-generation cephalosporins, and glycopeptides. Teaching hospitals averaged lower rates of total antibiotic use than nonteaching hospitals (834 vs 957 DOT per 1000 patient-days; P \u3c .001). In adjusted models, teaching hospitals remained associated with lower use of third- and fourth-generation cephalosporins and antipseudomonal agents (adjusted incidence rate ratio [95% confidence interval], 0.92 [.86-.97] and 0.91 [.85-.98], respectively). Significant regional differences in total and class-specific antibiotic use also persisted in adjusted models. CONCLUSIONS: Adult inpatient antibiotic use remains high, driven predominantly by broad-spectrum agents. Better understanding reasons for interhospital usage differences, including by region and teaching status, may inform efforts to reduce inappropriate antibiotic prescribing

Electronically available patient claims data improve models for comparing antibiotic use across hospitals: Results from 576 US facilities

BACKGROUND: The Centers for Disease Control and Prevention (CDC) uses standardized antimicrobial administration ratios (SAARs)-that is, observed-to-predicted ratios-to compare antibiotic use across facilities. CDC models adjust for facility characteristics when predicting antibiotic use but do not include patient diagnoses and comorbidities that may also affect utilization. This study aimed to identify comorbidities causally related to appropriate antibiotic use and to compare models that include these comorbidities and other patient-level claims variables to a facility model for risk-adjusting inpatient antibiotic utilization. METHODS: The study included adults discharged from Premier Database hospitals in 2016-2017. For each admission, we extracted facility, claims, and antibiotic data. We evaluated 7 models to predict an admission\u27s antibiotic days of therapy (DOTs): a CDC facility model, models that added patient clinical constructs in varying layers of complexity, and an external validation of a published patient-variable model. We calculated hospital-specific SAARs to quantify effects on hospital rankings. Separately, we used Delphi Consensus methodology to identify Elixhauser comorbidities associated with appropriate antibiotic use. RESULTS: The study included 11 701 326 admissions across 576 hospitals. Compared to a CDC-facility model, a model that added Delphi-selected comorbidities and a bacterial infection indicator was more accurate for all antibiotic outcomes. For total antibiotic use, it was 24% more accurate (respective mean absolute errors: 3.11 vs 2.35 DOTs), resulting in 31-33% more hospitals moving into bottom or top usage quartiles postadjustment. CONCLUSIONS: Adding electronically available patient claims data to facility models consistently improved antibiotic utilization predictions and yielded substantial movement in hospitals\u27 utilization rankings

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Dose Ratios between High Dose Oral Morphine or Equivalents and Oral Methadone

Background: Methadone is a commonly used opioid in hospice and palliative care for patients with refractory pain. Various methadone dose conversion methods utilize progressively higher morphine equivalent dose (MED) to methadone dose ratios to compensate for increased methadone potency with escalating opioid doses. Objective: The purpose of this study was to determine the dose ratio between equianalgesic doses of high dose oral morphine (daily doses \u3e1200 mg morphine or MED) and oral methadone. Methods: This study was a retrospective chart review of 324 patients who received methadone at Strong Memorial Hospital or the associated outpatient clinic during a nine-month period in 2011. Ten patients met the study inclusion and exclusion criteria. A Wilcoxon signed-rank test was used to compare the pain scale scores. The Spearman correlation coefficient was used to assess level of correlation between morphine dose and methadone dose. Results: Patients rotated to methadone from high opioid doses had a two-point improvement in median pain scale scores after conversion (p=0.039). However, there was no correlation identified for patients taking daily doses \u3e1200 mg oral morphine or MED prior to methadone rotation (p=0.19). There were no reported methadone adverse effects during the study. Conclusions: No correlation was identified between high MED doses and methadone at dose stabilization after opioid rotation. A fixed maximum methadone dose of 30 mg/day produced clinically meaningful improvements in pain scores without adverse drug effects. Caution should be exercised before considering rotation to methadone doses higher than 30 mg/day in a patient receiving \u3e1200 mg oral MED/day