Bronchopulmonary disposition of IV cefepime/taniborbactam (2-0.5 g) administered over 2 h in healthy adult subjects.

INTRODUCTION: Taniborbactam (formerly VNRX-5133) is an investigational ß-lactamase inhibitor in clinical development in combination with cefepime for the treatment of MDR Gram-negative pathogens. OBJECTIVES: To assess the safety profile and pulmonary disposition of 2-0.5 g cefepime/taniborbactam administered as a 2 h IV infusion every 8 h following three doses in healthy adult subjects. METHODS: In this Phase 1 trial, open-label study, plasma samples were collected over the last dosing interval, and subjects (n = 20) were randomized to undergo bronchoalveolar lavage (BAL) at four timepoints after the last dose. Drug concentrations in plasma (total and free as determined by protein binding), BAL fluid and alveolar macrophages (AM) were determined by LC-MS/MS, and the urea correction method was used to calculate epithelial lining fluid (ELF) drug concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: Mean (±SD) taniborbactam Cmax and AUC0-8 in plasma were 24.1 ±â€Š4.1 mg/L and 81.9 ±â€Š13.9 mg·h/L, respectively. Corresponding values for cefepime were 118.4 ±â€Š29.7 mg/L and 346.7 ±â€Š71.3 mg·h/L. Protein binding was 0% for taniborbactam and 22.4% for cefepime. Mean taniborbactam concentrations (mg/L) at 2, 4, 6 and 8 h were 3.9, 1.9, 1.0 and 0.3 in ELF and 12.4, 11.5, 14.3 and 14.9 in AM, with corresponding AUC0-8 ELF of 13.8 and AUC0-8 AM of 106.0 mg·h/L. Cefepime AUC0-8 ELF was 77.9 mg·h/L. No serious adverse events were observed. CONCLUSION: The observed bronchopulmonary exposures of taniborbactam and cefepime can be employed to design optimal dosing regimens for clinical trials in patients with pneumonia.

Selexipag, an Oral Prostacyclin-Receptor Agonist for Pulmonary Arterial Hypertension.

OBJECTIVE: To evaluate the data supporting the approval of selexipag and discuss its potential place in therapy for managing pulmonary arterial hypertension (PAH). DATA SOURCES: A systematic review of the literature for all relevant articles was performed through January 16, 2017, using MEDLINE and SCOPUS. A manual search of references from reports of clinical trials, review articles, and recent conference abstracts was performed to identify additional relevant studies. STUDY SELECTION AND DATA EXTRACTION: Eligible citations included in vitro or in vivo evaluations of selexipag, with no restrictions on patient population or indication. Data related to the patient populations and outcomes of interest were extracted from each citation. DATA SYNTHESIS: Single phase II and phase III trials have been published evaluating selexipag in patients with PAH. In 43 patients, the phase II trial showed that selexipag significantly reduced pulmonary vascular resistance by 30% versus placebo ( P = 0.0045) and improved 6-minute walk distance by 24 m ( P < 0.05). The larger phase III trial enrolled 1156 patients with PAH, showing that selexipag lowered the incidence of death or PAH-related complications by 40% versus placebo ( P < 0.001). Selexipag also improved 6-minute walk distance and lowered hospitalization risk. Common adverse events included headache, diarrhea, nausea, and jaw pain. CONCLUSIONS: The specific role of selexipag for managing PAH patients is unclear because of its modest efficacy, lack of mortality reduction, and cost similar to intravenous prostacyclins. Additional clinical trials exploring combination therapy as well as its role in other types of pulmonary hypertension are needed.

An evaluation of a short chest radiograph learning intervention to evaluate internal medicine residents' ability to identify basic pathologic abnormalities and normal anatomy.

BACKGROUND: The correct interpretation of chest radiographs is an essential skill for internal medicine residents. Little formal training in radiology occurs in the graduate medical curriculum for internal medicine residents. OBJECTIVE: To assess the performance of internal medicine residents in the interpretation of chest radiographs through a 1.5-hour didactic and practical session. DESIGN: Baseline performance was assessed in the first week of a four-week rotation. An intervention was performed in the second week. Post-intervention assessment was performed in the fourth week. SETTING: A university-based internal medicine residency. PARTICIPANTS: Internal medicine residents at all levels of training. INTERVENTION: A 1.5-hour review session addressing: technique, anatomy, pathophysiology and disease pattern recognition through small group didactics. MEASUREMENTS: 38 multiple choice question assessment tool designed to assess comprehension of fundamental knowledge of chest radiograph interpretation. RESULTS: At baseline, residents were able to answer 64% of questions correctly. After the intervention, 77% of questions were answered correctly, an improvement of 13 percentage points (95% CI = 8.4 percentage points to 16.3 percentage points; P = 0.0001). No significant differences in performance were demonstrated between PGY1 and upper level residents (PGY2 and PGY3) at baseline (P = 0.11), however senior residents (PGY2 and 3) were found to perform significantly better than interns after the intervention (P = 0.002). CONCLUSIONS: Internal medicine residents perform poorly at baseline in the assessment of chest films. Interventions designed to address core competencies in chest radiograph interpretation can be efficacious in improving residents' interpretive skills. The incorporation of formal education in chest radiograph diagnostic skills into graduate medical education may be of significant benefit to internal medicine residency training.

Discharge patterns of patients with asthma from the emergency department: a retrospective review.

BACKGROUND: Despite evidence that specific therapies improve outcomes in patients with asthma, they are often not used. Combining several evidence-based therapies into a treatment "bundle" to be offered at the time of discharge from the emergency department, might reduce variation and potentially optimize clinical outcomes. OBJECTIVE: To assess the utilization of four evidence-based therapies for asthma by analyzing the visits of patients with acute exacerbations of asthma discharged from the emergency department. DESIGN: A retrospective chart review. SETTING: Single 650-bed inner-city hospital emergency department. PATIENTS: Two hundred and twenty six patients discharged from the emergency department after 500 acute exacerbations of asthma. MEASUREMENTS: All visits were reviewed for the presence of the four evidence-based components of asthma treatment upon discharge: follow-up referral, oral steroids, asthma education, and inhaled corticosteroids. Visits were also assessed for medications prescribed upon discharge, medication history, and patient's asthma severity based on national guidelines. RESULTS: The four components of asthma treatment were documented as follows: follow-up referral (86.2%), oral steroids (67.8%), asthma education (19.6%), and inhaled corticosteroids (16.2%). Only 3.4% of visits documented all four components in the aggregate. Twenty-three distinct combinations of medication were prescribed upon discharge. The majority of visits failed to document asthma severity. CONCLUSIONS: This retrospective chart review reveals significant variation in the discharge management of patients with asthma, specifically regarding medications prescribed. While follow-up referral was sufficiently documented, the remaining three components were not. With only 3.4% of visits containing all four components, implementing an asthma "bundle" may present an opportunity to improve outcomes in asthma management.