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 Unusual Cause of a Solitary Lung Cavity.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary involvement is common, but lung nodules in sarcoidosis are uncommon, and solitary nodules that cavitate are extremely rare. Nodular sarcoidosis is usually found in young, healthy, predominantly female individuals. These lesions need to be differentiated from multiple other conditions, including neoplasms and granulomatous infections. A thorough workup for other etiologies of cavitary lung lesions is required for diagnosis. Despite an ominous presentation, nodular cavitary sarcoidosis portends a favorable outcome. We report a patient who presented with a solitary cavitary nodular lung lesion that was diagnosed as sarcoidosis after extensive workup.

Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women.

This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC0-12) for each respective parameter against free drug AUC (fAUC0-12) in plasma. The total AUC0-12 in plasma was 4.56±0.94 µg·h/ml with a mean fAUC0-12 of 0.77±0.14 µg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means±the standard deviations (µg/ml) of 0.70±0.30, 0.57±0.20, 0.34±0.16, and 0.25±0.13 with a penetration ratio of 6.44 and 8.25±4.55, 5.15±1.25, 1.77±0.64, and 1.42±1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.

Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers.

This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC(0-24)) for ELF and AM relative to the free AUC(0-24) (fAUC(0-24)) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC(0-24) in plasma was 25.13 ± 5.78 µg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC(0-24) of 2.65 ± 0.72 µg · h/ml in plasma. Mean concentrations (µg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

Probable enoxaparin-induced hepatotoxicity.

PURPOSE: A case of probable enoxaparin-induced hepatotoxicity is described. SUMMARY: A 29-year-old woman sought treatment from a pulmonologist for a dry, hacking, constant cough not relieved by fast-acting inhalers or narcotic cough medications that had lasted for three weeks. Her primary care physician had earlier made a preliminary diagnosis of pertussis and prescribed a short course of azithromycin and corticosteroids, which did not help relieve the symptoms. Computed tomography angiography of her chest revealed multiple bilateral pulmonary emboli with a moderate clot burden, which resulted in her hospitalization. The pulmonary emboli were thought to be associated with her oral contraceptive, which was discontinued at hospital admission. Anticoagulant therapy was initiated with subcutaneous enoxaparin and oral warfarin. Beginning the second day of therapy, the patient complained of nausea and associated vomiting. Diagnostic procedures did not reveal any liver, kidney, splenic, or pancreatic abnormalities. The results of laboratory tests revealed elevated levels of hepatic enzymes, including alanine transaminase (ALT) and aspartate transaminase (AST). Tests for hepatitis A, B, and C were negative. Enoxaparin therapy was discontinued, and the patient was maintained on oral warfarin. Clinical and laboratory signs of liver injury resolved over the next few days, with a return to baseline levels of AST and ALT levels over the subsequent months. According to the Naranjo et al. adverse-reaction probability scale, enoxaparin was the probable cause of hepatotoxicity in this patient. CONCLUSION: A woman receiving enoxaparin every 12 hours developed signs and symptoms of hepatotoxicity after the second dose. The case was unusual in the rapidity and magnitude of hepatic enzyme elevation.

Pulmonary arterial hypertension: an overview of current pharmacologic treatment.

Various pharmacologic options exist for patients with PAH. Their overall effect on the disease is modest; however, with proper selection and monitoring they can improve symptoms and improve the quality and duration of life. Patient education is vital to ensure the proper use of these medications. Initial and continued responses vary greatly between patients necessitating trials of several different medications for some patients to achieve optimal outcomes. While newer agents may be better tolerated than older ones, improved efficacy has not yet been observed. In the future, improved outcomes may rely on determining optimal combination strategies.

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.