Eric Shore

A Pilot Study of the Safety and Efficacy of Tobramycin Solution for Inhalation in Patients With Severe Bronchiectasis

STUDY OBJECTIVE To evaluate the efficacy and safety of tobramycin solution for inhalation (TSI) in patients with severe bronchiectasis. DESIGN Open-label clinical trial consisting of three treatment cycles (14 days of drug therapy, and 14 days off drug) and an additional 40-week follow-up by chart review. SETTING Nine clinical sites throughout the United States. SUBJECTS Forty-one adult patients (>/= 18 years old) with diffuse bronchiectasis affecting two or more lung segments and a history of Pseudomonas aeruginosa infection. INTERVENTIONS TSI, 300 mg tobramycin per dose bid. MEASUREMENTS AND RESULTS During the 12-week treatment period, significant improvements (reduction of 1.5 U [p = 0.006]) occurred in mean pulmonary total symptom severity score, a composite score that assesses the severity of cough, shortness of breath, sputum production, fatigue, and wheezing. Significant improvements (reduction of 9.8 U [p < 0.001]) were also observed in St. George Respiratory Questionnaire scores, which measure health-related quality of life. Eradication or presumed eradication of P aeruginosa occurred in 6 of 27 evaluable subjects (22.2%). Tobramycin-resistant P aeruginosa developed in two subjects (minimal inhibitory concentration >/= 16 microg/mL). Ten subjects withdrew from the study due to adverse events; in nine of these subjects, adverse events were considered probably or possibly related to treatment. The most common adverse events were cough, wheezing, and dyspnea. CONCLUSIONS TSI therapy resulted in significant improvements in respiratory symptoms and health-related quality of life in subjects with severe bronchiectasis, but some subjects did not tolerate TSI therapy. Bronchiectasis patients receiving this therapy should be monitored for signs of intolerance.

Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia

BACKGROUND Because of the high frequency of multidrug resistant bacteria in our intensive care units (ICUs), we implemented a ventilator-associated pneumonia (VAP) clinical pathway based on unit-specific minimum inhibitory concentration (MIC) distributions and pharmacodynamic modeling in 3 of our ICUs. METHODS This was a prospective, observational evaluation with a historical control group in adult patients (n = 168) who met clinical and radiologic criteria for VAP. Monte Carlo simulation was used to determine antibiotic regimens having the greatest likelihood of achieving bactericidal exposures against Pseudomonas aeruginosa. Antibiotic regimens were incorporated into an ICU-specific computerized clinical pathway as empiric agents of choice. RESULTS Pharmacodynamic modeling found 3-hour infusions of cefepime 2 g every 8 hours or meropenem 2 g every 8 hours plus tobramycin and vancomycin would provide the greatest probability of empirically treating VAP in these ICUs. Infection-related mortality was reduced by 69% (8.5% vs 21.6%; P = .029), infection-related length of stay was shorter (11.7 +/- 8.1 vs 26.1 +/- 18.5; P < .001), and fewer superinfections were observed in patients treated on the pathway. A number of patients with nonsusceptible P aeruginosa were successfully treated with high-dose, 3-hour infusion regimens. CONCLUSIONS In our ICUs where multidrug resistant bacteria are common, an approach considering ICU-specific antibiotic MICs coupled with pharmacodynamic dosing strategies resulted in improved outcomes and shorter duration of treatments.

Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

ABSTRACT 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 (AUC0–24) for ELF and AM relative to the free AUC0–24 (fAUC0–24) 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 AUC0–24 in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC0–24 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.

Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults.

ABSTRACT Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC0-τ) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC0-τ in plasma. The mean (standard deviation) half-life and AUC0-τ were 6.9 (2.1) h and 39.5 (19.8) μg·h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) μg·h/ml, respectively, for anidulafungin. The AUC0-τ values for ELF and AM were 282 and 178 μg·h/ml, respectively, for voriconazole, and 21.9 and 1,430 μg·h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC90/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.

Phase I, Open-Label, Safety and Pharmacokinetic Study To Assess Bronchopulmonary Disposition of Intravenous Eravacycline in Healthy Men and Women

ABSTRACT 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.

Bronchopulmonary Disposition of Micafungin in Healthy Adult Volunteers

ABSTRACT By way of bronchoscopy and bronchoalveolar lavage, intrapulmonary steady-state concentrations of micafungin administered at 150 mg daily to 15 healthy volunteers were determined at 4, 12, and 24 h after the third dose. The micafungin disposition was predominantly intracellular, with approximately 106% penetration into alveolar macrophages and 5% penetration into epithelial lining fluid.

Tackling Empirical Antibiotic Therapy for Ventilator-Associated Pneumonia in Your ICU: Guidance for Implementing the Guidelines

Guidelines published jointly by the American Thoracic Society and Infectious Diseases Society of America endorse the practice of appropriate empirical antibiotic therapy for ventilator-associated pneumonia (VAP) and even provide recommendations for specific antibiotics based on whether a patient has risk factors for multidrug-resistant infections. Unfortunately, the current guidelines provide little insight into how a specific institution can best develop a strategy for providing empirical antibiotic therapy. This review article focuses on important steps that should be taken in developing a hospital-specific pathway for the empirical antibiotic treatment of VAP. Consideration should be given to developing a multidisciplinary group to obtain intensive care unit (ICU)-specific antibiograms for the most common causative organisms, real-time minimum inhibitory concentration (MIC) data or MIC distributions from surveillance studies over a representable time frame, and implementing empirical dosage strategies aimed at achieving not only appropriate therapy but also optimal therapy based on pharmacodynamic targets. A proper deescalation strategy will also be vital to managing antibiotic choices and dosages, as well as providing useful recommendations for discontinuation of therapy. Finally, continued feedback of program results is critical to maintaining compliance as well as for reevaluating empirical antibiotic choices.

Cerebral Edema During Treatment of Diabetic Ketoacidosis in an Adult With New Onset Diabetes

Introduction: Diabetic ketoacidosis (DKA) continues to be a medical emergency, in part because of a rare and devastating complication associated with its treatment, cerebral edema. In children, cerebral edema is the principal cause of mortality, but clinically significant cerebral edema in adults is rare.Methods and Results: We report the case of a 27-year-old male (not previously known to be diabetic) who presented with a first episode of DKA complicated by the development of fatal cerebral edema despite medical treatment.Conclusion: The pathophysiological mechanisms for cerebral edema associated with DKA occuring in children and adults are believed to be similar and are discussed in this report. However, patients who develop cerebral edema may deteriorate rapidly, and experience with successful treatment has been limited.