The use of tobramycin for Pseudomonas aeruginosa: a review.

INTRODUCTION: Pseudomonas aeruginosa is a common respiratory pathogen that contributes to chronic pulmonary infection in individuals with cystic fibrosis. Guidelines recommend early intervention upon positive P. aeruginosa culture. Tobramycin has in vitro activity against Gram-negative bacteria, including P. aeruginosa, and TOBI Podhaler is indicated for the management of individuals with cystic fibrosis with P. aeruginosa infection. The dry powder inhaler formulation decreases the time required for treatment compared with nebulized solution and therefore may improve quality of life and adherence, which have a positive impact on disease progression. AREAS COVERED: In this review, we discuss the safety and efficacy of tobramycin inhaled powder and provide insights into appropriate individuals who might benefit from a dry powder inhaler, keeping in mind that patient preference is an important consideration for therapy selection. EXPERT OPINION: Providing a less burdensome alternative to delivering inhaled antibiotics that is more portable with a significantly shorter administration time may help improve adherence, and therefore improve outcomes. Continued development of new antibiotics to add to current regimens for eradication and control of airway microbiology, combined with more efficient delivery systems such as tobramycin inhaled powder, will help evolve the treatment of patients with CF.

Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline.

BACKGROUND: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations. METHODS: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion. RESULTS: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD. CONCLUSIONS: This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.

Aerosolized antibiotics in cystic fibrosis: an update.

Inhaled antibiotic therapy, targeting Pseudomonas aeruginosa, is a fundamental component of cystic fibrosis (CF) management. Tobramycin inhalation solution (TIS) was approved in the United States (US) in 1998. Subsequent research efforts focused on developing products with a reduced treatment time burden. Aztreonam for inhalation solution (AZLI), administered via a more efficient nebulizer than TIS, was approved in the US in 2010. Dry powder for inhalation (DPI) formulations provide alternatives to nebulized therapy: tobramycin powder for inhalation (also known as TIP™) was approved in the US in 2013, and colistimethate sodium DPI received European approval in 2012. Other aerosolized antibiotics and regimens combining inhaled antibiotics are in development. Inhaled antibiotic rotation (e.g., TIS alternating with AZLI) is an important concept being actively tested in CF.

Evolution of pattern of breathing during a spontaneous breathing trial predicts successful extubation.

PURPOSE: Rapid shallow breathing may occur at any time during spontaneous breathing trials (SBT), questioning the utility of a single determination of the rapid shallow breathing index (RSBI). We hypothesize that change in RSBI during SBT may more accurately predict successful extubation than a single determination. METHODS: Prospective observational study. Seventy-two subjects were extubated. At 24 h, 63/72 remained extubated (Extubation Success), and 9 were re-intubated (Extubation Failure). Respiratory rate (RR), tidal volume (VT) and RSBI were measured every 30 min during 2-h T-piece SBT. Change in respiratory parameters was assessed as percent change from baseline. RESULTS: Initial RSBI was similar in Extubation Success and Extubation Failure groups (77.0 +/- 4.8, 77.0 +/- 4.8, p = ns). Nevertheless, RSBI tended to remain unchanged or decreased in the Extubation Success group; in contrast RSBI tended to increase in the Extubation Failure group because of either increased RR and/or decreased VT (p < 0.001 for mean percent change RSBI over time), indicating worsening of the respiratory pattern. Quantitatively, only 7/63 subjects of the Extubation Success group demonstrated increased RSBI >or=20% at any time during the SBT. In contrast, in the Extubation Failure group, RSBI increased in all subjects during the SBT, and eight of nine subjects demonstrated an increase greater than 20%. Thus, with a 2-h SBT the optimal threshold was a 20% increase (sensitivity = 89%, specificity = 89%). Similar results were obtained at 30 min (threshold = 5% increase). Percent change of RSBI predicted successful extubation even when initial values were >or=105. CONCLUSION: Percent change of RSBI during an SBT is a better predictor of successful extubation than a single determination of RSBI.

Aerosolized antibiotics in cystic fibrosis: current and future trends.

Chronic bacterial infection is one of the key challenges in caring for patients with cystic fibrosis (CF). Effective infection control requires appropriate administration of antibiotics. Inhaled antibiotics play a pivotal role in CF management. Pathogens in CF patients target the lumen of the lung, a cavity that is difficult to access via the oral or intravenous route. Aerosolized antibiotics deliver effective local drug concentrations to the infection site and decrease the risk of systemic side effects associated with oral or intravenous antibiotics. However, effective aerosolized antibiotic therapy must ensure reliable drug delivery to the lower respiratory tract with a beneficial pharmacodynamic profile and high potency.

Systemic corticosteroid therapy for acute asthma exacerbations.

Acute exacerbations of asthma may represent reactions to airway irritants or failures of chronic treatment. The costs to both the patient and society are high. Exacerbations often are frightening episodes that can cause significant morbidity and sometimes death. The emergency department (ED) visits and hospitalizations often required lead to significant health care expenses. Thus, preventing and optimizing management of acute exacerbations is critical. Corticosteroids are a cornerstone of asthma therapy. They have been shown to lower admission rates and reduce risk of relapse. This article provides an overview of the role of corticosteroids (including betamethasone, dexamethasone, methylprednisolone, and prednisolone) in the management of acute asthma exacerbations, with an aim toward effective decision making about the choice of therapy.

Utility of the breathing reserve index at the anaerobic threshold in determining ventilatory-limited exercise in adult cystic fibrosis patients.

OBJECTIVES: Cardiopulmonary exercise testing in cystic fibrosis (CF) patients is useful to assess functional status and prognosis. Using the current interpretation guidelines, the utility of this testing will be limited in those patients who cannot exercise to a near-maximal level. This study investigates the utility of the breathing reserve index at the anaerobic threshold (BRIAT), which is defined as minute ventilation at the anaerobic threshold (AT)/maximum voluntary ventilation (MVV), to distinguish ventilatory-limited (VL) CF patients from nonventilatory-limited (NVL) CF patients. DESIGN: Exercise studies on 53 adult CF patients at baseline clinical status performed from 1993 to 1999 were reviewed, of which 40 met the inclusion criteria. The studies were performed via ramp protocol to the symptom-limited maximum on a cycle ergometer with breath-by-breath expired gas analysis. AT was determined noninvasively via the V-Slope method. The patients were classified as VL if they had abnormal spirometry findings, reduced exercise capacity, and a breathing reserve index at maximum exercise (BRImax) of > or = 0.7. NVL patients had a normal BRImax and met the criteria for a maximal study. RESULTS: VL patients (21 patients) had significantly lower FVC, FEV(1), MVV, and body mass index than NVL patients (19 patients). The BRIAT for the VL group was significantly higher than that for the NVL group (p < 0.001). Logistic regression analysis revealed that BRIAT discriminated VL patients from NVL patients better than a variety of nonexercise variables tested. The BRIAT correlated extremely well with BRImax (r = 0.89; p < 0.01), FVC (r = -0.67; p < 0.001), FEV(1) (r = -0.76; p < 0.001), and FEV(1)/FVC ratio (r = -0.683; p < 0.001). A BRIAT value of 0.29 distinguished VL CF patients from NVL CF patients with 95.2% sensitivity and 84.2% specificity. CONCLUSIONS: The BRIAT assessed noninvasively correlates well with commonly used measurements of pulmonary function and accurately distinguishes CF patients with and without a ventilatory limitation to exercise. The BRIAT may have utility in the interpretation of exercise studies in CF patients who are unable to exercise to a maximal level.

Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis.

STUDY OBJECTIVE: To determine the relationship between the antibiotic susceptibility of Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis (CF) and the patient's response to parenteral antibiotic administration, we performed a retrospective analysis using data from patients in the placebo arm of a phase 3 trial of tobramycin solution for inhalation. All patients were chronically infected with P aeruginosa. Seventy-seven of the 262 patients receiving placebo experienced a pulmonary exacerbation during the trial for which they received therapy with IV tobramycin and ceftazidime. The susceptibility of the P aeruginosa isolates to ceftazidime and tobramycin was determined at trial enrollment by broth microdilution. DESIGN: The clinical response to combination antibiotic therapy was assessed by analyzing differences in spirometry before and after antibiotic administration. The FEV(1) percent predicted at the first visit after the conclusion of antibiotic administration was compared to the FEV(1) percent predicted prior to antibiotic therapy. The results were analyzed both descriptively and by regression analyses. RESULTS: The conditions of 54 patients improved, and those of 9 patients worsened, and in 14 patients there was no change in FEV(1) with antibiotic administration. No correlation was observed between the susceptibility of P aeruginosa to tobramycin or ceftazidime and clinical response. Only the three following variables were observed to significantly correlate with FEV(1) after antibiotic treatment on regression analysis: FEV(1) prior to treatment (p < 0.0001); number of days elapsed between the previous FEV(1) measurement and the initiation of IV antibiotic therapy (p < 0.002); and the number of days elapsed between the determination of the minimum inhibitory concentration and the initiation of IV therapy (p < 0.03). No significant trends were observed between the antibiotic susceptibility of P aeruginosa isolates and treatment outcomes. CONCLUSION: While lack of statistical significance for a trend between bacterial susceptibilities and the response to parenteral antibiotic administration does not mean that no such trend exists, the precision of the confidence intervals allows us to conclude that even if isolate antibiotic susceptibilities affect outcome, the impact would be small and not clinically relevant.

Aerosolized antibiotics in cystic fibrosis.

Inhaled antibiotics offer an attractive alternative to systemic administration in cystic fibrosis (CF) for several reasons. Antibiotics can be administered directly to the site of infection with little systemic absorption, thereby minimizing toxicity. Aerosolization will permit chronic administration of antipseudomonal antibiotics while avoiding the risks and inconvenience of intravenous access. Modern aerosolized drug delivery systems enable endobronchial delivery of very high antibiotic concentrations, resulting in clinical improvement even in patients with bacterial organisms that traditionally would have been considered resistant. This article summarizes basic concepts of aerosol drug administration and reviews available data on the administration of a variety of drug classes for both suppressive therapy and acute exacerbations of cystic fibrosis, including toxicity and safety data. The aminoglycosides have been by far the most extensively studied class of antibiotics, culminating in U.S. Food and Drug Administration (FDA) approval of a specifically formulated tobramycin solution for inhalation. The available data on the development of antibiotic resistance and emergence of other organisms with long-term use of this agent are reviewed. Finally, a brief guideline for initiating and monitoring patients on antibiotic aerosols is provided for the clinician caring for CF patients.