Clinical evaluation of the role of ceftaroline in the management of community acquired bacterial pneumonia

Ceftaroline fosamil (ceftaroline) was recently approved for the treatment of community- acquired pneumonia (CAP) and complicated skin infections. This newly developed cephalosporin possesses a broad spectrum of activity against gram-positive and gram-negative bacteria. Most importantly, ceftaroline demonstrates potent in vitro antimicrobial activity against multi-drug resistant Streptococcus pneumoniae and methicillin-resistant strains of Staphylococcus aureus. In two Phase III, double-blinded, randomized, prospective trials (FOCUS 1 and FOCUS 2), ceftaroline was shown to be non-inferior to ceftriaxone for the treatment of CAP in hospitalized patients. Ceftaroline exhibits low resistance rates and a safety profile similar to that of other cephalosporins. In this review, we will evaluate the pharmacological characteristics, safety, antimicrobial properties, and efficacy of ceftaroline and its applications in the treatment of CAP

Effect of tiotropium on COPD exacerbations: A systematic review

Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.Published (Open Access)This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site

Risk factors for exacerbations and pneumonia in patients with chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear. METHODS: This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo. Backward elimination via Cox's proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation. RESULTS: Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216. Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk. BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI <25 kg/m2. The modelled probability of pneumonia varied between 3 and 12% during the first year. Higher exacerbation risk was associated with a history of exacerbations, poorer lung function (GOLD stage), female sex and absence of ICS treatment. The influence of the other exacerbation risk factors was not modified by ICS treatment. Modelled probabilities of an exacerbation varied between 31 and 82% during the first year. CONCLUSIONS: The probability of an exacerbation was considerably higher than for pneumonia. ICS reduced exacerbations but did not influence the effect of risks associated with prior exacerbation history, GOLD stage, or female sex. The only identified risk factor for ICS-induced pneumonia was BMI <25 kg/m2. Analyses of this type may help the development of COPD risk equations

Tiotropium/Olodaterol Decreases Exacerbation Rates Compared with Tiotropium in a Range of Patients with COPD: Pooled Analysis of the TONADO®/DYNAGITO® Trials

Introduction Previous studies demonstrated that tiotropium/olodaterol reduced rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this should be examined in a wider population. Methods This post hoc analysis pooled data from TONADO® 1 + 2 and DYNAGITO®, three 52-week, parallel-group, randomised, double-blind, phase III trials investigating patients with moderate-to-very severe COPD, with and without previous exacerbations, who received tiotropium/olodaterol 5/5 µg or tiotropium 5 µg. Subgroup analyses were conducted on patients stratified by exacerbation history, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2–4 disease severity and baseline inhaled corticosteroid (ICS) use. Results In 9942 patients, tiotropium/olodaterol was associated with lower rates of moderate/severe exacerbations (0.68 vs. 0.77 per patient-year; rate ratio (RR) vs. tiotropium 0.89, 95% confidence interval (CI) 0.84, 0.95; P = 0.0003) and exacerbations requiring hospitalisation (0.11 vs. 0.13 per patient-year; RR 0.86, 95% CI 0.75, 0.99; P = 0.0380) versus tiotropium. Lower rates of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium were evident in patients with 0–1 moderate exacerbation in the previous year (0.54 vs. 0.60 per patient-year; RR 0.90, 95% CI 0.82, 0.98; P = 0.0187) and at least two moderate or at least one severe exacerbation(s) in the previous year (0.97 vs. 1.09 per patient-year; RR 0.89, 95% CI 0.82, 0.97; P = 0.0096). In patients with GOLD 2 and GOLD 3 COPD, moderate/severe exacerbation rates were lower with tiotropium/olodaterol versus tiotropium; GOLD 4 patients showed negligible difference between treatments. When evaluating patients by baseline ICS use, there was a significantly lower rate of moderate/severe exacerbations with tiotropium/olodaterol versus tiotropium in patients receiving ICS. Conclusions Tiotropium/olodaterol decreased the rate of moderate/severe exacerbations and exacerbations leading to hospitalisation versus tiotropium. Results from this large, pooled, post hoc analysis support the use of dual bronchodilation with tiotropium/olodaterol in a broad range of patients, reflective of patients with COPD in clinical practice

Prognosis factors and outcome of community-acquired pneumonia needing mechanical ventilation.

PURPOSE: To evaluate the variables associated with mortality of patients with community-acquired pneumonia who require mechanical ventilation and to determine the attributable morbidity and intensive care unit (ICU) mortality of community-acquired pneumonia. MATERIAL AND METHODS: Retrospective cohort study carried out in 361 ICUs from 20 countries including 124 patients who required mechanical ventilation on the first day of admission to the hospital due to acute respiratory failure secondary to severe community-acquired pneumonia. To assess the factors associated with outcome, a forward stepwise logistic regression analysis was performed, and to determine the attributable mortality of community-acquired pneumonia, a matched study design was used. RESULTS: We found 3 independent variables significantly associated with death in patients with community-acquired pneumonia requiring mechanical ventilation: simplified acute physiological score greater than 45 (odds ratio, 5.5 [95% confidence interval, 1.7-12.3]), shock (odds ratio, 5.7 [95% confidence interval, 1.7-10.1]), and acute renal failure (odds ratio, 3.0 [95% confidence interval, 1.1-4.0]). There was no statistically significant difference in ICU mortality among patients with or without community-acquired pneumonia (32% vs 35%; P=.59). CONCLUSIONS: Community-acquired pneumonia needing mechanical ventilation is not a disease associated with higher mortality. The main determinants of patient outcome were initial severity of illness and the development of shock and/or acute renal failure

Shortness of Breath with Daily Activities questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease

ObjectivesTo test the reliability, validity and responsiveness of the 13-item Shortness of Breath with Daily Activities (SOBDA) questionnaire, and determine the threshold for response and minimal important difference (MID).Design6 week, randomised, double-blind, placebo-controlled study.Setting40 centres in the USA between 29 October 2009 and 1 July 2010.Primary and secondary outcome measures547 patients with chronic obstructive pulmonary disease (COPD) were enrolled and 418 entered the 2-week run-in period. Data from the run-in period were collected to test internal consistency, test–retest reliability, convergent validity and known-groups validity of the SOBDA. Three hundred and sixty six patients were randomised 2:2:1 to fluticasone propionate/salmeterol 250/50 µg, salmeterol 50 µg or placebo, twice daily. Results from the SOBDA questionnaire, Patient Global Assessment of Change Question, modified Medical Research Council Dyspnoea Scale (mMRC), Clinician Global Impression of Dysponea Severity (CGI-S), Clinician Global Impression of Change Question and Chronic Respiratory Disease Questionnaire self-administered standardised version (CRQ-SAS) were evaluated; spirometry and safety parameters were measured. Study endpoints were selected to investigate the cross-sectional and longitudinal validity of the SOBDA questionnaire in relation to the clinical criteria.ResultsInternal consistency of the SOBDA questionnaire (Cronbach α) was 0.89. Test–retest reliability (intraclass correlation) was 0.94. The SOBDA weekly scores correlated with the patient-reported and clinician-reported mMRC, CGI-S and CRQ-SAS dyspnoea domain scores (0.29, 0.24, 0.24 and –0.68, respectively). The SOBDA weekly scores differentiated between the responders and the non-responders as rated by the patients and the clinicians. Anchor-based and supportive distribution-based analyses produced a range of the potential values for the threshold for the responders and MID.ConclusionsThe 13-item SOBDA questionnaire is reliable, valid and responsive to change in patients with COPD. On using anchor-based methods, the proposed responder threshold shows a −0.1 to −0.2 score change. A specific threshold value will be identified as more data are generated from future clinical trials.Trial registrationNCT00984659; GlaxoSmithKline study number: ASQ112989

Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation.

OBJECTIVE: To describe the use of sedatives and neuromuscular blocking agents (NMBs) and their impact in outcome in an international cohort of patients receiving mechanical ventilation. METHODS: We analyzed the database of a prospective, multicenter cohort of 5,183 adult patients who received mechanical ventilation for > 12 h. We considered that a patient received a given agent when it was administered for at least 3 h in a 24-h period. RESULTS: A total of 3,540 patients (68%; 95% confidence interval [CI], 67 to 69%) received a sedative at any time while receiving mechanical ventilation. The median number of days of use was 3 (interquartile range [IQR], 2 to 6 days). The persistent use of sedative was associated with more days of mechanical ventilation (median, 4 days [IQR, 2 to 8 days], vs 3 days [IQR, 2 to 4 days] in patients who did not receive sedatives [p < 0.001]); more weaning days (median, 2 days [IQR, 1 to 3 days], vs 2 days [IQR, 1 to 5 days] in patients who did not receive sedatives [p < 0.001]); and longer length of stay in the ICU (median, 8 days [IQR, 5 to 15 days], vs 5 days [IQR, 3 to 9 days] in patients who did not receive sedatives [p < 0.001]). Six hundred eighty-six patients (13%; 95% CI, 12 to 14%) received an NMB for at least 1 day. The median number of days of use was 2 (IQR, 1 to 4 days). The administration of an NMB was independently related with age, a normal previous functional status, main reason of mechanical ventilation (patients with ARDS received more NMBs), and with patient management (patients requiring permissive hypercapnia, prone position, high level of positive end-expiratory pressure, and high airways pressure). CONCLUSIONS: The use of sedatives is very common, and their use is associated with a longer duration of mechanical ventilation, weaning time, and stay in the ICU. NMBs are used in 13% of the patients and are associated with longer duration of mechanical ventilation, weaning time, stay in the ICU, and higher mortality

Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials

ABSTRACT The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n = 562; ceftriaxone, n = 554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria ( P = 0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P = 0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.