Casper S. de Graaff

Effect of Azithromycin Maintenance Treatment on Infectious Exacerbations Among Patients With Non-Cystic Fibrosis Bronchiectasis The BAT Randomized Controlled Trial

IMPORTANCE Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis. OBJECTIVE To determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis. DESIGN, SETTING, AND PARTICIPANTS The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in The Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. INTERVENTIONS Azithromycin (250 mg daily) or placebo for 12 months. MAIN OUTCOME MEASURES Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life. RESULTS Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16-0.51]). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 [95% CI, 0.97-56.88] for abdominal pain and 8.36 [95% CI, 1.10-63.15] for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group. CONCLUSIONS AND RELEVANCE Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00415350.

Efficacy of corticosteroids in community-acquired pneumonia - a randomized double blinded clinical trial

RATIONALE Some studies have shown a beneficial effect of corticosteroids in patients with community-acquired pneumonia (CAP), possibly by diminishing local and systemic antiinflammatory host response. OBJECTIVES To assess the efficacy of adjunctive prednisolone treatment in patients hospitalized with CAP. METHODS Hospitalized patients, clinically and radiologically diagnosed with CAP using standard clinical and radiological criteria, were randomized to receive 40 mg prednisolone for 7 days or placebo, along with antibiotics. Primary outcome was clinical cure at Day 7. Secondary outcomes were clinical cure at Day 30, length of stay, time to clinical stability, defervescence, and C-reactive protein. Disease severity was scored using CURB-65 (a severity index for community-acquired pneumonia evaluating Confusion, blood Urea nitrogen, Respiratory rate, Blood pressure, and age 65 or older) and Pneumonia Severity Index. MEASUREMENTS AND MAIN RESULTS We enrolled 213 patients. Fifty-four (25.4%) patients had a CURB-65 score greater than 2, and 93 (43.7%) patients were in Pneumonia Severity Index class IV-V. Clinical cure at Days 7 and 30 was 84/104 (80.8%) and 69/104 (66.3%) in the prednisolone group and 93/109 (85.3%) and 84/109 (77.1%) in the placebo group (P = 0.38 and P = 0.08). Patients on prednisolone had faster defervescence and faster decline in serum C-reactive protein levels compared with placebo. Subanalysis of patients with severe pneumonia did not show differences in clinical outcome. Late failure (>72 h after admittance) was more common in the prednisolone group (20 patients, 19.2%) than in the placebo group (10 patients, 6.4%; P = 0.04). Adverse events were few and not different between the two groups. CONCLUSIONS Prednisolone (at 40 mg) once daily for a week does not improve outcome in hospitalized patients with CAP. A benefit in more severely ill patients cannot be excluded. Because of its association with increased late failure and lack of efficacy prednisolone should not be recommended as routine adjunctive treatment in CAP.

Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease.

RATIONALE The role of antibiotics in acute exacerbations is controversial and their efficacy when added to systemic corticosteroids is unknown. OBJECTIVES We conducted a randomized, placebo-controlled trial to determine the effects of doxycycline in addition to corticosteroids on clinical outcome, microbiological outcome, lung function, and systemic inflammation in patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease. METHODS Of 223 patients, we enrolled 265 exacerbations defined on the basis of increased dyspnea and increased sputum volume with or without increased sputum purulence. Patients received 200 mg of oral doxycycline or matching placebo for 7 days in addition to systemic corticosteroids. Clinical and microbiological response, time to treatment failure, lung function, symptom scores, and serum C-reactive protein were assessed. MEASUREMENTS AND MAIN RESULTS On Day 30, clinical success was similar in intention-to-treat patients (odds ratio, 1.3; 95% confidence interval, 0.8 to 2.0) and per-protocol patients. Doxycycline showed superiority over placebo in terms of clinical success on Day 10 in intention-to-treat patients (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.2), but not in per-protocol patients. Doxycycline was also superior in terms of clinical cure on Day 10, microbiological outcome, use of open label antibiotics, and symptoms. There was no interaction between the treatment effect and any of the subgroup variables (lung function, type of exacerbation, serum C-reactive protein, and bacterial presence). CONCLUSIONS Although equivalent to placebo in terms of clinical success on Day 30, doxycycline showed superiority in terms of clinical success and clinical cure on Day 10, microbiological success, the use of open label antibiotics, and symptoms. Clinical trial registered with www.clinicaltrials.gov (NCT00170222).

The influence of COPD on mortality and severity scoring in community-acquired pneumonia

Background: Chronic obstructive lung disease (COPD) is a frequent co-morbidity in patients hospitalised with community-acquired pneumonia (CAP). In recent retrospective studies, higher mortality in patients with CAP and COPD was found. Objectives: The aim of the study was to determine the 30-day mortality and to evaluate the differences in CAP severity scoring in hospitalised patients with COPD. Methods: A subanalysis of a randomized clinical trial was performed. Results: A total of 262 patients with CAP were included. Ninety-five (36.3%) patients had COPD. A total of 28 (10.7%) patients died within 30 days. No differences between patients with and without COPD in 30-day mortality were observed [8 (8.4%) vs. 20 (12.0%), p = 0.37]. In the Pneumonia Severity Index (PSI), significant differences in age, gender and heart rate between patients with and without COPD were observed. Patients with COPD were stratified in higher PSI classes. In the CURB-65 score, age ≥65 years was significantly higher in patients with COPD [72 (75.8%) vs. 88 (52.7%), p = <0.01]. In a multivariate analysis, only the need for intensive care unit admission and high serum glucose were predictors of mortality [OR 32.50 (95% CI 6.87–153.75), p < 0.01; OR 7.34 (95% CI 1.19–45.4), p = 0.03]. Conclusions: Mortality was not increased in patients with COPD hospitalised with CAP. Severity scores are influenced by age and gender. Further studies evaluating CAP in patients with COPD are needed to explain these findings.

Evaluation of an algorithm for switching from IV to PO therapy in clinical practice in patients with community-acquired pneumonia.

BACKGROUND In patients with community-acquired pneumonia (CAP), switching from IV to PO antibiotics offers advantages over IV therapy alone, including improved cost-effectiveness through reductions in the length of hospital stay and treatment costs. OBJECTIVE The aim of this study was to determine whether a method for switching therapy in clinical practice could be used in patients with CAP and whether differences were found in the duration of IV treatment and length of hospital stay between the 5 risk classes of the Pneumonia Severity Index (PSI) after the therapy switch. METHODS This was a prospective, observational study of patients aged >/=18 years presenting with CAP at our teaching hospital between December 1998 and November 2000. Microbiological and serological tests were performed, and signs and symptoms of CAP, C-reactive protein levels, and white blood cell counts were assessed throughout treatment and at the 1-month follow-up. Patients were stratified by PSI risk class. When the patients temperature had been normalized for 72 hours and respiratory symptoms (dyspnea, coughing, and thoracal pain) had improved, patients were switched from IV to PO therapy (same drug). RESULTS The study included 180 patients with CAP Clinical cure was seen in 174 (97%) patients. No significant difference between the 5 risk classes was found in duration of therapy. Patients in risk class V remained hospitalized for a significantly longer period than patients in risk classes I through IV (P < 0.001). Furthermore, after patients were switched to PO antibiotics, the level of C-reactive protein decreased in patients in all risk classes and was normalized by follow-up. CONCLUSIONS In the population studied, use of specific criteria (ie, absence of fever for 72 hours and reduction in respiratory symptoms) allowed successful switch from IV to PO antibiotic therapy for the treatment of CAP Duration of therapy was not affected by PSI risk class, but those in risk class V were hospitalized longer than other risk classes.

Validation of a visual analogue score (LRTI-VAS) in non-CF bronchiectasis

Quality of life in patients with non‐cystic fibrosis (non‐CF) bronchiectasis is largely defined by respiratory symptoms. To date, no disease‐specific tool for symptom measurement in this patient group was available. We developed the lower respiratory tract infections – visual analogue scale (LRTI‐VAS) in order to quickly and conveniently quantify symptoms in non‐CF bronchiectasis. This study aimed to validate LRTI‐VAS for use in non‐CF bronchiectasis.