Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Department of General Practice, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Lancet Respir Med. 2017 Jun;5(6):492-499. doi: 10.1016/S2213-2600(17)30165-0. Epub 2017 May 5.
Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting.
In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1-3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1-2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499.
Between Dec 22, 2010, and Aug 6, 2013, we randomly allocated 305 (34%) patients from the cohort of 887 patients to doxycycline (152 [50%]) or placebo (153 [50%]), excluding four (1%) patients (two [1%] from each group) who were incorrectly randomly allocated from the analysis. 257 (85%) of 301 patients had a next exacerbation (131 [87%] of 150 in the doxycycline group vs 126 [83%] of 151 in the placebo group). Median time to next exacerbation was 148 days (95% CI 95-200) in the doxycycline group compared with 161 days (118-211) in the placebo group (hazard ratio 1·01 [95% CI 0·79-1·31]; p=0·91). We did not note any significant differences between groups in the frequency of adverse events during the first 2 weeks after randomisation (47 [31%] of 150 in the doxycycline group vs 53 [35%] of 151 in the placebo group; p=0·54) or in serious adverse events during the 2 years of follow-up (42 [28%] vs 43 [29%]; p=1).
In patients with mild-to-severe COPD receiving treatment for an exacerbation in an outpatient setting, the antibiotic doxycycline added to the oral corticosteroid prednisolone did not prolong time to next exacerbation compared with prednisolone alone. These findings do not support prescription of antibiotics for COPD exacerbations in an outpatient setting.
Netherlands Organization for Health Research and Development.
在门诊接受治疗的 COPD 急性加重患者中，抗生素并不能降低死亡率或短期治疗无反应。然而，抗生素的长期效果尚不清楚。本研究旨在调查抗生素多西环素是否能延长接受口服皮质类固醇泼尼松龙治疗的 COPD 患者的下一次加重时间。
这是一项随机双盲安慰剂对照试验，我们从荷兰的 9 家教学医院和 3 家初级保健中心的门诊招募了 COPD 患者。纳入标准为年龄至少 45 岁，吸烟史至少 10 包年，轻度至重度 COPD（GOLD 分期 1-3），过去 3 年至少有一次加重。排除标准为荷兰语掌握能力差，认知功能差，已知对多西环素过敏，怀孕，预期寿命短于 1 个月。如果患者出现加重，我们将他们随机分配（1:1；使用大小可变的随机分组[范围为 2 至 10]；根据 GOLD 分期 1-2 与 3 分层），接受为期 7 天的口服多西环素 100mg 每日一次（第 1 天为 200mg）或安慰剂。随机分组的排除标准为发热、住院和当前使用抗生素或在过去 3 周内使用抗生素。两组患者均接受为期 10 天的 30mg 口服泼尼松龙每日一次。患者、研究者和评估结局的人员对治疗分配均设盲。主要结局为所有随机分配患者的下一次加重时间，除了因未满足纳入标准或因排除标准而未纳入分析的错误随机分配的 4 名患者（每组各 2 名）。在随机分配的 305 名患者（887 名患者队列中的 34%）中，有 257 名（85%）发生了下一次加重（多西环素组 131 名[87%]，安慰剂组 126 名[83%]）。多西环素组的中位下一次加重时间为 148 天（95%CI 95-200），安慰剂组为 161 天（118-211）（风险比 1.01[95%CI 0.79-1.31]；p=0.91）。我们没有注意到两组在随机分组后 2 周内不良事件的频率（多西环素组 150 名患者中有 47 名[31%]，安慰剂组 151 名患者中有 53 名[35%]；p=0.54）或在 2 年随访期间严重不良事件的频率（多西环素组 42 名[28%]，安慰剂组 43 名[29%]；p=1）有显著差异。
在接受门诊治疗的轻至重度 COPD 患者中，与单独使用泼尼松龙相比，抗生素多西环素联合口服皮质类固醇泼尼松龙并不能延长下一次加重的时间。这些发现不支持在门诊环境中为 COPD 加重开具抗生素处方。
荷兰健康研究与发展组织。
