Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD)

  • Review
  • Intervention

Authors


Abstract

Background

There has been renewal of interest in the use of prophylactic antibiotics to reduce the frequency of exacerbations and improve quality of life in chronic obstructive pulmonary disease (COPD).

Objectives

To determine whether or not regular treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life.

Search methods

We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was August 2013.

Selection criteria

Randomised controlled trials (RCTs) that compared prophylactic antibiotics with placebo in patients with COPD.

Data collection and analysis

We used the standard methods of The Cochrane Collaboration. Data were extracted and analysed by two independent review authors.

Main results

Seven RCTs involving 3170 patients were included in this systematic review. All studies were published between 2001 and 2011. Five studies were of continuous antibiotics and two studies were of intermittent antibiotic prophylaxis (termed 'pulsed' for this review). The antibiotics investigated were azithromycin, erythromycin, clarithromycin and moxifloxacin. Azithromycin, erythromycin and clarithromycin are macrolides while moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. The study duration varied from three months to 36 months and all used intention-to-treat analysis. Most of the results were of moderate quality. The risk of bias of the included studies was generally low, and we did not downgrade the quality of evidence for risk of bias.

The trials recruited participants with a mean age of 66 years and with at least a moderate severity of COPD. Three trials included participants with frequent exacerbations and two trials recruited participants requiring systemic steroids or antibiotics, or both, or who were at the end stage of their disease and required oxygen.

The primary outcomes for this review were the number of exacerbations and quality of life.

With use of continuous prophylactic antibiotics the number of patients experiencing an exacerbation was reduced (odds ratio (OR) 0.55; 95% confidence interval (CI) 0.39 to 0.77, 3 studies, 1262 participants, high quality). This represented a reduction from 69% of participants in the control group compared to 54% in the treatment group (95% CI 46% to 63%) and the number needed to treat to prevent one exacerbation (NNTb) was therefore 8 (95% CI 5 to 18). The frequency of exacerbations was also reduced with continuous prophylactic antibiotic treatment (rate ratio 0.73; 95% CI 0.58 to 0.91).

Use of pulsed antibiotic treatment showed a non-significant reduction in the number of people with exacerbations (OR 0.87; 95% CI 0.69 to 1.09, 1 study, 1149 participants, moderate quality) and the test for interaction showed that this result was significantly different from the effect on exacerbations with continuous antibiotics.

There was a statistically significant improvement in quality of life with both continuous and pulsed antibiotic treatment but this was smaller than the four unit improvement that is regarded as being clinically significant (MD -1.78; 95% CI -2.95 to -0.61, 2 studies, 1962 participants, moderate quality).

Neither pulsed nor continuous antibiotics showed a significant effect on the secondary outcomes of frequency of hospital admissions, change in lung function, serious adverse events or all-cause mortality (moderate quality evidence).

The adverse events that were recorded varied among the trials depending on the different antibiotics used. Azithromycin was associated with a significant hearing loss in the treatment group. The moxifloxacin pulsed study reported a significantly higher number of adverse events in the treatment arm due to the marked increase in gastrointestinal adverse events (P < 0.001). Some adverse events that led to drug discontinuation, such as development of long QTc or tinnitus, were not significantly more frequent in the treatment group than the placebo group but pose important considerations in clinical practice.

The development of antibiotic resistance in the community is of major concern. One study found newly colonised patients to have higher rates of antibiotic resistance. Patients colonised with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant with the quinolone treatment.

Authors' conclusions

Use of continuous prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients. All trials of continuous antibiotics used macrolides hence the noted benefit applies only to the use of continuous macrolide antibiotics. The impact of pulsed antibiotics remains uncertain and requires further research.

The trials in this review included patients who were frequent exacerbators and needed treatment with antibiotics or systemic steroids, or who were on supplemental oxygen. There were also older individuals with a mean age of 66 years. The results of these trials apply only to the group of patients who were studied in these trials and may not be generalisable to other groups.

Because of concerns about antibiotic resistance and specific adverse effects, consideration of prophylactic antibiotic use should be mindful of the balance between benefits to individual patients and the potential harms to society created by antibiotic overuse.

Абстракт

Профилактическая антибиотикотерапия хронической обструктивной болезни легких (ХОБЛ).

Введение и актуальность

Возродился интерес к профилактическому использованию антибиотиков с целью снижения частоты обострений и улучшения качества жизни при хронической обструктивной болезни легких ( ХОБЛ).

Задачи

Определить, уменьшает или нет регулярное лечение больных ХОБЛ профилактическим использованием антибиотиков частоту обострений, или влияет ли на качество жизни.

Методы поиска

Мы провели поиск в Регистре клинических испытаний Кокрейновской группы по дыхательным путям и в библиографиях соответствующих исследований. Последний поиск литературы был проведён в августе 2013.

Критерии отбора

Рандомизированные контролируемые испытания (РКИ), в которых сравнивали профилактическое назначение антибиотиков с плацебо у пациентов с ХОБЛ.

Сбор и анализ данных

Мы использовали стандартные методы Кокрейновского Сотрудничества. Данные были извлечены и проанализированы двумя независимыми авторами обзора.

Основные результаты

Семь РКИ с участием 3170 пациентов были включены в этот систематический обзор. Все исследования были опубликованы в период между 2001 и 2011. Пять исследований были с непрерывным использованием антибиотиков, а два исследования - с прерывистой профилактикой антибиотиками (называемой "пульсовым" использованием в этом обзоре). Исследуемыми антибиотиками были азитромицин, эритромицин, кларитромицин и моксифлоксацин. Азитромицин, эритромицин и кларитромицин являются макролидами, в то время как моксифлоксацин - синтетическое фторхинолоновое антибактериальное средство четвертого поколения. Продолжительность исследования колебалась от трех месяцев до 36 месяцев, и все исследования использовали анализ по намерению лечить. Большинство результатов были среднего качества. Риск смещения во включенных исследованиях был в целом низким, и мы не снизили оценку качества доказательств по причине смещения.

В ипытаниях участвовали люди со средним возрастом 66 лет и, по крайней мере, со средней степенью тяжести ХОБЛ. Три исследования включали участников с частыми обострениями и в двух исследованиях участвовали пациенты, которым требовались системные стероиды или антибиотики, или и те, и другие, и участники, находившиеся на конечной стадии своей болезни и нуждавшиеся в кислороде.

Первичными исходами в этом обзоре были число обострений и качество жизни.

При непрерывном профилактическом использовании антибиотиков число пациентов, испытывающих обострения, было снижено (отношение шансов (ОШ ) 0,55; 95 % доверительный интервал (ДИ) от 0,39 до 0,77, 3 исследования, 1262 участников, высокое качество). Это представляет собой снижение с 69% участников в контрольной группе по сравнению с 54% в группе лечения (95% ДИ от 46% до 63 %) и число пациентов, которых нужно пролечить для предотвращения одного обострения (ЧБНЛ), составило, следовательно, 8 (95 % ДИ от 5 до 18). Частота обострений также была снижена при непрерывном профилактическом использовании антибиотиков (отношение частот 0,73; 95% ДИ от 0,58 до 0,91).

Использование пульсового лечения антибиотиками показало незначимое снижение числа людей с обострениями (ОШ 0,87, 95% ДИ от 0,69 до 1,09, 1 исследование, 1149 участников, среднее качество), а тест на взаимодействие показал, что этот результат значимо отличался от влияния на обострения непрерывного использования антибиотиков.

Было статистически значимое улучшение качества жизни как при непрерывном, так и при пульсовом лечении антибиотиками, но это [улучшение] было меньше, чем улучшение на четыре единицы, которое считается клинически значимым (MD -1,78; 95% ДИ от -2,95 до -0,61, 2 исследования, 1962 участников, среднее качество).

Ни пульсовое, ни непрерывное использование антибиотиков не показало значимого влияния на вторичные исходы - частоту госпитализаций, изменение функции легких, серьезные нежелательные явления или смертность от всех причин (среднее качество доказательств).

Неблагоприятные события, которые были зарегистрированы, различались в испытаниях, в зависимости от использования разных антибиотиков. Азитромицин был ассоциирован со значимой потерей слуха в группе лечения. В исследовании пульсового применения моксифлоксацина сообщили о значимо большем числе неблагоприятных событий в группе лечения в связи с существенным увеличением нежелательных явлений со стороны желудочно-кишечного тракта (р < 0,001). Некоторые неблагоприятные события, которые привели к отмене препарата, такие, как удлинение интервала QTc или шум в ушах, возникали в группе лечения не чаще, чем в группе плацебо. Но они имеют важное значение для клинической практики.

Развитие устойчивости к антибиотикам в обществе в целом вызывает большую озабоченность. Одно из исследований показало, что пациенты, со свежей колонизацией бактериями, имели более высокие показатели устойчивости к антибиотикам. Пациенты, колонизированные моксифлоксацин-чувствительными псевдомонадами (Pseudomonas) в начале терапии, быстро становились устойчивыми к лечению хинолонами.

Выводы авторов

Непрерывное профилактическое использование антибиотиков приводит к клинически значимой пользе, заключавшейся в снижении обострений у пациентов с ХОБЛ. Все испытания по непрерывному использованию антибиотиков проводились с макролидами, и, следовательно, отмеченная польза от непрерывного лечения относится только к макролидам. Влияние пульсового использования антибиотиков остается неопределенным, и требует дальнейших исследований.

Испытания в этом обзоре включали пациентов, у которых были частые обострения, и которые нуждались в лечении антибиотиками или системными стероидами, или которые были на дополнительном кислороде. Были также люди старшего возраста со средним возрастом 66 лет. Результаты этих испытаний применимы только к группе пациентов, которые были изучены в этих испытаниях, и не могут быть распространены на другие группы.

Из-за опасений по поводу развития устойчивости к антибиотикам и конкретных неблагоприятных эффектов, при рассмотрении профилактического применения антибиотиков необходимопомнить о балансе между пользой отдельным пациентам и потенциальным ущербом для общества, создаваемым чрезмерным использованием антибиотиков.

Заметки по переводу

Перевод: Раззакова Чинара Маратовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

Plain language summary

Preventative antibiotic therapy for people with COPD

What is COPD?

COPD is a common chronic respiratory disease mainly affecting people who smoke now or have done so previously. It could become the third leading cause of death worldwide by 2030. People with COPD experience gradually worsening shortness of breath and cough with sputum because of permanent damage to their airways and lungs. Those with COPD may have flare-ups (or exacerbations) that usually occur after respiratory infections. Exacerbations may lead to further irreversible loss of lung function with days off work, hospital admission, reduction in quality of life and they may even cause death.

Why did we do this review?

We wanted to find out if giving antibiotics to prevent a flare-up, 'prophylactic' antibiotics, would reduce the frequency of infections and improve quality of life. Studies that were taken into consideration used either continuous prophylactic antibiotics on a daily basis or prophylactic antibiotics that were used intermittently.

What evidence did we find?

We found seven randomised controlled trials (RCTs) involving 3170 patients. All studies were published between 2001 and 2011. Five studies were of continuous antibiotics and two studies were of intermittent antibiotic prophylaxis. The antibiotics investigated were azithromycin, erythromycin, clarithromycin and moxifloxacin. On average, the people involved in the trials were 66 years old and had either moderate or severe COPD. Three trials included participants with frequent exacerbations and two of the trials recruited participants requiring systemic steroids or antibiotics, or both, or who were at the end stage of their disease and required oxygen.

Results and conclusions

We found that with the use of continuous daily antibiotics the number of patients who developed an exacerbation reduced markedly. For every eight patients treated, one person would be prevented from suffering an exacerbation. There may have been a benefit on patient-reported quality of life with the antibiotics. On the other hand, use of antibiotics did not significantly affect the number of deaths due to any cause, the frequency of hospitalisation, or the loss of lung function during the study period.

Even though there may be fewer exacerbations with continuous antibiotics there are considerable drawbacks. First, there were specific adverse events associated with the antibiotics, which differed according to the antibiotic used; second, patients have to take antibiotics regularly for years or months; finally, the resulting increase in antibiotic resistance will have implications for both individual patients and the wider community through reducing the effectiveness of currently available antibiotics.

Because of concerns about antibiotic resistance and specific adverse effects, consideration of prophylactic antibiotic use should be mindful of the balance between benefits to individual patients and the potential harms to society created by antibiotic overuse.

Резюме на простом языке

Профилактическое лечение антибиотиками людей с ХОБЛ

Что такое ХОБЛ?

ХОБЛ является распространенным хроническим респираторным заболеванием, в основном поражающим людей, которые курят сейчас или курили ранее. Оно может стать третьей основной причиной смерти в мире к 2030 году. У людей с ХОБЛ постепенно усиливается одышка и кашель с мокротой из-за необратимого повреждения их дыхательных путей и легких. У лиц с ХОБЛ могут быть вспышки (или обострения), которые обычно возникают после респираторных инфекций. Обострения могут привести к дальнейшей необратимой потере функции легкого, к нетрудоспособности, госпитализации, снижению качества жизни, и даже к смерти.

Почему мы сделали этот обзор?

Мы хотели выяснить, уменьшило ли бы назначение антибиотиков для предотвращения обострений частоту инфекций и улучшили ли бы «профилактические» антибиотики качество жизни. В исследованиях, которые были приняты во внимание, использовали либо непрерывное назначение антибиотиков в ежедневном режиме, либо профилактические антибиотики - с перерывами.

Какие доказательства мы нашли?

Мы нашли семь рандомизированных контролируемых испытаний (РКИ) с участием 3170 пациентов. Все исследования были опубликованы в период между 2001 и 2011. Пять исследований были проведены с непрерывным назначением антибиотиков, а два исследования - с прерывистой профилактикой антибиотиками. Исследованными антибиотиками были азитромицин, эритромицин, кларитромицин и моксифлоксацин. В среднем, людям, вовлеченным в испытания, было 66 лет, они были с ХОБЛ средней тяжести, или тяжелой. Три исследования включали участников с частыми обострениями, и в двух исследованиях были участники, которым требовались системные стероиды или антибиотики, или и те, и другие, или участники, находившиеся на конечной стадии своей болезни, нуждавшиеся в кислороде.

Результаты и выводы

Мы обнаружили, что при непрерывном ежедневном использовании антибиотиков значительно снижалось число пациентов, у которых развивались обострения. Из каждых восьми леченных пациентов, у одного из них можно было бы предотвратить страдание от обострений. Судя по сообщениям пациентов, возможно, было повышено качество жизни при использовании антибиотиков. С другой стороны, применение антибиотиков значимо не влияло на число смертей по всем причинам, частоту госпитализаций или потерю функции легких в течение периода исследования.

Несмотря на то, что при непрерывном использовании антибиотиков может быть меньше обострений, все же существуют значительные недостатки. Во-первых, имели место конкретные неблагоприятные события, связанные с антибиотиками, которые различались в зависимости от используемого антибиотика; во-вторых, пациенты должны принимать антибиотики регулярно годами или месяцами; и, наконец, результирующее увеличение устойчивости к антибиотикам будет иметь последствия, как для отдельных пациентов, так и для общества в целом посредством снижения эффективности имеющихся антибиотиков.

Из-за опасений по поводу устойчивости к антибиотикам и конкретных неблагоприятных эффектов, при рассмотрении профилактического применения антибиотиков, необходимопомнитьо балансе между пользой отдельным пациентам и потенциальным ущербом для общества, созданным чрезмерным использованием антибиотиков.

Заметки по переводу

Перевод: Раззакова Чинара Маратовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. Antibiotics versus placebo for COPD
  1. 1 Clinical and statistical heterogeneity between trials
    2 Confidence intervals include the possibility that continuous antibiotics may increase or decrease the rate of exacerbations, mortality or serious adverse events

    3 Risk of attrition bias. Both studies have unclear attrition bias associated with this outcome as there is loss to follow up reported between 10-20% and reasons for the incomplete data were not given therefore we downgraded one for limitations

Antibiotics versus placebo for COPD (data from pulsed and continuous courses of antibiotics presented in the same table)

Patient or population: Adults (aged 40 or over) with COPD presenting with 1 or more exacerbations in the previous year. The 2 larger studies (Albert 2011; Sethi 2010) recruited patients who required systemic steroids or antibiotics for exacerbations or patients on supplemental oxygen

Settings: Outpatients presenting to hospital clinics

Intervention: Administration of an oral prophylactic antibiotic continuously or intermittently

Comparison: Administration of a placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Antibiotics versus placebo
Number of people with one or more exacerbations 60 per 100 49 per 100
(41 to 58)
OR 0.64
(0.45 to 0.9)
2411
(4 studies)
⊕⊕⊕⊝
moderate 1
The four studies looked at a different antibiotics (azithromycin and moxifloxacin) and the trial by Albert 2011 is on continuous antibiotics while Sethi 2010 trial is on pulsed antibiotics. Therefore there is clinical heterogeneity in the combined results and we downgraded by one point for inconsistency
Number of people with one or more exacerbations - Continuous antibiotics
Follow-up: 6 to 12 months
69 per 100 55 per 100
(46 to 63)
OR 0.55
(0.39 to 0.77)
1262
(3 studies)
⊕⊕⊕⊕
high
 
Number of people with one or more exacerbations - Pulsed antibiotics
Follow-up: 18 months
51 per 100 47 per 100
(42 to 53)
OR 0.87
(0.69 to 1.09)
1149
(1 study)
⊕⊕⊕⊝
moderate 2
 

Rate of exacerbation per patient/year

(Continuous antibiotic use)

6 to 12 months

   Rate Ratio 0.73 (0.58 to 0.91)

1262

(3 studies)

⊕⊕⊕⊝

moderate 1

I2=47%
HRQOL, SGRQ (change in total score)
Scale from: 0 to 100. SGRQ comprises of responses to 50 items, 0 being the best possible score and 100 the worst.
Follow-up: 6 to 18 months
The mean change in SGRQ ranged across control groups from
-0.6 to -2.8 units
The mean SGRQ (total score) in the intervention groups was
1.78 better
(2.95 to 0.61 better)
 1962
(3 studies)
⊕⊕⊕⊝
moderate 3
The minimally clinically important response to treatment is described as 4 points
All cause mortality
Follow-up: 6 to 36 months
83 per 1000 74 per 1000
(57 to 97)
OR 0.89
(0.67 to 1.19)
2841
(3 studies)
⊕⊕⊕⊝
moderate 2
 
Serious adverse events
Follow-up: 6 to 18 months
267 per 1000 243 per 1000
(210 to 281)
OR 0.88
(0.73 to 1.07)
2411
(4 studies)
⊕⊕⊕⊝
moderate 2
See Effects of interventions for specific adverse events related to the individual antibiotics
*The basis for the assumed risk was the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

The Global Initiative for Chronic Obstructive Lung Diseases (GOLD) and the World Health Organization (WHO) define chronic obstructive pulmonary disease (COPD) as "a common preventable and treatable disease, which is characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity in individual patients" (GOLD 2011). COPD is almost exclusively a disease of smoking; however, a small proportion of non-smokers have COPD secondary to passive smoking or genetic disease like alpha1 antitrypsin deficiency. Non-smokers with COPD are usually excluded from clinical trials. Most reported deaths due to COPD are from high socioeconomic countries while it is known that 90% of COPD related deaths occur in low socioeconomic countries (WHO). The age adjusted death rate from COPD in China is as high as 130.5/100,000, followed by Vietnam with 86.4/100,000 and India with 73.2/100,000 (Lancet 2007).

WHO predicts that COPD will become the third leading cause of death worldwide by 2030 (WHO). This projection has now proven to be a conservative estimate as in middle-income countries COPD has already become the third leading cause of death, with 2.79 million deaths per year by June 2011 (WHO).

COPD is diagnosed by clinical symptoms of dyspnoea, chronic cough or sputum production and a history of exposure to risk factors like smoking, together with spirometry. A post-bronchodilator cut off of a ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) less than 0.7 is used. Until recently, patients diagnosed with COPD based on the above clinical and spirometric criteria were then staged according to the severity of airflow limitation from stage I to stage IV according to the GOLD 2007 criteria (stage I, mild, FEV1 > 80%; stage II, moderate, FEV1 50% to 80%; stage III, severe, 30% to 50%; stage IV, very severe, FEV1 < 30% or FEV1 < 50% but with severe chronic symptoms.

An exacerbation of COPD is defined as an acute and sustained (lasting over 48 hours) increase in symptoms beyond a normal day to day variation. This generally includes one or more of an increase in frequency and severity of cough; increases in volume or changes in the character of sputum, or both; an increase in dyspnoea (GOLD 2011). The risk of exacerbation significantly increases in GOLD 3 and GOLD 4 stages.

Acknowledging the clinical importance of exacerbations in the natural history of COPD, the global COPD guidelines (GOLD 2011) have revised the severity criteria to incorporate two methods of assessing exacerbation risk. One is the previously mentioned population-based method using the GOLD spirometric classification, with GOLD 3 and 4 categories indicating high risk. The other is the individual patient's history of exacerbations, with two or more exacerbations in the preceding year indicating a high risk. Taking both the spirometric criteria and the risk of exacerbations as well as patient symptoms into account, in 2011 GOLD introduced a new classification for combined COPD assessment, grouped as Group A, B, C or D. Symptoms are assessed by either the COPD Assessment Tool score (CAT) (Jones 2009) or the Modified Medical Research Council Dyspnoea Scale (MMRC) (Bestall 1999). Group A is GOLD 1 or 2 or zero to one exacerbation per year, or both, and MMRC grade 0 to 1 or CAT score < 10; Group B is GOLD 1 or 2 or zero to one exacerbation per year, or both, and MMRC grade 2 or more or CAT score 10 or more; Group C is GOLD 3 or 4 or two or more exacerbations per year, or both, and MMRC grade 2 or more or CAT score 10 or more; Group D is GOLD 3 or 4 or two or more exacerbations per year, or both, and MMRC grade 2 or more /CAT score 10 or more) (GOLD 2011).

Published data suggest that 50% to 70% of exacerbations are due to respiratory infections (Ball 1995) (including bacteria, atypical organisms and respiratory viruses), 10% are due to environmental pollution (depending on the season and geographical placement) (Sunyer 1993) and up to 30% are of unknown aetiology.

Epidemiological research has identified more exacerbations during periods of increased pollution. Increases in black smoke particulate matter, sulfur dioxide (SO2), ozone (O3) and nitrogen dioxide (NO2) are associated with increases in respiratory symptoms, admissions for exacerbations and COPD associated mortality (Anderson 1997).

Studies using bronchoscopic sampling of the lower airways have found a relationship between bacteria and exacerbations, with approximately 30% of sputum cultures and 50% of bronchial secretion cultures showing the presence of potential pathogenic bacteria (Monso 1995). In severe exacerbations requiring ventilatory support this number is even higher (over 70%) (Soler 1998). Commonly isolated organisms include Haemophilus influenzae (11% of all exacerbating patients), Streptococcus pneumoniae (10%), Moraxella catarrhalis (10%), Haemophilus parainfluenzae (10%) and Pseudomonas aeruginosa (4%), with Gram negative bacteria occurring more rarely (Thorax 2006).

Infective exacerbations are a common cause of days off work and hospital admissions (TSANZ 2004).

There are numerous evidence-based approaches that reduce the number of COPD exacerbations.

An essential first step is the avoidance of cigarette smoke and air pollution wherever possible. Furthermore, vaccination against influenza is a universally-accepted measure to prevent COPD exacerbation. Vaccination for pneumococcal disease may also reduce pneumonia (Journal of General Internal Medicine 2007) and exacerbations. Inhaled COPD medicines shown to reduce exacerbation frequency include tiotropium (UPLIFT 2008), long acting beta agonists (Wang 2012) and corticosteroids (TORCH 2007). Oral medicines shown to reduce exacerbations include phosphodiesterase 4 (PDE4) inhibitors (Chong 2011) and mucolytic agents (Poole 2012).

Any cost-effective intervention that reduces exacerbations over and above the COPD treatments described above would be worthwhile. This is first, because of the morbidity and direct costs of exacerbations; and second, because of concern over possible loss of lung function due to inflammation that may not return to baseline. Finally, the resultant deconditioning may lead to days off work and loss of independence.

Description of the intervention

One approach has been to use prophylactic antibiotics. The word prophylactic comes from the Greek for 'an advance guard', an apt term for a measure taken to fend off a disease or another unwanted consequence. A prophylactic intervention is a medication or treatment designed and used to prevent a disease from occurring. Thirty years ago the use of prophylactic antibiotics was common for chronic bronchitis in both the United Kingdom and elsewhere, but concerns over effectiveness and antibiotic resistance led to a decline in this approach. 

How the intervention might work

COPD is characterised by persistent airways inflammation due to chronic bacterial colonisation of the damaged respiratory epithelium leading to the continuing release of bacterial and host mediated pro-inflammatory factors and additional epithelial damage. In an exacerbation there is superimposed acute inflammation. By reducing bacterial colonisation, chronic antibiotic therapy could help in reducing progression of the disease by breaking the above vicious cycle. In addition, some antibiotics have intrinsic anti-inflammatory properties.

There is renewed interest in the role of prophylactic antibiotics because they may prevent infective exacerbations that are costly. Furthermore, some may act as anti-inflammatory agents that may modify disease progression.

Why it is important to do this review

This review incorporates and builds upon an earlier Cochrane review that found that the use of prophylactic antibiotics in people with chronic bronchitis had a small but statistically significant effect in reducing the days of illness due to exacerbations of the bronchitis (Staykova 2003). The review methods, search results and the included trials were however out of date and a new review was needed. The earlier review did not support routine treatment with antibiotics because of concerns about the development of antibiotic resistance and the possibility of adverse effects. Since 2003, new classes of antibiotics have been introduced to the market including newer generation macrolides (for example roxithromycin, azithromycin, clarithromycin), quinolones (for example moxifloxacin, ciprofloxacin) and combinations with penicillins (amoxicillin and clavulanic acid); some of these are given in low doses, as pulsed or inhaled therapy. Therefore, there is a need to review whether or not the practice of using prophylactic antibiotics is effective in reducing exacerbations in people with chronic bronchitis. Secondly, since the previous review was performed it has become clear that many patients with chronic bronchitis have COPD, which is a distinct disease entity for which the diagnostic and therapeutic evidence base is growing (GOLD 2011). Thus, we felt justified in tightening the scope of this review to only include people with COPD. Finally, this review considers the use of antibiotics as anti-inflammatory as well as anti-infective agents.

We wished to update reports of harm resulting from the practice of treating COPD patients with prophylactic antibiotics, including the development of antibiotic resistance. An up-to-date review of the benefits and harms should enable patients and physicians to weigh the benefits and risks so as to make more rational decisions before embarking on long term treatment.

Objectives

To determine whether or not regular treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials of antibiotic versus placebo. Trials comparing different antibiotics head-to-head will form the basis of another review. We planned to include cluster randomised trials and crossover trials.

Types of participants

We included studies of adults (older than 18 years of age) with a diagnosis of COPD, as defined by the American Thoracic Society, European Respiratory Society or GOLD, with airflow obstruction evident by spirometry (post-bronchodilator FEV1 of less than 80% of the predicted value and an FEV1/FVC of 0.7 or less). The review included studies only if they confirmed diagnosis with lung function testing (spirometry).

We excluded studies of patients with bronchiectasis, asthma or genetic diseases such as cystic fibrosis or primary ciliary dyskinesia (which can also in the long term give chronic airflow limitation as part of a secondary process). Where we encountered trials that included patients with these diseases in addition to patients with COPD, we only extracted the data for the patients with COPD, where the data were presented separately.

Types of interventions

Oral antibiotics including penicillin (amoxycillin, amoxicillin, clavulanic acid), tetracycline (doxycycline, tetracycline), quinolones (ciprofloxacin, moxifloxacin), macrolides (clarithromycin, erythromycin, roxithromycin, azithromycin) and sulphonamides (co-trimoxazole) administered in appropriate daily doses at least three times a month for a period of at least three months.

Types of outcome measures

Primary outcomes
  1. Number of exacerbations, using an accepted definition. This included total numbers of patients with exacerbations as well as the frequency of exacerbations in the study period.

  2. Health-related quality of life, using an accepted measure such as the St Georges Respiratory Questionnaire (SGRQ) (Jones 2009a) or Chronic Respiratory Diseases Questionnaire (CRQ) (Guyatt 1987).

Secondary outcomes
  1. Duration and severity (using an accepted definition) of exacerbations

  2. Days of disability (defined as days where the participant was unable to undertake normal activities)

  3. Frequency and duration of hospital admissions

  4. Reduction in lung function from baseline as measured by FEV1 and FVC

  5. Drug resistance as measured by microbial sensitivity

  6. Death due to all-cause mortality as well as due to respiratory causes

  7. Adverse effects

Search methods for identification of studies

Electronic searches

We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (see Appendix 1).

All records in the CAGR coded as COPD or chronic bronchitis were searched using the following terms:

Chemoprophylaxis or (antibiotic* AND prophyla*) or (continuous AND antibiotic*) or antibiotic* or penicillin or phenoxymethylpenicillin or phenethicillin or amoxicillin or amoxycillin or "clavulanic acid" or tetracycline or oxytetracycline or doxycycline or quinolone or ciprofloxacin or moxifloxacin or macrolide or erythromycin or roxithromycin or azithromycin or sulphonamide or co-trimoxazole or sulphaphenazole or trimethoprim or sigmamycin or (tetracycline AND oleandomycin) or sulfamethoxazole or sulfaphenazole or sulfonamide

We conducted a search of ClinicalTrials.gov. All databases were searched from their inception to August 2013 and there were no restrictions on language of publication. References were managed using EndNote.

Searching other resources

We checked the reference lists of all eligible primary trials and review articles for additional references. We contacted the authors of one identified trial (Mygind 2010) and asked them to supply the data from their unpublished study. We have checked the references of the included and excluded studies from the previous review on chronic bronchitis for possible studies (Staykova 2003).

Data collection and analysis

Selection of studies

Two review authors (PP and SH) independently screened the abstracts of trials identified by the search as to whether or not they met our inclusion criteria. We obtained the full texts of publications for those that were considered definite or possible for inclusion. These were then reviewed independently by two review authors (PP and SH) to assess eligibility. We resolved any disagreement by discussion and consensus.

Data extraction and management

Both review authors independently extracted the data from the eligible studies.

We extracted the following data.

  • Methods: trial design, duration of follow-up.

  • Participants: age, gender, smoking status, study setting, inclusion and exclusion criteria.

  • Intervention: drug name, dose, duration of treatment, control or standard therapy.

  • Information on outcome measures.

Where appropriate, we have combined the data from trials using RevMan 5.

Assessment of risk of bias in included studies

Two investigators independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion. We assessed the risk of bias according to the following domains.

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding of participants and personnel.

  4. Blinding of outcome assessment.

  5. Incomplete outcome data.

  6. Selective outcome reporting.

  7. Other bias.

We graded each potential source of bias as high, low or unclear risk.

Measures of treatment effect

Results for continuous variables were expressed using a fixed-effect model mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI). Results for pooled outcomes with dichotomous variables were expressed using a fixed-effect model odds ratio (OR) with 95% CI. We regarded a P value of less than 0.05 as statistically significant.

The relative risk (RR) was used for dichotomous data and presented along with the 95% CI. The risk ratio was calculated for harmful events or 'bad' outcomes, for example increased exacerbations, development of antibiotic resistance, worsened quality of life.

For ease of communication and clarity, the number needed to treat to benefit (NNTb) was derived from the OR and mean control group event rate using Visual Rx.

Unit of analysis issues

We did not find any crossover trials or cluster randomised trials that met our inclusion criteria. However, if we had encountered them we planned to evaluate the cluster randomised trials for trial quality and if the design and analysis were of poor quality exclude them. We planned to analyse any eligible cluster randomised trials with the help of a statistician.

Dealing with missing data

We contacted in writing the investigators from Mygind 2010 in order to verify key study characteristics and to obtain missing numerical outcome data. We were unable to get more details.

Assessment of heterogeneity

From the forest plot, we tested for heterogeneity where the CIs did not overlap with each other. We used the I2 statistic to measure heterogeneity among the trials in each analysis. Where we identified substantial heterogeneity we explored this using a pre-specified subgroup analysis.

Assessment of reporting biases

Where we suspected reporting bias we attempted to contact the study authors to ask them to provide the missing outcome data. Where this was not possible, and the missing data were thought to introduce serious bias, the impact of including such studies in the overall assessment of results was explored by a sensitivity analysis

Data synthesis

We created a summary of findings table using the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and GRADEpro software for the following outcomes.

  1. Number of exacerbations, using an accepted definition.

  2. Days of disability (defined as days where the participant was unable to undertake normal activities).

  3. Frequency and duration of hospital admissions.

  4. Health-related quality of life, using an accepted measure such as SGRQ or CRQ.

  5. Death.

  6. Drug resistance.

  7. Other adverse effects of treatment.

Subgroup analysis and investigation of heterogeneity

If significant heterogeneity was found, we planned to carry out the following subgroup analyses for the primary outcome (number of exacerbations).

  1. Severity of COPD according to FEV1 and the GOLD criteria.

  2. Type of antibiotic.

  3. Duration of antibiotic use.

  4. Year of conduct of trial.

  5. Whether the antibiotic was used primarily as an antimicrobial or as an anti-inflammatory agent.

  6. Treatment regimen including dose, frequency, route of administration. 

  7. History of exacerbations (e.g. trials with frequent exacerbations versus trials with infrequent exacerbations, or trials with lower incidence rates versus trials with higher incidence rates).

Sensitivity analysis

We conducted a sensitivity analysis by removing trials judged to be at high or unclear risk of bias for the domains of sequence generation, allocation concealment or blinding.

Results

Description of studies

Results of the search

The electronic search identified 899 potentially eligible abstracts (Figure 1). A further 14 records were located from other sources which included abstracts screened for the previous review and screening the bibliographies of the most recently published editorials and reviews on this subject. Seven records had duplicates. Five abstracts did not have adequate information to assess the studies against the inclusion and exclusion criteria and were excluded. By screening the abstracts we identified 49 potentially eligible abstracts. The full text articles of these abstracts were reviewed. The articles in languages other than English were translated. There were seven studies that were eligible for inclusion in this systematic review. One study is still ongoing (NCT00985244) (Characteristics of ongoing studies).

Figure 1.

Study flow diagram.

Included studies

There were seven studies that were eligible for the systematic review (Albert 2011; Banerjee 2005; He 2010; Mygind 2010; Seemungal 2008; Sethi 2010; Suzuki 2001). Five studies were of continuous antibiotics (Albert 2011; Banerjee 2005; He 2010; Seemungal 2008; Suzuki 2001,) administered on at least a daily basis. Two studies were of intermittent or 'pulsed' antibiotic prophylaxis (Mygind 2010; Sethi 2010). The first gave treatment for 8 days every 8 weeks for 48 weeks; the second for 3 days per month for 36 months. Full details may be found in Characteristics of included studies.

All of these studies were randomised, placebo controlled, parallel group trials. All except one study (Suzuki 2001) were double blind. All studies investigated the use of prophylactic antibiotic versus placebo. All studies were published in journals except Mygind 2010, which was an oral presentation at the European Respiratory Society Conference in 2010. The trials were published or presented between 2001 and 2011.

The antibiotics investigated were azithromycin (Albert 2011; Mygind 2010), erythromycin (He 2010; Seemungal 2008; Suzuki 2001), clarithromycin (Banerjee 2005) and moxifloxacin (Sethi 2010). The study durations varied from three months to 36 months.

All studies listed exacerbation frequency and health-related quality of life as primary, co-primary or secondary outcomes. All studies were analysed using intention-to-treat analysis. Sethi 2010 reported both a per protocol analysis as well as an intention-to-treat analysis, but for the review we have included only the intention-to-treat analysis results.

All the studies included in this review were published prior to the 2011 GOLD revision, hence they used the previous GOLD stage I to IV spirometric criteria for classification of severity. In our analyses we have used the GOLD stage I to IV criteria as the details on symptom scores and exacerbation frequency were not available for individual patients, therefore we could not apply the new combined approach for grading severity into COPD Groups A to D.

Excluded studies

Excluded studies are listed in the Characteristics of excluded studies table along with the reasons for exclusion.

Risk of bias in included studies

Judgements and reasons for the judgements can be found in Characteristics of included studies and an overview of our judgements can be found in Figure 2.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence allocation and allocation concealment were well described in four of the seven studies (Albert 2011; Banerjee 2005; Seemungal 2008; Suzuki 2001). In three studies (He 2010; Mygind 2010; Sethi 2010) random sequence generation was not well described.

For Mygind 2010, being a conference presentation, we had access to limited data. Multiple attempts by email and post to obtain further information from the corresponding author were not successful.

Blinding

Blinding of the participants and personnel (performance bias) was well described in all included studies except for Suzuki 2001, which was not blinded. Blinding of the outcome assessment (detection bias) was well described in all studies except for Banerjee 2005 and He 2010.

Incomplete outcome data

All outcomes of the study participants were well described using either a CONSORT diagram (Albert 2011; Seemungal 2008; Sethi 2010) or by a dedicated paragraph or table (Banerjee 2005; He 2010; Suzuki 2001). Mygind 2010 was a conference presentation of unpublished data and thus we had limited information on which to judge the attrition bias. Withdrawal rates were similar between both studies and treatments and were in the order of 10%, except for Mygind which was over 40%.

Selective reporting

The studies reported all pre-specified primary and secondary outcomes in detail.

Other potential sources of bias

Albert 2011 was supported by grants from the National Institutes of Health, Banerjee 2005 received a grant from Abbott, Seemungal 2008 was supported by the British Lung foundation, and Sethi 2010 was supported by a research grant from Bayer HealthCare AB.

Effects of interventions

See: Summary of findings for the main comparison Antibiotics versus placebo for COPD

Seven randomised controlled trials involving 3170 patients were included in the systematic review and an overview of the results together with a summary of the quality of evidence per outcome is presented in Summary of findings for the main comparison. Five studies assessed the use of continuous prophylactic antibiotics, which included a total of 1438 patients. All five studies of continuous antibiotic prophylaxis used a macrolide. These included azithromycin (Albert 2011), erythromycin (He 2010; Seemungal 2008; Suzuki 2001) and clarithromycin (Banerjee 2005). There were two studies of pulsed antibiotic prophylaxis, which had a total of 1732 patients. The prophylactic antibiotics tested in these treatment protocols were moxifloxacin (Sethi 2010) and azithromycin (Mygind 2010).

Sethi 2010 analysed data on an intention-to-treat basis as well as per protocol; we have only utilised the intention-to-treat analysis results for our review. Sethi 2010 defined an exacerbation by two different definitions. The primary definition was: any confirmed acute exacerbation of COPD, unconfirmed pneumonia or any other lower respiratory tract infections; the secondary definition was: only confirmed exacerbations of COPD, excluding confirmed or unconfirmed pneumonia and any other lower respiratory tract infection. For this review, only the primary definition was used as it was an extended definition and hence was the more conservative definition.

Primary outcome: number of patients with exacerbations

Four trials (Albert 2011; He 2010; Seemungal 2008; Sethi 2010) involving 2411 participants reported the number of participants experiencing one or more exacerbations. However, there was high heterogeneity among the four trials (I2= 62%). We explored the heterogeneity using pre-planned subgroup analyses (Analysis 1.1; Figure 3).

Figure 3.

Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.1 Number of people with one or more exacerbations.

In studies using continuous antibiotic prophylaxis, the number of patients experiencing at least one exacerbation in the study period was explored by performing a meta-analysis on the data from three double-blind studies involving 1262 patients. The number of patients experiencing an exacerbation was reduced with continuous antibiotic treatment compared with placebo (OR 0.55; 95% CI 0.39 to 0.77; Analysis 1.1; Figure 3). This represented a reduction from 69% in the control group to 54% in the treatment group (95% CI 46% to 63%) and the number needed to treat (NNTb) to prevent one exacerbation was therefore 8 (95% CI 5 to 18), see Figure 4.

Figure 4.

In the control group 69 people out of 100 had one or more exacerbations of COPD over 6 to 18 months, compared to 55 (95% CI 46 to 63) out of 100 for the continuous antibiotics group.

We compared the effect of continuous antibiotics with pulsed antibiotics and there was a significant difference between the subgroups (test for difference between subgroups Chi2 = 4.66, df = 1, P = 0.03). There was no significant reduction in the number of patients with at least one exacerbation when pulsed antibiotic treatment was used, although this was based on only one study involving 1157 patients (OR 0.87; 95% CI 0.69 to 1.09; Analysis 1.1; Figure 3).

The degree of heterogeneity among the three trials of continuous antibiotics was low at 14%. Data from Suzuki 2001 were not included in the meta-analysis as this study was not blinded. If included, the heterogeneity increased to 78% (Analysis 1.2) as the treatment effect in the unblinded study was much greater than in the other studies.

Primary outcome: rate of exacerbations per patient per year

The exacerbation rate was expressed as a rate ratio, which was calculated using the generic inverse variance method in RevMan software.

The rate of exacerbations with continuous antibiotic use was assessed by performing a meta-analysis using data from three studies (Albert 2011; He 2010; Seemungal 2008) involving 1262 patients (Analysis 1.3; Figure 5). Use of continuous prophylactic antibiotic was associated with a reduction in the rate of exacerbations (rate ratio 0.73; 95% CI 0.58 to 0.91). This was statistically significant (P = 0.005). There was a moderate level of heterogeneity among the three included trials (I2= 47%).

Figure 5.

Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.3 Rate of exacerbation per patient per year.

A subgroup analysis according to the severity of COPD as defined by the GOLD criteria did not show a difference between the subgroups in the effect of antibiotics on exacerbation frequency (Analysis 1.5).

The median time to first exacerbation

The median time to first exacerbation was analysed using a Kaplan-Meier survival curve and log rank test (Analysis 1.4). Data were available on four studies involving 2419 patients.

There were three studies that used continuous prophylactic antibiotics, involving 1262 patients. Use of a prophylactic antibiotic lengthened the time to first exacerbation in all three studies compared with placebo. In Albert 2011 this was 266 days (antibiotic) versus 174 days (placebo) (P < 0.001); in He 2010,155 days versus 86 days (P = 0.032); in Seemungal 2008, 271 days versus 89 days (P = 0.02).

In contrast, the median time to the first exacerbation in the study done by Sethi 2010 using pulsed antibiotic prophylaxis did not show a significant difference: 364 days versus 336 days (P = 0.062).

In Albert 2011, which used azithromycin, a predefined subgroup analysis in 22 subgroups found that prophylactic antibiotics were associated with greater treatment effects in patients who had given up smoking (test for interaction P = 0.012), were not on steroid inhaler treatment at enrolment (P = 0.032), on oxygen therapy, or older than 65 years (P = 0.012).

Primary outcome: health-related quality of life

Health-related quality of life was explored in five studies (Albert 2011; Banerjee 2005; He 2010; Mygind 2010; Sethi 2010). All of these studies used the St George's Respiratory Questionnaire (SGRQ) (Jones 2009a). The data for inclusion in the meta-analysis were only available from the two larger studies involving 1926 patients (Albert 2011; Sethi 2010).

This found a significant improvement with antibiotic treatment in the total quality of life score (MD -1.78; 95% CI -2.95 to -0.61; Analysis 1.6; Figure 6).

Figure 6.

Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.6 HRQOL, SGRQ (total score).

The SGRQ comprises three subcomponents, namely symptom score, impact score and activity score. These subgroups were analysed separately. Both the symptom score (MD -3.75; 95% CI -5.48 to -2.01; Analysis 1.7) and impact score (MD -1.71; 95% CI -3.10 to -0.32; Analysis 1.8) were statistically improved with use of antibiotics compared with placebo. On the other hand, the activity score did not show any statistically significant improvement (MD -0.81; 95% CI -2.26 to 0.63; Analysis 1.9). There was no heterogeneity among the studies.

However, the improvements in the SGRQ scores did not reach the level of clinical significance according to the conventional cut off of at least a 4 point reduction (Jones 2009a). Among the subscales, the symptom score showed the most improvement, with a reduction of 3.3 points in the Albert 2011 study and 4.4 in Sethi 2010.

The study by Albert 2011 demonstrated that more participants in the azithromycin group (43%) than the placebo group (36%) had at least a 4 point reduction in the SGRQ score. This was statistically significant (P = 0.03). It was not possible to perform a responder analysis (for > 4 point improvement) for the other studies due to the required data not being available.

The authors of Banerjee 2005 and Mygind 2010 reported no statistically significant difference in the total score or subgroup scoring of the SGRQ between groups, in 642 patients. Banerjee 2005 found improvement only in the subcategory of symptom score in the patients treated with continuous prophylactic clarithromycin over a three months period (MD -10.2; 95% CI -1.6 to -18.7).

Three studies used the Short Form-36 (SF-36) in addition to the SGRQ (Albert 2011; Banerjee 2005; He 2010). There was no significant improvement in the SF-36 overall score with antibiotics in any of the studies. Banerjee 2005 showed an improvement in the physical functioning score alone in the group that used prophylactic clarithromycin for three months (MD -12.9; 95% CI 3.1 to 22.6).

Secondary outcome: frequency of hospitalisation

The frequency of hospitalisation was assessed using data from four studies involving 2958 patients (Albert 2011; Mygind 2010; Seemungal 2008; Sethi 2010; Suzuki 2001).

The trial by Sethi 2010, involving pulsed moxifloxacin in 1157 patients, did not show any improvement in the hospitalisation frequency (131/569 treatment arm versus 136/580 placebo arm; P = 0.46; Analysis 1.11).

The trial by Albert 2011, involving continuous azithromycin in 1117 patients, calculated the rate of exacerbations requiring hospitalisation per patient per year according to the severity of COPD by the GOLD criteria (Analysis 1.11). The rate ratio was 0.77 (GOLD stage 2), 0.89 (GOLD stage 3) and 0.72 (GOLD stage 4). There were not adequate data to calculate the statistical significance of this outcome but there did not appear to be a trend.

The other two studies had inadequate data to calculate the mean event rate per year. Of these, one study involving 109 patients found a statistically significant reduction (P < 0.001) in hospitalisation while using erythromycin 200 to 400 mg daily for a 12 month period (Suzuki 2001). The other study (Mygind 2010) did not show a statistically significant difference in the frequency of hospitalisations.

Secondary outcome: duration of exacerbations

The duration of exacerbations was addressed by only two studies involving 684 patients (Mygind 2010; Seemungal 2008). Seemungal 2008 showed that antibiotic use was associated with a lower median number of exacerbation days: 9 days (interquartile range (IQR) 6 to 13 days) compared to 13 days on placebo (IQR 6 to 24 days) (P = 0.036). Similar findings were reported by Mygind 2010. This study had 575 patients and used pulsed azithromycin over a 36 month period. The median number of exacerbation days (at home or in hospital) was 93 in the azithromycin group compared to 111 in the placebo group (P = 0.04). Prophylactic pulsed antibiotic use (Mygind 2010) reduced the number of days with severe exacerbations managed at home: a median of 31 days versus 42.5 days for the placebo group (P = 0.01). A meta-analysis was not carried out for this comparison due to paucity of data.

Furthermore, Mygind 2010 reported data on hospitalisation due to COPD exacerbations. The study showed no difference in the number of hospitalisations between the treatment and placebo arms; however, there was a median reduction in hospital stay from 18 days in the placebo group to 15.5 days in the treatment group. No P value was stated for this comparison.

Secondary outcome: days of disability

Only one study reported on the number of days the participant was unable to undertake normal activity (Mygind 2010). The median number of days spent at home due to a mild exacerbation was no different between the treatment and placebo arms (42 days in each arm). However, there was a reduction in the median number of days spent at home due to a moderate to severe exacerbation from 42.5 days in the placebo group to 31 days in the azithromycin group (P = 0.01).

Secondary outcome: change in lung function

Only three studies addressed change in lung function. No study demonstrated any statistically significant change in the spirometry at the end of the treatment period (Mygind 2010; Sethi 2010) or during the first exacerbation (Seemungal 2008).

Secondary outcome: death (all-cause and respiratory aetiology)

Mortality data were reported in three studies involving 2841 participants (Albert 2011; Mygind 2010; Sethi 2010) and were combined into a meta-analysis. There was no significant difference between the treatment and placebo arms in all-cause mortality (OR 0.89; 95% CI 0.67 to 1.19; Analysis 1.12; Figure 7). Data on mortality secondary to a respiratory cause were available in the two larger studies (Albert 2011; Sethi 2010), which again showed no significant difference between groups (OR 1.18; 95% CI 0.63 to 2.18; Analysis 1.13).

Figure 7.

Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.12 All cause mortality.

Secondary outcome: serious adverse events

Adverse events were well explained only in four out of the seven studies (Albert 2011; He 2010; Seemungal 2008; Sethi 2010), but there was no uniform system for reporting them. There were 2411 participants in these four studies with a total of 502 adverse events reported. Overall, there was no significant difference in the total numbers of adverse events between the treatment and placebo arms (OR 0.88; 95% CI 0.73 to 1.07; Analysis 1.14; Figure 8).

Figure 8.

Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.14 Serious adverse events.

There were no significant differences in the number of adverse events between the treatment and placebo arms related to the respiratory system (Analysis 1.15), nervous system (Analysis 1.21), hypersensitivity (Analysis 1.20) or QTc prolongation (Analysis 1.17).

The adverse event most frequently recorded in all trials (Albert 2011; He 2010 Seemungal 2008; Sethi 2010) was gastrointestinal in origin (OR 1.58; 95% CI 1.01 to 2.47; Analysis 1.16). There was significant heterogeneity among the trials with an I2 of 79%. This suggested differences among the antibiotics and their adverse events for each study.

Individual trials did show some differences which may have clinical relevance.

Sethi 2010 reported significantly higher numbers of adverse events in the treatment arm with moxifloxacin (P < 0.001) (Analysis 1.16) secondary to increased gastrointestinal adverse events including diarrhoea, nausea and vomiting (OR 7.17; 95% CI 2.49 to 20.63), representing a number needed to treat to harm (NNT(H)) of 25 (95% CI 98 to 9). The intervention group in this trial received moxifloxacin 400 mg daily for 5 days, every 8 weeks for 48 weeks. A single case of diarrhoea was reported secondary to Clostridium difficile in the placebo group. Sethi stated that the adverse events were drug related.

Albert 2011 reported that azithromycin 250 mg daily for a 12 month period was associated with a significant increase in hearing impairment (OR 1.39; 95% CI 1.05 to 1.85) representing a NNT(H) of 18 (95% CI 128 to 9). The authors reported that the majority of the drug discontinuations due to a drug-related adverse event were due to hearing impairment (treatment group N = 142 (25%) versus placebo group N = 110 (20%) by 3 months). It should be noted that all patients in this trial had baseline audiometry, with patients with hearing impairment below the 95% percentile excluded from the study. Since there were a large number of patients in both the treatment and placebo arms that had drug discontinuation secondary to hearing loss, the authors commented that this could be due to a measurement error.

In Albert 2011, while there were no statistically significant differences observed in cardiovascular disease or QTc prolongation, six patients in the treatment group had to discontinue the medication due to development of prolonged QTc compared to four patients in the placebo group (P = 0.55). This trial excluded patients with tachycardia, long QTc and patients taking medications that could prolong the QTc.

In the non-blinded study of Suzuki 2001, it was reported that patients in the treatment group did not have any apparent adverse effects from erythromycin therapy during the study period.

Secondary outcome: antibiotic resistance

The development of antibiotic resistance was assessed in five studies involving 2486 patients (Albert 2011; Banerjee 2005; He 2010; Seemungal 2008; Sethi 2010). Because of the variety of ways in which resistance was evaluated and reported, it has proved impossible to combine these results in a meta-analysis.

Albert 2011 used sputum from patients that could expectorate as well as nasopharyngeal swabs. They found only 15% of patients were able to expectorate at the end of the three month treatment period. The commonest organisms identified in the treatment versus placebo groups were: S.aureus (N = 60 (10.7%) versus N = 71 (12.7%)); Moraxella spp (N=13 (2.3%) versus N = 6 (1%)); and S.pneumoniae (N = 6 (1.1%) versus N = 6 (1.1%)). The predominance of S. aureus in this COPD population was out of keeping with the usual pathogens anticipated and was thought to be due to the nasopharyngeal sampling. During the study period, the patients in the placebo group without bacterial colonisation (N = 172) became colonised at a significantly higher rate than those treated with 250 mg of daily azithromycin (N = 66) (P < 0.001). However, in the group that became newly colonised throughout the study period, the resistance to macrolide was higher in the treatment group: 81% compared to 41% in the placebo group (P < 0.001).

In Sethi 2010, which used pulsed moxifloxacin over a 48 week period, the sampling for organisms was carried out using sputum sampling and rectal sampling. Only 24% of all patients could produce sputum. The commonest organisms isolated were: H.influenzae (8.3%), H.parainfluenzae (6.6%) and S.pneumoniae (4.3%); S. aureus was isolated in 2.6%. The Minimum Inhibitory Concentration (MIC) for moxifloxacin for H.influenzae, H.parainfluenzae, S.pneumoniae, M.catarrhalis and S. aureus did not change during the study period. A single moxifloxacin-resistant S.pneumoniae isolate was identified at the end of the study period (MIC 4 mg/L). There were one to three moxifloxacin-resistant isolates at different points of the study that were not persistent. Patients who had produced cultures of moxifloxacin-resistant pseudomonas were excluded from the study. However, patients with moxifloxacin-sensitive pseudomonas were included. During the 24th week of the study, the median MIC of moxifloxacin had increased to 4 mg/L, which returned to baseline at the end of the treatment period. The median MIC of the placebo group with pseudomonas-sensitive moxifloxacin increased from 0.5 mg/L to 2 mg/L at the end of the treatment period. The study authors recommended not using moxifloxacin in patients with known pseudomonas colonisation owing to the possibility of developing rapid resistance.

Seemungal 2008 investigated 109 patients with twice daily erythromycin 250 mg over a 12 month period. They encountered only one patient who developed resistance to S.pneumoniae at the end of the treatment period. All H.influenzae isolated (22/109) were found to be resistant to erythromycin. The microorganism milieu was as expected for the COPD population: H. influenzae (N = 22/36), S.pneumoniae (N = 6/36) and M.catarrhalis (N = 3/36).

The other two studies, by Banerjee 2005 using long acting clarithromycin 500 mg daily (Klaricid XL 500 mg) and He 2010 using erythromycin 125 mg Q8H, found a similar milieu of respiratory pathogens. They did not observe significant differences in the colonisation rate of the organisms or emergence of resistance. However these two studies were of a shorter duration than those mentioned above, six months and three months respectively.

Discussion

Summary of main results

The five studies in this review of continuous prophylactic antibiotics used macrolides, whereas of the two pulsed antibiotic studies one used a quinolone (moxifloxacin) for five days every eight weeks, for a total of six courses, and the other used azithromycin 500 mg daily for three days every month for three years (See Summary of findings for the main comparison for an overview of the results and quality of the evidence).

With the continuous use of a prophylactic macrolide antibiotic, for a duration of three to 12 months, there was a significant reduction in the number of patients with exacerbations (Analysis 1.1), the rate of exacerbations (Analysis 1.3), and the median time to the first exacerbation (Analysis 1.4) compared to placebo treatment. The NNT to prevent one patient from exacerbating was eight. Given that this is a preventive study these NNTs appear relatively favourable and are in keeping with those seen in treatment trials (Henry 1997). In prophylaxis studies, the expected NNT is greater as there is a large effect in a small number of patients who are subsets of a large population.

The use of pulsed antibiotics showed a reduced odds ratio, reducing the number of patients with exacerbations, but the effect was not statistically significant and the test for interaction indicated that there was a significant difference between the results from continuous and pulsed antibiotics. However, the data were not robust enough for a definite conclusion as only a single study had the necessary data for analysis (Analysis 1.1; Analysis 1.3).

The quality of life measured by the SGRQ showed a statistically significant improvement in the total score (Analysis 1.6) with the use of both pulsed and continuous antibiotics. However, this failed to reach a clinically significant level when using the accepted cut off of a 4 point reduction.

The data on duration of exacerbations (Analysis 1.10), frequency and duration of hospital admissions, and days of disability are sparse and need to be addressed in future research. All-cause mortality (Analysis 1.12) and mortality due to respiratory diseases (Analysis 1.13) were not significantly different between the treatment and placebo groups.

The favourable NNT seen with prophylactic antibiotics to prevent exacerbations needs to be balanced against the risk of harm. To achieve the benefits of prophylaxis requires the taking of another medicine every day, with cost and adherence implications. The commonest adverse event noted for all antibiotics was gastrointestinal side effects. These were commonest with moxifloxacin and reached statistical significance in Sethi 2010, with a NNT(H) of 25 (Analysis 1.16), even though moxifloxacin was given for only five days every eight weeks. Gastrointestinal side effects were also seen with macrolides, leading to drug discontinuation. Use of azithromycin was associated with a significant reduction in hearing, with a NNT(H) of 18 (Analysis 1.18). While some adverse events, such as the prolongation of the electrocardiogram (ECG) QTc interval (Analysis 1.17), did not reach statistical significance when comparing the treatment and placebo groups, an issue to address is the development of potentially life-threatening complications like a long QTc while on long term macrolide without proper surveillance, that is outside the study period. it is worth keeping in mind that the Albert et al study excluded all patients with an existing diagnosis of long QTc or tachycardia, and patients taking other medications that could prolong the QTc. Yet, during the study period there were six patients on the study drug who developed novel prolonged QTc, emphasising the need for ongoing close monitoring in this elderly patient group with multiple co-morbidities and poly-pharmacy.

The concern about development of antibiotic resistance with long term antibiotics is not allayed by the results of this review. The data from Albert 2011 show that even though the colonisation of organisms becomes lower with the prophylactic antibiotic treatment, the organisms that do colonise are more likely to be resistant to the antibiotic used. However, colonisation with a resistant organism was not necessarily associated with an increase in the exacerbation rate. This could be due to the anti-inflammatory effect of the macrolide. The data in this review support the fact that quinolones should be used with care in patients colonised with pseudomonas as resistance develops quickly. Once this happens, there are few available oral antibiotics that may be used against pseudomonas spp. We are unable to predict how the use of prophylactic antibiotics would affect the resistance patterns in the community in the next decade.

In this review we were unable to determine whether or not the improvement in exacerbations was due to the antimicrobial effect of the antibiotics or an anti-inflammatory effect.

Overall completeness and applicability of evidence

The patients in the studies in this review were aged 40 years or over (mean age 67 years) and had at least moderate severity COPD (mean FEV1 1.2 L). Three studies (Albert 2011; Mygind 2010; Sethi 2010) included patients who experienced one to two exacerbations during the previous year, and Albert 2011 and Sethi 2010 included patients who were on long term supplemental oxygen or systemic steroids, or both (see Characteristics of included studies, Summary of findings for the main comparison). Hence the results can be generalised only to this group of patients who are at the more severe end of the COPD spectrum.

Data from Albert 2011 suggest that prophylactic antibiotics may be most useful in patients who have given up smoking, who are not on any inhaler treatment (long acting beta agonist (LABA), long acting muscarinic antagonist (LAMA) or inhaled corticosteroid (ICS) in any combination), on oxygen therapy or older than 65 years.

Although these results were obtained from pre-specified subgroup analyses, the sample sizes were much smaller than the randomised sample size. There were 22 analyses carried out giving a 62% chance of one analysis yielding a statistically significant result. For this reason, the authors are aware that there may be false positives in these results and recommend additional studies that are adequately powered to explore these subgroups.

It is also important to note that the study participants had undergone strict exclusion criteria. Patients with tachycardia, arrhythmia, long QTc as well as being on medication that could potentially increase the QTc (a long list) or baseline hearing deficit based on audiometry were excluded. There was regular monitoring throughout the study period and drugs were discontinued in the event of a significant adverse event.

Quality of the evidence

Three trials (Albert 2011; Banerjee 2004; Seemungal 2008) provided detailed information on randomisation, blinding and outcomes as per trial protocols. Randomisation was not described in detail in Sethi 2010, however the blinding and outcomes were very clearly documented. These four trials could be considered to have good quality data and they carry the majority of the weight of the review. The primary outcome, number of people with one or more exacerbations was moderate quality evidence, we chose to downgrade due to the clinical and statistical heterogeneity between the four trials contributing data to it. In Summary of findings for the main comparison we presented the exacerbations subgrouped by delivery type, continuous antibiotics were of high quality, whereas pulsed antibiotics were of moderate quality owing to paucity of evidence leading to a wide confidence interval.

He 2010 was a double-blind randomised trial, however the randomisation was not explained in detail and allocation concealment was not outlined.

Suzuki 2001 was not a blinded trial and the results should be looked at keeping this in mind. This trial was not included in the meta-analysis.

Mygind 2010 had limited data due to it being a conference presentation. While the data on blinding and outcomes were adequate, randomisation details were not specified and the dropouts were high.

Potential biases in the review process

The bias was minimised during the review process by completing a comprehensive electronic search of all published and unpublished data, as well as handsearching the bibliographies from selected studies. The data were extracted and full text articles reviewed by both authors and disagreement was resolved by discussion to minimise bias.

Agreements and disagreements with other studies or reviews

Our findings are consistent with an earlier Cochrane review of prophylactic antibiotics in chronic bronchitis (Staykova 2003), even though the definitions of cases are tighter in the present review.

There was a recent case-based review article in the New England Journal of Medicine (NEJM) on antibiotic prevention of acute exacerbations of COPD (Wenzel 2012). This review recommended the use of azithromycin 250 mg three times a week to reduce exacerbation frequency in patients on maximal COPD treatment who were still having two or more exacerbations per year. Careful selection, prior investigations and proper follow-up were emphasised, which is concordant with our findings and recommendations.

Our review did not find systematic reviews or randomised controlled trials evaluating three times weekly azithromycin on exacerbation frequency; hence there are no data to support this approach. The effectiveness data exist only for continuous azithromycin therapy, and only in reducing the frequency, duration and number of patients with exacerbations; but not mortality, hospitalisation or quality of life.

There is an ongoing randomised trial that is currently recruiting (Uzun 2012) (www.ClinicalTrials.gov: NCT00985244) comparing azithromycin 500 mg, three times a week, versus placebo treatment. The results of this trial will add to what is known about this regimen and the effects of prophylactic antibiotics in general.

Authors' conclusions

Implications for practice

Use of continuous prophylactic macrolide antibiotics for a period of up to 12 months is likely to reduce the number of patients with exacerbations, exacerbation frequency, the median time to first exacerbation and possibly health-related quality of life. Reducing the frequency of exacerbations would reduce healthcare costs and might be expected to preserve lung function and quality of life as well as lower the risk of mortality, although we did not find evidence of any of the latter in this review. In part, this is due to the dearth of studies that have addressed the frequency and duration of hospital admissions and the relatively small numbers of patients in most of the studies, that is the studies were underpowered to measure these outcomes.

The benefit in prevention of exacerbations was seen in the group of patients that were included in the studies. These patients had at least moderately severe COPD and were already frequent exacerbators needing treatment with antibiotics or systemic steroids or who were on supplemental oxygen. Evidence available from a single study suggests that Iindividuals over 65 years benefited more than younger individuals. Hence, carefully identifying the patient group that would benefit most from the use of prophylactic antibiotics is of paramount importance. Although the selection of patients for prophylactic antibiotics is critical, the evidence base for making statements about patient selection is poor since not all trials have used the same selection criteria and only three trials used frequent exacerbations as an inclusion criterion, hence the trials are too small to assess effect modification

There are some potentially serious adverse effects with prophylactic antibiotics. Furthermore, development of antibiotic resistance remains of major concern. This is particularly so for those patients colonised with pseudomonas. More broadly, there are calls worldwide to reduce the total amount of antibiotics prescribed. Hence, even though the NNTs are relatively small in order to prevent an exacerbation or to prevent one person having an exacerbation, this has to be balanced with the risks of harm either to that individual or indirectly to others via antibiotic resistance.

It is not clear from the studies the extent to which participants had other treatments for their COPD optimised (for example smoking cessation programmes, pulmonary rehabilitation, vaccination). In current clinical practice, prophylactic antibiotics tend to be used as a last resort because of concerns about antibiotic resistance in the community. If an informed decision is made to start prophylactic antibiotics in a particular patient, there needs to be baseline checks to confirm the identity of the infection (for example sputum cultures) and ECG or audiometry, depending on the planned antibiotic, as well as ongoing monitoring of the same.

Implications for research

Patients in both arms of clinical trials should receive the full package of evidence-based interventions in COPD, as well as the trial interventions.

A trial comparing continuous versus pulsed use of the same antibiotic would answer the question of whether or not the regimens are equally effective and how they compare in terms of development of resistance and adverse effects. The relative effects seen in Mygind 2010 with pulsed azithromycin versus Albert 2011 with continuous azithromycin might have provided a rough estimate; however we were unable to obtain further data from the Mygind study. There is an ongoing trial (NCT00985244) on pulsed azithromycin that is still recruiting. More studies are needed to determine if the mechanism of reduction in exacerbations is due to anti-inflammatory or anti-infective effects, or both. These would need to incorporate markers of inflammation, in the airways or systemic.

Better identification of the subsets of patients who would benefit most would be of great value in future research so as to deliver targeted treatment to the right patient. Future trials that incorporate potential biomarkers might be useful for patient selection.

Shorter trials through winter months when exacerbations are more common might be a pragmatic strategy, but this needs to be tested.

Duration of hospital admissions and days of disability due to an exacerbation were not well addressed in the studies. Future studies should document these outcomes. Additionally, a cost-effectiveness analysis would be useful. Most of the costs in severe COPD are related to hospitalisation. On the face of it, antibiotics may be cheaper than some inhalers but there are hidden costs such as the cost of screening for adverse effects and the direct and indirect costs of antimicrobial resistance.

The maximal duration of continuous prophylactic antibiotic was 12 months, and for pulsed antibiotic it was 36 months. Hence, there are no data on the impact of very long term antibiotic use on antibiotic resistance patterns in the community. The latter will require local surveillance and the correlation of resistance and prescribing patterns.

Yet to be determined is whether prophylactic antibiotics are able to alter the rate of deterioration of lung function in COPD and, if they do, whether is this due to antibiotic or anti-inflammatory effects. This would be a helpful advance in the understanding of the pathophysiology of this common and debilitating disease. Long term follow-up studies of patients who have been in prophylactic antibiotic trials may help to answer these questions.

Future studies directed at the use of inhaled antibiotics, which may result in fewer systemic effects and higher local concentrations, would be useful in reducing the side effects noted during use of oral prophylactic antibiotic therapy.

Studies looking into continuous antibiotic therapy in clear relation to other interventions that are useful in frequent exacerbators would help determine the advantages and disadvantages of antibiotic therapy over the already established measures used to reduce exacerbations.

Acknowledgements

We would like to acknowledge the contribution made by Dr Peter Black to the earlier review as well as his lasting influence as a teacher, mentor, friend and colleague.

We would like to acknowledge the statistical support given by Ms Anne Sophie Vallerd (Statistician), University of Sydney, Australia.

We acknowledge the support of staff at the Cochrane Airways Group, especially Emma Welsh and Dr Chris Cates.

Milo Puhan was the Editor for this review and commented critically on the review.

Data and analyses

Download statistical data

Comparison 1. Antibiotics versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of people with one or more exacerbations42411Odds Ratio (M-H, Random, 95% CI)0.64 [0.45, 0.90]
1.1 Continuous antibiotics31262Odds Ratio (M-H, Random, 95% CI)0.55 [0.39, 0.77]
1.2 Pulsed antibiotics11149Odds Ratio (M-H, Random, 95% CI)0.87 [0.69, 1.09]
2 Number of patients with one or more exacerbations on continuous antibiotics (regardless of blinding)41371Odds Ratio (M-H, Random, 95% CI)0.31 [0.13, 0.72]
2.1 Continuous antibiotics41371Odds Ratio (M-H, Random, 95% CI)0.31 [0.13, 0.72]
3 Rate of exacerbation per patient per year3 Rate Ratio (Random, 95% CI)0.73 [0.58, 0.91]
3.1 Continuous antibiotics3 Rate Ratio (Random, 95% CI)0.73 [0.58, 0.91]
4 Time to the first exacerbation  Other dataNo numeric data
4.1 Continous antibiotic  Other dataNo numeric data
4.2 Pulsed antibiotics  Other dataNo numeric data
5 COPD exacerbations according to severity of COPD (Gold staging system)  Other dataNo numeric data
5.1 Continuous antibiotics  Other dataNo numeric data
5.2 Pulsed antibiotics  Other dataNo numeric data
6 HRQOL, SGRQ (total score)31962Mean Difference (IV, Fixed, 95% CI)-1.78 [-2.95, -0.61]
7 HRQOL, SGRQ (symptoms)21926Mean Difference (IV, Fixed, 95% CI)-3.75 [-5.48, -2.01]
8 HRQOL, SGRQ (impact)21926Mean Difference (IV, Fixed, 95% CI)-1.71 [-3.10, -0.32]
9 HRQOL, SGRQ (activity)21926Mean Difference (IV, Fixed, 95% CI)-0.81 [-2.26, 0.63]
10 Duration of exacerbation  Other dataNo numeric data
10.1 Continuous antibiotics  Other dataNo numeric data
10.2 Pulsed antibiotics  Other dataNo numeric data
11 Frequency of hospital admissions  Other dataNo numeric data
11.1 Continuous antibiotics  Other dataNo numeric data
11.2 Pulsed antibiotics  Other dataNo numeric data
12 All cause mortality32841Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.67, 1.19]
13 Respiratory related mortality22266Odds Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.18]
14 Serious adverse events42411Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.07]
15 Adverse events: respiratory disorders22266Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.31]
16 Adverse events: gastrointestinal disorders42408Odds Ratio (M-H, Fixed, 95% CI)1.58 [1.01, 2.47]
17 Adverse events: QTc prolongation1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
18 Adverse events: hearing impairment1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
19 Adverse events: musculoskeletal disorders1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
20 Adverse events: hypersensitivity/skin rash21258Odds Ratio (M-H, Fixed, 95% CI)1.63 [0.63, 4.26]
21 Adverse events: nervous system disorders1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Antibiotics versus placebo, Outcome 1 Number of people with one or more exacerbations.

Analysis 1.2.

Comparison 1 Antibiotics versus placebo, Outcome 2 Number of patients with one or more exacerbations on continuous antibiotics (regardless of blinding).

Analysis 1.3.

Comparison 1 Antibiotics versus placebo, Outcome 3 Rate of exacerbation per patient per year.

Analysis 1.4.

Comparison 1 Antibiotics versus placebo, Outcome 4 Time to the first exacerbation.

Time to the first exacerbation
StudyMEDIAN Time to 1st exacerbation (days) treatmentMEDIAN Time to 1st exacerbation (days) placeboP valueTest usedHazard ratio
Continous antibiotic
Albert 2011266 (227-313)174 (143-215) P<0.001log -rank test0.73 (0.63 ,0.84)
He 201015586P=0.032Kaplan -Meier survival analysisnot given
Seemungal 200827189P=0.02log -rank testnot given
Pulsed antibiotics
Sethi 2010364336P=0.062Kaplan-Meier survival analysisnot given

Analysis 1.5.

Comparison 1 Antibiotics versus placebo, Outcome 5 COPD exacerbations according to severity of COPD (Gold staging system).

COPD exacerbations according to severity of COPD (Gold staging system)
StudyGold stageRate of Exacerbations per patient year on azithromycin (Mean +/-SD)Rate on placebo (Mean +/-SD)
Continuous antibiotics
Albert 20112 : FEV1 (80%-50%)1.02 (+/- 0.15)1.68 (+/- 0.16)
Albert 20113 : FEV1 (50-30%)1.53 (+/- 0.13)1.75 (+/- 0.13)
Albert 20114 : FEV1 <30%1.75 (+/- 0.12)2.05 (+/- 0.28)
Pulsed antibiotics
Sethi 20102 : FEV1 (80%-50%)0.65 (0.39-1.06)0.091
Sethi 20103 : FEV1 (50-30%)0.81 (0.58 - 1.10)0.192
Sethi 20104 : FEV1 <30%0.83 (0.54 - 1.28)0.459
Analysis 1.6.

Comparison 1 Antibiotics versus placebo, Outcome 6 HRQOL, SGRQ (total score).

Analysis 1.7.

Comparison 1 Antibiotics versus placebo, Outcome 7 HRQOL, SGRQ (symptoms).

Analysis 1.8.

Comparison 1 Antibiotics versus placebo, Outcome 8 HRQOL, SGRQ (impact).

Analysis 1.9.

Comparison 1 Antibiotics versus placebo, Outcome 9 HRQOL, SGRQ (activity).

Analysis 1.10.

Comparison 1 Antibiotics versus placebo, Outcome 10 Duration of exacerbation.

Duration of exacerbation
StudyMedian days of exacerbation treatment armMedian days of exacerbation placebo armP value
Continuous antibiotics
Seemungal 20089 (6-14)13 (6-24)0.036 Mann-Whitney test
Pulsed antibiotics
Mygind 2010931110.04

Analysis 1.11.

Comparison 1 Antibiotics versus placebo, Outcome 11 Frequency of hospital admissions.

Frequency of hospital admissions
StudyRate of Hospitalisations per patient year on moxifloxacin (Mean +/-SD)Rate on placebo (Mean +/-SD)P value
Continuous antibiotics
Albert 20112 : FEV1 (80%-50%)0.50 +/-0.120.65 +/-0.11
Albert 20113 : FEV1 (50-30%)0.85 +/- 0.120.96+/-0.12
Albert 20114 : FEV1 <30%0.74 +/- 0.121.03 +/- 0.27
Pulsed antibiotics
Sethi 20101311360.46
Sethi 201023.02%23.45% 
Sethi 2010   
Analysis 1.12.

Comparison 1 Antibiotics versus placebo, Outcome 12 All cause mortality.

Analysis 1.13.

Comparison 1 Antibiotics versus placebo, Outcome 13 Respiratory related mortality.

Analysis 1.14.

Comparison 1 Antibiotics versus placebo, Outcome 14 Serious adverse events.

Analysis 1.15.

Comparison 1 Antibiotics versus placebo, Outcome 15 Adverse events: respiratory disorders.

Analysis 1.16.

Comparison 1 Antibiotics versus placebo, Outcome 16 Adverse events: gastrointestinal disorders.

Analysis 1.17.

Comparison 1 Antibiotics versus placebo, Outcome 17 Adverse events: QTc prolongation.

Analysis 1.18.

Comparison 1 Antibiotics versus placebo, Outcome 18 Adverse events: hearing impairment.

Analysis 1.19.

Comparison 1 Antibiotics versus placebo, Outcome 19 Adverse events: musculoskeletal disorders.

Analysis 1.20.

Comparison 1 Antibiotics versus placebo, Outcome 20 Adverse events: hypersensitivity/skin rash.

Analysis 1.21.

Comparison 1 Antibiotics versus placebo, Outcome 21 Adverse events: nervous system disorders.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
CENTRAL (T he Cochrane Library)Monthly
PSYCHINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

COPD/chronic bronchitis search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1-9

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

[The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases]

Feedback

Feedback, 30 June 2014

Summary

1) One of the conclusions in the review was that there was no significant difference in total serious adverse events (SAE) between treatment and placebo. The definition of a serious adverse event includes any untoward medical occurrence that results in death, is life-threatening, requires hospitalisation or prolongation of hospitalisation, or results in persistent or significant disability (1).

According to this definition, a moderate to severe COPD exacerbation would be considered a SAE. It is unclear whether the four analyzed studies (Albert, He, Seemungal, Sethi) included COPD exacerbation in their SAE data. The following concerns only exist if trial authors included moderate to severe COPD exacerbations as SAEs. If the total numbers of SAEs are approximately equal between the treatment arms and COPD exacerbations were decreased in the antibiotic group, one can expect another type of SAE to have increased in the antibiotic group. Our fear is that there may be an unidentified SAE occurring in the antibiotic arm that is not present in the placebo arm.

We noted your documentation of attempting to contact the Mygind authors for more information and were curious as to whether Banerjee or Suzuki could be reached to determine more about SAE reporting in their trials. We also emailed the authors of Albert 2011 to inquire about how SAEs were classified and documented in that trial.

Furthermore, the 3 studies for which SAE data was not available (Banerjee, Suzuki, Mygind) have 751 participants, which equates to 23.5% of the total review participants. The missing SAE data from these three studies could potentially change the conclusion of this review on SAEs. Based on the two concerns we expressed above, additional information will be needed to confirm any difference in SAEs between treatment and placebo.

In addition, these further conclusions about the possible SAEs associated with prophylactic antibiotics are required before patients can make an informed decision about whether the benefits of therapy justify the risks.

2) In the review, the authors discussed that a cost-effectiveness analysis would be useful in deciding the value of antibiotics in prophylaxis of COPD exacerbation. Upon reviewing the Albert 2011 trial, we noted that cost-effectiveness was a secondary outcome that was included in the study protocol but not reported in the final data. The protocol suggests that this would have been calculated as the ratio of incremental costs to the ratio of incremental quality-adjusted life years. If this missing data can be obtained from the authors and included into the review, it will be an added piece of valuable information for the readers when considering practice changes.

3) In the analysis on frequency of hospitalisation, the authors report the rate ratios of exacerbation requiring hospitalisation (/patient/year), but stated it as the rate ratios of exacerbation (/patient/year). Since the Albert 2011 trial reports both the rates of exacerbation (/patient/year) and the rates of exacerbation requiring hospitalisation (/patient/year), we feel it would be in the interest of clarity to state “rate of exacerbations requiring hospitalisation per patient per year according to the severity of COPD by the GOLD criteria.”

References

1. Therapeutics Initiative. Serious adverse event analysis: lipid-lowering therapy revisited. Therapeutics Letter. 2001 Aug-Oct; Issue 42. Available from: www.ti.ubc.ca/pages/letter42.htm [cited 2014 Jun 22]

Reply

Question 1

We agree that elucidating all antibiotic related SAEs is of paramount importance for patients and physicians prescribing these prophylactic antibiotics in order to make informed choices.

  1. Albert et al included COPD as a cause of fatal SAE causing death in 10 patients in antibiotic group and 7 patients in the placebo group. However, given that there were 317 exacerbations in 558 patients in the antibiotic group and 380 exacerbations in 559 patients in the placebo group, it does not seem possible that COPD exacerbations were looked upon and included as SAEs. However, we agree that this needs to be clarified with the authors and we have written to Albert et al requesting clarification as to whether they have included moderate to severe COPD exacerbations as a SAE.

  2. In the Seemungal et al study the only listed adverse events are upper GI, lower GI, rash and other. Relooking at the raw data, 28 out of the 53 patients in the treatment group and 42 out of the 56 patients in the placebo group had experienced COPD exacerbations; hence they have not included COPD exacerbations as SAEs

  3. In He study listed adverse events were abdominal pain and heart failure in two patients in the antibiotic group and respiratory insuffiencey in two patients in the placebo group. Again the COPD exacerbations were not included as a SAE.

  4. In Sethi et al study, COPD exacerbations were not reported as SAEs. Looking closely at the adverse event table from the paper only four patients reported dyspnoea in the treatment group and no patients reported dyspnoea in the placebo group. Given the much larger number of COPD exacerbations that had occurred in both groups it seems that exacerbations have not been included as a SAE.

  5. The Mygind study did not report SAEs in detail. However they have categorised adverse events as upper GI, lower GI, infection and other and did not include COPD exacerbation as an adverse event. However this data is from an oral presentation slide and as mentioned in the paper we did not receive a response from the authors.

  6. The Banerjee study had indicated in the paper that they had one patient withdrawing in the treatment arm due to GI disturbance.

  7. The Suzuki study had listed that one patient was excluded from the treatment group due to diarrhoea with no other antibiotic-related adverse event listed.

In summary all four papers with detailed data on adverse events (Albert, He, Seemungal, Sethi) have not included COPD exacerbations as a SAE according to the raw data we have. Albert had included COPD as a cause of death and we have written to them to clarify this point. The three studies with limited data (Banerjee, Suzuki and Mygind) had not listed COPD exacerbations as a SAE.

While moderate to severe COPD exacerbations by definition qualify as a SAE, the most likely rationale for reporting these as separate entities was that exacerbations are the primary outcome assessed by these studies. Separating exacerbations out from adverse events will give a better idea of whether there are other SAE that would occur in the treatment group (other than the assessed primary outcome of exacerbations)

Question 2

We agree with this point. Assessing cost-effectiveness of this intervention is of fundamental importance and we have written to Albert group requesting to supply this data. This certainly is a factor that we will explore during the future updates.

Question 3

We agree that the sentence you have suggested clarifies the meaning better and have made the suggested change.

At the time of publication of this feedback, we await a response from Albert.

Contributors

Debbie Au and Caitlin Lang, Lower Mainland Pharmacy Services, Pharmacy Residents, UBC

Dr. Aaron Tejani, Lower Mainland Pharmacy Services, Medication Use Evaluation Coordinator

What's new

Last assessed as up-to-date: 29 August 2013.

DateEventDescription
26 August 2014Feedback has been incorporatedFeedback and author response added to the review.

Contributions of authors

Equal contributions were made from both authors to the protocol, data extraction, analysis, write up, response to reviewers comments. Both authors approved the final version of the review.

Declarations of interest

None known

Sources of support

Internal sources

  • Authors did not receive any grant, salary or other internal source of support for this review, Other.

External sources

  • Authors did not receive any grant, salary or any other form of external support for this review, Other.

Differences between protocol and review

The protocol stated: including studies using antibiotics at least three times a week for a minimum period of three months.

We have amended this to include a regular schedule of pulsed antibiotics for a period of at least three months in order to include more studies using pulsed antibiotics.

Some additional text has been added to the background.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Albert 2011

Methods

Prospective, randomised, double-blind, placebo controlled clinical trial with 12 month treatment duration

Intention-to-treat analysis

Participants

N=1142. Aged 40 or over. Mean age 65 years (azithromycin) and 66 (placebo)

41% female

Severity of COPD moderate or worse as defined by GOLD criteria

Mean FEV1 1.10±0.50 (azithromycin) and 1.12±0.52 (placebo)

Presence of either a) using continuous supplemental oxygen or b) received systemic glucocorticoids within the previous year /had gone to an emergency room/hospitalisation for an acute exacerbation

No acute exacerbation of COPD for at least 4 weeks

Exclusions: asthma, resting heart rate>100/min, Prolonged QT interval > 450 ms, using medications that prolong QTc, hearing impairment documented by audiometry

Interventions

Prophylaxis:

1. Azithromycin 250 mg daily

2. Placebo

Outcomes

Primary:

1. Time to the first acute exacerbation of COPD

Secondary:

1. Quality of life

2. Nasopharyngeal colonisation of selected respiratory pathogens

3. Compliance to the treatment

4. Adverse events

NotesFunding: Grants listed from National Institutes of Health
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe stratified random sequence generation was well described in the journal article under "protocol"
Allocation concealment (selection bias)Low riskWell explained. Central allocation was pharmacy controlled
Blinding of participants and personnel (performance bias)
All outcomes
Low riskActive drug and placebo will be identical in appearance. Both patients and treating medical staff were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskTrial staff were unaware of the randomisation
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

All outcome data accounted for in a consort diagram for the entire study

However data on the secondary outcome: HRQOL had reported loss to follow-up of 20% in the prophylactic antibiotic arm and 18% on the placebo arm. The reasons for the missing data pertaining to HRQOL were not given

Selective reporting (reporting bias)Low riskAll pre-specified outcomes have been reported
Other biasLow riskNo other bias identified

Banerjee 2004

MethodsProspective, randomised, double-blind, placebo controlled clinical trial. Treatment duration of 3 months. Intention-to-treat analysis
Participants

N=67

Mean age 65.1 (clarithromycin) versus 68.1 years (placebo)

Mean FEV1 1.12 (clarithromycin) versus 1.13 (placebo)

Severity of COPD moderate or worse according to BTS guidelines. All patients were taking inhaled corticosteroids

Patients enrolled from hospital clinics

No acute exacerbations of COPD over the last 6 weeks

Exclusions: Previous documented allergies to macrolides; a clinical history of lung cancer, asthma or bronchiectasis

Interventions

Prophylaxis:

1. Clarithromycin (long acting Klaricid XL 500 mg/daily)

2. Placebo

Outcomes

Primary:

1. Health-related quality of life

Secondary:

1. Infective exacerbation rate

2. Shuttle walk test

3. Serum C-reactive protein level

4. Sputum bacterial quantities load

NotesFunding: Received grant support from Abbott Pharmaceuticals
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation was carried out
Allocation concealment (selection bias)Low riskPatient randomisation was not known to the trial staff. Randomisation carried out by the Birmingham Hospital pharmacy department
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskTrial staff were unaware of the randomisation
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcome data described
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias identified

He 2010

MethodsProspective, randomised, double-blind, placebo controlled clinical trial. Treatment duration was 6 months. Intention-to-treat analysis
Participants

N=36. Patients were 40 years or older. Mean age 68.8y (erythromycin) versus 69.3 (placebo)

Females 17% (erythromycin) versus 10% (placebo)

FEV1 between 30-70% predicted. Mean FEV1 1.12 (erythromycin) versus 1.02 (placebo)

At least 10 pack/year smoking history

No acute exacerbations during the previous 1 month

Exclusions: Patients with significant other respiratory disorders other than COPD; history of unstable cardiovascular disease; hypersensitivity to macrolides

Interventions

Prophylaxis:

1. Erythromycin 250 mg 3 times a day

2. Placebo

Outcomes

Primary:

1. Number of acute COPD exacerbations

2. Neutrophil count in sputum

Secondary:

1. Quality of life

2. Spirometry

NotesFunding: Not stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation done but not clearly explained
Allocation concealment (selection bias)Unclear riskAllocation concealment not well explained
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind trial
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnknown
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcome data described using a CONSORT diagram
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias identified

Mygind 2010

MethodsProspective, randomised, placebo controlled double-blind study. Treatment duration was 36 months. Intention-to-treat analysis
Participants

N=575. Aged >50 years.

Severity of COPD was moderate or severe with FEV1<60% predicted. Mean FEV1 was 0.9 (both treatment and placebo arms)

At least one admission to hospital with exacerbation of COPD

Ex or current smokers

Exclusions: End stage COPD patients (if not expected to survive over 3 years), or bedridden patients; patients with a history of asthma, bronchiectasis or other significant respiratory disease; history of azithromycin allergy; patients with heart, liver or renal insufficiency; already receiving prophylactic antibiotic

Interventions

Intermittent prophylaxis:

1. Azithromycin 500 mg/daily for 3 days every months, for 36 months

2. Placebo daily for 3 days every month, for 36 months

Outcomes

Primary:

1. Rate of decline in lung function (FEV1)

Secondary:

1. Frequency of exacerbation

2. Health-related quality of life (SGRQ)

3. Adverse events

4. Mortality

5. Duration of exacerbations

6. Number of days of hospitalisation

7. Frequency of hospitalisation

NotesFunding: Not stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but paucity of data on sequence generation
Allocation concealment (selection bias)Unclear riskNot explained well
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was a double-blind study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnknown
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll outcome data were presented. Only 55% completed 3 years
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasUnclear riskThis was a conference presentation and not a full publication. Attempts to contact the authors was not successful. Only limited data are available for evaluation of the risk of bias

Seemungal 2008

MethodsProspective, randomised, double-blind, placebo controlled clinical trial with 12 month follow-up
Participants

N=109. Patients recruited from outpatient chest clinic from a single centre

Mean age 66 ( treatment arm) versus 68 in placebo arm

Females 38% (treatment arm) versus 36% in placebo arm

Severity of COPD was moderate to severe. FEV1 between 30-70%). Mean FEV1 1.27 (treatment arm) versus1.36 (placebo arm)

Exclusions: History of asthma, bronchiectasis, neoplasia, unstable cardiac status (including prolonged QTc and arrhythmias), macrolide allergy or history of abnormal liver functions

Interventions

Prophylaxis:

1. Erythromycin 250 mg twice daily

2. Placebo

Outcomes

Primary:

1. Exacerbation frequency

2. Airway inflammation

Notes

Calculated sample size was 115 for 90% power and P value 0.05. However only 109 patients were recruited

Funding: British Lung Foundation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated permuted block random sequence generation carried out
Allocation concealment (selection bias)Low riskRandomisation numbers were stored in sealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo and erythromycin were concealed in identical capsules
Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnblinding occurred only after data entry
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes/dropouts explained in a CONSORT diagram
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias identified

Sethi 2010

Methods

Prospective double-blind randomised controlled clinical trial. Total treatment period was 48 weeks

1. Analysis was done using intention-to-treat and per protocol. For this review only the results of the intention-to-treat analysis were taken

2. Exacerbation of COPD was defined by two definitions. A primary definition (any confirmed acute exacerbation of COPD, unconfirmed pneumonia or any other lower respiratory tract infections) and a secondary definition (only confirmed exacerbations of COPD, excluding confirmed/unconfirmed pneumonia and any other lower respiratory tract infection)

For this review only the primary definition was used as it was an extended definition and hence was the more conservative definition

Participants

N= 1157. Aged 45 or over. Severity of COPD was GOLD stage 2 or worse. Had at least 2 exacerbations requiring treatment with antibiotics and/or oral steroids in the 12 months prior to enrolment

Total follow-up period was 72 weeks. Total treatment period was 48 weeks

Interventions

Pulsed prophylaxis:

1. Moxifloxacin 400 mg/daily for 5 days. Treatment repeated every 8 weeks for a total of 6 courses

2. Placebo daily for 5 days. Treatment repeated every 8 weeks for a total of 6 courses

Outcomes

Primary:

1. Frequency of exacerbations

Secondary:

1. Health-related quality of life (assessed using SGRQ)

2. Hospitalisations

3. Mortality

4. Changes in lung function

5. Adverse events

NotesFunding: Received grant support from Bayer HealthCare AG
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation was done but sequence generation not well explained
Allocation concealment (selection bias)Unclear riskNot explained
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskNot explained
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

All outcome data were described using a CONSORT diagram for the entire study

However data on the secondary outcome: HRQOL had reported loss to follow-up of 12% in the prophylactic antibiotic arm and 10% in the placebo arm. The reasons for the missing data pertaining to HRQOL outcome were not given

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were well described
Other biasLow riskData was analysed as intention-to-treat as well as per protocol analysis.Both analysis were published

Suzuki 2001

MethodsProspective, randomised, placebo controlled clinical trial. Non-blinded
Participants

n=109

Mean age 69y in erythromycin group and 72 in placebo group

Mean FEV1 1.47 in erythromycin group versus1.30 in placebo group

Females 13% in erythromycin group versus 18% in placebo group

All study participants were treated with sustained release theophylline and inhaled anticholinergic agents

Exclusions: Patients diagnosed with bronchiectasis or diffuse pan bronchiolitis

Interventions

Prophylaxis:

1. Erythromycin 200 mg to 400 mg/daily

2. Placebo

Outcomes

1. Acute exacerbations of COPD

2. Adverse events

NotesFunding: not stated
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation performed by random-number table
Allocation concealment (selection bias)Low riskThe randomisation list was held independently from the investigators
Blinding of participants and personnel (performance bias)
All outcomes
High riskThis study was not blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskAs the study was not blinded the assessment of outcome would be biased
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patient outcomes were presented in a graph
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias identified

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Banerjee 2004aDuplicate of the study by Banerjee et al 2004 published in Respiratory Medicine 2005;99:208-15
Bier 1971

Comparison: Doxycyclin versus placebo

Problem: Spirometric criteria were not used in diagnosing COPD

Blasi 2010

Comparison: Azithromycin 500 mg three day a week for 6 months versus placebo

Problem: Pilot study, uncontrolled

Study done on tracheostomy patients

Bruninx 1973

Comparison: Bactrim versus Ledermycin over 1070 months

Problem: 1) Heterogenic patient population including bronchiectasis, anthracosilicosis and bronchitis; 2) No placebo arm

Buchanan 1958

Comparison: tetracycline 250 mg BD versus placebo for 12 months duration

Problems: Single blinded (only patients were blinded); Spirometric criteria were not used to diagnosed COPD

Bussi 1980

Comparison: Intermittent tetracycline 200 mg /weekly for 3 years versus placebo

Problem: Spirometry criteria not used for diagnosis of COPD. Heterogenic group of patients

Calder 1968Duplicate of Fletcher et al 1966
Davies 1961

Comparison: Tetracycline for 2 days each week versus placebo

Problem: Spirometric criteria were not used in diagnosing COPD; blinding not known

Douglas 1957

Not a randomised controlled trial

Heterogenic group of patients including large proportion with bronchiectasis

Intial treatment with intramuscular penicillin

Patients who failed penicillin were allocated to either chloramphenicol 0.5g Q6h or oxytetracycline 0.5g Q6h.

Edwards 1958

Comparison: Oxytetracycline or sulphonamide versus placebo

Problems: H. influenzae vaccination co-administered; no suitable outcome measures

Elmes 1957

Comparison: Oxytetracycline versus placebo

Problem: Not truly prophylactic, antibiotic versus placebo at the onset of symptoms

Fletcher 1966

Comparison: Treatment for 7 months/year over 5 year period. 1) Oxytetracycline 0.5g daily for 7 months over years 1 to 3; 2) Oxytetracycline 0.5g BD over 7 months in year 4; 3) Oxytetacyline 1g BD over 7 months in year 5; versus placebo

Problem: Spirometric criteria not used to diagnose COPD

Frances 1964Problem: Spirometric criteria were not used to diagnose COPD
Francis 1960

Comparison: 3 groups: 1) Tetracycline 250 mg BD for 3 months; 2) Penicillin V 312 mg BD for 3 months; 3) Placebo for 3 months

Problems: Spirometric criteria were not used in diagnosing COPD

Goslings 1967

Comparison: 1) Sulfaphenazole 500 mg BD; 2) Tetracycline 500 mg BD; 3) saccharum 500 mg BD (placebo)

over 5 month period

Problem: Spirometric criteria were not used to diagnose COPD

Grossman 1998

Comparison: Ciprofloxacin 500 mg BD versus placebo for acute exacerbations of chronic bronchitis, treatment given during acute exacerbations during 12 month period versus usual care during an acute exacerbation

Problem: Ciprofloxacin was given during an exacerbation of chronic bronchitis. Not truly prophylaxis

Hahn 1972

Comparison: Tetracycline or ampicillin versus placebo

Problems: Not a true long term prophylaxis. Prophylaxis is defined as antibiotics instituted by the patients at the first sign of a cold and were continued only for 5 days

Hallett 1959

Comparison: Erythromycin 250 mg 4 times a day versus placebo for 12 week duration

Problem: Not a randomised controlled trial; Patients were matched in pairs (treatment and placebo groups) on the basis of similar clinical characteristics

Helm 1956Not a randomised controlled trial
Johnston 1961

Comparison:

Four treatment arms

1.Tetracycline 500 mg BD for 6 months treatment per year for 5 years

2. Placebo for 6 months treatment per year for 5 years

3. Tetracycline for the first 2 winters and placebo for the next three

4. Placebo for 2 winters and tetracycline for the next three

Problem:

Partial crossover due to re: randomisation after two years

Spirometric criteria were not used to diagnose COPD

Johnston 1961

Comparison: Phenethicillin versus placebo

Problems: Spirometric criteria were not used to diagnose COPD

Kilpatrick 1954

Comparison: Sulphadimidine 0.5 g TDS versus placebo for 3 to 6 months

Problem: Spirometric criteria were not used when diagnosing COPD

Legler 1977

Problem: Not randomised

Spirometric criteria were not used for diagnosing COPD

Liippo 1987

Comparison: Trimethoprim 300 mg day versus placebo. Treatment for 6 months duration

Problem: Heterogenic group of patients. Patients with bronchiectasis and asthma included. Spirometry criteria for COPD not used

Maraffi 2010Review article on 13 previous randomised controlled trials from 1957 to 2010
May RJ 1956

Comparison: Oxytetracycline or tetracycline versus "controlled group" who were observed and antibiotic prophylaxis was not given

Problem: Not a true randomised controlled trial. The "controlled group" consisted of 14 patients who were observed without any prophylactic therapy. They were not randomly selected

Miravitlles 2009

Comparison: Moxifloxacin 400 mg daily versus placebo

Problem: Short duration of study with only 5 days of treatment

Moyes 1959

Comparison: Four groups: 1) Erythromycin 1g daily for 7 days ,then a course of 1g daily for five days taken at the sign of first infection; 2) Erythromycin 1g daily for 7 days, then a regular course of 1g daily for five days every 4 weeks; 3) Tetracycline 1g daily for 7 days , then a course of 1g daily for five days taken at the sign of first infection

4) Tetracycline 1g daily for 7 days , then 750 mg/daily for 4 months

Problems: No placebo group

Murdoch 1959

Comparison: Sigamycin (167 mg of tetracycline and 83 mg of oleandomycin ) versus placebo for 3 months

Problem: Spirometric criteria not used in diagnosing COPD

Murray 1964

Comparison: Ampicillin 250 mg 4 times daily versus placebo over 17 months

Problem: Spirometric criteria were not used to diagnose COPD. Unclear whether randomisation took place

Norman 1962

Comparison: Tetracycline 1 g daily or placebo for 3 months and crossover the groups with continuation of treatment for further 3 months

Problem: Randomised crossover trial. Spirometry criteria not used when diagnosing COPD

Pines 1967

Comparison: Sulphormethoxine 2 g weekly for 10 weeks versus placebo

Problems: Spirometric criteria were not used in diagnosing COPD patients

Pridie 1960

Comparison: Penicillin-sulphonamide, oxytetracycline versus placebo

Problem: Spirometric criteria were not taken into account when diagnosing COPD

Ras 1984

Comparison: 1) Erythromycin 1500 mg/day for 2 weeks followed by 100 mg/day for 12 weeks; 2) Amoxycillin 1500 mg/day for 2 weeks followed by 100 mg/day for 12 weeks; 3) Placebo

Problem: Randomisation not well explained. Spirometric criteria not used when diagnosing COPD

Takizawa 1994

Comparison: Three oral prophylactic antibiotic regimens: 1) Ciprofloxacin 200 mg daily for 6 months (Regimen A); 2) Erythromycin 200 mg daily for 6 months (Regimen B); 3) Ciprofloxacin 200 mg/d and Erythromycin 200 mg/d for 6 months (Regimen C)

Problems: No placebo arm. Heterogenic group of patients including large number with bronchiectasis

Torrence 1999Duplicate of Grossman 1998
Vandenbergh 1970

Comparison: sulphonamide 2 g once a week versus placebo for 6 months

Problem: None of the primary outcomes were measured (frequency of exacerbations or quality of life)

Spirometric criteria were not used in diagnosing COPD

Watanabe 1991

Comparison; 1) Ofloxacin 200 mg daily for 6 months; 2) Ofloxacin 200 mg TDS for 2 weeks followed by 2 weeks without treatment for 6 months

Problem: Prophylaxis was given to patients with ANY chronic respiratory tract infection, including bronchiectasis and pulmonary tuberculosis. No placebo arm

Watanabe 1994

Comparison: ciprofloxacin 200 mg/daily versus erythromycin 200 mg/daily versus combined ciprofloxacin 200 mg/d + erythromycin 200 mg/d

Problem: No placebo. Patients with bronchiectasis included

Watanabe 1995Duplicate study of Watanabe 1991 with addition of 7 patients
Webster 1971

Comparison: Trimethoprim-sulphamethoxazole versus sulphamethoxazole

Problem: No placebo group. Treatment duration was only 10 days

Characteristics of ongoing studies [ordered by study ID]

Uzun 2012

Trial name or titleInfluence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD
MethodsRandomised controlled trial
Participants

Inclusion criteria:

Age 18 years and older

Diagnosis of COPD according to GOLD criteria and classified according to GOLD 1-1V

Three or more exacerbations of COPD in one year for which a course of prednisone and/or antibiotic therapy was started

Clinically stable for 1 months prior to recruitment in to the trial

Exclusion criteria:

Use of antibiotics or high dose systemic steroids within a month prior to involvement in the study

Addition of inhalation steroids to the patient's therapy shortly before entering the study

Pregnant or lactating women

Allergy to macrolides

Use of drugs that could adversely interact with macrolides for which therapeutic monitoring could not be undertaken

A diagnosis of malignancy, heart failure,bronchiectasis or asthma

InterventionsAzithromycin 500 mg, 3 times a week versus placebo 3 times a week for 12 months
Outcomes

Primary:

1. Reduction in number of exacerbations

Secondary outcomes:

1. Lung function parameters

2. Health related quality of life measured by SGRQ

3. Indication of anxiety and depression by Hospital anxiety and depression scale.

4. Microbiology in sputum

5. Measurement of inflammatory markers in sputum

6. Adverse events on treatment

7. Length of hospital stay

8. Time till next exacerbation

9. Effect of maintenance macrolides on intestinal bacterial resistance patterns

10. Serology and PCR for atypical microorganisms in serum

11. intestinal bacterial resistance patterns

Starting dateMay 2010. Estimated primary completion date June 2013
Contact informationDr Djamin R.S, Amphia Hospital, Netherlands
NotesInformation from www.ClinicalTrials.gov NCT00985244

Ancillary