Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Review) Herath SC, Poole P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 11 http://www.thecochranelibrary.com

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 1.6. 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 1.12. 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) Samantha C Herath1 , Phillippa Poole2 1 Woolcock Institute

of Medical Research, 431 Glebe Point Road, Sydney, Australia. 2 Department of Medicine, University of Auckland, Auckland, New Zealand Contact address: Samantha C Herath, Woolcock Institute of Medical Research, 431 Glebe Point Road, Sydney, New South Wales, 2037, Australia. [email protected]. Editorial group: Cochrane Airways Group. Publication status and date: New, published in Issue 11, 2013. Review content assessed as up-to-date: 29 August 2013. Citation: Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD009764. DOI: 10.1002/14651858.CD009764.pub2. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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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.

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? Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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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.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

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 Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Control

Antibiotics placebo

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence (GRADE)

Comments

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

versus

Number of people with 60 per 100 one or more exacerbations

49 per 100 (41 to 58)

OR 0.64 (0.45 to 0.9)

2411 (4 studies)

⊕⊕⊕ moderate1

Number of people with 69 per 100 one or more exacerbations - Continuous antibiotics Follow-up: 6 to 12 months

55 per 100 (46 to 63)

OR 0.55 (0.39 to 0.77)

1262 (3 studies)

⊕⊕⊕⊕ high

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Number of people with 51 per 100 one or more exacerbations - Pulsed antibiotics Follow-up: 18 months

47 per 100 (42 to 53)

Rate of exacerbation per patient/year (Continuous antibiotic use) 6 to 12 months

OR 0.87 (0.69 to 1.09)

1149 (1 study)

⊕⊕⊕ moderate2

Rate Ratio 0.73 (0.58 to 1262 0.91) (3 studies)

⊕⊕⊕ moderate1

I2 =47%

1962 (3 studies)

⊕⊕⊕ moderate3

The minimally clinically important response to treatment is described as 4 points

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)

All cause mortality Follow-up: 6 to months

83 per 1000

74 per 1000 (57 to 97)

OR 0.89 (0.67 to 1.19)

2841 (3 studies)

⊕⊕⊕ moderate2

243 per 1000 (210 to 281)

OR 0.88 (0.73 to 1.07)

2411 (4 studies)

⊕⊕⊕ moderate2

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Serious adverse events 267 per 1000 Follow-up: 6 to 18 months

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

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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. 1

Clinical and statistical heterogeneity between trials 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 2

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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


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(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.

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 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

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


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(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).

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

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).

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.


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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 fixedeffect 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.

identified substantial heterogeneity we explored this using a prespecified 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).

Assessment of heterogeneity

Sensitivity analysis

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

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.


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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).


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Figure 1. Study flow diagram.


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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 intentionto-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.


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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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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%.

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.

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

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).


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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.


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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%).


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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 KaplanMeier 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).


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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 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 hospital-

isation 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


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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 2010Seemungal 2008; Sethi 2010) was gastrointestinal


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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.


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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 comorbidities 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


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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


23

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.


24

REFERENCES

References to studies included in this review Albert 2011 {published data only} Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, et al.Azithromycin for prevention of exacerbations of COPD. New England Journal of Medicine 2011;365:689–98. Banerjee 2004 {published data only} Banerjee D, Khair O, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respiratory Medicine 2005;99:208–15. He 2010 {published data only} He ZY, Ou LM, Zhang JQ, Bai J, Liu GN, Li MH, et al.Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease. Respiration 2010; 80:445–52. Mygind 2010 {published data only} Mygind LH, Pedersen C, Vestbo J, Christensen JJ, FrimodtMoller N, Kristiansen IS, et al.A randomised, placebocontrolled 3 years study of prophylactic azithromycin in 575 patients with chronic obstructive pulmonary disease. European Respiratory Society Annual Congress; 2010 Sep 18-22; Barcelona. Barcelona, Spain, 2010. Seemungal 2008 {published data only} Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. American Journal of Respiratory and Critical Care Medicine 2008;178:1139–47. Sethi 2010 {published data only} Sethi S, Jones PW, Theron MS, Miravitlles M, Rubinstein E, Wedzicha JA, et al.Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: A randomized control trial. Respiratory Research 2010;11: 10. Suzuki 2001 {published data only} Suzuki T, Yani M, Yamaya M, Satoh Nakagawa T, Sekizawa K, Ishida S, et al.Erythromycin and common cold in COPD. Chest 2001;120:730–3.

Blasi 2010 {published data only} Blasi F, Bonardi D, Aliberti S. Long term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy [Article in French]. Pulmonary Pharmacology and Theraputics 2010;23:200–7. Bruninx 1973 {published data only} Bruninx M, Koster J, Golard P, Libert P, Minette A, Mottard L, et al.Prophylactic administration of Bactrim in chronic bronchitis. Acta Tuberculosea et Pneumologica Belgica 1973; 5-6:483–502. Buchanan 1958 {published data only} Buchanan J, Buchanan W, Melrose A, McGuinness J, Price A. Long term prophylactic administration of tetracycline to chronic bronchitis. Lancet 1958;2(7049):719–22. Bussi 1980 {published data only} Bussi S, Murciano D, Botto MJ, Pariente R. Assessment if chemoprophylaxis with intermittent tetracycline in chronicbronchitis - a functional follow-up for 3 years. Revue Francaise des Maladies Respiratoires 1980;8(5):351–6. Calder 1968 {published data only} Calder M, Lutz W, Schonell ME. A five year study of bacteriology and prophylactic chemotherapy in patients with chronic bronchitis. British Journal of Diseases of the Chest 1968;62:93–9. Davies 1961 {published data only} Davies A, Grobow E, Tompsett R, McClement J. Bacterial Infection and some effects of chemoprophylaxis in chronic pulmonary emphysema. American Journal of Medicine 1961;31:365–81. Douglas 1957 {published data only} Douglas A, Somner A, Marks B, Grant I. Effect of antibiotics on purulent sputum. Lancet 1957;273(6988): 214–8. Edwards 1958 {published data only} Edwards G, Fear E. Adult chronic bronchitis-continuous antibiotic therapy. British Medical Journal 1958;2(5103): 1010–2.

References to studies excluded from this review

Elmes 1957 {published data only} Elmes P, Fletcher C, Dutton A. Prophylactic use of oxytetracycline for exacerbations of chronic bronchitis. British Medical Journal 1957;2(5056):1272–5.

Banerjee 2004a {published data only} Banerjee D, Honeybourne D, Khair OA. The effect of oral Clarithromycin on bronchial airway inflammation in moderate -to-severe stable COPD: A randomised controlled trial. Treatments in Respiratory Medicine 2004;3:59–65.

Fletcher 1966 {published data only} ∗ Fletcher. Value of chemoprophylaxis and chemotherapy in early chronic bronchitis. A report to the Medical Research Council by their working party on trials of chemotherapy in early chronic bronchitis. British Medical Journal 1966;1: 1317–22.

Bier 1971 {published data only} Beier VA. Trial of preventive treatment of patients with chronic bronchitis [Versuch einer prophylaktischen Behandlung chronischer Bronchitiker]. Wiener Medizinische Wochenschrift 1971;37:642–3.

Frances 1964 {published data only} Frances R, May J, Spicer C. Influence of daily penicillin, tetracycline, erythromycin and sulphamethoxypyridazine on exacerbation of bronchitis. British Medical Journal 1964; 1:728–32.


25

Francis 1960 {published data only} Francis R, Spicer C. Chemotherapy in chronic bronchitis.Influence of daily penicillin and tetracycline on exacerbations and their cost. British Medical Journal 1960; 30(1):297–303. Goslings 1967 {published data only} Goslings W, Djajadiningrat R, Bergstein P, Holle P. Continous suppressive antimicrobial treatment in chronic infected bronchitis during winter months. Disease of the Chest 1967;52(3):376–80. Grossman 1998 {published data only} Grossman R, Mukherjee J, Vaughan D, Cook R, LaForge J, Lampron N, et al.A 1-year community based health economic study of ciprofloxacin treatment in acute exacerbations of chronic bronchitis: The Canadian Ciprofloxacin Health Economics Study Group. Chest 1998; 113:131–41. Hahn 1972 {published data only} Hahn HH, MacGregor RR, Counts CK, Smith HE, Beaty HN. Ampicillin and tetracyclin in the treatment and prophylaxis of chronic bronchitis. Antimicrobial Agents and Chemotherapy 1972;2(1):45–8. Hallett 1959 {published data only} Hallet WY, Beali GN, Kirby WMM. Chemoprophylaxis in chronic obstructive pulmonary emphysema. Chemoprophylaxis in Emphysema 1959;80:716–23. Helm 1956 {published data only} Helm W, May JR, Livingstone JL. Long-term oxytetracycline (Terramycin) therapy in advanced chronic respiratory infections. Lancet 1956;267(6839):775–7. Johnston 1961 {published data only} Johnston R, Lockhart W, Smith D, Cadman D. A trial of phenethicillin in chronic bronchitis. British Medical Journal 1961;2(5258):985–6. Johnston 1961 {published data only} Johnston R, Mcneil R, Smith D, Dempster M, Nairn J, Purvis M, et al.Five year winter prophylaxis for chronic bronchitis. British Medical Journal 1969;4:265–9. Kilpatrick 1954 {published data only} Kilpatrick G, Oldham P. Sulphonmide prophylaxis in chronic bronchitis. British Medical Journal 1954;2(4884): 385–7. Legler 1977 {published data only} Legler F, Jansen W. Double blind long term study on a combination of tetracycline, theophylline, doxylamine succinate , etafedrine, phenylephedrine and guaifenesine in chronic bronchitis. Arzneimittel-Forschung 1977;27:883–8. Liippo 1987 {published data only} ∗ Liippo K, Pelliniemi T, Lehto H. Trimethoprim prophylaxis of acute exacerbations in chronic obstructive pulmonary disease. Acta Medica Scandinavica 1987;221: 455–9. Maraffi 2010 {published data only} Maraffi T, Piffer F, Cosentini R. Prophylactic antibiotic therapy in chronic obstructive pulmonary disease. Theraputic Advances in Respiratory Disease 2010;4:135–7.

May RJ 1956 {published data only} May RJ. Long term chemotherapy in chronic bronchitis. Lancet 1956;271(6947):814–9. Miravitlles 2009 {published data only} Miravitlles M, Marin A, Monso E, Vila S, Roza dela, Hervas R, et al.Efficacy of Moxifloxacin in the treatment of bronchial colonisation in COPD. European Respiratory Journal 2009;34:1066–71. Moyes 1959 {published data only} Moyes EN, Kalinowski SZ. Prophylactic chemotherapy in chronic bronchitis. Tubercle 1959;40:112–8. Murdoch 1959 {published data only} Murdoch J, Leckie W, Downie J, Swain R, Gould J. An evaluation of continuous antibiotic therapy in chronic bronchitis. British Medical Journal 1959;2(5162):1277–85. Murray 1964 {published data only} Murray EA. A trial of ampicillin in chronic bronchitis. The Journal of the College of General Practitioners 1964;7:244–52. Norman 1962 {published data only} Norman PS, Hook EW, Petersdorf RG, Cluff LE, Godfrey MP, Levy AH. Long term tetracycline treatment of chronic bronchitis. JAMA 1962;179(11):833–7. Pines 1967 {published data only} Pines A. Controlled trials of a sulphonamide given weekly to prevent exacerbations of chronic bronchitis. British Medical Journal 1967;3:202–4. Pridie 1960 {published data only} Pridie RB, Datta N, Massey DG, Poole GW, Schneeweiss J, Stradling P, et al.A trial of continuous winter chemotherapy in chronic bronchitis. Lancet 1960;2(7153):723–7. Ras 1984 {published data only} Ras J, Anderson R, Eftychis H, Koch U, Theron A, Vanwyk H, et al.Chemoprophylaxis with erythromycin stearate or amoxacillin in patients with chronic bronchitis-effects on cellular and humoral immune functions. South African Medical Journal 1984;66:955–8. Takizawa 1994 {published data only} Watanabe A, Motomiya M, Nukiwa T, Nakai Y, Honda Y, Konno K. A well-controlled comparative clinical study of the combination regimen of ciprofloxacin plus erythromycin for the treatment of repeated acute exacerbations of chronic respiratory tract infections. Chemotherapy 1994;42(10): 1194–201. Torrence 1999 {published data only} Torrance G, Walker V, Grossman R, Mukherjee J, Vaughan D, La Forge J, et al.Economic evaluation of ciprofloxacin compared with usual anti-bacterial care for the treatment of acute exacerbations of chronic bronchitis in patients followed for 1 year. Pharmacoeconomics 1999;16:499–520. Vandenbergh 1970 {published data only} Vandenbergh E, Clement J, Woestijne K. Prevention of exacerbations of bronchitis: trial of a long acting sulphonamide. British Journal of Diseases of the Chest 1970; 64:58–62.


26

Watanabe 1991 {published data only} Watanabe A. Once daily versus every two week multidose ofloxacin in patients with acute exacerbations of chronic respiratory disease. Infection 1991;19:S384–7.

GOLD 2011 Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com [Accessed 23rd November 2012].

Watanabe 1994 {published data only} Watanabe A, Motomiya M, Nukiwa T, Nakai Y, Honda Y, Konno K. A well controlled comparative clinical study of the combination regimen of ciprofloxacin plus erythromycin. Chemotherapy 1994;42:1194–201.

Guyatt 1987 Guyatt G, Berman L, Townsend M, Pugsley S, Chambers L. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987;42:773–8.

Watanabe 1995 {published data only} Watanabe A, Oizumi K, Motomiya M, Nukiwa T. Daily single-dose regimen and alternate two-week triple dose/day regimen of oral ofloxacin for the prophylaxis and control of exacerbations of chronic respiratory tract infections. Tohoku Journal of Experimental Medicine 1995;176:25–33. Webster 1971 {published data only} Webster I. A double blind cross-over trail of trimethoprim and sulphamethoxazole in chronic bronchitis. Thorax 1971; 26:319–24.

References to ongoing studies Uzun 2012 {unpublished data only} Uzun S, Djamin R, et al.Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD [NCT 00985244]. www.ClinicalTrials.gov 2012.

Additional references Anderson 1997 Anderson H R, Spix C, Medina S, Schouten JP, Castellsague J, Rossi G, et al.Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. European Respiratory Journal 1997;10(5):1064-71. Ball 1995 Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108(2 Suppl):43S-52S. Banerjee 2005 Banerjee D, Khair O, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respiratory Medicine 2005;99:208–15. Bestall 1999 Bestall J, Paul E, Garrod R, Garnham R, Jones P, Wedzicha J. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999;54(7): 581–6. Chong 2011 Chong J, Poole P, Leung B, Black PN. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI: 10.1002/14651858.CD002309.pub3]

Henry 1997 McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice. Annals of Internal Medicine 1997;126:712–20. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Jones 2009 Jones P, Harding G, Berry P, Wiklund I, Chen W, Leidy N. Development and first validation of the COPD Assessment Test. European Respiratory Journal 2009;34:648–54. Jones 2009a Jones P. St George’s Respiratory Questionnaire Manual. Version 2.3 2009:1–16. Journal of General Internal Medicine 2007 Lee TA, Pharm D, Weaver FM, et al.Impact of pneumococcal vaccination on pneumonia rates in patients with COPD and asthma. Journal of General Internal Medicine 2007;22(1):62–7. Lancet 2007 Mannino D, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370: 765–73. Monso 1995 Monsó E, Ruiz J, Rosell A, Manterola J, Fiz J, Morera J, et al.Bacterial infection in chronic obstructive pulmonary disease: a study of stable and exacerbated outpatients using the protected specimen brush. American Journal of Respiratory and Critical Care Medicine 1995;152(4 pt 1): 1316-20. NCT00985244 NCT00985244. Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD. http://clinicaltrials.gov/ct2/ show/NCT00985244 (accessed 19/02/2013). Poole 2012 Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 8. [DOI: 10.1002/14651858.CD001287.pub4] RevMan 5 Copenhagen, The Nordic Cochrane Centre: The Cochrane Collaboration. Review Manager (RevMan) Version 5.1. Copenhagen, The Nordic Cochrane Centre: The Cochrane Collaboration, 2008.


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Soler 1998 Soler N, Torres A, Ewig S, Gonzalez J, Celis R, El-Ebiary M, et al.Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. American Journal of Respiratory and Critical Care Medicine 1998;157:1498-505. Staykova 2003 Staykova T, Black PN, Chacko EE, Poole P. Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: 10.1002/ 14651858.CD004105] Sunyer 1993 Sunyer J, Saez M, Murillo C, Castellsague J, Martinez F, Anto J. Air pollution and emergency room admission for chronic obstructive pulmonary disease: A 5-year study. American Journal of Epidemiology 1993;137(7):701-5. Thorax 2006 Sapey E, Stockley RA. COPD exacerbations · 2: Aetiology. Thorax 2006;61(3):250–8. TORCH 2007 Kardos P, Wencker M, Glaab T, et al.Impact of salmeterol/ fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2007;175 (144):149.

TSANZ 2004 A document produced for the Thoracic Society of Australia and New Zealand (New Zealand Branch). Standards for adult respiratory and sleep services in New Zealand. www.moh.govt.nz Initial Report 1989, revised 1996, 2002 and 2004, issue Accessed 18th November 2011. UPLIFT 2008 Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al.4-year trial of tiotropium in chronic obstructive pulmonary disease. New England Journal of Medicine 2008; 359:1543–54. Visual Rx Visual Rx. www.nntonline.net/visualrx/ Accessed October 2013. Wang 2012 Wang J, Nie B, Xiong W, Xu Y. Effect of long-acting betaagonists on the frequency of COPD exacerbations: a metaanalysis. Journal of Clinical Pharmacy and Therapeutics 2012;37:204–11. Wenzel 2012 Wenzel RP, Fowler AA, Edmond MB. Antibiotic prevention of acute exacerbations of COPD. New England Journal of Medicine 2012;367(4):340–7. WHO World Health Organization. Chronic obstructive pulmonary disease. http://www.who.int/respiratory/copd/ en/ Accessed 18th November 2011. ∗ Indicates the major publication for the study


28

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

Notes

Funding: Grants listed from National Institutes of Health

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

The stratified random sequence generation was well described in the journal article under “protocol”

Allocation concealment (selection bias)

Low risk

Well explained. Central allocation was pharmacy controlled

Blinding of participants and personnel Low risk (performance bias) All outcomes

Active drug and placebo will be identical in appearance. Both patients and treating medical staff were blinded


29

Albert 2011

(Continued)

Blinding of outcome assessment (detection Low risk bias) All outcomes

Trial 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 risk

All pre-specified outcomes have been reported

Other bias

Low risk

No other bias identified

Banerjee 2004 Methods

Prospective, 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

Notes

Funding: Received grant support from Abbott Pharmaceuticals

Risk of bias Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

30

Banerjee 2004

(Continued)

Bias



Random sequence generation (selection Low risk bias)

Block randomisation was carried out


Patient randomisation was not known to the trial staff. Randomisation carried out by the Birmingham Hospital pharmacy department

Low risk


Double-blind study

Blinding of outcome assessment (detection Low risk bias) All outcomes

Trial staff were unaware of the randomisation


Low risk

All outcome data described


Low risk

All pre-specified outcomes were reported

Other bias

Low risk


He 2010 Methods

Prospective, 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


31

He 2010

(Continued)

2. Spirometry Notes

Funding: Not stated

Risk of bias Bias



Random sequence generation (selection Unclear risk bias)

Randomisation done but not clearly explained


Allocation concealment not well explained

Unclear risk


Double-blind trial

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Unknown


Low risk

All outcome data described using a CONSORT diagram


Low risk

All pre-specified outcomes were reported

Other bias

Low risk


Mygind 2010 Methods

Prospective, 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

Prophylactic antibiotic therapy in chronic obstructive pulmonary disease.

WITHDRAWN: Prophylactic antibiotic therapy for chronic bronchitis.

COPD: Journal of Chronic Obstructive Pulmonary Disease. Preface.

Pneumocystis jirovecii colonization in Chronic Obstructive Pulmonary Disease (COPD).

Biomarkers of progression of chronic obstructive pulmonary disease (COPD).

Risk factors in chronic obstructive pulmonary disease (COPD).

Asymmetric dimethylarginine in chronic obstructive pulmonary disease (ADMA in COPD).

[Chronic obstructive pulmonary disease (COPD) and the interior environment].

Lumbar hernia associated with chronic obstructive pulmonary disease (COPD).

Cognitive behaviour therapy reduces dyspnoea ratings in patients with chronic obstructive pulmonary disease (COPD).

Lung Regeneration Therapy for Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease.

Grading obstructive lung disease using tomographic pulmonary scintigraphy in patients with chronic obstructive pulmonary disease (COPD) and long-term smokers.

Developing a service for patients with very severe chronic obstructive pulmonary disease (COPD) within resources.

Bronchoscopic interventions for chronic obstructive pulmonary disease.

Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study.

Selective polypharmacy for chronic obstructive pulmonary disease.

Lights and shadows of non-invasive mechanical ventilation for chronic obstructive pulmonary disease (COPD) exacerbations.

Screening tools for evaluation of depression in Chronic Obstructive Pulmonary Disease (COPD). A systematic review.

Drugs for chronic obstructive pulmonary disease.

Once-daily glycopyrronium bromide (Seebri Breezhaler(®)) for the treatment of chronic obstructive pulmonary disease (COPD).

Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study.

The Saudi guidelines for chronic obstructive pulmonary disease: A fresh "Real-World" approach to COPD.

Adiponectin: an attractive marker for metabolic disorders in Chronic Obstructive Pulmonary Disease (COPD).