Prophylactic antibiotic therapy for chronic obstructive pulmonary disease(copd)(review)

Cochrane Database of Systematic Reviews Prophylactic antibiotic therapy for chronic obstructive pulmonary disease(copd)(review) HerathSC,PooleP 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. www.cochranelibrary.com Prophylactic antibiotic therapy for chronic obstructive pulmonary disease(copd)(review) Copyright 2013 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

T A B L E O F C O N T E N T S HEADER....................................... 1 ABSTRACT...................................... 1 PLAIN LANGUAGE SUMMARY.............................. 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON................... 4 BACKGROUND.................................... 7 OBJECTIVES..................................... 8 METHODS...................................... 8 RESULTS....................................... 11 Figure 1...................................... 12 Figure 2...................................... 14 Figure 3...................................... 16 Figure 4...................................... 17 Figure 5...................................... 18 Figure 6...................................... 18 Figure 7...................................... 20 Figure 8...................................... 20 DISCUSSION..................................... 21 AUTHORS CONCLUSIONS............................... 23 ACKNOWLEDGEMENTS................................ 24 REFERENCES..................................... 25 CHARACTERISTICS OF STUDIES............................. 28 DATA AND ANALYSES.................................. 42 Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Number of people with one or more exacerbations. 43 Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Number of patients with one or more exacerbations on continuous antibiotics (regardless of blinding)....................... 44 Analysis 1.3. Comparison 1 Antibiotics versus placebo, Outcome 3 Rate of exacerbation per patient per year.... 45 Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 HRQOL, SGRQ (total score)........ 46 Analysis 1.7. Comparison 1 Antibiotics versus placebo, Outcome 7 HRQOL, SGRQ (symptoms)........ 47 Analysis 1.8. Comparison 1 Antibiotics versus placebo, Outcome 8 HRQOL, SGRQ (impact)......... 48 Analysis 1.9. Comparison 1 Antibiotics versus placebo, Outcome 9 HRQOL, SGRQ (activity)......... 48 Analysis 1.12. Comparison 1 Antibiotics versus placebo, Outcome 12 All cause mortality........... 50 Analysis 1.13. Comparison 1 Antibiotics versus placebo, Outcome 13 Respiratory related mortality....... 50 Analysis 1.14. Comparison 1 Antibiotics versus placebo, Outcome 14 Serious adverse events......... 51 Analysis 1.15. Comparison 1 Antibiotics versus placebo, Outcome 15 Adverse events: respiratory disorders..... 51 Analysis 1.16. Comparison 1 Antibiotics versus placebo, Outcome 16 Adverse events: gastrointestinal disorders... 52 Analysis 1.17. Comparison 1 Antibiotics versus placebo, Outcome 17 Adverse events: QTc prolongation..... 52 Analysis 1.18. Comparison 1 Antibiotics versus placebo, Outcome 18 Adverse events: hearing impairment..... 53 Analysis 1.19. Comparison 1 Antibiotics versus placebo, Outcome 19 Adverse events: musculoskeletal disorders... 53 Analysis 1.20. Comparison 1 Antibiotics versus placebo, Outcome 20 Adverse events: hypersensitivity/skin rash... 54 Analysis 1.21. Comparison 1 Antibiotics versus placebo, Outcome 21 Adverse events: nervous system disorders... 54 APPENDICES..................................... 54 FEEDBACK...................................... 56 WHAT S NEW..................................... 58 CONTRIBUTIONS OF AUTHORS............................. 58 DECLARATIONS OF INTEREST.............................. 58 SOURCES OF SUPPORT................................. 58 DIFFERENCES BETWEEN PROTOCOL AND REVIEW..................... 58 INDEX TERMS.................................... 59 i

[Intervention Review] Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD) Samantha C Herath 1, Phillippa Poole 2 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. scherath@yahoo.com. Editorial group: Cochrane Airways Group. Publication status and date: New, published in Issue 11, 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. Background A B S T R A C T There has been renewal of interest in the use of prophylactic antibiotics to reduce the frequency of exacerbations and improve quality of life in chronic obstructive pulmonary disease (COPD). Objectives To determine whether or not regular treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life. Search methods We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was August 2013. Selection criteria Randomised controlled trials (RCTs) that compared prophylactic antibiotics with placebo in patients with COPD. Data collection and analysis We used the standard methods of The Cochrane Collaboration. Data were extracted and analysed by two independent review authors. Main results Seven RCTs involving 3170 patients were included in this systematic review. All studies were published between 2001 and 2011. Five studies were of continuous antibiotics and two studies were of intermittent antibiotic prophylaxis (termed pulsed for this review). The antibiotics investigated were azithromycin, erythromycin, clarithromycin and moxifloxacin. Azithromycin, erythromycin and clarithromycin are macrolides while moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. The study duration varied from three months to 36 months and all used intention-to-treat analysis. Most of the results were of moderate quality. The risk of bias of the included studies was generally low, and we did not downgrade the quality of evidence for risk of bias. The trials recruited participants with a mean age of 66 years and with at least a moderate severity of COPD. Three trials included participants with frequent exacerbations and two trials recruited participants requiring systemic steroids or antibiotics, or both, or who were at the end stage of their disease and required oxygen. 1

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. P L A I N L A N G U A G E S U M M A R Y Preventative antibiotic therapy for people with COPD What is COPD? COPD is a common chronic respiratory disease mainly affecting people who smoke now or have done so previously. It could become the third leading cause of death worldwide by 2030. People with COPD experience gradually worsening shortness of breath and cough with sputum because of permanent damage to their airways and lungs. Those with COPD may have flare-ups (or exacerbations) that usually occur after respiratory infections. Exacerbations may lead to further irreversible loss of lung function with days off work, hospital admission, reduction in quality of life and they may even cause death. Why did we do this review? We wanted to find out if giving antibiotics to prevent a flare-up, prophylactic antibiotics, would reduce the frequency of infections and improve quality of life. Studies that were taken into consideration used either continuous prophylactic antibiotics on a daily basis or prophylactic antibiotics that were used intermittently. 2

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. 3

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) Relative effect (95% CI) Number of people with one or more exacerbations Assumed risk Corresponding risk Control Antibiotics versus placebo 60 per 100 49 per 100 (41 to 58) OR 0.64 (0.45 to 0.9) No of Participants (studies) 2411 (4 studies) Quality of the evidence (GRADE) moderate 1 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 4 Number of people with one or more exacerbations - Continuous antibiotics Follow-up: 6 to 12 months 69 per 100 55 per 100 (46 to 63) OR 0.55 (0.39 to 0.77) 1262 (3 studies) high

Number of people with one or more exacerbations - Pulsed antibiotics Follow-up: 18 months Rate of exacerbation per patient/ year (Continuous antibiotic use) 6 to 12 months 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 All cause mortality Follow-up: 6 to 36 months 51 per 100 47 per 100 (42 to 53) 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) 83 per 1000 74 per 1000 (57 to 97) OR 0.87 (0.69 to 1.09) Rate Ratio 0.73 (0.58 to 0.91) OR 0.89 (0.67 to 1.19) 1149 (1 study) 1262 (3 studies) 1962 (3 studies) 2841 (3 studies) moderate 2 I 2 =47% moderate 1 moderate 3 moderate 2 The minimally clinically important response to treatment is described as 4 points Serious adverse events Follow-up: 6 to 18 months 267 per 1000 243 per 1000 (210 to 281) OR 0.88 (0.73 to 1.07) 2411 (4 studies) See Effects of moderate 2 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 5

GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. M oderate 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 2 Confidence intervals include the possibility that continuous antibiotics may increase or decrease the rate of exacerbations, mortality or serious adverse events 3 Risk of attrition bias. Both studies have unclear attrition bias associated with this outcome as there is loss to follow up reported between 10-20% and reasons for the incomplete data were not given therefore we downgraded one for limitations xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 6

B A C K G R O U N D 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 alpha 1 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 (FEV 1 /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, FEV 1 > 80%; stage II, moderate, FEV 1 50% to 80%; stage III, severe, 30% to 50%; stage IV, very severe, FEV 1 < 30% or FEV 1 < 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 (SO 2 ), ozone (O 3 ) and nitrogen dioxide (NO 2 ) 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 (PDE 4 ) inhibitors (Chong 2011) and mucolytic agents 7

(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. 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 O B J E C T I V E S To determine whether or not regular treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life. M E T H O D S 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 FEV 1 of less than 80% of the predicted value and an FEV 1 /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 8

(which can also in the long term give chronic airflow limitation as part of a secondary process). Where we encountered trials that included patients with these diseases in addition to patients with COPD, we only extracted the data for the patients with COPD, where the data were presented separately. Types of interventions Oral antibiotics including penicillin (amoxycillin, amoxicillin, clavulanic acid), tetracycline (doxycycline, tetracycline), quinolones (ciprofloxacin, moxifloxacin), macrolides (clarithromycin, erythromycin, roxithromycin, azithromycin) and sulphonamides (co-trimoxazole) administered in appropriate daily doses at least three times a month for a period of at least three months. Types of outcome measures Primary outcomes 1. Number of exacerbations, using an accepted definition. This included total numbers of patients with exacerbations as well as the frequency of exacerbations in the study period. 2. Health-related quality of life, using an accepted measure such as the St Georges Respiratory Questionnaire (SGRQ) (Jones 2009a) or Chronic Respiratory Diseases Questionnaire (CRQ) (Guyatt 1987). Secondary outcomes 1. Duration and severity (using an accepted definition) of exacerbations 2. Days of disability (defined as days where the participant was unable to undertake normal activities) 3. Frequency and duration of hospital admissions 4. Reduction in lung function from baseline as measured by FEV 1 and FVC 5. Drug resistance as measured by microbial sensitivity 6. Death due to all-cause mortality as well as due to respiratory causes 7. Adverse effects Search methods for identification of studies Electronic searches We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (see Appendix 1). All records in the CAGR coded as COPD or chronic bronchitis were searched using the following terms: Chemoprophylaxis or (antibiotic* AND prophyla*) or (continuous AND antibiotic*) or antibiotic* or penicillin or phenoxymethylpenicillin or phenethicillin or amoxicillin or amoxycillin or clavulanic acid or tetracycline or oxytetracycline or doxycycline or quinolone or ciprofloxacin or moxifloxacin or macrolide or erythromycin or roxithromycin or azithromycin or sulphonamide or co-trimoxazole or sulphaphenazole or trimethoprim or sigmamycin or (tetracycline AND oleandomycin) or sulfamethoxazole or sulfaphenazole or sulfonamide We conducted a search of ClinicalTrials.gov. All databases were searched from their inception to August 2013 and there were no restrictions on language of publication. References were managed using EndNote. Searching other resources We checked the reference lists of all eligible primary trials and review articles for additional references. We contacted the authors of one identified trial (Mygind 2010) and asked them to supply the data from their unpublished study. We have checked the references of the included and excluded studies from the previous review on chronic bronchitis for possible studies (Staykova 2003). Data collection and analysis Selection of studies Two review authors (PP and SH) independently screened the abstracts of trials identified by the search as to whether or not they met our inclusion criteria. We obtained the full texts of publications for those that were considered definite or possible for inclusion. These were then reviewed independently by two review authors (PP and SH) to assess eligibility. We resolved any disagreement by discussion and consensus. Data extraction and management Both review authors independently extracted the data from the eligible studies. We extracted the following data. Methods: trial design, duration of follow-up. Participants: age, gender, smoking status, study setting, inclusion and exclusion criteria. Intervention: drug name, dose, duration of treatment, control or standard therapy. Information on outcome measures. Where appropriate, we have combined the data from trials using RevMan 5. 9

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 FEV 1 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 From the forest plot, we tested for heterogeneity where the CIs did not overlap with each other. We used the I 2 statistic to measure heterogeneity among the trials in each analysis. Where we Sensitivity analysis We conducted a sensitivity analysis by removing trials judged to be at high or unclear risk of bias for the domains of sequence generation, allocation concealment or blinding. 10

R E S U L T S 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). 11

Figure 1. Study flow diagram. 12

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. 13

Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included study. 14

Allocation Random sequence allocation and allocation concealment were well described in four of the seven studies (Albert 2011; Banerjee 2005; Seemungal 2008; Suzuki 2001). In three studies (He 2010; Mygind 2010; Sethi 2010) random sequence generation was not well described. For Mygind 2010, being a conference presentation, we had access to limited data. Multiple attempts by email and post to obtain further information from the corresponding author were not successful. Blinding Blinding of the participants and personnel (performance bias) was well described in all included studies except for Suzuki 2001, which was not blinded. Blinding of the outcome assessment (detection bias) was well described in all studies except for Banerjee 2005 and He 2010. Incomplete outcome data All outcomes of the study participants were well described using either a CONSORT diagram (Albert 2011; Seemungal 2008; Sethi 2010) or by a dedicated paragraph or table (Banerjee 2005; He 2010; Suzuki 2001). Mygind 2010 was a conference presentation of unpublished data and thus we had limited information on which to judge the attrition bias. Withdrawal rates were similar between both studies and treatments and were in the order of 10%, except for Mygind which was over 40%. Selective reporting The studies reported all pre-specified primary and secondary outcomes in detail. Other potential sources of bias Albert 2011 was supported by grants from the National Institutes of Health, Banerjee 2005 received a grant from Abbott, Seemungal 2008 was supported by the British Lung foundation, and Sethi 2010 was supported by a research grant from Bayer HealthCare AB. Effects of interventions See: Summary of findings for the main comparison Antibiotics versus placebo for COPD Seven randomised controlled trials involving 3170 patients were included in the systematic review and an overview of the results together with a summary of the quality of evidence per outcome is presented in Summary of findings for the main comparison. Five studies assessed the use of continuous prophylactic antibiotics, which included a total of 1438 patients. All five studies of continuous antibiotic prophylaxis used a macrolide. These included azithromycin (Albert 2011), erythromycin (He 2010; Seemungal 2008; Suzuki 2001) and clarithromycin (Banerjee 2005). There were two studies of pulsed antibiotic prophylaxis, which had a total of 1732 patients. The prophylactic antibiotics tested in these treatment protocols were moxifloxacin (Sethi 2010) and azithromycin (Mygind 2010). Sethi 2010 analysed data on an intention-to-treat basis as well as per protocol; we have only utilised the intention-to-treat analysis results for our review. Sethi 2010 defined an exacerbation by two different definitions. The primary definition was: any confirmed acute exacerbation of COPD, unconfirmed pneumonia or any other lower respiratory tract infections; the secondary definition was: only confirmed exacerbations of COPD, excluding confirmed or unconfirmed pneumonia and any other lower respiratory tract infection. For this review, only the primary definition was used as it was an extended definition and hence was the more conservative definition. Primary outcome: number of patients with exacerbations Four trials (Albert 2011; He 2010; Seemungal 2008; Sethi 2010) involving 2411 participants reported the number of participants experiencing one or more exacerbations. However, there was high heterogeneity among the four trials (I 2 = 62%). We explored the heterogeneity using pre-planned subgroup analyses (Analysis 1.1; Figure 3). 15

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. 16

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 Chi 2 = 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 (I 2 = 47%). 17

Figure 5. Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.3 Rate of exacerbation per patient per year. A subgroup analysis according to the severity of COPD as defined by the GOLD criteria did not show a difference between the subgroups in the effect of antibiotics on exacerbation frequency (Analysis 1.5). The median time to first exacerbation The median time to first exacerbation was analysed using a Kaplan- Meier survival curve and log rank test (Analysis 1.4). Data were available on four studies involving 2419 patients. There were three studies that used continuous prophylactic antibiotics, involving 1262 patients. Use of a prophylactic antibiotic lengthened the time to first exacerbation in all three studies compared with placebo. In Albert 2011 this was 266 days (antibiotic) versus 174 days (placebo) (P < 0.001); in He 2010,155 days versus 86 days (P = 0.032); in Seemungal 2008, 271 days versus 89 days (P = 0.02). In contrast, the median time to the first exacerbation in the study done by Sethi 2010 using pulsed antibiotic prophylaxis did not show a significant difference: 364 days versus 336 days (P = 0.062). In Albert 2011, which used azithromycin, a predefined subgroup analysis in 22 subgroups found that prophylactic antibiotics were associated with greater treatment effects in patients who had given up smoking (test for interaction P = 0.012), were not on steroid inhaler treatment at enrolment (P = 0.032), on oxygen therapy, or older than 65 years (P = 0.012). Primary outcome: health-related quality of life Health-related quality of life was explored in five studies (Albert 2011; Banerjee 2005; He 2010; Mygind 2010; Sethi 2010). All of these studies used the St George s Respiratory Questionnaire (SGRQ) (Jones 2009a). The data for inclusion in the meta-analysis were only available from the two larger studies involving 1926 patients (Albert 2011; Sethi 2010). This found a significant improvement with antibiotic treatment in the total quality of life score (MD -1.78; 95% CI -2.95 to - 0.61; Analysis 1.6; Figure 6). Figure 6. Forest plot of comparison: 1 Antibiotics versus placebo, outcome: 1.6 HRQOL, SGRQ (total score). 18

The SGRQ comprises three subcomponents, namely symptom score, impact score and activity score. These subgroups were analysed separately. Both the symptom score (MD -3.75; 95% CI - 5.48 to -2.01; Analysis 1.7) and impact score (MD -1.71; 95% CI -3.10 to -0.32; Analysis 1.8) were statistically improved with use of antibiotics compared with placebo. On the other hand, the activity score did not show any statistically significant improvement (MD -0.81; 95% CI -2.26 to 0.63; Analysis 1.9). There was no heterogeneity among the studies. However, the improvements in the SGRQ scores did not reach the level of clinical significance according to the conventional cut off of at least a 4 point reduction (Jones 2009a). Among the subscales, the symptom score showed the most improvement, with a reduction of 3.3 points in the Albert 2011 study and 4.4 in Sethi 2010. The study by Albert 2011 demonstrated that more participants in the azithromycin group (43%) than the placebo group (36%) had at least a 4 point reduction in the SGRQ score. This was statistically significant (P = 0.03). It was not possible to perform a responder analysis (for > 4 point improvement) for the other studies due to the required data not being available. The authors of Banerjee 2005 and Mygind 2010 reported no statistically significant difference in the total score or subgroup scoring of the SGRQ between groups, in 642 patients. Banerjee 2005 found improvement only in the subcategory of symptom score in the patients treated with continuous prophylactic clarithromycin over a three months period (MD -10.2; 95% CI -1.6 to -18.7). Three studies used the Short Form-36 (SF-36) in addition to the SGRQ (Albert 2011; Banerjee 2005; He 2010). There was no significant improvement in the SF-36 overall score with antibiotics in any of the studies. Banerjee 2005 showed an improvement in the physical functioning score alone in the group that used prophylactic clarithromycin for three months (MD -12.9; 95% CI 3.1 to 22.6). Secondary outcome: frequency of hospitalisation The frequency of hospitalisation was assessed using data from four studies involving 2958 patients (Albert 2011; Mygind 2010; Seemungal 2008; Sethi 2010; Suzuki 2001). The trial by Sethi 2010, involving pulsed moxifloxacin in 1157 patients, did not show any improvement in the hospitalisation frequency (131/569 treatment arm versus 136/580 placebo arm; P = 0.46; Analysis 1.11). The trial by Albert 2011, involving continuous azithromycin in 1117 patients, calculated the rate of exacerbations requiring hospitalisation per patient per year according to the severity of COPD by the GOLD criteria (Analysis 1.11). The rate ratio was 0.77 (GOLD stage 2), 0.89 (GOLD stage 3) and 0.72 (GOLD stage 4). There were not adequate data to calculate the statistical significance of this outcome but there did not appear to be a trend. The other two studies had inadequate data to calculate the mean event rate per year. Of these, one study involving 109 patients found a statistically significant reduction (P < 0.001) in hospitalisation while using erythromycin 200 to 400 mg daily for a 12 month period (Suzuki 2001). The other study (Mygind 2010) did not show a statistically significant difference in the frequency of hospitalisations. Secondary outcome: duration of exacerbations The duration of exacerbations was addressed by only two studies involving 684 patients (Mygind 2010; Seemungal 2008). Seemungal 2008 showed that antibiotic use was associated with a lower median number of exacerbation days: 9 days (interquartile range (IQR) 6 to 13 days) compared to 13 days on placebo (IQR 6 to 24 days) (P = 0.036). Similar findings were reported by Mygind 2010. This study had 575 patients and used pulsed azithromycin over a 36 month period. The median number of exacerbation days (at home or in hospital) was 93 in the azithromycin group compared to 111 in the placebo group (P = 0.04). Prophylactic pulsed antibiotic use (Mygind 2010) reduced the number of days with severe exacerbations managed at home: a median of 31 days versus 42.5 days for the placebo group (P = 0.01). A meta-analysis was not carried out for this comparison due to paucity of data. Furthermore, Mygind 2010 reported data on hospitalisation due to COPD exacerbations. The study showed no difference in the number of hospitalisations between the treatment and placebo arms; however, there was a median reduction in hospital stay from 18 days in the placebo group to 15.5 days in the treatment group. No P value was stated for this comparison. Secondary outcome: days of disability Only one study reported on the number of days the participant was unable to undertake normal activity (Mygind 2010). The median number of days spent at home due to a mild exacerbation was no different between the treatment and placebo arms (42 days in each arm). However, there was a reduction in the median number of days spent at home due to a moderate to severe exacerbation from 42.5 days in the placebo group to 31 days in the azithromycin group (P = 0.01). Secondary outcome: change in lung function Only three studies addressed change in lung function. No study demonstrated any statistically significant change in the spirometry at the end of the treatment period (Mygind 2010; Sethi 2010) or during the first exacerbation (Seemungal 2008). Secondary outcome: death (all-cause and respiratory aetiology) Mortality data were reported in three studies involving 2841 participants (Albert 2011; Mygind 2010; Sethi 2010) and were combined into a meta-analysis. There was no significant difference between the treatment and placebo arms in all-cause mortality (OR 19