Abstract: We included two RCTs, both published in 2015 involving a total of 391 participants with treatment duration of 12 to 13 weeks. One RCT compared a quinolone (moxifloxacin pulsed, for 5 days every 4 weeks), with a tetracycline (doxycycline continuous) or a macrolide (azithromycin intermittent). The second RCT compared a tetracycline (doxycycline continuous) plus a macrolide (roxithromycin continuous), with roxithromycin (continuous) alone. The trials recruited participants with a mean age of 68 years, with moderate-severity COPD. Both trials included participants who had between two and five exacerbations in the previous one to two years. In one trial, 17% of patients had previously been using inhaled corticosteroids. In the other study, all patients were positive for Chlamydophila pneumoniae (C pneumoniae). Overall, we judged the evidence presented to be of very low-certainty, mainly due to imprecision, but we also had concerns about indirectness and methodological quality of the included studies. The primary outcome measures for this review included exacerbations, quality of life, drug resistance and serious adverse events. Macrolide + tetracycline versus macrolide There was no clear difference between treatments in improvement in quality of life as assessed by the Chronic Respiratory Questionnaire (CRQ). The CRQ scale ranges from 0 to 10 and higher scores on the scale indicate better quality of life. CRQ sub-scales for dyspnoea (mean difference (MD) 0.58, 95% confidence interval (CI) -0.84 to 2.00; 187 participants; very low-certainty evidence), fatigue (MD 0.02, 95% CI -1.08 to 1.12; 187 participants; very low-certainty evidence), emotional function (MD -0.37, 95% CI -1.74 to 1.00; 187 participants; very low-certainty evidence), or mastery (MD -0.79, 95% CI -1.86 to 0.28; 187 participants; very low-certainty evidence) at 12 weeks. For serious adverse events, it was uncertain if there was a difference between combined roxithromycin and doxycycline versus roxithromycin alone at 48 weeks follow-up after active treatment of 12 weeks (odds ratio (OR) 1.00, 95% CI 0.52 to 1.93; 198 participants; very low-certainty evidence). There were five deaths reported in the combined treatment arm, versus three in the single treatment arm at 48 weeks follow-up after active treatment of 12 weeks (OR 1.63, 95% CI 0.38 to 7.02; 198 participants; very low-certainty evidence). Quinolone versus tetracycline There was no clear difference between moxifloxacin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants, very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Quinolone versus macrolide There was no clear difference between moxifloxacin and azithromycin for the number of participants experiencing one or more exacerbations (OR 1.00, 95% CI 0.32 to 3.10; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Marcolide versus tetracycline There was no clear difference between azithromycin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. We did not find head-to-head evidence for impact of antibiotics on drug resistance. It is not clear from the evidence included in this review whether there is a difference in efficacy or safety between different classes or regimens of prophylactic antibiotic, given for 12 to 13 weeks to people with COPD. Whilst no head-to-head comparisons of antibiotic resistance were identified, concerns about this continue. The sample size in this review is small and both included studies are of short duration. Thus, there is considerable uncertainty in effects observed and the effects of different prophylactic antibiotics requires further research.

Plain-language summary: We found two randomised trials, including 391 people with COPD. The participants had an average age of 68 years. The first study included three groups of COPD patients taking either moxifloxacin (daily for 5 days every 4 weeks), doxycycline (daily for 13 weeks) or azithromycin (3 times per week for 13 weeks). The second study investigated the use of doxycycline (daily) in addition to roxithromycin (daily) for 12 weeks in COPD. Our main outcomes were number of exacerbations, quality of life, serious side effects (known as 'adverse events') and antibiotic resistance. Overall, we were unable to determine any difference between one antibiotic compared with each other in improving the main outcomes we measured. We were unclear whether one antibiotic was better or worse than another in terms of reducing exacerbations or improving quality of life. Neither of the studies reported a comparison between antibiotics for drug resistance. In one study lasting 13 weeks we found no serious side effects of taking moxifloxacin, azithromycin or doxycycline, and no deaths were reported. In the other study, very similar numbers of people experienced serious side effects in both the combined antibiotic and single antibiotic treatment groups after 12 weeks of treatment and 48 weeks of follow-up. However, the numbers were small so we are not sure if one treatment option may cause more side effects than the other. In the same study, five people in the combined treatment group died, compared to three people in the single treatment group. Again, these numbers are too small to draw any conclusions. We were very uncertain about the results due to finding only two small studies that gave people with COPD antibiotics for only 12 or 13 weeks. The studies only looked at four different antibiotics and did not measure all the things we were interested in.